RU2369387C2 - Pharmaceutical composition for local and external application when treating traumatic and post-operation injuries of peripheral nervous system - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: according to the present invention, there is provided a pharmaceutical composition for local and external application when treating traumatic and post-operation injuries of peripheral nervous system. The composition is characterised by stephaglabrine sulphate content, emulsion of perfluoro-organic compounds and if required hydrophilous base with the following component ration (wt %): stephaglabrine sulphate 0.001-2.0; emulsion of perfluoro-organic compounds - 5.00-90.00; the rest is hydrophilous base.

EFFECT: enhanced therapeutic effect, enlarged application range of known medicine stephoglabrine, integration of skin integument and absence of soreness during the treatment, strengthened disposition to treatment.

3 cl, 15 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=5-554-10 -25c-38-36-45 × 1).

Known drugs for external use based on glucocorticosteroids, for example, hydrocortisone butyrate, available in the form of 0.1% cream, 0.1% and 1% ointment, 0.1% lotion (trade name is Licort). These drugs have anti-inflammatory, anti-allergic antipruritic, antiexudative effect, reduce capillary permeability. They inhibit the activity of phospholipase A ₂ , which leads to 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/d_3578/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=10143 t).

When using glucocorticosteroids, the T-cell system of immunity can be violated, 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 is increased, 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 movement joints, decrease contractures and preventing 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 of the interstitial type: pneumofibrosis, tuberculosis, alveolitis, tuberculoma; chronic interstitial cystitis, adhesions 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 dermatology: 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 scar-changed tissues) 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 treating traumatic and postoperative peripheral injuries is unknown 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 hyaluronic acid-hyaluronidase system to a large extent regulates tissue permeability. 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 use.

The drug is released in the form of lyophilized powder or porous mass or porous mass, compacted into a light colored tablet with a beige tint. It 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, the 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 administered 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 RA "On the effectiveness of the enzymatic treatment of posttraumatic neuritis with lidase." - Abstract of diss. Cand. - 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 with a shelf life of 3 years (FS 42-2438-86).

Stefaglabrin 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 stefaglabrin sulfate with its parenteral administration is 75%, which is 37.5% more than with traditional methods of treatment - anticholinesterase drugs (proserin, galantamine and p), herbal medicine with lidase, vitamin therapy, etc. (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 growth 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 a neuroma in the scar area are 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 preventive and therapeutic use of stefaglabrin sulfate at doses of 0.1 and 1 mg / kg 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).

Stefaglabrina 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 characterizes the high distribution rate 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 the active substance stefaglabrin.

The objective of the invention is the creation of pharmaceutical preparations for local and external use based on stefaglabrin as an active substance in the form of physiologically acceptable compounds.

Technical results that can be obtained using the invention:

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

- strengthening the therapeutic effect;

- 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 provides a pharmaceutical preparation for local and external use, containing as active substance stefaglabrin in the form of a physiologically acceptable compound, for example stefaglabrin sulfate, and a base, for example, in the following ratio of components (wt.%):

stefaglabrin 0.001-2.0 the basis rest

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

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, such as an ointment, gel or cream, or a formulated soft dosage form, such as suppositories or gelatin capsules for rectal use.

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 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 Bugner ribbons, which play a supporting and guiding role. Glial cells form a new myelin sheath. The entire recovery process takes several months. Collaterals 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 section 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-1797-1.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 a dehydration effect, preventing scar adhesions (//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 medicines and cosmetics, the fragments of the skin processed by these agents 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 the microcapillaries of the circulatory system into the tissues, including the epidermis. Returning to the circulatory and lymphatic systems, they carry away 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, accordingly, act on all body tissues (A.N. Decina, "Theory of soft cosmetic effects. Modern cosmetology", Novosibirsk: Nauka, 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 proposed 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 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 not very different 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 transepidermal 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 styloid and granular layers, which leads to a decrease in the size of cellular 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 cavity cavities are saturated with positively charged metal ions (such as Na ^+, the channel structures are transformed into a structure (according to the flip type mechanism -flop ") with a tendency to expand the diameter of the channel due to electrostatic repulsion of positive charges localized on metal atoms (A. N. Decina," Soft Theory of their cosmetic 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 transepidermal 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 local and external use are made: solutions, linimentes, emulsions and suspensions, which have high penetrating ability and ensure the transport of active substances deep into the open wound, as well as through trans-epidermal barrier and blood flow to the site of damage to peripheral nerve fibers.

Adding hydrophilic solvents to hydrophilic solvents, such as high molecular weight polyethylene oxides (for example, PEO-1500), proxanols (for example, proxanol-268), medical polyvinylpyrrolidones (for example, 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, pp. 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.

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. Microcirculatory disorders are divided into intravascular changes, disorders of the vessels themselves 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.

The use of a hyperosmolar base improves microcirculation in wound tissues due to its dehydrating effect.

Hydrophilic bases that can be used with stefaglabrin in the proposed drug 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, glycerin, ethyl cellosolve, dimexide, and water-soluble polymers: polyethylene oxide, for example PEO-1500, proxanol, for example proxanol-268, polyvinylpyrrolidone, for example 8000 ± 2000 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 (PEO) - water-soluble products of 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 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", under the editorship of professor 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 liquefies with the addition of alcohol, glycerol, with vigorous stirring, the pH of a 20% aqueous suspension is 4.0-8.0.

The chemical composition of the hydrogel: PEO-1500 - 3.5%; distilled water - 96%; preservative (sodium benzoate) - 0.5%. It is used as the basis for 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 - a 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 deep into the wound ("Theory and practice of local treatment of purulent wounds", under the editorship of 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 functions, 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 - the sodium salt of hyaluronic acid is readily 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 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 conduct medicinal substances, the dose of these substances in pharmaceutical compositions can be reduced (www.uran.ru/gazetanu/2007/04/nu11/wvmnu_p3_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 trace element - silicon for the regulation of silicon metabolism in the body (Boyakovskaya TG “Development of organosilicon glycerohydrogels and a comparative assessment of their transcutaneous activity”, abstract of the dissertation, www.vita.chel.su/files/docs /diss/bojakovskii.doc).

It is known that organofluorocarbon emulsions with gas-transporting properties, such as perfluorane, were used in the complex treatment of wounds and wound infections (Krylov NL et al. “Hemosorption and infusion of perftoran in the complex treatment of wounds and wound infection.” Problems of intensive care in the clinic. Abstracts scientific conference. December 12-13, 1985 - M .: B.I., 1985 - pp. 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 (activate redox, hydrolytic reactions, 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, 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, A61K 33/16, 1995.04. twenty). Organofluorine emulsions with gas transporting properties are known (for example, patent RU No. 2088217, A61K 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 proposed preparation.

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 therapeutic activity longer, is cheaper to manufacture, convenient to use, which enhances the patient's motivation for treatment.

Using stefaglabrin and hydrophilic bases with hyperosmolar properties, 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 administration, are proposed.

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

Hydrophilic ointments are hyperosmolar, as a result of which, when applied, they provide effective transport of the active substance - stefaglabrin deep into the wound to the place of growth of the connective tissue, and also, increasing the permeability of the epithelium, transport the active substance - stefaglabrin through the skin and mucous membranes to the site of damage to the nerve fiber for a long time time to dry the ointment. In this case, stefaglabrin is evenly distributed in the lesion, and its concentration in the lesion is maintained for a long time approximately at a level close to the initial concentration of the drug in the ointment dressing due to diffusion from it, which provides the maximum therapeutic effect. This also increases the duration of exposure to the active substance on 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. They also include colloidal dispersed systems, consisting of water-dispersed or mixed water-glycol solvents, 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 they have a lower viscosity than ointments, therefore they penetrate deeper into the wound and through the transepidermal 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 have been developed at the present time, which are indicated above - Geko hydrogel, 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 contained in the hydrophilic gel layer on the wound surfaces, on the surface of the skin or mucous membrane, diffuses 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 - increased blood pressure, in high doses - its reduction, treatment of syringomyelia, progressive muscular dystrophy, lateral alimotrophic sclerosis, traumatic plexitis, polyradiculoneuritis, polyradiculoneuritis facial nerve, polyneuritis.

The use of a hydrophilic and hyperosmolar base in the proposed pharmaceutical preparation ensures fast delivery of the active substance to the cells of the tissue and into 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, it is well kept on it, 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 in a polyethylene oxide base increases its 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 carrying out 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 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 dimexide 10.0 1,2-propylene glycol 20,0 perfluororganic emulsion compounds 30,0 proxanol-268 5,0 purified water up to 100 g

Example 3. Liniment No. 3.

100 g of 1.5% emulsion contains:

stefaglabrin sulfate 1,5 perfluororganic emulsion compounds 30,0 purified water up to 100 g

Example 4. Cream No. 1.

100 g of 0.125% cream contains, g:

stefaglabrin sulfate 0.125 perfluororganic emulsion compounds 20,0 glycerol 17.00 1,2-propylene glycol 12.00 PEO-1500 10.00 purified water up to 100 g

Example 5. Cream No. 2.

In 100 g of 0.05% cream contains, g:

stefaglabrin sulfate 0.05 perfluororganic emulsion compounds 20,0 glycerol 17.00 1,2-propylene glycol 12.00 proxanol-268 20.00 purified water up to 100 g

Example 6. Cream No. 3.

100 g of 0.125% cream contains, g:

stefaglabrin sulfate 0.125 perfluororganic emulsion compounds 35.00 PEO-400 25.00 proxanol-268 18.00 purified water up to 100 g

Example 7. Ointment No. 1.

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

stefaglabrin sulfate 0,025 perfluororganic emulsion compounds 20,0 PEO-400 polyethylene oxide 44.0 proxanol-268 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 proxanol-268 24.0 perfluororganic emulsion compounds 20,0 1,2-propylene glycol 27.0 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 perfluororganic emulsion compounds 20,0 PEO-1500 30,0 PEO-400 22.0 purified water up to 100 g

Example 10. Gel No. 1.

100 g of 0.125% gel contains, g:

stefaglabrin sulfate 0.125 perfluororganic emulsion compounds 20,0 sodium hyaluront 0.30 purified water up to 100 g

Example 11. Gel No. 2.

100 g of 0.05% gel contains, g:

stefaglabrin sulfate 0.05 perfluororganic emulsion compounds 20,0 dimexide 5,0 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 perfluororganic emulsion compounds 20,0 glycerohydrogel based silicon glycerates 50,0 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 proxanol-268 50,0 perfluororganic emulsion compounds 10.0 polyethylene oxide-400 15.0 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 tilorone content of 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 proxanol-268 64.0 perfluororganic emulsion compounds 10.0 polyethylene oxide-400 16,0 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 tilorone content of 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:

stefaglabrin sulfate 0,025 proxanol-268 60.0 perfluororganic emulsion compounds 6.0 polyethylene oxide-400 8.0 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 tilorone content of 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 16. Gelatin capsules.

The ointment from example 10 is filled with 500 pieces. gelatin capsules No. 00, a volume of 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).

Based on the proposed solution, a number of new drugs were created in the form of liquid and soft dosage forms containing the active substance stefaglabrin and a hydrophilic osmolar base, including an emulsion of organofluorine compounds.

The therapeutic activity of the physiologically acceptable compounds of stefaglabrin in a base containing an emulsion of organofluorine compounds with gas transport properties in a mixture with osmolar substances, for example, for liquid and soft dosage forms for topical and external use, has not been known and does not follow from the prior art. In addition, the proposed composition of physiologically acceptable compounds of stefaglabrin and a base containing an emulsion of perfluororganic compounds and 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 preparation based on stefaglabrin and a base consisting of an emulsion of perfluororganic compounds or its combination with osmolar substances expands the field of application of the known active substance - stefaglabrin, namely, provides its use in the form of a preparation for local and external use, ensures bioavailability of the drug without violating the integrity of the skin integument, increases the therapeutic effect of stefaglabrin and the duration of its exposure, increases the predisposition of patients 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, polyradiculoneuritis, 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 (3)

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 also, if necessary, a hydrophilic base, in the following ratio, wt.%:
Stefaglabrin 0.001-2.0 Organofluorine emulsion 5.0-90.0 Hydrophilic base Rest 2. 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-1500 gel, glycerohydrogel on based on silicon glycerates, polyvinylpyrrolidone, hyaluronic acid, sodium hyaluronate, purified water or a physiologically acceptable mixture thereof. 3. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a liquid dosage form - a solution for local and external use, suspension, emulsion, liniment; or in the form of a soft dosage form - cream, ointment, gel; or in the form of a formulated soft dosage form - suppositories or capsules for rectal or vaginal administration.