RU2371172C2 - Stephaglabrin-based pharmaceutical composition of local and external application for treatment of traumatic and post-operation injury of peripheral nervous system - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention concerns chemical and pharmaceutical industry and medicine, particularly pharmaceutical drugs applied in case of traumatic and post-operation injuries of peripheral nervous system, namely fluid and soft medicine forms of stephaglabrin drug. Invention claims pharmaceutical composition for local and external application in treatment of traumatic and post-operation injuries of peripheral nervous system, containing stephaglabrin sulfate, perfluoro-organic compound emulsion and at least one target additive out of: reparative process stimulation agent, anesthetic, antioxidation agent, vitamins, biogenic elements, or mix thereof, and hydrophilic base if necessary, at the following component ratio (wt %): stephaglabrin sulfate - 0.001-2.0; target additive - 0.000001-60.6; perfluoro-organic compound emulsion - 5.0-90.0, the rest is hydrophilic base.

EFFECT: enhanced therapeutic effect and its duration.

8 cl, 16 ex

Description

The invention relates to the pharmaceutical industry and medicine, in particular to pharmaceutical preparations used for traumatic and postoperative injuries of the peripheral nervous system, in particular to liquid and soft dosage forms of the drug stefaglabrin.

The main reason for the difficulty of post-traumatic regeneration of nerve fibers is the formation of a dense scar at the site of damage due to the activation of neuroglia cells (“Regeneration of the damaged spinal cord”, Medicus Amicus 2002, No. 3, www.medicusamicus.com/index.php?action=5x54-10-25c -38-36-45x1).

Known drugs for external use on the basis of glucocorticosteroids, for example hydrocortisone butyrate, available in the form of 0.1% cream, 0.1% and 1% ointment, 0.1% lotion (trade name - laticort). These drugs have anti-inflammatory, anti-allergic antipruritic, antiexudative effect, reduce capillary permeability. They inhibit the activity of phospholipase A ₂ , which leads to a suppression of the synthesis of prostaglandins and leukotrienes, inhibit the migration of leukocytes and lymphocytes to the inflammation site, inhibit the proteolytic activity of tissue kinins, inhibit the growth of fibroblasts, inhibit the development of connective tissue in the lesion, reduce the manifestations of hypersensitivity reactions, proliferative and exudative processes occurring in the connective tissue in the focus of inflammation reduce hyperemia (www.vidal.ru/vidal/info/drugs/d3578/htm).

In the complex therapy of traumatic-compression neuropathies, an emulsion of hydrocortisone or 1% hydrocortisone ointment is used (//formen.narod.ru/osteo_ft_tn.htm).

Contraindications for the appointment of topical corticosteroids are fungal, purulent, viral skin diseases, perioral dermatitis. With prolonged use of glucocorticosteroids, skin atrophy, telangiectasia, steroid acne, hypertrichosis, and secondary infection can occur. When used on large areas of the skin, it is possible to develop systemic side effects characteristic of glucocorticosteroids (A.G. Pashinyan, “Drugs for the treatment of dermatitis”, www.remedium, ru / drugs / drugs / detail.php & ID = 10143t).

When using glucocorticosteroids, the T-cell system of immunity can be disrupted, which plays a large role in the development of pyoderma (T.A. Belousova, M.V. Goryachkina, “Bacterial skin infections: the problem of choosing the optimal antibiotic”, www.rmj, ru / articles _ 3825.htm).

Known drug longidase, which has a proteolytic (hyaluronidase) activity of prolonged action, immunomodulating, chelating, antioxidant and anti-inflammatory properties. The prolongation of the action of the enzyme is achieved by covalent binding of the enzyme to a physiologically active high molecular weight carrier (activated poly-1,4-ethylene piperazine N-oxide derivative, an analog of polyoxidonium), which has its own pharmacological activity. It has an immunomodulatory, detoxifying, antioxidant effect.

The covalent bond significantly increases the resistance of the enzyme to the denaturing and inhibitory effects: the enzymatic activity of longidase is maintained when heated to 37 ° C for 20 days, while native hyaluronidase loses its activity during the day. The covalent bond in the Longidase preparation provides the simultaneous local presence of a hydrolytic enzyme and a carrier capable of binding released enzyme inhibitors and collagen synthesis stimulants (iron, copper ions, heparin, etc.).

Due to these properties, longidase possesses not only the ability to depolymerize the matrix of connective tissue in fibro-granulomatous formations, but also suppress the reverse (regulatory) reaction aimed at the synthesis of components of the connective tissue. A specific substrate for testicular hyaluronidase is glycosaminoglycans (hyaluronic acid, chondroitin, chondroitin-4-sulfate, chondroitin-6-sulfate), which form the basis of the matrix of connective tissue.

As a result of depolymerization (rupture of the bond between C1 acetylglucosamine and C4 glucuronic or inductronic acids) under the influence of hyaluronidase, glycosaminoglycans lose their main properties: viscosity, the ability to bind water, metal ions, the formation of collagen proteins into fibers is difficult, the permeability of tissue barriers increases, the movement of fluid into the fluid is facilitated intercellular space, the elasticity of the connective tissue increases, which is manifested in a decrease in swelling of the tissue, flattening of scars, an increase in volume joint movements, reduction of contractures and prevention of their formation, reduction of adhesions. Longidase weakens the course of the acute phase of inflammation, regulates (increases or decreases, depending on the initial level) the synthesis of inflammatory mediators (interleukin-1 and tumor necrosis factor), increases the body's resistance to infection and the humoral immune response.

Longidase does not have antigenic properties, mitogenic, polyclonal activity, does not have allergenic, mutagenic, embryotoxic, teratogenic and carcinogenic effects. With parenteral administration, the drug is rapidly absorbed into the systemic circulation and reaches a maximum concentration in the blood after 20-25 minutes, characterized by a high distribution rate in the body.

The half-life (a-phase) is about 0.5 hours, the half-life (b-phase) with different routes of administration is from 42 to 84 hours. It is excreted mainly by the kidneys. In the body, hyaluronidase undergoes hydrolysis, and the carrier is degraded to low molecular weight compounds (oligomers), which are excreted by the kidneys.

Longidase is indicated as part of complex therapy for diseases accompanied by connective tissue hyperplasia, in pulmonology, urology, gynecology with the development of inflammation according to the interstitial type: pneumofibrosis, tuberculosis, alveolitis, tuberculoma; chronic interstitial cystitis, adhesion in the pelvis, tubal peritoneal infertility, in orthopedics, surgery, cosmetology: keloid, hypertrophic, inverted scars after pyoderma, injuries, burns, operations; long healing wounds; joint contractures, arthritis, hematomas; adhesive disease, in dermatovenerology: limited scleroderma of various localization.

It is also used to increase the bioavailability of drugs and diagnostics. Longidase is administered subcutaneously (near the lesion site or under scarred tissue) or intramuscularly at a dose of 3000 ME with a course of 5 to 15 injections (depending on the severity of the disease) with an interval between administrations of 3 to 10 days. To increase the bioavailability of drugs, a dose of 1,500 ME is recommended. For intramuscular, subcutaneous or intradermal administration, the contents of the ampoule are dissolved in 1.5-2.0 ml of 0.25% or 0.5% procaine solution. In case of procaine intolerance, the drug is dissolved in 0.9% sodium chloride solution or water for injection.

For electrophoresis, the solution is prepared in distilled water, for inhalation - in a 0.9% sodium chloride solution. The prepared solution for parenteral administration is not subject to storage. With the introduction of longidase, pain appears at the injection site, rarely allergic reactions. In individual individuals, local reactions are possible, which are expressed in the development of skin hyperimia and, in some cases, in swelling of the tissue at the injection site. Longidase can be combined with antibiotics, antiviral, antifungal and antihistamines, glucocorticosteroids, bronchodilators, cytostatics. It increases the bioavailability of drugs, accelerates the onset of analgesia with the introduction of local anesthetics (www.apteka-ifk.ru/art/111461/).

Despite the fact that longidase has the ability not only to dissolve adhesions, keloid scars, sclerotic tissue, but also to inhibit the growth of connective tissue when it is excessively formed (www.medkosmetolog.ru), its use as an agent for the treatment of traumatic and postoperative is unknown damage to the peripheral nervous system.

In addition, this enzyme preparation is thermolabile, its solution requires special preparation in compliance with sterility and is not subject to long-term storage, which complicates its use in the treatment process. Preparations for local and external use based on longidase are not developed due to its instability.

Known drug lidase containing the enzyme hyaluronidase. Hyaluronidase is an enzyme whose specific substrate is hyaluronic acid. The latter is a mucopolysaccharide, which includes acetylglucosamine and glucuronic acid. Hyaluronic acid has a high viscosity. Its biological significance lies mainly in the fact that it is a cementing substance of connective tissue. Hyaluronidase, or the "distribution factor", causes the breakdown of hyaluronic acid to glucosamine glucuronic acid and thereby reduces its viscosity.

Hyaluronidase causes an increase in tissue permeability and facilitates the movement of fluids in interstitial spaces. Hyaluronidase is found in various tissues of the body. The ratio of the system "hyaluronic acid - hyaluronidase" is largely regulated by the permeability of tissues. The anti-inflammatory effect of various drugs (salicylates, pyrazolone derivatives, ACTH, glucocorticoids, steroids, etc.) is partially associated with their ability to reduce the activity of hyaluronidase. On the contrary, the effect of certain substances causing an increase in permeability (for example, bee and snake venom) is partly due to the presence of hyaluronidase in them.

The action of hyaluronidase is reversible. With a decrease in its concentration, the viscosity of hyaluronic acid is restored. Thus, hyaluronidase can be used to temporarily reduce the viscosity of hyaluronic acid. Preparations containing hyaluronidase (lidase and ronidase) are obtained from the testes of cattle.

Lidase is a specially purified preparation suitable for parenteral (subcutaneous, intramuscular) and inhalation applications: lyophilized powder or porous mass or porous mass packed in a tablet, light in color with a beige tint. The drug is readily soluble in water. The activity of the drug is expressed in arbitrary units (UE). Available in bottles sealed with rubber stoppers with aluminum caps containing 64 UE of sterile substance.

For injection, the contents of the vial are dissolved in 1 ml of isotonic sodium chloride solution or in 1 ml of 0.5% novocaine solution, for inhalations - in 5 ml of isotonic sodium chloride solution. The main indications for the use of lidase are joint contractures, scars after burns and operations, ankylosing spondylitis, hematomas, and others. A lidase solution (1 ml) is administered in these cases near the lesion under the skin or under scarred tissues. Injections are performed daily or every other day. The course of treatment consists of 6, 10, 15 or more injections. The therapeutic effect is manifested by softening of scars, the appearance of mobility in the joints, elimination or reduction of contractures, resorption of hematomas; the effect is more pronounced in the initial stages of the pathological process.

The use of lidase in rheumatoid arthritis (in combination with anti-inflammatory drugs) is known by electrophoresis. In eye practice, lidase is used to finely scar the affected cornea, in the treatment of keratitis with antibacterial drugs (sulfonamides, antibiotics). It is also administered under the skin of the temple with retinopathies, under the conjunctiva; retrobulbar, with vitreous hemorrhages. With fresh hemorrhages, lidase is not used, lidase is also prescribed to accelerate the absorption of drugs introduced under the skin and intramuscularly (local anesthetics, muscle relaxants, isotonic solutions, etc.).

Patients with pulmonary tuberculosis with a productive nature of inflammation are prescribed lidase in the form of injections and inhalations in complex therapy to increase the concentration of antibacterial substances in the lesions. The drug is usually well tolerated, and allergic skin reactions can sometimes occur. There is evidence of the effectiveness of lidase in patients with traumatic lesions of the plexuses and peripheral nerves (brachial plexitis after bruising, traumatic mononeuritis, etc.) (Amasyants R.A. “On the effectiveness of the enzymatic treatment of post-traumatic neuritis with lidase” - Abstract of dissertation. - Tashkent, 1972). The drug is administered subcutaneously in the area of the affected nerve (64 UE solution in novocaine solution) every other day; on a course of 12-15 injections. (www.neuronet.ru/bibliot/bme/drug/drug1060).

This enzyme preparation is thermolabile, its solution requires special preparation in compliance with sterility and is not subject to long-term storage, which complicates its use in the treatment process. Preparations for local and external use on the basis of lidase are not developed due to its instability.

Stephaglabrin is an alkaloid obtained by extraction from the stem-tubers of the perennial herbaceous creeper Stephania smooth (Stephania glabra Miers). The main feature of the pharmacological action of stefaglabrin is its ability to inhibit cholinesterase activity and increase the sensitivity of organs to acetylcholine. It has a tonic effect on smooth muscles, in small doses it increases, and in large doses it lowers blood pressure. Currently, stefaglabrin is used in the form of stefaglabrin sulfate, which is effective in the treatment of syringomyelia, progressive muscular dystrophy, alimotrophic lateral sclerosis, traumatic plexitis, polyradiculoneuritis, facial neuritis, polyneuritis (//c-bajun-v.narod.ru/t.marod.ru/t.ru/t )

Stefaglabrina sulfate is produced as a 0.25% aqueous solution in 1 ml ampoules (2.5 mg in ampoule) (sls.e-help.ru/action/show_prep_info/id/244/index.html). This drug is stable, shelf life of 3 years (FS 42-2438-86).

Stefagalabrina sulfate is administered intramuscularly in 1-2 ml of a 0.25% solution per day for 20-30 days. Along with this, B vitamins are recommended (//c-bajun-v.narod.ru/Fit2_8c.htm).

The molecular weight of stefaglabrin sulfate is 692.8 (VFS-42-2438-86).

Stefaglabrina sulfate in injectable form is used to treat traumatic and postoperative damage to the peripheral nervous system. It provides improved functional results by preventing the growth of coarse connective tissue. This drug has a specific inhibitory activity on the development of connective tissue. A histological study of the area of traumatic damage to nerve trunks showed that in the experimental group (daily intramuscular injection of stefaglabrin sulfate at a dose of 1 mg / kg), there was a pronounced inhibition of connective tissue growth. Collagen fibers are loose, their number is small with moderate proliferation of fibroblasts. In the control group, in the area of the nerve suture, connective tissue is more pronounced than in the experimental group, and is represented mainly by mature collagen fibers, which are densely lying, often in the transverse direction with respect to the regenerating axons.

It has been experimentally shown that when using stefaglabrin sulfate in the form of a 0.25% aqueous solution, the regeneration of damaged peripheral nerve fibers is faster than when using complex treatment - anticholinesterase drugs (proserin, galantamine, etc.), phytotherapy with lidase, vitamin therapy, etc. Moreover, the positive effect in the treatment of stefagabrine with sulfate when administered parenterally is 75%, which is 37.5% more than with traditional methods of treatment - anticholinesterase agents (proserin, galantamine and .), Phytotherapy with Lydasum, vitamin et al. (Patent RU 1713151, A61K 35/78, 1995.02.09).

The mechanisms of the therapeutic effect of the drug associated with the prevention of the formation of connective tissue scar at the site of traumatic nerve damage and due to this faster germination of regenerating nerve fibers into the peripheral segment of the nerve are determined. Intramuscular administration of stefaglabrin sulfate in case of traumatic injuries of the peripheral nervous system prevents the formation of a coarse connective scar at the site of an anatomical break of a nerve, surgical suture or at the site of injury and increases the number of germinating nerve fibers from the central segment to the peripheral. Under the influence of stefaglabrin sulfate, excessive formation of connective tissue and the development of neuroma in the scar area is prevented, which ensures the unhindered penetration of nerve fibers from the central segment of the nerve into the peripheral.

On models of thermal burns in mice, it was found that with the prophylactic and therapeutic use of stefaglabrin sulfate in doses of 0.1 and 1 mg / kg, it has anti-inflammatory and wound healing properties; at a dose of 10 mg / kg, the drug retains these properties only with prophylactic use. Stefaglabrina sulfate is a low-toxic substance.

In the range of therapeutic doses of 0.1-1 mg / kg, stefaglabrin sulfate is characterized by a moderate sedative effect and pronounced antihypoxic and hypothermic properties. Stefaglabrin sulfate does not possess embryotoxic, teratogenic, mutagenic, allergenic, immunomodulatory and local irritating properties (Yu.B. Kuznetsov, “New Aspects of the Pharmacological Action and Toxicological Characterization of Stefaglabrin Sulfate”, author. 1987, pp. 9-21).

Stefaglabrin sulfate is administered intramuscularly with traumatic damage to the peripheral nervous system. With parenteral administration, the drug is rapidly absorbed into the systemic circulation. This provides a high rate of distribution of the drug in the body. The drug, administered intramuscularly, is brought to the place of growth of the coarse connective tissue by the systemic circulation, while its concentration in this place is not more than 1/5000 of the initial concentration of the drug due to its dilution in the systemic circulation (5000-6000 ml is an approximate amount of blood in the systemic circulation of an adult).

In reality, its concentration at the site of scar tissue formation will be even less due to the drug entering other tissues from the systemic circulation, which reduces the therapeutic effect of the drug. Intramuscular or subcutaneous administration of the drug next to traumatic injury will give its higher concentration at the site of connective tissue growth. However, due to the localized administration of the drug, it will enter not only the site of scar tissue formation, but also in other directions, spreading (absorbed by diffusion and capillary blood flow) into intact organs and tissues, and also entering the systemic circulation. This reduces the concentration of the drug at the site of formation of connective tissue in comparison with the initial concentration of the administered drug. A decrease in the concentration of the drug acting on the connective tissue reduces its therapeutic effect, which consists in suppressing its growth.

The bioavailability of low molecular weight drugs during transdermal administration is close to injectable subcutaneous and intramuscular administration, but does not give painful sensations. For local and external use, part of the drug is deposited in the epidermis, subcutaneous fat layer, mucous membrane. Moreover, part of the drug from the epidermis, subcutaneous fat layer and mucous membrane, gradually entering the bloodstream, contributes to the stability of the concentration of the drug in blood plasma.

Currently unknown pharmaceutical preparations in the form of finished dosage forms for local and external use containing stefaglabrin as an active substance.

The objective of the invention is the creation of pharmaceutical preparations for local and external use based on stefaglabrin.

Technical results that can be obtained using the invention:

- expanding the scope of the well-known drug stefaglabrin;

- enhancing the therapeutic effect and increasing its duration;

- the exclusion of a violation of the integrity of the skin and the manifestation of pain during administration of the drug;

- Increased patient predisposition to treatment.

To solve this problem, the present invention proposes a pharmaceutical preparation for local and external use containing the active substance - stefaglabrin, in the form of a physiologically acceptable compound, for example stefaglabrin sulfate, the target additive and base, for example, in the following ratio of components (wt.%):

stefaglabrin 0.001-2.0 target additive 0.000001-60.6 the basis rest

As a target additive, it contains a stimulant of reparative processes, or an anesthetic, or a hypoxidant, for example, succinic acid, or vitamins, or biogenic elements in the form of physiologically acceptable compounds, or their physiologically acceptable mixture, for example, with the following amount in the composition (wt. %):

reparative stimulant 0.5-10.0 anesthetic 0.25-5.0 hypooxidant 0.001-2.0 vitamins 0.00001-35.0 nutrients 0.000001-8.6

As a stimulant of reparative processes, the preparation contains, for example, methyluracil, xymedon, or a physiologically acceptable mixture thereof.

As anesthetic, for example, lencaine, or lidocaine, or pyromecaine, or trimecaine, or novocaine, or a physiologically acceptable mixture thereof, can be used.

Succinic acid, for example, can be used as a hypooxidant.

The composition of the proposed drug may include, for example, the following vitamins: thiamine (vitamin B ₁ ), or folic acid (vitamin B ₉ ), or cyanocobalamin (vitamin B ₁₂ ), or pyridoxine (vitamin B ₆ ), or calcium pantothenate (vitamin B ₅ ), or riboflavin (vitamin B ₂ ), or nicotinic acid (vitamin PP), or d-α-tocopherol (vitamin E), or beta-carotene (provitamin A), or their physiologically acceptable mixture with the following vitamin content in the preparation (wt.%):

thiamine 0.00003-5.0 folic acid 0.00015-0.5 pyridoxine 0.00015-5.0 cyanocobalamin 0.00001-0.5 vitamin C 0.000018-10.0 riboflavin 0.000015-2.0 calcium pantothenate 0.00015-5.0 a nicotinic acid 0.005-1.0 d-α-tocopherol (in water-soluble form) 0.000047-4.0 beta-carotene (in water-soluble form) 0.000025-2.0

The composition of the proposed drug may include the following biogenic elements in the form of physiologically acceptable compounds, for example zinc, or manganese, or copper, or silicon, or their physiologically acceptable mixture with the following elements in the preparation (wt.%):

zinc 0.00002-5.0 manganese 0.000001-0.5 copper 0.00001-0.1 silicon 0.00003-3.0

In accordance with the invention, the pharmaceutical preparation for local and external use based on stefaglabrin is made in the form of a liquid, for example, a suspension or emulsion in the form of a liniment, or a ointment-like soft dosage form, for example, an ointment, gel or cream, or a formulated soft dosage form, for example, suppositories or gelatin capsules for rectal use.

An emulsion of perfluororganic compounds or its mixture with osmolar hydrophilic substances in the following ratio of components in the base (wt.%) Is proposed as a basis in a preparation for local and external use containing stefaglabrin:

organofluorine emulsion 5.0-90.0 osmolar hydrophilic substances rest

The healing processes of primary purulent wounds proceed in the following sequence. Initially, the wound is cleaned of necrotic tissue, cells, blood clots, etc. Then, in some parts of the walls of the purulent cavity, cell growths appear in the form of red nodules, which, gradually increasing in number and size, cover all walls and the bottom of the wound. These red nodules are composed of young mesenchymal cells (fibroblasts), reticular and collagen fibers, newly formed vessels and are called granulation tissue, which fills the entire cavity of the purulent wound to the skin. Then the skin epithelium, growing, covers granulation, the cells of which gradually form connective tissue.

Unlike primary healing, when the capillaries of the blood vessels of one wall of the wound are connected to the capillaries of the other wall, during the secondary healing of the capillaries, growing, they do not reach the opposite wall of the wound due to the presence of a significant wound cavity, but form loops. Around the loops of the capillaries appear cells of young connective tissue, which makes up individual grains of granulation tissue. Growing on the formed loops of capillaries, granulation tissue, as on a vascular scaffold, fills the entire cavity of the wound. As granulations grow in the deeper layers, changes in fibroblasts occur: on the granulation surface and in the layers adjacent to the surface, plasma cells predominate, in the deeper layers the number of spindle-shaped cells increases and fibrous connective tissue appears, and in the deepest layers there is already fibrous connective tissue - scar.

This process of cicatricial transformation of the deep layers of granulation tissue leads to a gradual contraction of the purulent wound, to a decrease in its size. Epithelization of a granulating wound begins from the first days. The epithelium, multiplying, grows on granulation tissue. From the ends of the destroyed nerve branches of the walls of the wound and skin, regeneration of nerve fibers begins (“Open wound damage”, www.medicreferat.com.ru/pageid-1797-1.html).

Large wounds require significant efforts by the body to grow new tissue to replace an existing defect, so scars form. Scars are all the more pronounced, the more intensive is the healing process (//vulnus.aptekonline.ru).

According to the theory of codogenesis during the regeneration of nerve fibers, the sprouting of the axial cylinder from the central segment of the damaged fiber to the peripheral is stimulated and directed by its contact with denser than tissue fluid substrates (cells, fibers) of the peripheral segment of the nerve (www.medicalipedia.com/1/213/ 223715.html).

The restoration of fibers in the peripheral nervous system involves a complex sequence of processes during which a segment of a neuron actively interacts with glial cells. During the first week after the violation of the nerve fiber, upward degeneration of the proximal (closest to the neuron body) part of the axon develops, at the end of which an extension (retraction flask) is formed. The glial (myelin) membrane in the area of damage breaks up into individual cells, which begin to actively divide, the body of the neuron swells, the nucleus moves to the periphery. In the distal (remote from the neuron’s body) part of the fiber after its rupture, downward degeneration is observed with complete destruction of the axon and subsequent phagocytosis of the residues by macrophages and glia. After 4-6 weeks, the structure and functions of the neuron are restored, thin branches (growth cones) begin to grow from the retraction bulb in the direction of the distal part. Glial cells along the destroyed fiber proliferate, forming Bugner ribbons parallel to the course of the fiber. In the distal part of the fiber, glial cells also persist and mitotically divide, forming ribbons connecting with similar structures in the proximal part. The regenerating axon grows in the distal direction at a rate of 3-4 mm per day along the Burger ribbons, which play a supporting and guiding role.

Glial cells form a new myelin sheath. The entire recovery process takes several months. Collateral organs and axon terminals, interacting with the muscle, are restored within a few months. During the body's ontogenesis, the direction of nerve fiber growth is determined by contact interactions with other cells and distant chemical signals sent by the innervated organ (target organ) (www.nsu.ru/materials/ssl/distance Biology / Archives / 002.html).

Regeneration depends on the location of the injury. In both the central and peripheral nervous systems, dead neurons are not restored. Full regeneration of nerve fibers in the central nervous system usually does not occur, but nerve fibers in the composition of peripheral nerves usually regenerate well. In this case, the neurolemmocytes of the peripheral segment and the area of the central segment closest to the injury area proliferate and line up in compact cords. The axial cylinders of the central segment give numerous collaterals that grow at a speed of 1-3 mm per day along neurolemmal cords, creating an excessive growth of nerve fibers. Only those fibers survive that reach their respective endings. The rest degenerate. If there is an obstacle to the axon ingrowth of the central segment of the nerve into the cord of peripheral neurolemmocytes (for example, in the presence of a scar), the axons grow randomly and can form a tangle called an amputation neuroma. When it is irritated, severe pain occurs, which is perceived as originating from the originally innervated area (www.morphology.dp.ua/_mp3/neural3.php).

Ischemia in tunnel syndromes leads to the development of hypoxymic disorders in the nerve trunks. At the same time, microcirculation and oxygen tension are reduced in them, which is exacerbated by the development of edema and impaired delivery of energy-giving substances to the nerves (//formen.narod.ru/osteo_ft_tn.htm). Increased edema causes even greater compression of the veins, lymphatic vessels and contributes to stasis, the development of thrombosis, tissue anoxia and their necrosis. Moreover, the less loose tissue in the tissues, the faster and more extensive the foci of tissue necrosis ("Open wound damage", www.medicreferat.com.ru/pageid-1797-l.html).

The goal in the treatment of traumatic injuries of the peripheral nervous system is the elimination of pain and swelling of the nerve and perineural tissues by providing analgesic dehydration effects, stimulating nerve conduction, enhancing the regeneration of nerve fibers, improving microcirculation in peripheral vessels, preventing scar adhesions, eliminating trophic disorders, stiffness in the joints, contracture and other changes that impede the restoration of movement (//formen.narod.ru/osteo_ ft_tn.htm).

From the foregoing, it is clear that the regeneration of nerve fibers is an integral part of wound healing. Moreover, restoration of nerve fibers can be much later than wound epithelization, since tissues with a complex structure and highly differentiated function (nervous, parenchymal organs, muscles, etc.) are less capable of regeneration than tissues of a simpler structure (connective tissue, integument epithelium )

In this regard, when restoring peripheral nervous tissue, it is important not only the delivery of active substances that contribute to the regeneration of nerve fibers to the lesion in the open wound, but also their delivery to the site of nerve damage through the transepidermal barrier in the case of closure of the wound with integumentary epithelium.

It is known that in the intact stratum corneum of the epidermis there are no channels through which particles with sizes above 10 nm could penetrate into the depth of the skin. Moreover, the larger the size of the substance’s molecule, the lower its permeability through the transepidermal barrier. It was found that substances with a molecular weight of 100 kilodaltons do not overcome the transepidermal barrier, that is, this value is the limit of skin permeability. Through microchannels that determine the permeability of the skin characterize the most likely intercellular pathway of the transport of substances through the upper scaly keratin layer of the epidermis.

The most important role in the implementation of barrier-protective functions in the permeability of the skin is played by the state of water molecules present in the microcapillary holes of the horny and shiny skin layers. The water inside the microchannels is largely in a structured state, which significantly slows down the processes of Brownian motion, which are responsible for equalizing the concentration gradient, i.e. permeability. The ordered structural organization of water in the microcapillary holes of the stratum corneum prevents the intensive evaporation of water from the skin surface, creating an additional barrier to the dehydration process. However, water, oxygen, nitrogen and other low molecular weight substances sufficiently easily diffuse through the skin. In this case, substances capable of reacting (binding) with fragments of the epidermis, including cellular systems, first reach saturation in the epidermis, and then begin to interact with deeper layers of the skin. The intercellular substance of the epidermis and dermis is a gel formed, for example, from hyaluronic acid or from a substance similar to it.

Such gel-like structures with a reticular structure are convenient for binding various low- and high-molecular substances (salts, sugars, amino acids, vitamins, peptides, proteins, epidermal cell metabolism products, etc.). Living cells of the epidermis with greater or lesser efficiency retain some of the substances that pass through the horny and shiny layers. With the regular use of the same type of medicinal and cosmetic products for external use, the fragments of the skin treated with these products are in a state of constant saturation, in which their concentration in the skin remains almost unchanged.

Moreover, many low molecular weight components of the drug used can quite easily overcome the transepidermal barrier. 60% of plasma and 45% of plasma proteins daily penetrate from microcapillaries of the circulatory system into tissues, including the epidermis. Returning to the circulatory and lymphatic systems, they carry with them metabolites associated with proteins (cell waste products - toxins) and catabolites (biologically active substances - peptides, proteins, etc., synthesized inside the cell). Substances that have overcome the transepidermal barrier also appear in the blood and, in accordance with this, act on all body tissues (A. N. Decina. "Theory of soft cosmetic effects. Modern cosmetology", Novosibirsk, "Science", 2000, www.golkom .ru / book / 48_1.htm).

Thus, the main requirement for drugs for local and external use with stefaglabrin is the effective transport of the active substance to the site of damage to nerve fibers in an open wound, as well as through the transepidermal barrier to the site of traumatic damage to nerve tissue when it is subcutaneous with the deposition of part of the active substance into fragments epidermis, mucous membrane, and subcutaneous fat surrounding the wound.

For external use, especially with open injuries, the drug is applied in the form of a solution, liniment, cream, ointment or gel directly to the growth area of coarse connective tissue in the wound, that is, to the place of damage to nerve fibers, as well as to areas of intact tissue adjacent to the perimeter to damage. When used in conjunction with stephaglabrin with a hydrophilic osmolar base, which has a high penetrating ability and conducts stefaglabrin directly into the growth area of the connective tissue, both in an open wound and subcutaneously, the maximum therapeutic effect of using stefaglabrin due to its high concentration in the lesion is slightly different from its initial concentration in the drug.

Moreover, the uniform saturation of the undamaged tissue sites adjacent directly to the wound by applying an external preparation containing stefaglabrin to them significantly reduces its diffusion from the growth region of the connective tissue into the undamaged areas, thereby ensuring a constant concentration of stefaglabrin in the growth area for a long time connective tissue. This gives a longer and more stable therapeutic effect, which consists in inhibiting the growth of coarse connective tissue and its loosening.

With the transdermal administration of active substances, their effective transport through the transepidermal barrier to the site of damage to the nervous tissue most fully provides hydrophilic bases with hyperosmolar properties. Osmolar hydrophilic solvents, for example, aqueous solutions of salts, alcohols and their aqueous solutions (e.g., ethyl or isopropyl), glycerin, low molecular weight polyethylene oxides (e.g., PEO-400), propylene glycols (e.g., 1,2-propylene glycol), etc., easily penetrate through the tranepidermal barrier or deep into the wound, transporting the active substances dissolved in them to the site of connective tissue growth and displacing toxic metabolic products from the affected area.

At the same time, due to their osmolar properties, they bind water located in the cellular systems of the spike and granular layers, which leads to a decrease in the size of cell systems and, consequently, to an increase in the intercellular space and cross section of microchannels, i.e., an increase in the permeability of the epidermis. In addition, they thin the gel of hyaluronic acid filling the intercellular space, which is an additional factor in increasing the permeability of the epidermis. If hyperosmotic conditions are created by adding salt systems, the permeability of the epidermis will additionally increase due to a change in the structure of the microcapillary channels of the horn and shiny layers, since when the channel cavities are saturated with positively charged metal ions (Na ⁺ type), the channel structures are transformed into a structure (according to the " flip-flop ") with a tendency to expand the diameter of the channel due to the electrostatic repulsion of positive charges localized on metal atoms (A. N. Decina." Theory of FIR beauty effects. Modern cosmetology ", Novosibirsk," Nauka ", 2000, www.golkom.ru/book/48_1.htm).

Stefaglabrin in the form of, for example, stefaglabrin sulfate, being a low molecular weight substance dissolved in a liquid hydrophilic and hyperosmolar base, with local and external use, it easily and quickly penetrates deep into the open wound, as well as through the tranepidermal barrier and mucous membranes. Moreover, with transdermal administration, the active substance is partially deposited in fragments of the epidermis and subcutaneous fat. The gradual diffusion of active substances from there to the lesion site ensures there a fairly stable level for a long time.

On a liquid low molecular weight hydrophilic and hyperosmolar base and physiologically acceptable compounds of stefaglabrin, for example stefaglabrin sulfate, liquids for topical and external use are made: solutions, liniment, emulsions and suspensions, which have high penetration and ensure the transport of active substances deep into the open wound, as well as through the tranepidermal barrier and blood flow to the site of damage to peripheral nerve fibers.

Adding hydrophilic thickeners to hydrophilic solvents, such as high molecular weight polyethylene oxides (e.g. PEO-1500), proxanols (e.g. proxanol-268), medical polyvinyl pyrrolidones (e.g. with a molecular weight of 12600 ± 2700 or 8000 ± 2000) or other substances possessing sorption properties (for example, calcium or magnesium alginate), enhances the transport of toxic metabolic products from the site of subcutaneous lesions or the depth of the wound to the skin surface. For example, PEO-1500 molecules stably maintain primary localization due to a sufficiently high molecular weight: they remain in the microchannels of the stratum corneum of the epidermis or in the wound cavity and actively bind inflammatory exudate, transporting it to the surface of the skin with which the liquid evaporates. The released PEO-1500 molecules reattach water to themselves, and the process repeats (“Theory and practice of local treatment of purulent wounds.” Edited by Prof. B. M. Dotsenko. Kiev, “Health”, 1995, p. 234- 235).

On a soft hydrophilic and hyperosmolar basis, consisting of a low molecular weight hydrophilic solvent with hyperosmolar properties, a hydrophilic thickener-sorbent and stefaglabrin, soft forms for topical and external use are made: creams, ointments, gels, suppositories that have high penetrating and sorption ability and provide transport and active sorption ability and provide transport substances deep into the open wound, as well as through the transepidermal barrier and blood flow to the site of damage to peripheral nerve fibers.

Gelatin capsules for rectal administration are also filled with liquid and soft hydrophilic compositions on a hyperosmolar basis, which ensure the transport of active substances by the bloodstream to the site of damage to peripheral nerve fibers.

One of the main tasks of treating traumatic injuries of peripheral nerve fibers is the problem of suppressing pain. To ensure local anesthesia, a local anesthetic is introduced into the tissue that innervates the lesion and the surrounding wound with damaged peripheral nerve fibers (conduction method of local anesthesia). To solve this problem, the proposed drug used an anesthetic as the target additive, which can be used novocaine lnecain, lidocaine, trimecaine, which retains its activity in an acidic environment, which is characterized by a purulent wound, pyromecaine, anestesin, dibucaine. Lidocaine, trimecaine and pyromecaine are the most promising in the composition of the proposed drug on a hydrophilic basis.

Another important task in the treatment of traumatic damaged peripheral nerve fibers is to stimulate their regeneration. For this, a substance that accelerates the regeneration of peripheral nervous tissue, methyluracil, or xymedon, or vitamin B ₁₂ , or their physiologically acceptable mixtures, is introduced in the proposed preparation based on stefaglabrin.

It is known that methyluracil and pentaxyl (pyrimidine derivatives) accelerate the regeneration of nerve fiber damaged as a result of trauma and various diseases. Therefore, they are used in the treatment of patients with damage to the spinal cord and peripheral nervous system in the form of oral preparations (www.promednov.info/neuro-015/neuro-150098.shtml). On the basis of methyluracil, 10% ointment is made. In addition, methyluracil is part of ointments for the treatment of purulent wounds, for example, ointments such as levomekol, levosin, containing 4 g of methyluracil in 100 g of ointment.

Pentaxyl is not used in topical and topical preparations because of its low solubility in water and because of the irritating effect of topical application (www.medicalipedia.com/4/207/232155.html).

The property of the drug Xymedon, which is also a derivative of pyrimidine, is known to stimulate the regeneration of myelin nerve fibers (Yu.F. Chelyshev et al. “Stimulation of the regeneration of the peripheral nerve by drugs.” Experimental and Clinical Pharmacology - 200- E63, No. 4, pp. 17-19 ) Xymedon is very soluble in water, easily soluble in alcohol (www.medtrust.ru/pls/farmspravochnic/show.html? OntosObjectId = 17606).

It does not irritate the skin and mucous membranes of the eyes, does not have skin-resorption and sensitizing effects, improves microcirculation, improves regional blood circulation, increases the immune status, phagocytic activity of T-lymphocytes and nonspecific resistance of the body (www.ncmed.ru/words3.php? id_w = 1318). The properties of methyluracil and xymedon allow their use as a target additive in the composition of the proposed drug.

The stimulation of the regeneration process under the influence of pyrimidine derivatives is associated with increased synthesis of nucleic acids and protein throughout the body and in regenerating tissue. Pyrimidine derivatives increase the body's defenses, stimulate the absorption capacity of macrophages, humoral immunity (A.F. Ismagilova et al. “Pyrimidine derivatives increase the effectiveness of antibiotic therapy with ionizing radiation,” Antibiotics and Chemotherapy, 1998, No. 7, pp. 12-14-14 , //nature.web.ru/db/msg.html&mid=1176541&s=).

Microcirculation is one of the main factors for the effective transportation of the active substance during transdermal administration or through the mucous membranes. It includes not only blood flow through arterioles, capillaries and venules, but also transcapillary exchange, which provides tissue homeostasis necessary for life. Microcyclic disorders are divided into intravascular changes, vascular disorders and extravascular changes. The therapeutic spectrum of drugs used to improve microcirculation in tissues can be largely realized due to their antihistamine, anti-inflammatory and dehydrating effects.

Succinic acid (or its salts, for example succinate) is a hypooxidant, normalizes histamine and serotonin in the body, increases microcirculation in organs and tissues (A.I. Fedin “Oxidative stress and the use of antioxidants in neurology. Www.medmoskva.ru/news/ Out.aspx? Item = 19107). With an increase in the load on any of the body systems, the maintenance of its work is ensured mainly due to the oxidation of succinic acid. The power of an energy production system using succinic acid is hundreds of times greater than all other energy systems in the body. This provides a wide range of non-specific therapeutic effects of succinic acid and its salts. In addition, succinic acid also has such effects as actoprotective and antiviral (S.V. Obolensky “Reamberin - a new tool for infusion therapy in the practice of critical state medicine”, www.critical.ru/consult/pages/reamberin.htm).

In addition, the use of a hyperosmolar base also improves microcirculation in the tissues of the wound due to its dehydrating effect.

Water-soluble vitamin B ₁ (thiamine) is used in the treatment of polyneuritis, radiculitis, neuralgia, and peripheral paralysis. It is used subcutaneously, intramuscularly or intravenously in the form of a 2.5% or 5% aqueous solution of thiamine chloride. Subcutaneous and intramuscular injections are painful (//dobralbert.narod.ru/medicamentb/b70.html). The simultaneous parenteral administration of thiamine and pyridoxine (vitamin B ₆ ) or cyanocobalamin (vitamin B ₁₂ ) is not recommended. B ₁₂ enhances the allergenic effect of thiamine.

B ₆ makes it difficult to convert thiamine to a biologically active form. Nicotinic acid destroys vitamin B ₁ (www.recipe.ru). Thiamine takes part in regeneration during wound healing along with vitamins B ₂ , B ₅ and A (//vulnus.aptekonline.ru), as well as in the localization of pain along with vitamin B ₁₂ , analgesics and tranquilizers (//formen.narod. com / osteo_ft_tn.htm).

Folic acid (pteroylglutamic acid; folacin; vitamin B ₉ ) belongs to the B vitamins. Its molecular weight is 441.4 g / mol, slightly soluble in water (1-2 μg / ml), soluble in dilute acid, easily soluble in diluted alkalis (//uniargo.ru/spictures/56.jpg). Folic acid together with vitamin B ₆ and B ₁₂ provides the basis for the normalization of collagen (Description of the drug Osteo Complex, www.dolgolet.ru/bad/bad-kosti-03.html), which is part of the skin, bones, blood vessels and other body tissues . It supports the immune system, contributes to the normal formation and functioning of white blood cells. The folic acid is required by the body to adsorb other B vitamins, that is, a deficiency of folic acid can lead to a deficiency of other vitamins of this complex. It is necessary for the formation and optimal functioning of the nervous system and bone marrow (//vita.x51.ru/publ/3-1-0-5).

The action of folic acid: nootropic, restoring the structure of nerve tissue, etc. (Drug Reference, www.recipe.ru). Folic acid is more effective when taken with cyanocobalamin and pyridoxine (www.medolina.ru. Daily Health News August, 15, 2005). Folic acid functions in combination with cyanocobalamin in the formation of new cells, which maintains the necessary level of folic acid in the cells. Without it, cells cannot retain folic acid. In these cells, the division process is disrupted or completely stopped. Folic acid is essential for the absorption of cyanocobalamin and vice versa.

Cyanocobalamin together with folic acid is involved in the synthesis of nucleotides, in the formation of red blood cells and cells of the nerve membranes. It is also involved in the metabolism of fats and carbohydrates, it is important for normal growth, as well as the regeneration of folic acid (www.dsm.com/ru_RU/html/dnpru/hnh_maininfovit_index_basics_b12.htm).

Cyanocobalamin (vitamin B ₁₂ ) is commercially available in the form of 0.02% and 0.05% aqueous solution (www.37.com.ua/notes.php?lek=3809). Vitamin B _{12 is} involved in the processes of transmethylation, hydrogen transfer, activates the synthesis of methionine. Enhancing the synthesis and ability to accumulate protein in the body, cyanocobalamin also has an anabolic effect. Increasing the phagocytic activity of leukocytes and activating the activity of the reticuloendothelial systems, vitamin B ₁₂ enhances immunity. When taken orally, cyanocobalamin is poorly absorbed, its absorption improves while taking folic acid.

It is advisable to use vitamin B ₁₂ for diseases of the nervous system: multiple sclerosis, encephalomyelitis, radiculitis, polymyelitis, cerebral palsy, etc. (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=24). Vitamin B _12, together with piracetam and cerebrolysin, enhances the regeneration of nerve fibers. In the treatment of neuropathies in complex therapy, vitamin B _12, together with vitamin B _1, provides localization of the pain syndrome (//formen.narod.ru/osteo_ft_tn.htm). Vitamin B ₁₂ in the form of an aqueous solution containing 2.5 mg of cyancobolamine in 1 ml of distilled water, as part of Ambene, is involved in the formation of the myelin layer of nerve fibers and enhances the analgesic effect of the drug (www.sakh-cgan5.ru/info/doctors.php )

Pyridoxine is commercially available as a 5% aqueous solution (www.37.com.ua/notes.php?lek=1916). It promotes the conversion of folic acid into its active form; plays an important role in metabolism, is necessary for the normal functioning of the central and peripheral nervous system. Pyridoxine as a coenzyme is involved in the metabolism of amino acids and proteins, in the synthesis of neurotransmitters, etc. (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=22).

Riboflavin (vitamin B ₂ ), being a synergist of pyridoxine, is required for the interconversion of various forms of vitamin B ₆ (www.dsm.com/ru_RU/html/dnpru/hnh_maininfovit_index_basics_b6.htm). The water-soluble vitamin riboflavin acts as a mediator in electron transfer in various redox reactions. Thus, he participates in many reactions of the metabolism of carbon, fat and protein, as well as in reactions for the production of energy in the respiratory chain. Riboflavin coenzymes play an important role in the conversion of pyridoxine and folic acid to their active coenzyme forms (Essentials about Vitamins, DSV Nutritional Products, www.dsm.com/ru_RU/html/dnpru/hnh_maininfovit_index_basics_b2.htm).

Riboflavin deficiency affects tissues rich in capillaries and small vessels (brain tissue). With deficiency, cerebral insufficiency of varying severity may be a frequent manifestation (http://vitamim.solvay-pharma.ru/encyclopedia/info.aspx?id=16). It is produced in the form of a 1% solution of riboflavin mononucleotide, which allows it to be dissolved in a hydrophilic base in the production of ointments, creams, emulsion gels.

Water-soluble pantothenic acid (vitamin B ₅ ), as a component of coenzyme A, plays a key role in the metabolism of carbohydrates, proteins and fats, and therefore is important for maintaining and restoring all tissue cells. She is involved in reactions that provide energy to the cell, and also take part in the synthesis of vital compounds such as sterols (e.g. cholesterol), hormones (e.g. growth hormones, stress and sex hormones), neurotransmitters (e.g. acetylcholine), phospholipids (components of cell membranes), porphyrin (a component of hemoglobin), antibodies, and also takes part in the metabolism of drugs. Calcium pantothenate or panthenol are usually used, which are readily soluble in water and are easily converted into pantothenic acid in the body. Vitamin B ₁₂ promotes the incorporation of free pantothenic acid into coenzyme A.

Ascorbic acid reduces the severity of pantothenic acid deficiency. Pyridoxine, folic acid, and biotin are essential for the efficient utilization of pantothenic acid (Essential Vitamins, DSV Nutritional Products, www.dsm.com/en_US/html/dnpru/hnh_maininfovit_index_basics_panto.htm). Pantothenic acid is necessary for the normal absorption and metabolism of folic acid (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=20).

Water-soluble ascorbic acid (vitamin C) is involved in the metabolism of folic acid, in the synthesis of steroid hormones and catecholamines (cyanocobalamin and folic acid, www.recipe.ru.). Ascorbic acid significantly increases the resistance of vitamins B ₁ , B ₂ , A, E, pantothenic and folic acids (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=13).

It plays an important role in the regulation of redox processes; participates in the synthesis of collagen and procollagen, providing the structure of muscles, vascular tissues, bones and cartilage; regulates blood coagulation; normalizes capillary permeability; necessary for blood formation; It has anti-inflammatory and anti-allergic effects; It is a factor that protects the body from the effects of stress; enhances reparative processes; increases resistance to infections. It is advisable to use vitamin C together with vitamin E, since they act synergistically in the body, enhancing each other's action as antioxidants (patent RU No. 2275192, АКК 31/015, 2006.04.27). It is commercially available in the form of a solution for injection of 5% or 10%, which allows it to be dissolved in a hydrophilic base in the production of ointments, creams, emulsion gels.

Water-soluble vitamin PP (nicotinic acid) is involved in the metabolism of fats, proteins, amino acids, purines, tissue respiration, glycogenolysis, and synthetic processes. Niacin has a vasodilating effect at the level of small vessels, improves microcirculation, and has a weak anticoagulant effect. It is used as a 1% aqueous solution administered subcutaneously, intramuscularly and intravenously. With subcutaneous and intramuscular administration, a painful reaction is observed. The highest dose for adults: single 0.1 g; daily - 0.3 g (www.webapteka.ru/drugbase/name4356_desc3539.html). Niacin is used in the treatment of traumatic injuries of the peripheral nerves together with B vitamins, dibazole, etc. (www.drnona.net.ua/_korl_4_1.htm), with stimulators of neural conductivity, caviton, trental (www.nedug.ru/library/ doc.aspx? item = 56116).

Vitamin E (d-α-tocopherol) is involved in the formation of collagen and elastic fibers of the intercellular substance. It improves blood circulation, necessary for tissue regeneration. Vitamin E provides normal blood coagulation and healing; reduces the possibility of scarring from some wounds; relieves leg cramps; supports the health of nerves and muscles; strengthens the walls of capillaries; prevents anemia. As an antioxidant, vitamin E protects cells from damage, slowing down the oxidation of lipids (fats) and the formation of free radicals. It protects other fat-soluble vitamins from being destroyed by oxygen, promotes the absorption of vitamin A and protects it from oxygen. Vitamin E prevents increased blood coagulability, favorably affects peripheral blood circulation, participates in the biosynthesis of heme and proteins, cell proliferation.

Its effectiveness is enhanced in the presence of other antioxidant nutrients. (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=12). At present, a water-soluble form of vitamin E has been obtained (www.akvion.ru/catalog/skk/), which allows it to be used with a hydrophilic base in the production of ointments, creams, emulsion gels.

Retinol (Vitamin A) is one of the main antioxidants. It is able to suppress cell destruction by free radicals. Vitamin A plays a significant role in the formation of epithelial tissue, which is part of the skin, glands and mucous membranes, respiratory system, digestive and genitourinary tract. It supports local immunity of vital organs, promotes the renewal of skin cells and their normal functioning. Vitamin A is effectively used in the complex treatment of many skin diseases. It enhances the body's immunity. To enhance the effectiveness of retinol, it must be used simultaneously with tocopherol. In addition, with a low zinc content in the body, vitamin A is poorly absorbed (http // vita.x51.ru / publ / 4-l-0-10).

Currently, a water-soluble form of vitamin A is obtained in the form of provitamin A - beta-carotene (www. Akvion.ru/catalog/skk/), which allows it to be used with a hydrophilic base in the production of ointments, creams, emulsion gels. The water-soluble form of beta-carotene has a regulatory effect on various parts of cellular and humoral immunity (T and B lymphocytes, immunoglobulins, phagocytic activity). In addition, this drug has both antioxidant and antihypoxic properties. Its administration normalizes lipid peroxidation and increases the activity of protective enzymes of the antioxidant system (E.G. Bochkarev, Yu.V. Sergeev, “The effect on the immune system of drugs with antioxidant and antihypoxant properties,” www.olifen-corp.ru/3 .html).

Zinc is a component of more than 200 enzymes (www.osteoform.ru/products/calc.htm). It provides carbon dioxide transfer, stability of biological membranes, and promotes wound healing (http://vitamini.solvay-pharma.ru/elements/article.aspx?id=1816). Zinc takes part in the processes of cell division and differentiation, the formation of T-cell immunity, the functioning of many enzymes, insulin of the pancreas, the antioxidant enzyme superoxide dismutase, the sex hormone dihydrocorticosterone, and plays an important role in the regeneration of skin, hair, nails, and secretion of the sebaceous glands. It helps to absorb vitamin E and maintain a normal concentration of this vitamin in the blood. Zinc strengthens the body's immune system, promotes wound healing, as it plays an important role in protein synthesis (www.microelements.ru/Zn).

Copper is necessary for the production of collagen; it gives excellent results in the treatment of rheumatoid arthritis. (//mirzdorovia,com.ua/spravka2.php). Copper is a vital element that is part of many hormones, enzymes, respiratory pigments, participates in metabolic processes, in tissue respiration, etc. Copper is of great importance for maintaining the normal structure of bones, cartilage, tendons (collagen), elasticity of the walls of blood vessels, pulmonary alveoli, skin (elastin). Copper is part of the myelin sheaths of nerves, as well as many enzymes. Increased intake of zinc and molybdenum can lead to copper deficiency. Manganese, iron, ascorbic acid can reduce the absorption of copper. Zinc, iron, cobalt (in moderate physiological doses) increase the absorption of copper by the body. In turn, copper can inhibit the body's absorption of iron, cobalt, zinc, vitamin A (www.microelements.ru/Cu).

Manganese is an essential element for protecting body cells. It is required for the growth, reproduction, healing of wounds, the maximum efficiency of the brain and the proper metabolism of sugars, insulin and cholesterol. Without an optimal amount of manganese, the risk of rheumatoid arthritis, osteoporosis, cataracts, multiple sclerosis and diseases such as epilepsy increases. The absorption of manganese is facilitated by zinc and vitamin C. (// mirzdorovia, com.ua / spravka2.php). Manganese is involved in the synthesis and metabolism of neurotransmitters in the nervous system; interferes with free radical oxidation; provides stability of the structure of cell membranes; provides the normal functioning of muscle tissue; provides the development of connective tissue; participates in the regulation of the exchange of vitamins C, E, group B, choline, copper. Vitamins B ₁ , E, phosphorus and calcium (in moderation) contribute to the absorption of manganese in the gastrointestinal tract, and the excess intake of phosphorus and calcium is an obstacle (www.microelements.ru/Mn). Manganese gluconate stimulates the activity of the natural enzyme contained in the skin, SOD (superoxide dismutase).

Silicon is the main element in the structure of connective tissue - the main protein of muscles, tendons and ligaments. The main role of silicon is to participate in a chemical reaction that bonds individual fibers of collagen and elastin. Silicon is important for cartilage and skeletal growth. It is indicated for disorders of connective tissue, diseases of bones, ligaments, cartilage, osteoporosis, periodontal disease, arthrosis, poor growth and fragility of nails and hair (www.osteoform.ru/products/calc.htm). In the highest concentrations, silicon is found in the walls of the aorta, trachea, ligaments, bones, skin (especially in the epidermis), hair, and lymph nodes. With a silicon deficiency in the body, connective tissue weakness (bronchopulmonary system, ligaments, cartilage), bone tissue weakness (osteoporosis), thinning, brittleness, hair loss, tendency to inflammatory diseases of the stomach and intestines, cholesterolemia, early development of atherosclerosis (www. microelements.ru/Si).

Silicon is found in large quantities in connective tissue, since it serves as a binding agent between collagen and hydrolyzed amino acids, present in proteoglycans. Its deficiency in the body leads to multiple bone deformities due to damage and delayed maturation of collagen and glycosaminoglycans, as well as to a decrease in extracellular matrix synthesis. Organosilicon substances that can be dissolved and absorbed are the most biologically active. Moreover, the bioavailability of, for example, methylsilanotriolsilicate is much higher than magnesium-aluminosilicate: 80% versus 1% (Rozhinskaya L.Ya. “Systemic osteoporosis: a practical guide”, www.medlibrary.ru/library/).

The proposed concentrations of vitamins and nutrients depend on the purpose of the pharmaceutical product for external and local use. Small concentrations are used in compositions to enhance the proliferative activity of cells (A. N. Decina. "Theory of soft cosmetic effects. Modern cosmetology", Novosibirsk, "Science", 2000, www.golkom.ru/book/48_1.htm). High concentrations of these substances are used for external and local injection into the lesion and bloodstream in acceptable daily doses equivalent to oral administration.

Hydrophilic bases that can be used with stefaglabrin in the proposed preparation are divided into two groups:

- water-soluble bases, which usually contain purified water, hydrophilic non-aqueous solvents: polyethylene oxide, for example PEO-400, 1,2-propylene glycol, glycerol, ethyl cellosolve, dimexide, and water-soluble polymers: polyethylene oxide, for example PEO-1500, proxanol, for example proxanol-268, polyvinylpyrrolidone, for example 8000 ± 200 or 12600 ± 2700;

- water-washable bases, which in addition to water-soluble polymers and hydrophilic non-aqueous solvents contain lipophilic substances: higher fatty alcohols, petroleum jelly, liquid paraffin, lanolin, waxes (these bases are usually oil / water emulsions and require the presence of an oil / water emulsifier) .

Basics with hyperosmolar properties play an important role in local therapy of purulent-destructive skin lesions. They provide an outflow of purulent exudate from a wound or lesion, have an anti-inflammatory effect due to the absorption of fluid and reduce tissue edema, and also protect tissues from overhydration. Often they contribute to enhancing the action of antibacterial substances.

In addition, the use of a hyperosmolar base also improves microcirculation in the tissues of the wound due to its dehydrating effect. In this case, the applied base, consisting of hyperosmolar substances, has an indirect anti-inflammatory effect due to the absorption of fluid and reduction of edema of the wound tissue or in the subcutaneous lesion.

Substances with high hyperosmolar properties include polyethylene oxides - water-soluble products of the polymerization of ethylene oxide, which are physiologically indifferent compounds. This class of substances includes hydrophilic non-aqueous solvents - PEO-400, 1,2-propylene glycol, glycerin, ethyl cellosolve, dimexide - and polymers (polyethylene oxide, for example PEO-1500, proxanol-268, polyvinylpyrrolidone). They are easily applied to the wound surface and evenly distributed on it, improving the contact of the ointment with the tissues and contents of the wound, mix well with wound exudate and maintain their uniformity, low toxicity and do not irritate tissues, do not violate their physiological functions.

The ability of polyethylene oxides (PEO) to provide the drug with an interstitial action fundamentally distinguishes this ointment base from fatty bases or solutions of antibiotics (antiseptics), the antimicrobial effect of which is limited only by the wound surface, although it is the deep microflora that determines the severity and direction of the purulent process.

The main property of PEO is that they have a pronounced dehydrogenating (moisture-absorbing) effect on the tissue. Due to the high ability to hydrate, these polymers actively absorb wound exudate, and with it microbial toxins, pro-inflammatory cytokines, tissue breakdown products, as well as various biologically active substances - lysosomal enzymes and other inflammatory mediators, thereby interrupting its progressive course. Of fundamental importance is the fact that in a purulent wound or subcutaneous lesion, the dehydrating effect of PEO extends not only to tissues, but also to microbial cells contained in the wound or lesion.

The dissolution of active substances in PEO leads to an increase in their dispersion with an increase in therapeutic activity, which is also facilitated by a faster release of the active substances from the base.

PEO is an active conductor of drugs across the skin barrier. The important thing is that this penetrating without damage to the cells ability of PEO is enhanced in conditions of inflammation.

Hydrophilic bases on polyethylene oxides are able to dissolve in the secrets of the mucous membranes, completely release medicinal substances, not irritate the mucous membranes, have a long shelf life, high physiological indifference, which contributes to their use in liquid, ointment-like and formable soft dosage forms.

An important biomedical requirement for ointment soft dosage forms is the ability to wet the wound surface and spread over it, due to the surface-active properties of solvents, polymers, surfactants and the base as a whole. The most pronounced surface activity are alcohols and ethyl cellosolve, which are unsuitable for inclusion in the composition of the base in high concentrations. Of the glycols, it is preferable to use 1,2-propylene glycol and PEO-400 compared to glycerol having weak surface-active properties.

When mixing the PEO-400 solvent with PEO-1500 polymer, the latter acts as a thickener, which, depending on the amount in the total mass, provides the required consistency of the created dosage form. In addition, PEO-1500 is an osmotically active substance that absorbs purulent exudate due to the binding of water molecules to hydroxyl and ether groups. 1,2-Propylene glycol, PEO-400, PEO-1500, proxanol-268 can be preservatives in the developed dosage forms ("Theory and practice of local treatment of purulent wounds" edited by prof. B.M.Dotsenko. Kiev, "Health" , 1995, p. 174; 227-235).

On the basis of PEO-1500 polyethylene oxide, the Geko hydrogel is commercially available, which represents a colorless gel-like mass formed by the action of ionizing radiation on a solution of polyethylene oxide in water. The gel is biologically inert, non-toxic. It has a widely varying structural viscosity. It is liquefied by adding alcohol, glycerol, with vigorous stirring, the pH of a 20% aqueous suspension of 4.0-8.0. Chemical composition: PEO-1500 3,5%; distilled water 96%; preservative (sodium benzoate) 0.5%. It is used as a basis in the production of ointments, creams, gels, liniments in the pharmaceutical and cosmetic industries (www.medpeterburg.ru/news/Out.aspx?Item=21284). The gel has a stabilizing effect on enzymes (patent RU No. 2089177, A61K 7/48, 1997.09.10).

Dimexide - 30% solution of dimethyl sulfoxide (DMSO) - is used as an anti-inflammatory drug for external use, inactivating hydroxyl radicals and improving the course of metabolic processes in the focus of inflammation. It also has a local anesthetic, analgesic and antimicrobial effect, has moderate fibrinolytic activity. Penetrates through the skin, mucous membranes, the membrane of microbial cells (increases their sensitivity to antibiotics) and other biological membranes without damaging them, and can carry a variety of drugs into the depths of the wound ("Theory and practice of local treatment of purulent wounds" edited by prof. B .M.Dotsenko. Kiev, "Health", 1995, pp. 177-174). DMSO mixed with a 0.5% solution of novocaine is used in the treatment of a number of tunnel neuropathies. The high transporting and activating ability of DMSO in relation to many medicinal substances is the basis for the use of the drug in the manufacture of dosage forms used for transdermal use (//formen.narod.ru/osteo_ft_tn.htm).

Polyvinylpyrrolidone is a synthetic polymer inert to the body and not degraded by enzyme systems. It is the basis of detoxification blood substitute fluid that binds toxic substances of various structures and removes them from the body. (Blood-replacing fluids, www.nedug.ru/libraru/doc.aspx?item=38053).

Hyaluronic acid - a polysaccharide from the glucosaminoglycan family, has the ability to bind 1000 times more water than it weighs. Hyaluronic acid has the highest hygroscopicity compared to other moisturizing agents such as glycerin and sorbitol. In this case, the absorbed water is retained inside the gel and does not evaporate even when the relative humidity of the surrounding air decreases. Due to its high hydrophilicity, hyaluronic acid forms highly viscous gels with water that moisturize the skin and mucous membranes. Hyaluronic acid is non-toxic. As part of the gels, hyaluronic acid has an antimicrobial, wound healing and anti-inflammatory effect, promotes the regeneration of the epithelium, prevents the formation of granulation tissues, adhesions, scars, normalizes blood circulation, and does not cause clinical complications.

Hyaluronic acid has a positive effect on the course of local inflammatory processes, binds the microflora, as well as the products of its decay and vital activity, has a pronounced anti-inflammatory effect and a local anesthetic effect. At the same time, hyaluronic acid also provides mechanical protection for wounds, as it forms a thin film that prevents the penetration of environmental factors, pathogenic agents, into the wound. Gels based on hyaluronic acid are used to treat local and general purulent-inflammatory processes, thermal and chemical burns, trophic ulcers in chronic venous insufficiency, radiation injuries of the skin, cracks, abrasions, as well as for the treatment of long-healing wounds of various etiologies (patent RU No. 2195262 , A61K 9/06, 2002.12.27).

Sodium hyaluronate is a sodium salt of hyaluronic acid, it is soluble in water with the formation of a viscous colorless gel with a pH of 6.0 -7.5 (0.1% solution). In its activity, sodium hyaluronate is a complete analogue of hyaluronic acid, promotes tissue regeneration without scarring, and has the ability to stimulate cell migration and proliferation. Used in concentrations ranging from 0.01 to 0.5%.

Organosilicon glycerohydrogel is a new ointment base for external cosmetic and medicinal products, because it combines the beneficial properties inherent in many other ointment bases. This gel conducts various medicines well, has anti-inflammatory, decongestant and antioxidant activity, is able to protect tissues from drying out, saturate them with oxygen, it is non-toxic, economical, and stable during storage. The presence of silicon has a beneficial effect on all types of tissues: epithelial, connective, skin, bone, promotes regenerative processes, enhances blood supply.

Due to the fact that silicon glycerates and glycerohydrogels based on them penetrate well through the skin and carry drugs, the dose of these substances in pharmaceutical compositions can be reduced (www.uran.ru/gazetanu/2007/04/nu11/wvmnu_р3_11_042007.htm). Given the high transcutaneous activity of organosilicon glycerohydrogel, it can be used to create drugs for local and external use, transdermal therapeutic systems. This gel can be used as a source of an essential microelement - silicon - to regulate silicon metabolism in the body (Boyakovskaya TG “Development of organosilicon glycerohydrogels and a comparative assessment of their transcutaneous activity”, dissertation abstract, www.vita.chel.su/files/ docs / diss / bojakovsku.doc).

It is known that organofluorocarbon emulsions with gas-transporting properties such as perftoran were used in the complex treatment of wounds and wound infections (Krylov N.L. et al. “Hemosorption and infusion of perftoran in the complex treatment of wounds and wound infection.” Problems of intensive care in a clinic. Abstracts of a scientific conference December 12-13, 1985 - M .: B.I., 1985, p. 12-13).

Experimental studies have shown that perfluorocarbon compounds have a membrane effect and have a stimulating effect on the metabolic processes of living cells (they activate redox, hydrolytic reactions, the synthesis of nucleic acids, proteins, lipids, etc.). The contact of perfluorocarbons with damaged cells leads to rapid detoxification, suppression of the inflammatory reaction and active cell proliferation. A positive effect was obtained with the cutaneous use of perfluorocarbon compounds in the treatment of patients with atopic dermatitis, eczema, trophic ulcers, herpes, acne, and pyoderma.

A characteristic property of perfluorocarbons is their antipruritic effect, which is not inferior to hormonal drugs (Umerov Zh.G., Filippov EA “Perfluorocarbon compounds are promising anti-inflammatory drugs for the treatment of skin diseases.” IX All-Union Congress of Dermatovenerologists. Almaty, September 23-27 1991 Abstracts of reports. - M., 1991, p. 354). Perfluorocarbons with gas transporting properties stimulate wound healing and / or improve metabolism in integumentary tissues, which is associated with their effect on gas exchange of adjacent tissues, since wound damage is accompanied by increasing tissue cell hypoxia and increasing acidosis (patent RU No. 2033163, АКК 33/16, 1995.04. twenty). Organofluorine emulsions with gas-transporting properties are known (for example, patent RU No. 2088217, АКК 9/10, 1997.08.27), which can be stored at room temperature for at least 1 year.

If necessary, a preservative, for example, nipogin, can be added to the drug.

The type of dosage form of the proposed pharmaceutical preparation depends on the molecular weight of the used hyperosmolar substances, their ratio in the composition of the mixture, the rheological properties of the mixture, as well as the quantitative ratio of the hyperosmolar base with other components of the pharmaceutical preparation. Based on these quantitative ratios and rheological properties of the mixture, the dosage form of the proposed pharmaceutical product for topical and external use can be a liquid, gel, cream, ointment or suppository.

The ointment form is most preferable for external use, since it is well fixed and held on the surface, has longer therapeutic activity, is cheaper to manufacture, convenient to use, which enhances the patient's motivation for treatment.

Using stefaglabrin, target additives, organofluorine compounds or organofluorine compounds in combination with hyperosmolar substances, for example polyethylene oxides, compositions of hydrophilic liquids for external and local use, hydrophilic ointments, hydrophilic creams, hydrophilic gels, which can also be used for the manufacture of suppositories and gelatin or other capsules for rectal use.

Hydrophilic liquids, being hyperosmolar (solutions, emulsions, suspensions in the form of liniments), easily penetrate into the depth of the wound, transporting the active substance and target additives to the growth site of the connective tissue, and also increasing the permeability of the epithelium, transport the active substance - stefaglabrin and target additives through the skin and mucous membranes to the site of damage to the nerve fiber.

Hydrophilic ointments are hyperosmolar, as a result of which they ensure the effective transportation of the active substance - stefaglabrin - and target additives deep into the wound to the place of connective tissue growth, and also increasing the permeability of the epithelium, transport the active substance - stefaglabrin - and target additives through the skin and mucous membranes to the lesion of the nerve fiber for a long time until the ointment dries. At the same time, stefaglabrin and target additives are evenly distributed in the lesion, and their concentration in the lesion is maintained for a long time approximately at a level close to their concentration in the preparation applied to the ointment dressing due to diffusion from it, which ensures the maximum therapeutic effect. This also increases the duration of exposure of the active substance and targeted additives to the lesion, that is, the duration of the therapeutic effect increases.

Hydrophilic creams are prepared on the basis of a water / oil or water / oil / water emulsion stabilized with suitable emulsifiers. These also include colloidal dispersed systems consisting of water-dispersed or mixed water-glycol solvents of higher fatty alcohols or acids, stabilized by hydrophilic surfactants. Creams are biphasic or multiphase disperse systems, the dispersion medium of which at the set storage temperature, as a rule, has a Newtonian type of flow and low values of rheological parameters. The action of hydrophilic-based creams is similar to the action of hydrophilic-based ointments, but at the same time they have a lower viscosity than ointments, therefore they penetrate deeper into the wound and through the tranepidermal barrier to the site of damage to the nerve fiber. According to the rheological properties, they occupy an intermediate position between the liquid and the ointment.

Hydrophilic gels (hydrogels) are prepared on the basis of water, a hydrophilic mixed or non-aqueous solvent (glycerin, 1,2-propylene glycol, PEO-400 polyethylene oxide) and a hydrophilic gelling agent (carbomers, cellulose derivatives, tragacanth, sodium hyaluronate, hyaluronic acid, etc. .). In addition, new hydrophilic gels mentioned above are currently being developed - Geko hydrogel and organosilicon glycerohydrogel. Gels are single, double, or multiphase disperse systems with a liquid disperse medium, the rheological properties of which are due to the presence of gelling agents in relatively low concentrations. In this dosage form, the gelling agents can additionally play the role of stabilizers of disperse systems: suspensions or emulsions.

Hydrophilic gels containing bound water in their composition do not have a dehydrating effect, like liquids, creams or ointments on a hydrophilic basis with hyperosmolar properties. They moisturize the focus of inflammation, protecting the wound from drying out. In this case, the heat transfer of the gel-coated part of the surface is reduced, as a result of which it is heated. Under the gel layer, moisture does not evaporate, wound surfaces, the upper layers of the skin or mucous membrane macerate (soak), which contributes to the absorption into the wound surface and skin thickness of various medicinal substances contained in the gel. In this case, the active substance and the target additives contained in the hydrophilic gel layer on the wound surfaces, on the surface of the skin or mucous membrane, diffuse into the tissue.

It is known that in suppositories for rectal administration, the pharmacological effect in time of exposure approaches injection preparations, but their administration does not violate the integrity of the skin. This is due to the rapid absorption of the drug in the large intestine and its entry into the blood, bypassing the liver, through the middle and lower hemorrhoidal veins.

Hydrophilic suppositories, prepared on hydrophilic hyperosmolar bases, dissolve easily with rectal administration, evenly distributing medicinal substances throughout the mucosa, which have both local and resorptive effects on the body.

Rectal gelatine capsules are more promising compared to suppositories from a technological, biopharmaceutical and economic point of view. The gelatin shell protects the drug from environmental factors and has advantages over suppositories, since it can encapsulate substances in the form of ointment, liniment, cream, gel, emulsion, suspension, etc.

The release of the drug substance occurs faster and easier than in suppositories, since under the influence of a weakly alkaline medium (pH 7.3-7.6) of the mucous membranes, the gelatinous membranes swell, and in this state even a weak effect on them is enough to break it and release the contents . The amount of drug substance in the capsule, which has the necessary therapeutic effect, is a double dose of suppositories.

Thus, the production of rectal agents in a gelatin shell allows you to save expensive biologically active ingredients and reduce the cost of drugs. Rectal gelatin capsules with the proposed pharmaceutical product meet all the requirements for ideal suppositories.

In the proposed pharmaceutical preparation, stefaglabrin provides suppression of connective tissue growth, anti-inflammatory and wound healing properties, moderate sedative effect, pronounced antihypoxic and hypothermic properties, inhibition of cholinesterase activity and increased organ sensitivity to acetylcholine. Its use provides faster healing of traumatic injuries of peripheral nerve fibers; tonic effect on smooth muscles; in small doses - an increase in blood pressure, in large doses - its decrease; treatment of syringomyelia, progressive muscular dystrophy, alimotrophic lateral sclerosis, traumatic plexitis, polyradiculoneuritis, facial neuritis, polyneuritis.

To suppress the pain syndrome that accompanies the process of regeneration and restoration of damaged nerve fibers, a local anesthetic, for example, lencaine or lidocaine, or trimecaine, or novocaine, is additionally introduced into the composition of the drug.

To enhance the regeneration of nerve tissues, a substance is added to the proposed preparation that accelerates the regeneration of peripheral nervous tissue, for example, methyluracil or xymedon. In addition, pyrimidine derivatives, which include methyluracil and xymedon, improve microcirculation, enhance regional blood circulation, increase the immune status, phagocytic activity of T-lymphocytes and nonspecific resistance of the body.

To improve microcirculation in the focus of nerve tissue damage, a substance enhancing microcirculation, for example, succinic acid, is additionally introduced into the proposed preparation. In addition, it is a hypoxidant, has actoprotective and antiviral effects, and also enhances the energy supply of regenerating nerve tissues, which improves the conditions of regeneration.

The composition of this drug also includes

- thiamine (vitamin B ₁ ), which takes part in regeneration during wound healing, as well as in the localization of pain;

- folic acid (vitamin B ₉ ), which is involved in the restoration of the structure of the nervous tissue and is necessary for the absorption of cyanocobalamin;

- cyanocobalamin (vitamin B ₁₂ ), which is involved in the formation of the myelin layer of nerve fibers, enhances the analgesic effect of the drug, improves immunity, and also increases the effectiveness of folic acid;

- pyridoxine (vitamin B ₆ ), which is necessary for the normal functioning of the central and peripheral nervous system, is involved in the synthesis of neurotransmitters, helps to convert folic acid into its active form,

- riboflavin (vitamin B ₂ ), whose coenzymes play an important role in the conversion of pyridoxine and folic acid into their active coenzyme forms;

- pantothenic acid (vitamin B ₅ ) in the form of, for example, calcium pantothenate, which is important for maintaining and restoring all tissue cells, is involved in reactions that provide cell energy, takes part in the synthesis of neurotransmitters, is necessary for normal absorption and metabolism of folic acid;

- ascorbic acid (vitamin C), which is involved in the metabolism of folic acid, significantly increases the stability of folic acid and other vitamins B ₁ , B ₂ , A, E, pantothenic and folic acid, plays an important role in the regulation of redox processes, is involved in synthesis of collagen and procollagen, normalizes capillary permeability, has anti-inflammatory and anti-allergic effects, enhances reparative processes; it is advisable to use it together with vitamin E, since in the body they act synergistically, enhancing the action of each other, as antioxidants;

nicotinic acid (vitamin PP), which has a vasodilating effect at the level of small vessels, improves microcirculation, has a weak anticoagulant effect, is used in the treatment of traumatic injuries of peripheral nerves together with B vitamins;

d-α-tocopherol (vitamin E) in a water-soluble form, which is involved in the formation of collagen and elastic fibers of the intercellular substance, improves blood circulation, is necessary for tissue regeneration, ensures normal blood coagulation and healing, reduces the possibility of scar formation from some wounds, strengthens the walls capillaries, is an antioxidant, promotes the absorption of vitamin A, prevents increased blood coagulation, favorably affects peripheral blood circulation, participates in the proliferation of glue ok;

- Vitamin A in the form of water-soluble beta-carotene, which plays a significant role in the formation of epithelial tissue, supports local immunity of vital organs, promotes the renewal of skin cells and their normal functioning; to enhance its effectiveness, it must be used simultaneously with tocopherol, in addition, with a low zinc content in the body, vitamin A is poorly absorbed;

- zinc, for example, in the form of chloride or gluconate, which promotes wound healing, takes part in the processes of cell division and differentiation, the formation of T-cell immunity, the functioning of many enzymes, plays an important role in the regeneration of the skin, promotes the absorption of vitamin E and maintains normal the concentration of this vitamin in the blood;

- copper, for example, in the form of sulfate or gluconate, which is necessary for collagen production, participates in metabolic processes, in tissue respiration, is of great importance for maintaining the normal structure of bones, cartilage, tendons (collagen), elasticity of the walls of blood vessels, pulmonary alveoli , skin (elastin), is part of the myelin sheaths of nerves, as well as many enzymes;

- Manganese, for example, in the form of acetate or gluconate, which is involved in the synthesis and metabolism of neurotransmitters in the nervous system; prevents free radical oxidation, ensures the stability of the structure of cell membranes; provides the normal functioning of muscle tissue; provides the development of connective tissue, is involved in the regulation of the exchange of vitamins C, E, group B, choline, copper;

- silicon, for example, in the form of methylsilanotriolsilicate (or 1-chloromethylsilatran or hydrophilic silatran), which is involved in a chemical reaction that bonds individual collagen and elastin fibers, is indicated for connective tissue disorders.

The use of a hydrophilic and hyperosmolar base in the proposed pharmaceutical preparation ensures the fast delivery of the active substance and targeted additives to tissue cells and the bloodstream, bypassing the liver, which reduces the side effects of the proposed drug, in addition, the hyperosmolar base is a preservative for the proposed drug.

The use of a hyperosmolar base further improves microcirculation at the site of application of the drug due to its dehydrating effect, and also has an additional anti-inflammatory effect due to absorption of the liquid and reduction of tissue edema. It is easily applied to the surface of the skin, holds well on it, is evenly distributed on it, improving the contact of the ointment with tissues, has low toxicity and does not irritate tissues, does not violate their physiological functions.

The dissolution of the active substance and target additives in a polyethylene oxide base increases their dispersion and the ability to more quickly release from the base, which increases the therapeutic activity of the proposed drug. This base is a conductor of active substances through the skin barrier, while such a penetrating without damage to cells is enhanced in conditions of inflammation. The hydrophilic base on polyethylene oxides is able to dissolve in the secrets of the mucous membranes, completely releasing medicinal substances without irritating the mucous membrane, has a long shelf life and high physiological indifference.

The emulsion of perfluorocarbon compounds has a membrane effect and has a stimulating effect on the metabolic processes of living cells (it activates redox, hydrolytic reactions, the synthesis of nucleic acids, proteins, lipids, etc.). Contact of the perfluorocarbon emulsion with damaged cells leads to rapid detoxification, suppression of the inflammatory response and active cell proliferation.

The drug is obtained by mixing the components by known methods.

The possibility of implementing the invention is illustrated by the following examples, but is not limited to.

Example 1. Liniment No. 1.

100 g of 0.5% liniment contains, g:

stefaglabrin sulfate 0.5 xymedon 2.0 lidocaine 1,0 succinic acid 1,5 zinc chloride 0.006 manganese acetate 0.002 copper sulfate 0.0001 1-chloromethylsilatran 0.01 vitamin b ₉ 0.001 vitamin b ₁₂ 0.25 vitamin C 0.1 water-soluble tocopherol 0.00005 water soluble beta carotene 0.001 1,2-propylene glycol 40,0 perfluororganic emulsion compounds 20,0 purified water up to 100 g

Example No. 2. Liniment number 2.

100 g of 1.0% liniment contains, g:

stefaglabrin sulfate 1,0 xymedon 4.0 vitamin B ₁ 2.5 dimexide 10.0 1,2-propylene glycol 20,0 proxanol - 268 5,0 perfluororganic emulsion compounds - 30.0 purified water up to 100 g

Example 3. Liniment No. 3.

100 g of 1.5% emulsion contains, g:

stefaglabrin sulfate 1,5 methyluracil 4.0 trimecaine 2.0 PEO-400 20,0 perfluororganic emulsion compounds 20,0 purified water up to 100 g

Example 4. Cream No. 1.

100 g of 0.125% cream contains, g:

stefaglabrin sulfate 0.125 xymedon 2.0 novocaine 0.5 succinic acid 0.5 zinc chloride 0.006 manganese acetate 0.002 copper sulfate 0.0001 1-chloromethylsilatran 0.01 vitamin b ₁₂ 0.02 vitamin C 0.01 water-soluble tocopherol 0.00005 water soluble beta carotene 0.001 perfluororganic emulsion compounds 20,0 glycerol 17.00 1,2-propylene glycol 12.00 PEO-1500 20.00 purified water up to 100 g

Example 5. Cream No. 2.

100 g of 0.125% cream contains, g:

stefaglabrin sulfate 0.125 xymedon 4.0 trimecaine 3.0 succinic acid 1,5 vitamin b ₁₂ 0.25 perfluororganic emulsion compounds 20,0 glycerol 17.00 1,2-propylene glycol 12.00 proxanol-268 20,0 purified water up to 100 g

Example 6. Cream No. 3.

100 g of 0.125% cream contains, g:

stefaglabrin sulfate 0.125 methyluracil 4.0 1,2-propylene glycol 15.0 PEO-400 25.00 proxanol-268 18.00 perfluororganic emulsion compounds 20,0 purified water up to 100 g

Example 7. Ointment No. 1.

In 100 g, 0.025% ointment is contained, g:

stefaglabrin sulfate 0,025 methyluracil 2.0 trimecaine 1,0 succinic acid 0.5 zinc chloride 0.006 manganese acetate 0.002 copper sulfate 0.0001 1-chloromethylsilatran 0.01 PEO-400 polyethylene oxide 44.0 proxanol-268 20,0 perfluororganic emulsion compounds 20,0 purified water up to 100 g

Example 8. Ointment No. 2.

In 100 g of 0.05% ointment is contained, g:

stefaglabrin sulfate 0.05 xymedon 4.0 proxanol-268 24.0 1,2-propylene glycol 27.0 perfluororganic emulsion compounds 20,0 purified water up to 100 g

Example 9. Ointment No. 3.

In 100 g of 0.05% ointment is contained, g:

stefaglabrin sulfate 0.05 methyluracil 2.0 lidocaine 1,0 PEO-1500 30,0 PEO-400 27.0 perfluororganic emulsion compounds 15.0 purified water up to 100 g

Example 10. Gel No. 1.

100 g of 0.125% gel contains, g:

stefaglabrin sulfate 0.125 xymedon 2.0 lnecain 1,0 succinic acid 0.5 zinc chloride 0.006 manganese acetate 0.002 copper sulfate 0.0001 1-chloromethylsilatran 0.01 sodium hyaluront 0.30 perfluororganic emulsion compounds 10.0 purified water up to 100 g

Example 11. Gel No. 2.

100 g of 0.05% gel contains, g:

stefaglabrin sulfate 0.05 methyluracil 4.0 vitamin b ₁₂ 0.25 dimexide 5,0 perfluororganic emulsion compounds 10.0 polyethylene oxide gel 1500 up to 100 g

Example 12. Gel No. 3.

100 g of 0.05% gel contains, g:

stefaglabrin sulfate 0.05 xymedon 4.0 vitamin B ₁₂ 0.05 glycerohydrogel based silicon glycerates 50,0

perfluororganic emulsion

compounds 10.0 purified water up to 100 g

Example 13. A mixture for the preparation of suppositories No. 1.

In 100 g of 0.025% of the mixture for the preparation of suppositories contains, g:

stefaglabrin sulfate 0,025 methyluracil 4.0 trimecaine 2.0 succinic acid 0.5 vitamin b ₁₂ 0.02 proxanol-268 60.0 polyethylene oxide-400 10.0 perfluororganic emulsion compounds 5,0 purified water up to 100 g

300 pieces were made from this mixture. rectal suppositories in the form of a “cigar” with a diameter of 10 mm, weighing 2.5 g with a content of stefaglabrin 0.125 g in one suppository. The solubility of hydrophilic suppositories is no more than 1 hour at a temperature of (37 ± 1) ° С, which corresponds to the requirements of the Global Fund XI (Art. Suppositories, pp. 151-153).

Example No. 14. Mix for the preparation of suppositories No. 2.

In 100 g of 0.025% of the mixture for the preparation of suppositories contains, g:

stefaglabrin sulfate 0,025 methyluracil 4.0 proxanol-268 64.0 polyethylene oxide-400 10.0 perfluororganic emulsion compounds 6.0 purified water up to 100 g

300 pieces were made from this mixture. rectal suppositories in the form of a "cigar" with a diameter of 10 mm, weighing 2.0 g with a content of stefaglabrin 0.1 g in one suppository. The solubility of hydrophilic suppositories is no more than 1 hour at a temperature of (37 ± 1) ° С, which corresponds to the requirements of the Global Fund XI (Art. Suppositories, pp. 151-153).

Example No. 15. Mix for the preparation of suppositories No. 3.

In 100 g of 0.025% of the mixture for the preparation of suppositories contains, g:

stephagalbria sulfate 0,025 xymedon 4.0 vitamin B ₁₂ 0.25 proxanol-268 56.0 polyethylene oxide-400 10.0 perfluororganic emulsion compounds 8.0 purified water up to 100 g

300 pieces of rectal suppositories in the form of a “cigar” with a diameter of 10 mm and a weight of 2.5 g with a stefaglabrin content of 0.125 g in one suppository were made from this mixture. The solubility of hydrophilic suppositories is no more than 1 hour at a temperature of (37 ± 1) ° С, which corresponds to the requirements of the Global Fund XI (Art. Suppositories, pp. 151-153).

Example 16. Gelatin capsules.

The ointment obtained in example 10 is filled with 500 pieces. gelatin capsules No. 00 0.95 ml. The disintegration of the obtained capsules is less than 20 min, which meets the requirements of the Global Fund XI (Art. Capsules, p. 143).

On the basis of the proposed solution, a number of new drugs were created in the form of liquid and soft dosage forms containing the active substance stefaglabrin, the target additive and a hydrophilic osmolar base containing an emulsion of perfluororganic compounds.

The therapeutic activity of the physiologically acceptable compounds of stefaglabrin in the base for liquid and soft dosage forms for local and external use, consisting of an emulsion of perfluororganic compounds or a combination of an emulsion of perfluororganic compounds with hydrophilic osmolar substances, for example, polyethylene oxides, in the presence of the above target additives has not been known to date and does not follow from the prior art. In addition, the proposed composition of physiologically acceptable compounds of stefaglabrin, target additives and a base consisting of an emulsion of perfluororganic compounds or an emulsion of perfluororganic compounds in combination with hydrophilic osmolar substances has a synergistic effect, which consists in enhancing the therapeutic activity of the drug and increasing the duration of its therapeutic effect.

The proposed drug based on stefaglabrin, target additives and a base consisting of an emulsion of perfluororganic compounds or an emulsion of perfluororganic compounds in combination with hydrophilic osmolar substances, expands the scope of application of the known active substance - stefaglabrin, namely, provides its use in the form of a preparation for local and external use, provides bioavailability of the drug without violating the integrity of the skin, reduces pain during the use of the drug, increases ter the apeptic effect of stefaglabrin and the duration of its exposure enhances the patient's predisposition to treatment.

The search for information did not reveal identical and similar technical solutions.

Until now, a similar solution has not been proposed, although the drug stefaglabrin in the form of an injection is recommended for medical use since 1969 (Protocol of the Pharmacological Committee of the USSR Ministry of Health No. 11 of June 27, 1969).

The inventive pharmaceutical preparation can be recommended for the treatment of traumatic injuries of peripheral nerves, syringomyelia, progressive muscular dystrophy, alimotrophic lateral sclerosis, traumatic plexitis, polyradiculo-neuritis, facial neuritis, polyneuritis, burns. In addition, it is promising to use it for connective tissue hyperplasia, for the treatment of keloid, hypertrophic, retracted scars after pyoderma in orthopedics, surgery, cosmetology, the treatment of long-healing wounds, joint contracture, arthritis, and hematomas; in dermatovenerology for the treatment of limited scleroderma of various localization, etc.

The proposed pharmaceutical product for local and external use based on stefaglabrin can be used for industrial serial production of liquid and soft dosage forms, such as solutions, emulsions, suspensions, liniments, ointments, creams, gels, as well as for industrial production of formed soft dosage forms: suppositories and gelatin capsules for rectal use.

Claims (8)

1. A pharmaceutical composition for local and external use in the treatment of traumatic and postoperative injuries of the peripheral nervous system, characterized in that it contains stefaglabrin sulfate, an emulsion of perfluororganic compounds, and at least one target additive from a number: a stimulant of reparative processes, anesthetic, antioxidant, vitamins, nutrients, or a mixture thereof, and, if necessary, a hydrophilic base, in the following ratio of components, wt.%:
stefaglabrin sulfate 0.001-2.0 target additive 0.000001-60.6 emulsion of perfluororganic compounds 5.0-90.0 hydrophilic base rest 2. The pharmaceutical composition according to claim 1, characterized in that as a stimulator of reparative processes, it contains substances selected from the series: methyluracil, xymedon, or a mixture thereof. 3. The pharmaceutical composition according to claim 1, characterized in that as an anesthetic it contains substances selected from the series: lencaine, lidocaine, pyromecaine, trimecaine, novocaine or a mixture thereof. 4. The pharmaceutical composition according to claim 1, characterized in that as an antioxidant it contains substances selected from the range: succinic acid, sodium succinate or a mixture thereof. 5. The pharmaceutical composition according to claim 1, characterized in that as a vitamin it contains substances selected from the range: thiamine, folic acid, cyanocobalamin, pyridoxine, ascorbic acid, calcium pantothenate, riboflafin, nicotinic acid, or da-tocopherol, retinol , or a mixture thereof. 6. The pharmaceutical composition according to claim 1, characterized in that as biogenic elements it contains substances selected from the series: zinc, manganese, copper, silicon, or a physiologically acceptable mixture thereof. 7. The pharmaceutical composition according to claim 1, characterized in that as a hydrophilic base it contains substances selected from the series: proxanol - 268, polyethylene oxide - 1500, dimexide, glycerin, 1,2-propylene glycol, polyethylene oxide gel 1500, glycerohydrogel based silicon glycerates, polyvinylpyrrolidone, hyaluronic acid, sodium hyaluronate, purified water or a physiologically acceptable mixture thereof. 8. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a liquid dosage form: solution for external or topical use, suspension, emulsion, liniment, or in the form of a soft dosage form: cream, ointment, gel, or in the form formulated soft dosage form: suppositories or capsules for rectal use.