RU2286781C2 - Method for treatment of endophagus chemical burn in infants - Google Patents

Abstract

FIELD: medicine, in particular treatment of endophagus chemical burns.

SUBSTANCE: claimed method includes application of pharmaceutical compositions in form of two regencur-based gel-like compositions perorally or through catheter, wherein for one week in second/third steps of burn process development method includes application of composition containing (g per 100 g): metronidazole 0.75; prednisolone 0.05; lidocaine hydrochloride 0.1; sodium saccharinate 0.24; natural-identical food flavoring 0.5; regencur 4.0; glycerol 8.0; and balance: water. Then in fourth step of burn process development for two weeks composition is used that contains (g per 100 g): metronidazole 0.75; methyluracil 2.0; lidase 128 U; sodium saccharinate 0.24; natural-identical food flavoring (strawberry) 0.5; regencur 4.0; glycerol 8.0; and balance: water.

EFFECT: formation of more smooth cicatrix; shorter time of endophagus mucous epithelialization.

5 tbl, 9 dwg

Description

The invention relates to medicine, namely to pediatrics, and can be used to treat chemical burns of the esophagus in children.

The largest number of victims of chemical burns of the esophagus of various etiologies are children aged 1 year to 5 years. In this age category of childhood, esophageal burns occur 2.5-3 times more often than in children from 5 to 10 years.

A known method of treating chemical burns of the esophagus in children using a 5-10% solution of novocaine once with the subsequent intake of vegetable (olive, corn, sunflower) oils, fish oil (Shalimov A.A., Saenko V.F., Shalimov S.A. Surgery the esophagus. - M.: Medicine, 1975. - P.130).

The disadvantage of this method is the lack of a complex effect on the pathological process, as well as the absence of antimicrobial, anti-inflammatory effects, unpleasant organoleptic properties of drugs.

The closest in essence (prototype) is a method of treating chemical burns of the esophagus in children using a fat-hormonal mixture in the form of a suspension on a lipophilic basis in the form of two formulations used sequentially in the course of treatment. Composition No. 1 of a fat-hormonal mixture, containing in grams: prednisone 0.4; anestezin 3.0; tetracycline 3 million units; methyluracil 6.0; sodium bicarbonate 6.0; vegetable oil 100.0; apply for 6 days 5-6 times a day for 1 teaspoon. After taking it for 30-40 minutes, you should refrain from taking any liquid for a better and longer exposure of the components to the burn surface. Composition No. 2 of the fat-hormonal mixture (the anestezin in the composition has been replaced by lidase 124 IU) is used for the next 2 weeks of treatment, 1 teaspoon 3-4 times a day. The method reduces the treatment time and reduces the possibility of developing stenosis of the esophagus (Zhukov MD On the treatment of chemical burns of the digestive tract in the acute period // Clinical Surgery, 1973. - No. 1. - S.60-63).

The disadvantage of this method of treatment is the special organotropy to the digestive tract and toxicity to the epithelium of the intestinal mucosa of the antibiotics of the tetracycline group; allergenicity of anestezin; the absence in the composition of the suspension on a lipophilic basis of surface-active substances, which leads to the separation of the compositions and complicates the dosage of medicinal substances; as well as unpleasant organoleptic properties of the fat-hormonal mixture, which significantly complicates the administration of the drug.

A positive result of the invention is to increase the effectiveness of treatment of chemical burns of the esophagus in children by reducing the likelihood of scar stenosis by reducing the time of epithelialization of the mucosa and the formation of a smoother scar as a result of applying a composition of medicinal substances in the form of two compounds acting on different components of the pathological process; the choice of basic components that provide the necessary viscosity of the dosage form, which ensures a longer contact of the medicinal substances with the burn surface, and also improves the organoleptic properties of the drug.

A positive result is achieved by the fact that for the treatment of chemical burns of the esophagus in accordance with the phase of the development of the burn process, corrected jelly-based compositions based on the regenecur polymer are used that have anti-inflammatory and wound healing activity, optimal viscosity and organoleptic properties, which ensures ease of use.

The novelty of the invention lies in the fact that theoretically substantiated and experimentally selected compositions of medicinal substances in the form of two compounds acting on different components of the pathological process, a methodology for the treatment of esophageal burns using these compounds has been developed.

The authors suggest a method of treating chemical burns of the esophagus in children by using the following formulations.

Composition No. 1 contains the following ingredients in grams:

Metronidazole 0.75

Prednisone 0.05

Lidocaine hydrochloride 0.1

Sodium saccharinate 0.24

Fragrance food, identical to natural, "strawberry" 0,5

Regencourt 4.0

Glycerin 8.0

Water up to 100.0

Technology:

Under aseptic conditions, weighed portions of metronidazole and sodium saccharinate are crushed and dissolved in a small amount of sterile purified water (120 ± 2 ° С - 8 min). Solutions of prednisolone and lidocaine hydrochloride are added to the resulting solution. Then add a portion of the sterile sorbent regenecur (160 ± 2 ° С - 8 min) and leave to swell for 30-40 minutes. Then add sterile glycerin (120 ± 2 ° C - 8 min), mix until a viscous transparent gel is obtained. A flavor is added to the gel thus obtained and homogenized. Samples are packed in plastic tubes or glass jars of 100.0 g each. A transparent, slightly yellowish, viscous gel with a strawberry smell, a sweetish-bitter taste, causing a slight numbness of the tongue.

Mode of application:

Composition No. 1 is used to treat esophageal burns in children after pre-hospital measures of 5.0 orally or through a probe 6-8 times a day for 1 week at 2-3 phases of the development of the burn process. After taking the drug, do not take any liquid or food for at least 40 minutes.

Composition No. 2 contains the following ingredients in grams:

Metronidazole 0.75

Methyluracil 2.0

Lidase 128 units

Sodium saccharinate 0.24

Fragrance food, identical to natural, "strawberry" 0,5

Regencourt 4.0

Glycerin 8.0

Water up to 100.0

Technology:

Under aseptic conditions, weights of metronidazole, methyluracil and sodium saccharinate are crushed, metronidazole and sodium saccharinate are dissolved, and methyluracil is dispersed in a small amount of purified sterile water (120 ± 2 ° С - 8 min). In the obtained solution-dispersion of drugs, lidase, previously dissolved in a small amount of sterile water, is purified (120 ± 2 ° С - 8 min). Then add a weighed portion of the regenecour sterile sorbent (160 ± 2 ° С - 1 hour) and fill it with sterile purified water (120 ± 2 ° С - 8 min) and leave it to swell for 30-40 minutes. Then add sterile glycerin (120 ± 2 ° C - 8 min), mix until a viscous, transparent gel is obtained. A food flavor identical to the natural one is added to the gel thus obtained, homogenized. Samples are packaged in plastic tubes or glass vials of 100.0. Transparent, slightly yellowish, viscous gel with the smell of strawberries, sweet bitter taste.

Mode of application:

Composition No. 2 is used to treat esophageal burns in children after applying composition No. 1 at 5.0 orally or through a probe 6-8 times a day for at least 2 weeks at stage 4-5 of the development of the burn process. After taking the drug, do not take any liquid or food for at least 40 minutes.

The rationale for the choice of drugs and excipients

In order to select the optimal formulations for the treatment of esophageal burns in children, drugs and excipients approved for medical use and industrial production were used. Requirements for drugs for the treatment of esophageal burns in children

1. Antimicrobial activity.

2. Anti-inflammatory effect.

3. Local anesthetic effect in the first phase of the development of the pathological process.

4. High regenerative effect.

5. Reducing the formation of coarse connective tissue at the burn site.

6. Adequate viscosity to ensure a longer stay on the affected surface of the mucous membrane of the esophagus.

7. Optimal organoleptic properties.

8. The absence of a general toxic effect on the body.

Metronidazole was introduced into the composition as an antibacterial agent, the choice of which is due to the fact that the main contaminating factor of the esophagus is the microflora of the oral cavity. As an anesthetic component - lidocaine. Prednisone is an anti-inflammatory, anti-allergic component. Methyluracil has anabolic and anti-catabolic activity, accelerates cell regeneration processes; accelerates wound healing, stimulates cellular and humoral defense factors, and also has an anti-inflammatory effect. Lidase contains the enzyme hyaluronidase, a specific substrate of which is hyaluronic acid - a cementing component of connective tissue, and therefore lidase has a resolving effect.

The determination of the optimal amount of the drug substance at one time and in the composition of the dosage form was carried out taking into account that the average body weight of a 2-year-old child is 15 kg, and the average weight of a 4-year-old child is 20 kg. The calculation of the quantities of drugs in the compositions for children 2-4 years of age are presented in tables 1 and 2.

In order to ensure the necessary viscosity, starch gels, regenecur and a water-in-oil emulsion with MHD emulsifier (distilled monoglycerides) were used as the forming components of the compositions. The concentration of regenecur in the composition of the gels was reduced to 4% in order to eliminate the osmotic effect and ease of taking the dosage form.

Modern children's medications intended for oral use should have optimal organoleptic properties. Correction of the organoleptic properties of medicinal substances should be carried out only in cases where the smell, taste and color are unpleasant and interfere with the drug, excessive correction of drugs is not recommended. Flavoring agents of taste and smell are selected depending on the organoleptic properties of the incoming ingredients, the purpose of the drug, the preferences of the ethnic and age groups for the treatment of which the dosage form is intended. Based on the foregoing, as well as determining the organoleptic properties of the developed compositions (pronounced bitter taste), the need for correction of the taste and smell of the dosage form is revealed. The following sweeteners were used as organoleptic properties: sodium saccharinate and stevioside — a natural sweetener from Rebo leaves, lemon oil, sweet orange oil, peppermint oil, as well as flavorings identical to natural ones, “lemon”, “orange”, “strawberry”. Studies on 84 volunteers aged 4 to 68 years according to the author's method of Professor A. Tentsova showed that the best corrective properties are: sodium saccharinate for all formulated compositions, strawberry flavoring for formulations based on regenecur and starch, lemon oil and sweet orange for emulsion-based formulations.

Thus, 3 compositions of composition No. 1 and 3 compositions of composition No. 2, containing drugs and excipients, approved for medical use and industrial production, were developed.

Composition No. 1 based on starch, in grams:

Metronidazole 0.75

Prednisone 0.05

Lidocaine hydrochloride 0.1

Sodium saccharinate 0.24

Flavor identical to natural, "strawberry" 0.5

Starch 7.0

Purified water to 100.0

Composition "No. 2 based on starch, in grams:

Metronidazole 0.75

Methyluracil 2.0

Lidase 128 units

Sodium saccharinate 0.24

Flavor identical to natural, "strawberry" 0.5

Starch 7.0

Purified water to 100.0

Composition No. 1 on the basis of regencour, in grams:

Metronidazole 0.75

Prednisone 0.05

Lidocaine hydrochloride 0.1

Sodium saccharinate 0.24

Fragrance food, identical to natural, "strawberry" 0,5

Regencourt 4.0

Glycerin 8.0

Water up to 100.0

Composition No. 2 on the basis of regencour, in grams:

Metronidazole 0.75

Methyluracil 2.0

Lidase 128 units

Sodium saccharinate 0.24

Fragrance food, identical to natural, "strawberry" 0,5

Regencourt 4.0

Glycerin 8.0

Water up to 100.0

Composition No. 1 on an emulsion basis, in grams:

Metronidazole 0.75

Prednisone 0.05

Lidocaine hydrochloride 0.1

Sodium saccharinate 0.24

Lemon Oil 0.5

Vegetable oil 25.0

Emulsifier distilled monoglycerides 4.0

Water up to 100.0

Composition No. 2 on an emulsion basis, in grams:

Metronidazole 0.75

Methyluracil 2.0

Lidase 128 units

Sodium saccharinate 0.24

Sweet Orange Oil 0.5

Vegetable oil 25.0

Emulsifier distilled monoglycerides 4.0

Water up to 100.0

Based on the fact that dosage forms for the treatment of wounds and burns must meet the requirement of sterility and be prepared under aseptic conditions, sanitary preparation of the premises, processing of equipment and training of personnel for work were carried out in accordance with OST 42-510-98 "Rules for the organization of production and quality control Medicines (GMP). "

The determination of shelf life has shown that starch-based formulations have a shelf life of no more than 2 days and can only be recommended for extemporaneous manufacture. In this regard, the determination of anti-inflammatory and wound healing effects was carried out for compositions based on regenecur and emulsion base.

The study of anti-inflammatory and wound healing activity of the developed formulations for the treatment of esophageal burns

The anti-inflammatory and wound healing effects of the developed formulations are established on laboratory animals of the Chinchilla breed. Due to the impossibility of creating a chemical burn of the esophagus in laboratory animals, the experiment was carried out on a skin model of a chemical burn. In the experiment, 30 animals were used, which were divided into three groups of 10 rabbits.

A chemical burn model was created according to the following methodology: The surgical field was preliminarily prepared — hair removal. Further, under laboratory conditions, under intravenous anesthesia (5% ketamine solution or 2% thiopental sodium solution), after deep immersion of animals in a medical sleep, the epidermal layer of the skin was excoriated in the same areas in all rabbits and the same area was 1.5 cm ² ( 3 plots for each rabbit). Subsequently, wounds were treated with a solution of 70% acetic acid.

In the control group of animals (group No. 1), wounds were not treated. The wounds in animals of the second and third groups were treated 6 times a day for 21 days with the compositions developed by us.

Rabbits of the second group were treated with a wound surface with composition No. 1 on a hydrophilic basis for 7 days, followed by treatment with a composition of No. 2 on a hydrophilic basis for 14 days. In general, the treatment and observation process was 21 days.

The third group of animals received treatment in the form of composition No. 1 on an emulsion basis for 7 days and subsequent treatment with composition No. 2 on an emulsion basis for 14 days. The treatment and observation of the third group of animals was also 21 days.

The healing process was evaluated according to clinical and morphological criteria on days 3, 7, 10, 14, 21. For morphological evaluation under anesthesia under aseptic conditions, the wound surface was collected within healthy tissues, followed by hemostasis and layered wound closure. Rabbits were not withdrawn from experience, because all animals survived.

The clinical course of a chemical burn without treatment on a model performed on the skin of laboratory animals is presented in table 3. The clinical course of a chemical burn on a model performed on the skin of laboratory animals during treatment with the formulations developed by us on the basis of regenera and on an emulsion basis are presented in tables 4 and 5, respectively.

The data presented in tables 3, 4 and 5 indicate that on the 3rd day after the burn in all groups, edema, infiltration, hyperemia and local hyperthermia are observed in all animals, but these phenomena are more pronounced in animals of the control group than in animals of the second and third groups. On the 7th day of the development of the burn process, the manifestations of all these symptoms in animals of the second and third groups are significantly reduced, while in the control group these symptoms last for quite a long time. At the same time, on day 7, in animals of groups No. 2 and No. 3, the wounds begin to heal, granulation appears, while in the control group scanty granulations appear only on day 14. The tenth day of the development of the burn process for groups No. 2 and No. 3 is the beginning of the epithelization process. Complete epithelialization of wounds in animals treated with the compositions developed by us occurs at 21 days of the development of the burn process. At the same time, in the control group of animals on the 21st day only the beginning of the epithelization process is observed. Thus, the subsidence of the clinical manifestations of a chemical burn, the appearance of granulations, the onset and complete epithelization occur in a much shorter time in the groups of animals in respect of which treatment was carried out by the compositions developed by us, in comparison with the control group. According to the results of the clinical picture, there were no significant differences between the group of animals treated with regencur formulations and group No. 3 treated with emulsion-based formulations, no significant differences were found.

The results of histological studies of morphological changes occurring during the course of a chemical burn with therapeutic measures and without appropriate treatment are presented in figures 1-9.

Figure 1 presents the histological picture of morphological changes that occurred on the 3rd day of the development of the burn process without treatment (control group). The morphological picture indicates the presence of coagulation necrosis of the skin and appendages with the capture of subcutaneous fatty tissue, pronounced leukocyte infiltration with an admixture of macrophages is observed in the underlying fatty tissue and muscle tissue, while the infiltration is more pronounced at the border with the necrosis zone. There is also vascular congestion, moderate tissue edema and a weak fibroblastic reaction at the border with the necrosis zone.

Figure 2 presents the histological picture of morphological changes that occurred on the 3rd day of the development of the burn process as a result of the application of composition No. 1 based on the regenecur. Analysis of the picture presented in figure 2, allows to conclude the presence of coagulation necrosis of the skin and appendages with the capture of subcutaneous fat. In the underlying fatty tissue and in muscle tissue, marked leukocyte infiltration with an admixture of macrophages is observed, while infiltration is more pronounced at the border with the necrosis zone. There is also vascular congestion, moderate swelling of the tissues, a weak fibroblastic reaction at the border with the zone of necrosis.

A similar morphological picture (figure 3) is observed on the 3rd day of the development of the burn process when applying composition No. 1 on an emulsion basis, namely: coagulation necrosis of the skin and appendages with the capture of subcutaneous fat; pronounced leukocyte infiltration with admixture of macrophages in deep-lying fatty tissue and muscle tissue, moreover, infiltration is more pronounced at the border with the necrosis zone, plethora of blood vessels, moderate swelling of the tissues, weak fibroblastic reaction (at the border with the zone of necrosis).

The histological picture of morphological changes that occurred on the 7th day of the development of the burn process as a result of the use of composition No. 1 on the basis of regeneration indicates that the necrosis zone is compacted, well delimited from the underlying tissue, in which the fibroblastic reaction is emphasized. Macrophages, eosinophilic leukocytes predominate in the infiltrate, there is an admixture of plasma cells, neutrophilic leukocytes, lymphocytes. Vascular neoplasm is observed. A similar picture is observed in the development of the burn process as a result of applying composition No. 1 on an emulsion basis, namely: the necrosis zone is densified, well delimited from the underlying tissue, in which the fibroblastic reaction is emphasized; macrophages, eosinophilic leukocytes predominate in the infiltrate, there is an admixture of plasma cells, neutrophilic leukocytes, lymphocytes; vascular neoplasm is observed.

The histological picture of morphological changes that occurred on the 7th day of the development of the burn process without treatment (control group) indicates that the necrosis zone of burns in untreated animals is also compacted, well delimited from the underlying tissue, macrophages, eosinophilic leukocytes predominate in the infiltrate, there is an admixture plasma cells, neutrophilic leukocytes, lymphocytes, vascular neoplasm is observed. At the same time, the fibroblastic reaction is much more pronounced; diffuse fields of mature fibrous tissue appear (fibrocytes with coarse collagen fibers), there is also a deeper proliferation of connective tissue with the capture of muscle tissue. All this indicates a more severe scarring of the wound and the duration of the healing process.

On the 10th day of the development of the burn process in animals of the second group as a result of treatment with composition No. 2 based on regenecur, mature fibrous tissue with moderate collagenization (fibers are thin, sometimes in the form of a thin mesh) predominates, with a small number of fibroblasts. The proliferation of fibrous tissue is widespread, diffuse. Mature vessels predominate. The regenerative epidermis "grows" under necrotic masses.

An analysis of the morphological picture on the 10th day of the development of the burn process in animals of group No. 3 allows us to conclude that mature fibrous tissue with moderate collagenization predominates (fibers are thin, sometimes in the form of a thin mesh), with a small number of fibroblasts. Fibrous tissue is located mainly under the densified necrotic masses. Mature vessels predominate. Granulomatous reaction with the appearance of single giant cells of foreign bodies. The regenerative epidermis "grows" under necrotic masses.

Histological studies of morphological changes on the 10th day of the development of the burn process without treatment in the control group revealed the presence of gross collagenization with the growth of fibrous tissue. At the same time, with the growth of fibrous tissue, areas with edema and diffuse leukocyte infiltration remain, which suggests the development of a secondary infection.

On the 14th day of research in animals of group No. 2 (Fig. 4), mature connective tissue predominates at the site of the development of the burn process, while leukocyte infiltration is weakly expressed, mainly in the surface sections. Single granulomas of foreign bodies are observed. The epidermis is well expressed (epidermis regeneration).

The morphological picture on the 14th day of studies of the development of chemical burns in animals of group No. 3 is presented in figure 5. Analysis of the picture allows us to conclude that at the site of the burn process, mature connective tissue predominates, leukocyte infiltration is poorly expressed, epidermis (epidermis regeneration) is well pronounced in the surface departments.

The morphological picture on the 14th day of the development of the burn process without treatment (Fig. 6) indicates that, along with the formation of coarse-fiber connective tissue of a diffuse nature, pronounced leukocyte infiltration at the border with the necrosis zone (at the bottom of the ulcer) is preserved. At the same time, epidermis is weakly expressed, granulomatous reaction with numerous giant cells of foreign bodies is observed throughout the entire thickness of the histological preparation.

On day 21 in groups No. 2 (Fig. 7) and No. 3 (Fig. 8), a complete epidermization of the burn is observed, while there is weak leukocyte infiltration in the area of the former damage (under the regenerating epidermis). The growth of connective tissue within the dermis with a small capture of subcutaneous fat.

In the animals of the control group, on the 21st day of research (Fig. 9), there is a weak epidermis without rejection of necrotic masses, pronounced diffuse focal leukocyte infiltration in the bottom of the ulcer and in the deeper parts (dermis, fatty tissue) with the formation of microabscesses and large granulomas of foreign bodies with giant cell reaction. Fibrous tissue is developed unevenly, roughly fibrous.

Thus, as a result of studies of the anti-inflammatory and wound healing activity of the compositions in the form of two compositions based on the polymer recur and emulsion based, the timing of healing of a chemical burn is ahead of schedule in comparison with the control group of animals without treatment of the burn process. In later periods, a significant difference in the severity of the scar is determined: when using the compositions developed by us, the growth of connective tissue occurs with moderate collagenization in the superficial sections of the wound, and in the control group collagenization is expressed with capture of both the superficial and deep parts of the tissues up to the muscle layer (P less 0.01). The formation of a rough scar in the control group is associated with a long-lasting inflammatory process in the damage zone, which is not observed during treatment with the formulations developed by us.

There were no significant differences when using compositions based on regenecur (group No. 2) and based on emulsion (group No. 3) in the experiment (P less than 0.01).

At the same time, it should be noted that the taste and convenience of reception are more pronounced in the compositions based on polymer regenecur.

As a result of the studies, it was found that the proposed compositions in the form of two compositions on different bases: hydrophilic and emulsion have a pronounced antimicrobial and wound healing effect, the necessary viscosity and organoleptic properties and can be used to treat esophageal burns.

Table 1
Calculation of the number of medicinal substances in dosage form for children aged 2 years Drug substance Daily doses indicated in ND Daily therapeutic dose Single therapeutic dose Content in lek. 100.0 form The number of receptions per day Metronidazole 0.25 0.1875 0,03125 0.625 6 Lidocaine 2 mg / kg 0,03 0.005 0.1 6 Prednisone 1 mg / kg 0.015 0.0025 0.05 6 Methyluracil 0.75 0.564 0,094 1.88 6 Lidase - 38,4 6.4 128 units 6 table 2
Calculation of the amount of medicinal substances in dosage form for children aged 4 years Drug substance Daily doses indicated in ND Daily therapeutic dose Single therapeutic dose Content in lek. 100.0 form The number of receptions per day Metronidazole 0.25 0.25 0,03125 0.625 8 Lidocaine 2 mg / kg 0.04 0.005 0.1 8 Prednisone 1 mg / kg 0.02 0.0025 0.05 8 Methyluracil 0.75 0.752 0,094 1.88 8 Lidase - 51,2 6.4 128 units 8

Table 3
The clinical course of a chemical burn of the skin without treatment
(control group)

3 days 7 days 10 days 14 days 21 days Swelling, infiltration +++ +++ ++ + Hyperemia +++ ++ + Hyperthermia is local +++ + The appearance of granulations + ++ Start of epithelialization + Complete epithelization Table 4
The clinical course of chemical skin burn during treatment with compounds No. 1 and No. 2 based on the polymer regenecur (group of animals No. 2)

3 days 7 days 10 days 14 days 21 days Swelling, infiltration ++ + Hyperemia +++ + Hyperthermia is local ++ The appearance of granulations +++ Start of epithelialization +++ Complete epithelization +++

Table 5
The clinical course of chemical skin burn during treatment with compounds No. 1 and No. 2 on an emulsion basis (group of animals No. 3)

3 days 7 days 10 days 14 days 21 days Swelling, infiltration ++ + Hyperemia +++ + Hyperthermia is local ++ The appearance of granulations +++ Start of epithelialization +++ Complete epithelization +++

Claims (1)

A method of treating chemical burns of the esophagus by using compositions of medicinal substances in the form of two compositions, characterized in that the jelly-like formulations based on the regenecur polymer are administered orally or via a tube, and a composition of the following composition is used for one week in the second or third phases of the development of the burn process, g: Metronidazole 0.75 Prednisone 0.05 Lidocaine hydrochloride 0.1 Sodium saccharinate 0.24 Food flavor identical to natural 0.5 Regencourt 4.0 Glycerol 8.0 Water Up to 100.0 then in the fourth phase of the development of the burn process, a composition of the following composition is used for at least 2 weeks, g: Metronidazole 0.75 Methyluracil 2.0 Lidase 128 units Sodium saccharinate 0.24 Fragrance food identical to natural "strawberry" 0.5 Regencourt 4.0 Glycerol 8.0 Water Up to 100.0

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