RU2751037C1 - Pharmaceutical composition based on human urine autobiocomponents for transdermal application for therapeutic or cosmetic purposes - Google Patents

Abstract

FIELD: cosmetology.SUBSTANCE: pharmaceutical composition for targeted impact on human skin structures is comprised of at least six pharmacologically acceptable autocomponents isolated, purified and concentrated from individual urine of a single person, such as proteoglycans and glycosaminoglycans selected from chondroitin sulphates, heparan sulphates and keratan sulphates; peptides selected from homomeric homodetic tripeptides with amino acid sequence: CDY, WTM, NKM, PTF and GHL; sulphonated fatty acids selected from decanoic, hydroxydecanoic, oxoundecanoic, 3-hydroxydodecanoic, tetracosodecanoic, hydroxypentadecanoic acids; steroid hormones selected from estradiol, cortisol, cortisone, testosterone, progesterone; adenosylmethionine; amino acids selected from cysteine, asparagine, tyrosine, tryptophan, histidine, lysine, methionine, proline, phenylalanine, and threonine. Also disclosed is an application of biological active autocomponents for targeted impact on human skin structures.EFFECT: group of inventions provides individual treatment for cosmetic purposes.5 cl, 6 tbl, 2 ex

Description

The invention relates to medical biotechnology, pharmaceuticals, as well as dermatovenerology and cosmetology. It is intended for individual treatment or use for cosmetic purposes of autobiocomponents combined into a pharmaceutical composition obtained from individual urine, which, after purification and concentration, are used by transdermal administration to the same person from whose urine they were obtained. The composition of the pharmaceutical composition and the ratio of autobiocomponents correspond to the physiological composition of the biological fluid and is as safe as possible when used. Each of the autobiocomponents of the pharmaceutical composition has a proven targeted, combined and potentiating effect, which increases the effectiveness of their use.

Ostroinflammatory and chronic skin diseases, as well as the processes accompanying its induced or chronological aging, despite the difference in etiological factors of their occurrence and specific, different manifestations of pathogenesis, represent a general, evolutionarily formed reaction of the body. The pattern and sequence of responses to acute or chronic aggression depends on many factors, of which one of the main factors is the degree of the organism's adaptive capabilities, based in turn on the genetic, or chronologically formed, but individual characteristics of each individual. To a large extent, the above applies to those conditions when the time factor has a decisive influence on the formation, the rate of increase and the degree of irreversible changes, the elimination of which at the present stage of development of medical science is impossible. On the contrary, timely and adequate treatment or preventive actions can radically change or suspend the course of adverse processes. Ultimately, success in the treatment and correction of a pathological condition largely depends on an adequate assessment of the degree of impact on the body of a set of negative factors, as well as the ability to control and use naturally formed defense mechanisms of the body itself.

It seems to us that the development of an approach based on a biological, and even better an autobiological way of implementing the achievements of medical science in biotechnology and pharmaceuticals, will maximize the effective achievement of successful results. The basis for such prerequisites is that in the process of evolution, natural substances were created that are maximally acceptable for the body, the combination of properties of which is in a close balance of the surrounding metabolic structures and does not violate their coordination. On the contrary, the emergence of new and promising analogues of natural biological active substances of the body, at the present stage of the development of medicine, does not allow one to judge with confidence both the early multidirectional effects and the long-term consequences of their use. From these positions, the development of the possibility of using biological active autocomponents with a therapeutic and restorative purpose and methods of their use to eliminate negative conditions deserves attention and undoubtedly has a promising value.

One of the most well-known and studied areas of practical use of biological substances is transfusiology, where the receipt and transfusion of whole blood or its components for the purpose of correcting various pathological conditions is a routine process. On the contrary, the use of autohemotransfusion of blood or its components has a strictly specific purpose, is intended for general stimulation of immunity and does not have a narrowly focused character of correction of specific immunobiological disorders. The relative safety and obvious disadvantages of autohemotransfusion stimulated the development and implementation of new methods of using autocomponents, the vast majority of which were also based on the general principle of influencing immunobiological processes, both in local and general metabolism of the body. An example of such an application of autobiocomponents (ABA) is a method called "Plasmolifting", based on the receipt and subcutaneous administration of a suspension of destroyed autoplatelets for the purpose of treatment and in cosmetology. Despite the visible effects in the early stages after the plasmolifting procedure, the long-term consequences of its use seem to be extremely dangerous, primarily due to the high proven risk of oncological diseases (38, 39). The list of such attempts to use autocomponents is quite wide, however, in our opinion, this is a potentially dangerous path that requires continuation of research, as well as strict control and consideration of real long-term consequences.

The safest can be the localized transdermal application of highly active biological ABA, which do not have an immunomodulatory effect, without their direct injection. In this context, a fundamentally new and most preferable direction is the isolation of ABA from individual human urine, followed by their purification from unwanted substances, concentration and targeted local application in the form of a pharmaceutical composition (FC) in a natural, physiological composition and in relation to therapeutic and / or a cosmetic purpose for the same person from whose urine they were isolated. It is important to note that PK based on ABA, which correspond to the natural composition of biological body fluids, is as safe as possible and does not carry the risk of autoimmune reactions characteristic and described in other ways of using ABA. At the same time, each of the ABA in FC performs both a combined and a targeted, proven biological effect on specific skin structures. Moreover, the concentrate of each of the pre-purified ABA has an incomparably greater effect compared to the original product, which also contains undesirable substances.

The claimed invention provides PK based on ABA of human urine for transdermal use for therapeutic or cosmetic purposes.

Substantiation of the composition of FC based on ABA of human urine and the method of its use for medical or cosmetic purposes. The rationale is based on three main criteria, namely:

1. Substantiation of the developed principle of using ABA isolated from human urine.

2. Substantiation of the method for obtaining FA from ABA.

3. Justification of the method of using ABA.

According to clause 1, the FC was created on the basis of a highly purified concentrate of biocompatible and bioactive ABA isolated from individual human urine. Each of ABA FA has a proven biological effect, the use of which in combination with other ABA provides a combined and potentiating effect necessary to obtain a therapeutic or cosmetic effect when used by the same person from whose urine they were isolated.

Each of the isolated ABA from individual human urine is purified from unwanted substances, concentrated, used transdermally in the form of FA in a natural, physiological composition and in a ratio with other ABA FA.

The purpose of creating a PK is to obtain an individual, biocompatible PK, consisting of several ABA in a natural, physiological proportion for an individual person, namely: an autohormonal concentrate, a matrix based on highly purified autoproteoglycan and autoglycosaminoglycan, conductors in the form of a complex of auto-fatty acids, a complex of autoaminomethion, adenosine , as well as bioactive urinary autotripeptides, which are used in the form of applications for the purpose of targeted action on the intradermal structures of the skin to obtain a therapeutic or cosmetic effect to the same person from whom they were isolated.

FC consists of at least six ABKs. The ABK composition is as follows:

The first ABA, one of the pharmacologically acceptable ABA or its pharmacologically acceptable derivatives, is a group of proteoglycans and glycosaminoglycans, which includes at least chondroitin sulfates and keratan sulfates, is used in the form of a biogel to create a volume in which other ABA FAs are retained on the skin surface. This ABA is a concentrate of highly purified proteoglycans and glycosaminoglycans obtained from the individual urine of the patient himself according to the method described in the patent of the Russian Federation No. 2621311 "Method for obtaining proteoglycan" (3).

1. Justification for obtaining GAG and GHG as ABK FC.

One of the promising areas in medicine and cosmetology is the production and use of bioadaptive high-polymer substances from available natural biological products, specifically from human urine. The most suitable for these purposes are proteoglycans (PG) and glycosaminoglycans (GAG), which are found in human urine in significant quantities. These high-polymer substances have unique properties, primarily in the ability to retain water in their structure in a ratio of 1: 100 or more, do not possess immunogenicity, toxicity, do not have group differences and can be used without restrictions in the treatment of people with different blood groups or other isoantigenic systems. An important feature of PG-GAGs is their complete biocompatibility.

PG is a general name referring to a glycoprotein with various types of structure and usually consisting of one core protein with at least two or more covalently attached linear polysaccharide chains (4). PG is a complex compound, however, since the connection of the polysaccharide chain and the core protein has a weak binding strength, they tend to be easily separated from each other. For this reason, the extraction or purification of GHGs is an extremely delicate process requiring the most gentle separation at all stages. This requirement implies the exclusion of procedures that damage the structure of the steam generator, in particular high-speed centrifugation, as well as filtration through a fine-pore filter, not to mention ultrafiltration and ultracentrifugation. Thus, conventional methods are not suitable for GHG isolation due to complex or manual steps.

GAG polysaccharide chains are extremely hydrophilic, as a result of which they retain a large amount of water and even at very low concentrations form a hydrated gel. This property is further enhanced by the high density of negative charges that attract osmotically active cations. This hydrophilic effect of GAG solutions contributes to the maintenance of oncotic pressure in the vascular bed and pressure in the intracellular matrix.

In an aspect of the present invention, the main functions of PG-GAG can be distinguished:

1. The main component of the extracellular matrix;

2. Provide hydrophilicity of the extracellular matrix

3. Affect cell migration;

4. Participate in the processes of collagen and elastin synthesis.

5. Form intercellular contacts;

Currently, six main types of PG are distinguished: hyaluronic acid, chondroitin sulfates, keratan sulfates, dermatan sulfates, heparin and heparan sulfates. In an aspect of the present invention, the following are of greatest interest:

1. Hyaluronic acid - found in many organs and tissues. Participates in the formation of GHG aggregates. The repeating disaccharide unit in hyaluronic acid is composed of D-glucuronic acid and N-acetylglucosamine. It is known that hyaluronic acid, which is the largest polysaccharide of all GAGs, contains 20-30 thousand disaccharide units and a high molecular weight - up to 15 million daltons, is a hydrophilic compound, one molecule of which can hold 200-500 water molecules (1) ...

2. Chondroitin sulfates are the most abundant GAGs in the human body. They are found in cartilage, tendons, ligaments, arteries, and the cornea of the eye. Chondroitin sulfates are an important component of aggrecan, the main PG of the cartilage matrix. There are 2 types of chondroitin sulfates in the human body: chondroitin-4-sulfate and chondroitin-6-sulfate. They are built in the same way: from D-glucuronic acid and N-acetyl-D-galactosamine-4-sulfate or N-acetyl-D-galactosamine-6-sulfate, respectively.

3. Keratan sulfates are the most heterogeneous GAGs. They differ from each other in the total content of carbohydrates and distribution in different tissues. They contain a galactose residue and N-acetyl-D-galactosamine-6-sulfate. They are part of the cornea of the eye, cartilage, intervertebral discs.

4. Dermatan sulfates - characteristic of the skin, blood vessels, heart valves, menisci, intervertebral discs. The repeating disaccharide unit is L-iduronic acid and N-acetyl-D-galactosamine-4-sulfate.

5. Heparin is an important component of the blood anticoagulant system. Synthesized by mast cells. The largest amounts of heparin are found in the lungs, liver and skin. The disaccharide unit is composed of D-glucuronate-2-sulfate and N-acetylglucosamine-6-sulfate.

6. Heparan sulfate - part of the basement membrane PG. The structure of the disaccharide unit is the same as that of heparin, but contains more N-acetyl groups.

In the extracellular matrix, there are PG groups of various sizes. Among them are very large ones - for example: aggrecan and vorsikan, as well as the so-called small PGs, for example: decorin, biglycan, fibromodulin, lumikan, perlecan. These PGs have a small core protein to which one or two GAG chains are attached (11).

Connective tissue is capable of self-healing and remodeling of two main components of connective tissue - collagen and PG. When connective tissue is damaged, the reproduction of collagen and PG will significantly increase compared to normal amounts.

Aging of the skin is clinically characterized by wrinkles, lethargy, and a leathery appearance. These aging symptoms are causally related to histological and ultrastructural changes in the connective tissue of the dermis. Changes include both enzymatic degradation and decreased de novo collagen synthesis, which causes premature wrinkling of the skin. Qualitative age-related changes in the structure of hyaluronic acid, PG and collagen lead to dehydration of the hydrophilic structures of the skin, a decrease in the content of fixed water and, as a consequence, to a decrease in skin elasticity. In addition, the influence of other factors, such as exogenous xenobiotics, constant or long-term exposure to physical factors, affects the regenerative capacity of dermal fibroblasts (66).

The study of the physicochemical, immunological and biochemical properties of the obtained biopreparations based on PG and GAG suggests that they have a high and ultra-high degree of purification, in the range from 10 to 100,000 times and correspond to the required parameters. At the same time, it was found that the obtained high-polymer glucuronides are presented in the form of monomers with a molecular weight in the range of 64 kDa, in the form of dimers with a molecular weight in the range of 150 kDa, and larger structures with a molecular weight in the range of 450-500 kDa. In terms of composition, they are 80% represented by keratan sulfates and chondroitin sulfates, as well as GAGs. The above high-polymeric glucuronides are basic, basic in quantitative content, components of almost all cells and tissues of the human and mammalian body and fully meet the requirements of maximum bio-responsiveness.

There is a known therapeutic composition for the protection, treatment and restoration of connective tissue in mammals and a method for the treatment of connective tissue in mammals by administering the composition (46). The composition comprises glucosamine, and preferably chondroitin sulfate, and further comprises manganese ascorbate, which catalyzes the production of collagen and PG from glucosamine and chondroitin sulfate. According to claim 1 of the formula of the above invention, the therapeutic composition is intended for the treatment and restoration of connective tissue in mammals and contains therapeutic amounts of glucosamine and its salts in combination with chondroitin sulfate and soluble manganese salts, which are used to stimulate the production of PG and collagen for the treatment and restoration of connective tissue ...

Known patent (47), which describes a composition for protection, treatment and recovery, as well as for reducing inflammation of connective tissue in mammals and a method for treating connective tissue in mammals by introducing a composition that includes S-adenosylmethionine (SAM) and a component selected from amino sugar or its salts (eg glucosamine) or glycosaminoglycans (eg chondroitin salts), or mixtures or fragments thereof. In this case, the dose of GAG is from 15 to 30,000 mg.

The disadvantages of the above analogs are that they are all obtained from xenogenic material and their use in humans can cause undesirable effects that require therapeutic intervention.

It is known that glucuronic acid (GA) in hepatocytes enters into conjugation reactions with a wide range of endogenous substances appearing in the blood plasma. The resulting paired acids are HA esters with compounds such as bilirubin, creatinine, indican, skatole, phenol, adrenaline, female, male sex and other steroid hormones and many other substances of various structures. The formation of a strong covalent bond ensures the resistance of the HA complex to degradation under the action of most enzyme systems, and in this form it freely passes through the excretory systems of the body. At the same time, excreted in the urine, glucuronides are not subject to reduction and desorption in this environment. Thus, the urine is dominated by GAGs and PGs, which are conjugates of HA with endogenous metabolites.

From these positions, the isolation of GAGs or PGs from urine for the purpose of their re-introduction into the body as biocomponents is meaningless and unacceptable due to the real potentiation of intoxication during their use.

The situation changes radically if the PGs or GAGs isolated from urine are preliminarily purified from toxic metabolites by destroying the ether bond. It is known that a number of compounds are capable of purposefully and selectively destroying the ether bond without the participation of enzyme systems. One of the most effective reactions is hydrolysis with alkalis, which is accompanied by the destruction of the ether bond and the separation of the previously attached metabolite from HA. The formed HA salt with an alkaline compound, in particular an alkali metal, loses its solubility and precipitates.

This process is technologically controllable and can facilitate the recovery of HA in the GAG or GHG structure. It is natural to assume that the newly obtained, reactivated and purified from impurities product can be used as a highly effective, completely biocompatible natural substance, suitable even for parenteral use.

The previously developed method for restoring the activity of GAG - PG, isolated from human urine and not containing ETM, is described in the patent (3) and consists of several stages, which are as follows:

Stages of obtaining and restoring the complex (GAG-PG) - ETM.

1. Isolation (precipitation) of the complex (GAG-PG) - ETM.

2. Alkaline hydrolysis of the ether bond HA-ETM with the formation of an insoluble alkali metal salt with HA.

3. Separation of HA salt sediment from ETM.

4. Reduction of HA salt to obtain a soluble form of GAG-PG.

5. Concentration of GAG-PG gel for application.

The first component proposed in the claimed FC, one of the pharmacologically acceptable ABA or its pharmacologically acceptable derivatives, is a group of PG and GAG, which includes at least chondroitin sulfates and keratan sulfates, is used to create a volume of autobiogel, in which other components of the pharmaceutical composition are retained on the surface skin.

The second pharmacologically acceptable ABA or pharmacologically acceptable derivatives thereof is a group of fatty acids (FA) derivatives of decanoic acid, predominantly in the sulphurized state, which includes at least: decanoic, hydroxydecanoic, oxoundecanoic, 3-hydroxydodecanoic, tetracosodecanoic, hydroxypentadecanoic acids. This ABA is used as a conductor to facilitate the penetration of other ABA of the pharmaceutical composition into the intradermal structures of the skin, as well as to provide a protective effect on the phospholipid base of the cell membrane.

Sodium and potassium salts of higher FAs are effective surfactants and are used as soaps. In the food industry, ZhK are registered as a food additive E570 as a foam stabilizer, glazing agent and antifoam, which gives grounds to consider ZhK as a class of substances safe for topical use.

It is known that the above-mentioned FAs affect the surface of the skin, as well as the upper layers of the epidermis, as they pass through the stratum corneum. The effectiveness of the cosmetic and / or pharmaceutical action of FAs penetrating into the upper layers of the epidermis is enhanced against the background of an increase in their concentration (45).

Thiol compounds such as cysteine, taurine, coenzyme A are directly involved in FA metabolism. Sulfurization of hydrophobic FAs with the participation of thiol compounds leads to their modification and a radical change in their properties, which are manifested in the fact that sulfurized FAs exhibit a protective effect on the phospholipid base of the cell membrane, in contrast to the damaging effect of hydrophobic FAs (43, 45).

One of the problems of the direct use of the so-called. short peptides are to overcome cell membranes to penetrate into the cell. One approach to solving this problem is to attach compounds to peptides during their synthesis, which facilitate their penetration into the cell. Among the protectors, FAs are most often used, including such as decanoic acid (49). The use of the conductive effect of FA is described in the patent (13), which describes a vaccine composition for transdermal or transmucosal administration for the induction of cellular immunity in the treatment of cancer. The vaccine contains: (i) an antigen and (ii) a pharmacologically acceptable organic acid or a pharmacologically acceptable salt thereof as the first stimulator of the induction of cellular immunity. It is further specified in the claims that an organic acid or a pharmacologically acceptable salt thereof is an organic compound having a carboxyl group, or an organic compound having a sulfo group, or a pharmacologically acceptable salt thereof. Moreover, the organic acid or pharmacologically acceptable salt thereof is an FA selected from the group consisting of decanoic acid, lauric acid, myristic acid, isostearic acid, palmitic acid, stearic acid and oleic acid, or lactic acid, salicylic acid, citric acid , methanesulfonic acid. The invention described above is provided for the specific treatment of cancer and is not intended for use in cosmetology or for the treatment of skin diseases. However, it involves transdermal or transmucosal administration.

Describes the use of the cream "Physiogel" for therapeutic purposes to restore the damaged hydrolipid layer of the epidermis in atopic dermatitis (atopic eczema, diffuse neurodermatitis, constitutional eczema - a chronic inflammatory skin disease with a recurrent course). " The cream contains phospholipids and ceramides, which are identical to the essential lipids of the skin. Physiogel cream with Derma-Membrane Structure contains the following components according to INCI (International Nomenclature of Cosmetic Ingredients): water, caprilic / capric triglyceride, glycerin, pentylene glycol, coconut oil, hydrogenated lecithin, shea butter, hydroxyethyl cellulose, sodium squalane, carbomer xanthine gum, carbomer, ceramide-3. The clinical efficacy of the composition used has been established. The author claims that when using the Physiogel cream, dry skin prone to atopy becomes smooth and moisturized, its elasticity increases, and a reliable moisturizing effect is achieved, which gives grounds for use in dermatological practice (9).

ZhK are widely used in cosmetology, which is due to a pronounced biologically active effect when applied topically to the skin of the face and body. It is known from the technical literature that acyclic carboxylic acids, starting with butyric acid, are considered fatty. In cosmetology, the use of ointments, creams containing fatty acids is described. Known moisturizing cream with oligosaccharides, fatty acids, oils, vitamins A, E and silkworm lipids, which is produced under the brand name "Christina Silk". Designed to moisturize and restore the lipid barrier of the skin as an FA in the cream.

The above brief analysis of the available technical literature in order to substantiate the feasibility of using FA, including decanoic acids, allows us to consider the participation of at least decanoic acid or its derivatives in the composition of the proposed composition as justified.

The third pharmacologically acceptable ABA or pharmacologically acceptable derivatives thereof is a group of peptides that includes at least di-, tri, tetrapeptides. In this case, the group of tripeptides is represented by homomeric homodetic tripeptides with the amino acid sequence CDY, WTM, HKM, PTF and GHL. These biologically active substances have a proven stimulating effect on the activation of metabolism in the intradermal structures of the skin.

The discovery of natriuremic peptides (NP), and the results of intensive research in recent years, allow us to consider this direction as one of the breakthrough medical technologies for the treatment of a wide range of skin diseases, as well as in cosmetology.

When studying the effects of NP, it was found that they are caused by a peptide secreted by atrial muscle cells (32). The most common term has become "atrial natriuretic peptide" (ANP).

A peptide very similar in structure with similar biological properties was extracted from brain tissue; it was named brain natriuretic peptide (BNP) (71).

A C-type natriuretic peptide (CNP) was also identified, which is structurally similar to the two previous ones (72).

For the formation of active molecules - ANP, BNP or CNP, preliminary narrowly targeted proteolysis of their precursors, which are pre-pro-substances, is required. During post-translational processing, the pro-peptide is first formed from the pre-pro-peptide. By the example of pro-ANP and pro-BNP, it has been established that they or their fragments have biological activity (48). Further proteolytic cleavage leads to the formation of biologically active peptides ANP, BNP, CNP.

The effect of ANP / BNP on the permeability of blood and lymphatic microvessels of the skin and adipose tissue was established by increasing the permeability of the glycocalyx of endotheliocytes (74). These peptides regulate the growth and migration of endotheliocytes, which play a major role in the formation of the vascular structure (51, 54). At the same time, an increase in endothelial permeability is caused separately by both ANP and BNP (34). CNP is also involved in the regulation of microvascular permeability, increasing it by modifying the structure of the endotheliocyte glycocalyx (36). ANP / BNP inhibit the production of collagen fibers and matrix synthesis, thereby reducing the proliferative and functional activity of fibroblasts (73). It is believed that this peptide is involved in anti-inflammatory reactions, suppresses cell proliferation and fibrosis (65), and helps to weaken the differentiation and migration of fibroblasts. The research results allow us to draw conclusions that are fundamental for practical implementation:

1. ANP and BNP increase endothelial permeability. This leads to an increase in the permeability of the glycocalyx of endothelial cells in the blood and lymphatic microvessels of various tissues, including the skin, adipose tissue.

2. ANP reduces the tone of the smooth muscles of the arteries, ANP / BNP inhibits the growth, proliferative and functional activity of fibroblasts, the production of collagen fibers and the synthesis of matrix.

3. CNP helps to reduce the inflammatory response by inhibiting cell proliferation, fibroblast differentiation and migration, and the development of fibrosis.

4. CNP suppresses the expression of genes of collagen types I and III.

One of the topical directions is the study of the biological effects of regulatory peptides. It is known that in blood plasma the free form of ANP, BNP, CNP quickly loses its biological activity and, as a rule, within 2-3 minutes for ANP / CNP and 20-30 minutes for BNP, their complete inactivation occurs. On the contrary, pro- and especially, pre-forms of NP, outside the blood plasma retain the ability to activate biological activity for a long time, but only in the absence of contact with plasma proteases. These include peptides that are detected in urine due to excretion from organs and blood. Other, secondary factors, also contributing to degradation, have a significantly lesser effect and their effect can be reduced in the process of technological separation of NPP.

It was unexpectedly found that human peptides isolated by us from urine are predominantly homodetic tri-peptides, the main ones of which are represented by the composition: CDY, WTM, NKM and PTF with an arbitrary unknown amino acid sequence. For convenience, these peptides are grouped into the group of non-renal urinary tripeptides (URTs). Studies of the amino acid sequence of MTP have established differences in the amino acid composition: These information are presented in Table 1.

Taking into account certain difficulties existing in the verification of the individual chemical and biological properties of each of the tripeptides of this group, we studied the combined complex properties of the entire MTP group and, first of all, their local action, including the effect on reparative processes in intact and pathologically altered skin. A preliminary review of the literature on the study of the biological action of other known tripeptides showed the following.

One of the most studied peptides with a proven pronounced reparative effect is the human GHL peptide, discovered in 1973 (57). In the process of studying GHL, its effect on the course of local reparative processes was established, which manifested itself in a direct effect on various cell populations of the skin, the main tissue-forming substances and the metabolism of individual substances, which determine the direction of regenerative and restorative processes in intact and pathologically altered skin. The stimulating effect of GHL on collagen synthesis by fibroblasts in vitro is manifested at minimal concentrations and does not depend on the number of cells in culture. The amino acid sequence of GHL is identical to the α2-chain of type I collagen, which suggests that collagen is the original location of GHL, from where it is released under the influence of proteases. It was found that GHL selectively stimulates the synthesis of sulfated glycosaminoglycans - extracellular dermatan sulfate and heparan sulfate associated with the cell monolayer, since the effect of GHL on the synthesis of hyaluronic acid is not observed (29). GHL accelerates the formation of connective tissue and the accumulation of intercellular substance, exerting a stimulating effect on the healing of wounds and sluggish ulcers (76). A similar effect was previously established for peptides that are formed as a result of proteolysis of other proteins, in particular albumin, myelin, immunoglobulins, hemoglobin. In most tissues, 30-90% of all known peptides are fragments of the a- or b-subunits of hemoglobin (50).

The reparative effects of GHL are manifested mainly in low concentrations, in the range of units or even tenths of a nanomolar (10 ^-9 M), and can be associated with the direct action of the peptide on skin cells.

It can be assumed that the local action of GHL and other similar peptides does not affect or only indirectly affects the immune processes in the body, since according to most of the studied parameters, no pronounced immunostimulatory activity of GHL in conditions of skin wounds was revealed.

It should be noted that the combination of GHL amino acids (glycine + histidine + lysine) also stimulated skin wound healing. However, it was found that when administered alone, glycine and histidine did not affect the healing of skin wounds, while the administration of lysine accelerated regeneration. The reparative effect upon administration of a composition of all three amino acids and lysine was confirmed by morphological studies of wound sections. Compared with the control group of animals, in rats receiving a composition of three separate amino acids, there is a decrease in edema in the wound area, a decrease in the density of cell infiltrate is expressed due to a smaller number of lymphocytes and macrophages, as well as a predominance of mature fibroblasts over immature, which indicates a more favorable the course of the regeneration processes. These data show that the effects of GHL can be associated with lysine formed as a result of peptide proteolysis (10). Further studies revealed a strong affinity of GHL for copper, due to the formation of the Gly-His-Lys - Cu (GHL-Cu) complex (62).

When studying the effect of a peptide modified with copper ions, GHL-Cu, in skin wounds, it was found that this peptide enhances the synthesis of type I collagen and, at the same time, the breakdown of old collagen (68). It was also found that GHL-Cu regulates the restructuring of the skin (its remodeling), activating metalloproteinases - enzymes responsible for the destruction of components of the extracellular matrix of the dermis. In addition, GHL-Cu promotes the acceleration of cell growth, migration of endothelial cells to the zone of wound damage, as well as immune factors that stimulate regeneration processes (61).

Local administration of GHL-Cu to the wound area stimulates the synthesis of collagen and glycosaminoglycans, in particular dermatan sulfate and chondroitin sulfate, and also increases the level of two other proteoglycans, biglucan and decorin, which are involved in the formation of homogeneous elastic fibrils based on collagen (69).

One of the most important directions in the study of the biological action of peptides is the study of their permeability through intact skin and the creation of subsequent various local metabolic effects. First of all, this concerns dermatology and cosmetology, where the expediency of using these substances to stimulate regenerative, reparative, anti-inflammatory processes is undeniable. From this point of view, it is important to note that the locality of the peptides effect compares favorably with other biologically active substances, such as immunomodulators, immunosuppressants, as well as a wide and diverse group of hormonal drugs of synthetic or natural origin, which affect the immune system and metabolism of the whole organism.

With regard to GHL, it was found that its metal-modified form GHL-Cu penetrates through the intact stratum corneum of the epidermis, significantly altering metabolism, in particular, in the direction of increasing collagen levels up to 70% from the original (28).

Restoration of the functional state of damaged skin cells, in particular, fibroblasts, is the most important factor influencing the effectiveness of the rejuvenating and reparative effects of peptides. It was found that GHL is an active modulator of the functional state of damaged skin cells, in particular, fibroblasts (60).

The effect of GHL on accelerating collagen synthesis and stimulating the level of antioxidants in sluggish chronic wounds and ulcers caused by severe somatic diseases, in particular diabetes mellitus, has been shown (58).

The results of the study of peptides as substances with a pronounced and targeted biological effect create the basis for their widespread use in modern cosmetology.

In extensive reviews of the literature on one of the peptides, GHL, the properties most demanded for practical medicine and cosmetology have been identified, the main of which are realized in: reparative, antioxidant, regenerative, anti-inflammatory, rejuvenating, photoprotective effects (22, 58, 59).

In cosmetology, the use of GHL is based on the fact that it tightens flabby skin and improves skin elasticity, density and firmness, reduces fine lines and wrinkles, reduces photodamage and hyperpigmentation, and increases keratinocyte proliferation. The antioxidant and anti-inflammatory activity of GHL makes its use promising in sunscreen cosmetics by suppressing inflammation and reducing oxidative stress, as well as protecting the skin from UV-induced aging (61).

There is a known invention related to biotechnology, according to which a protein-polypeptide complex, which has a tissue-specific regenerative-reparative and rejuvenating effect on skin tissue, is obtained from the nervous and skin tissues of ungulate embryos with gestational age from the middle of the first third to the middle of the last third of pregnancy by homogenization in a buffer solution with simultaneous extraction in the presence of reversible proteolysis inhibitors, non-ionic detergents, solubilizers at pH 5.2-8.5. The resulting homogenate is centrifuged and filtered. Proteins are separated on a chromatographic column with an anion exchange carrier. The obtained fractions are combined and subjected to sterilizing filtration. The complex includes negatively charged, weakly acidic, neutral proteins and polypeptides with molecular weights from 0.5 to 200 kDa. The complex is characterized by an absorption maximum at a wavelength of 215 ± 5 nm when the ultraviolet spectrum is taken in the wavelength range from 200 to 500 nm. The pharmaceutical composition contains, as an active ingredient, a protein-polypeptide complex at a concentration of 0.01-2.0 mg / ml, polynucleotides in the form of a sodium salt of deoxyribonucleic acid, and a pharmaceutically acceptable diluent (17).

Known pharmaceutical composition consisting of a hormone and a peptide comprising at least one amino acid residue of a basic nature and at least one amino acid residue of an acidic nature, for use in accordance with this invention can be a peptide containing up to 20 amino acid residues, preferably 3 to 10 amino acid residues, more preferably 3 to 6 amino acid residues, such as 3 or 4 amino acid residues (eg Lys-Gly-Asp-Ser). In accordance with one aspect of the invention, the basic and acidic amino acid residues of the shorter peptides are separated by 1 or 2 amino acid residues. The peptides preferably include naturally occurring alpha amino acid residues. The amino acid (s) can be L or D amino acid (s) or a mixture thereof. "Acidic amino acid residues" are, for example, Glu or Asp, and "basic amino acid residues" are, for example, Lys (6).

The biological activity of oligopeptides determines the variety of their functions. It has now been proven that many oligopeptides have geroprotective and adaptogenic properties. Peptides are involved in maintaining a balance between three main cellular processes - cell proliferation, differentiation, and apoptosis (25).

The known properties of high permeability of cellular biomembranes for many di- and tripeptides allow one to explain the high biological activity and consider the possibility of their use to create a powerful target effect by activating local cellular and vascular metabolism, without significantly affecting the main systems of human homeostasis.

The fourth pharmacologically acceptable ABA or pharmacologically acceptable derivatives thereof is a group of steroid hormones, which includes at least: estradiol, cortisol, cortisone, testosterone, progesterone.

From the current state of the art, the content in urine of an extremely wide spectrum of biologically active hormonal substances is known. Some of them are successfully used in medicine and cosmetology, primarily as hormonal drugs.

Most of the known methods for producing natural hormones are based on the use of animal or human urine, as the most biologically compatible starting product.

Almost all methods of hormone release require preliminary purification of raw materials and their concentration.

The overwhelming majority of known methods for the isolation of hormones use technical means, most of them various chromatographic ones using gels or adsorbents, as well as ultrafiltration, centrifugation, etc.

Depending on the goals set for the release of hormonal substances, the priority of using one or another technical means remains the choice of the performer, however, the general tendency to use them in the technological process has common criteria, first of all, such as: safety and purity of the final product, maximum possible productivity and minimization stages of the technological process, the availability of technical means and components, as well as the economic efficiency and cost of the final product.

Most of the known methods have been developed taking into account the release of predominantly steroid hormones, as the most in demand in modern medicine and cosmetology, and also due to the rather large possibilities of obtaining the initial product, including urine.

The classification of steroid hormones distinguishes two main groups that differ in their source of origin: hormones of the adrenal cortex - corticosteroids and hormones of the sex glands - gonadosteroids. In turn, corticosteroids are also divided into two subgroups. One of them is represented by glucocorticoids, such as: cortisone, cortisol, deoxycortisol.

The second subgroup is made up of mineralocorticoids, such as: deoxycorticosterone, corticosterone, aldosterone.

Gonadosteroids are represented by three subgroups, among which progestogens are distinguished, such as pregnenolone, progesterone, allopregnenolone. The second subgroup is made up of androgens: androstenediol, testosterone, dehydrotestosterone. The third subgroup is represented by estrogens: estrone, estradiol, estriol. In addition, steroids include compounds of plant origin that have valuable pharmacological properties: steroid alkaloids, digitalis glycosides (cardiac glycosides) and steroid saponins.

Despite the fact that a complete synthesis of the main steroid hormones has now been developed, the demanded demand for natural hormones remains extremely high. This is associated with and determined by the intensive search for ways to optimize the production of natural hormones from plant and biological raw materials. From this perspective, urine is the ideal, most readily available and constantly renewable source of virtually all hormones of animal origin.

The urine contains a natural mixture of hormones, in particular steroid hormones, which is presented mainly in a conjugated form, for example, in the form of the sodium salt of a half-ester of sulfuric acid. The content of conjugated hormones (calculated for estrogen sulfate) can range from 0.3 to 1 wt. % based on dry matter weight.

A pharmaceutical composition containing prolactin and methods of its use is known (41). The invention relates to a composition containing a peptide hormone of the pituitary gland (prolactin, PRL) alone and in combination with ascorbic acid (vitamin C) or with ascorbate in order to improve the appearance and restore and preserve the skin and preserve and restore the performance of physiological structures in which the connective tissue and its components play a major role. The inventors emphasize that a new method and composition is proposed, in which the administration of appropriate amounts of PRL increases the tensile strength of the skin while reducing or delaying the maturation of said skin by reducing the total number of collagen cross-links and the proportion of non-recoverable cross-links and reducing the amount of collagen present type III. This finding implies that PRL wound treatment can introduce tissue regeneration into the healing process, leading to tissue healing and avoiding cicatricial hypertrophy.

The disadvantage of this invention is that the claimed advantages are not confirmed by the data of its use on human skin. The examples provide descriptions of experiments on rats and birds with the introduction of prolactin from sheep. Unfortunately, we have not found the fact that this patent was terminated on 2020-03-21 and further information confirming its application.

Known invention, which relates to new pharmaceutical compositions containing growth hormone or a derivative of growth hormone and an amino acid selected from the group Asp, Ile, Val, Leu or His, or a derivative of histidine or a peptide comprising at least one basic amino acid and at least at least one acidic amino acid, and a nonionic detergent such as polysorbate or poloxamer. The invention also relates to a method for the preparation of these compositions and to a method of treatment that involves their use. According to the description, a pharmaceutical composition containing a growth hormone or a derivative of a growth hormone and an amino acid selected from the group Asp, Ile, Val or Leu, a histidine or a histidine derivative, or a peptide comprising at least one basic amino acid residue and at least one amino acid residue acidic character, and a nonionic detergent, where the amount of peptide, or Asp, Il, Val, Leu or His or histidine derivative is from about 0.01 to about 10 mg per mg GH, exhibits high resistance against deamidation and aggregation. The stability of the product allows it to be stored and transported in a lyophilized state or as a dissolved preparation (6).

Known liquid composition containing luteinizing hormone or its variant, its use, presentation form, method of its preparation and pharmaceutical composition (64). The invention relates to liquid pharmaceutical compositions of luteinizing hormone. The composition is intended for single or multi-dose administration through the skin in an invasive manner and provides for intramuscular, intravenous, arterial, subcutaneous administration.

Known invention "Purified follicle-stimulating hormone, pharmaceutical composition, component of pharmaceutical composition", (2), according to which follicle-stimulating hormone (FSH), having an α-subunit of gonadotropin and β-subunit of 111 amino acids, is isolated from climacteric urine. FSH is free of luteinating hormone, has an activity of at least 6,200 IU of FSH per mg of lyophilized powder, and is glycosylated. The isolated FSH is used in a pharmaceutical composition suitable for subcutaneous administration. It has been shown that human FSH can be isolated from postmenopausal urine concentrate to such a degree of purity that it is completely free of even trace amounts of luteinizing hormone and other urinary proteins.

There is a known invention related to biotechnology, according to which a protein-polypeptide complex, which has a tissue-specific regenerative-reparative and rejuvenating effect on skin tissue, is obtained from the nervous and skin tissues of ungulate embryos with gestational age from the middle of the first third to the middle of the last third of pregnancy by its homogenization in a buffer solution with simultaneous extraction in the presence of reversible proteolysis inhibitors, non-ionic detergents, solubilizers at pH 5.2-8.5. The resulting homogenate is centrifuged and filtered. Proteins are separated on a chromatographic column with an anion exchange carrier. The obtained fractions are combined and subjected to sterilizing filtration. The complex includes negatively charged, weakly acidic, neutral proteins and polypeptides with molecular weights from 0.5 to 200 kDa. The complex is characterized by an absorption maximum at a wavelength of 215 ± 5 nm when the ultraviolet spectrum is taken in the wavelength range from 200 to 500 nm. The pharmaceutical composition contains, as an active ingredient, a protein-polypeptide complex at a concentration of 0.01-2.0 mg / ml, polynucleotides in the form of a sodium salt of deoxyribonucleic acid, and a pharmaceutically acceptable diluent (17).

Summarizing the selected data presented above, it can be argued that the currently available proven positive results of the use of hormones both individually and in pharmaceutical compositions allow us to consider their use as scientifically substantiated and expedient.

The fifth of the pharmacologically acceptable ABA or pharmacologically acceptable derivatives thereof is a group of amino acids that includes at least cysteine, asparagine, tyrosine, tryptophan, histidine, lysine, methionine, proline, phenylalanine, and threonine. This ABA is used as a donor of substances necessary to provide metabolic processes stimulated by other components of the pharmaceutical composition in the intradermal structures of the skin.

The composition described below is effective for treating and ameliorating degenerative inflammatory processes in tissues and for accelerating the healing of wounds caused by trauma or surgery. To prevent an inflammatory disease, or after treatment has removed such an inflammatory condition, the composition is suitably modified by replacing glucosamine or other anti-inflammatory sugar or amino sugar with an amino acid having anti-inflammatory action. This substitution of an anti-inflammatory amino acid for glucosamine or another anti-inflammatory sugar or amino sugar can also be accomplished in the compositions used to promote wound healing in accordance with the present invention. For this, cysteine is preferred because it has a bactericidal effect against Streptococcus mutans and also has an anti-inflammatory effect. Other suitable amino acids include creatine, creatinine, L-tryptophan, valine, alanine, glycine, glutamine, aspartic acid, and S-methylcysteine, as well as esters, N-benzenesulfonyl derivatives and diazomethyl ketone and chloromethyl ketone N analogs, their tosyl derivatives, and the like. Jain et al., Agents and Actions, 11.3 (1981); Gualano et al., Pharmacol. Res Commun., Jul. 1983, 15 (7), p. 683-96; Thomas et al., J. Pharmacol., Feb. 74, 26 (2), p. 151-2; Borne et al., J. Med. Chem., Dec. 72, 15 (12), p. 1325-6; Hall et al., J. Pharm. Sci., Dec. 1980, 69 (12), p. 1451-2; Kwapiszewski et al., Arch. Immunol. Ther. Exp. (Warsz.), 1979, 27 (6), p. 729-31. Other suitable amino acids include creatine, creatinine, L-tryptophan, valine, alanine, glycine, glutamine, aspartic acid, and S-methylcysteine, as well as esters, N-benzenesulfonyl derivatives and diazomethyl ketone and chloromethyl ketone N analogs, their tosyl derivatives, and the like. Jain et al., Agents and Actions, 11.3 (1981); Gualano et al., Pharmacol. Res Commun., Jul. 1983, 15 (7), p. 683-96; Thomas et al., J. Pharmacol., Feb. 74, 26 (2), p. 151-2; Borne et al., J. Med. Chem., Dec. 72, 15 (12), p. 1325-6; Hall et al., J. Pharm. Sci., Dec. 1980, 69 (12), p. 1451-2; Kwapiszewski et al., Arch. Immunol. Ther. (cited from LF Meissner. Method for accelerated wound healing. US patent 4772591. 04/16/1986. (14)

Known invention, which relates to PK containing an amino acid selected from the group Asp, Ile, Val, Leu or His, or a histidine derivative or peptide comprising at least one basic amino acid and at least one acidic amino acid, and a nonionic detergent such as polysorbate or poloxamer. The invention also relates to a method for the preparation of these compositions and to a method of treatment that involves their use. According to the description, a PK containing growth hormone or a derivative of growth hormone and an amino acid selected from the group Asp, Ile, Val or Leu, a histidine or a histidine derivative, or a peptide comprising at least one basic amino acid residue and at least one acidic amino acid residue character, for use in accordance with this invention may be a peptide containing up to 20 amino acid residues, preferably from 3 to 10 amino acid residues, more preferably from 3 to 6 amino acid residues, such as 3 or 4 amino acid residues (for example, Lys-Gly -Asp-Ser). In accordance with one aspect of the invention, the basic and acidic amino acid residues of the shorter peptides are separated by 1 or 2 amino acid residues. The peptides preferably include naturally occurring alpha amino acid residues. The amino acid (s) can be L or D amino acid (s) or a mixture thereof. "Acidic amino acid residues" are, for example, Glu or Asp, and "basic amino acid residues" are, for example, Lys. (6). Amino acids included in peptides can also regulate the processes of cell proliferation and apoptosis (21). The sixth of the pharmacologically acceptable ABA or its pharmacologically acceptable derivatives is adenosyl methionine. This component is applied on the basis of a proven stimulating effect on metabolism in the intradermal structures of the skin. Ademethionine (SAM) is the international name for the internal salt of (S) -5 '- [(3-amino-3-carboxypropyl) methylsulfonio] -5'-deoxyadenosine hydroxide, synonymous with S-adenosyl-L-methionine. SAM is involved in various metabolic processes in the body (5, 35). SAM was found to be involved in transmethylation, transsulfonation, and aminopropylation reactions (30). Transmethylation reactions are an important stage in the synthesis of phospholipids, primarily phosphatidylcholine. All cell membranes have a typical structure and mainly consist of phospholipids, of which 80-90% are represented by phosphatidylcholine (16). In addition to the structural function, phospholipids are involved in the processes of cell division and differentiation, stimulate the activity of various enzyme systems. Violation of transsulfonation leads to a deficiency of the essential cellular antioxidant glutathione (75). In turn, the lack of glutathione reduces the resistance of cells to the damaging action of free radicals, which are constantly formed during metabolism. In addition, SAM serves as a precursor of other thiol compounds, such as cysteine, taurine, coenzyme A. Sulfurization of hydrophobic fatty acids with the participation of such thiol compounds leads to their modification, which consists in the fact that sulfurized acids, in contrast to the damaging effect of hydrophobic fatty acids, exhibit a protective effect on the phospholipid base of the cell membrane (43). Aminopropylation reactions involving SAM accompany the synthesis of polyamines, which are actively involved in the processes of cell proliferation and regeneration. The resulting polyamines such as putrescine, spermine, and spermidine have analgesic and anti-inflammatory properties (52). The anti-aging effect of SAM is due to the fact that transmethylation leads to the biotransformation of proteins and nucleic acids of the skin, which activate the metabolism of epidermal cells, which stimulates their regeneration. Along with this, the combined increase in the level of methylated phospholipids increases the fluidity of cell membranes, which together helps to slow down the aging process of the skin.

Currently existing SAM-based drugs have shown high efficacy and safety in clinical trials. (19, 53). The substance of ademetionine is not produced in Russia. The disadvantages of SAM-based drugs are manifested in the high cost of the drug, but most importantly, in chemical instability, due to the gradual disintegration of the active substance, which limits their shelf life and use (16). In this regard, SAM is used in FA to stabilize SAM in the form of salts, such as citrate, tartrate, malate or ascorbate, or with strong mineral acids, or with organic sulfonic acids; the preferred salt is p-toluenesulfonate sulfate or di-p- disulfate. toluenesulfonate. Also, salts with polyanions and based on chitosan have been proposed as stabilizers (44, 26). Slowing down aging by maintaining optimal fluidity of skin cell membranes, promotes the activation of local metabolism. The effect of SAM on increasing the fluidity of membranes of human epidermal cells has been established (70). The results of experiments using a fluorescent marker showed that SAM in a molar concentration of 10 ^-6 to 10 ^-4 reduces the membrane viscosity by 10-25%.

PK is known for protection, treatment and recovery, as well as for reducing inflammation of connective tissue in mammals and a method for treating connective tissue in mammals by administering the composition (45). PK includes SAM and a component selected from an amino sugar or its salts (eg glucosamine) or glycosaminoglycans (eg chondroitin salts), or mixtures or fragments thereof. FA does not necessarily include manganese, which contributes to the production of connective tissue matrix. The composition also optionally includes methyl donors or methyl donor cofactors such as vitamin B12, vitamin B6, folic acid, dimethylglycine, or trimethylglycine. The disadvantage of this method is the invasiveness of its application, as well as an extensive component composition, which complicates and increases the cost of the FC manufacturing process, as well as increases the risk of adverse reactions.

SAM is now known to counteract skin aging, giving it a pleasant appearance and firmness. In this aspect, a patent (44) is known, which describes a pharmaceutical composition comprising SAM used against skin aging. The disclosure discloses a method of treating skin to counteract aging, which consists in the use of SAM or one of its salts in combination with a cosmetically or pharmaceutically acceptable carrier. As disclosed, SAM is preferably used in the form of a salt in these compositions and, if necessary, is mixed with a stabilizer such as mannitol, lactose, maltose or cyclodextrin, the preferred stabilizer being mannitol. When a mixture of SAM with a stabilizer salt is used, the preferred mixture is ademetionine disulfate and di-p-toluenesulfonate mannitol in a ratio of 3: 1. The cosmetic compositions of the known invention may also contain adjuvants such as saturated or unsaturated fatty acids containing from 1 to 18 carbon atoms, which may or may not be substituted by a hydroxyl group, or an alkali metal salt of said fatty acids. The disadvantage of this method is the invasiveness of its use, which provides for the injection route of administration, as well as the forced addition of various SAM stabilizers, which reduce the biocompatibility of the drug and increase the risk of adverse reactions.

The above short list of the already known and proven basic properties of SAM serves as a convincing basis for its practical use in our proposed pharmaceutical composition, specifically for targeted action on intradermal skin structures to activate metabolic processes in them. The intended use of SAM for a short time after its isolation, purification and concentration, mainly in the interval of 10-12 hours, contributes to a significant preservation of biological activity and ensures maximum efficiency of its action without the use of exogenous stabilizers.

An analogue is the invention, which relates to pharmaceutical compositions containing growth hormone or a derivative of growth hormone and an amino acid selected from the group Asp, Ile, Val, Leu or His, or a histidine derivative or a peptide comprising at least one basic amino acid and at least at least one acidic amino acid, and a nonionic detergent such as polysorbate or poloxamer (6). The invention also relates to a method for the preparation of these compositions and to a method of treatment that involves their use. According to the description, a pharmaceutical composition containing a growth hormone or a derivative of a growth hormone and an amino acid selected from the group Asp, Ile, Val or Leu, a histidine or a histidine derivative, or a peptide comprising at least one basic amino acid residue and at least one amino acid residue acidic character, and a nonionic detergent, where the amount of peptide, or Asp, Il, Val, Leu or His or histidine derivative is from about 0.01 to about 10 mg per mg GH, exhibits high resistance against deamidation and aggregation. The stability of the product allows it to be stored and transported in a lyophilized state or as a dissolved or redissolved product. A peptide comprising at least one basic amino acid residue and at least one acidic amino acid residue for use in accordance with the present invention may be a peptide containing up to 20 amino acid residues, preferably from 3 to 10 amino acid residues, more preferably from 3 to 6 amino acid residues such as 3 or 4 amino acid residues (eg Lys-Gly-Asp-Ser). In accordance with one aspect of the invention, the basic and acidic amino acid residues of the shorter peptides are separated by 1 or 2 amino acid residues. The peptides preferably include naturally occurring alpha amino acid residues. The amino acid (s) can be L or D amino acid (s) or a mixture thereof. "Acidic amino acid residues" are, for example, Glu or Asp, and "basic amino acid residues" are, for example, Lys.

The disadvantage of this invention is, confirmed by the author himself, the instability of one of the components of the composition - growth hormone, which leads to its degradation and aggregation. In order to prevent this process, a stabilizer is additionally introduced into the composition, which is one or more amino acids, or a peptide, as well as a nonionic detergent. Such a composition of the composition practically excludes not only its parenteral and oral administration, but also suggests questionable biocompatibility when applied topically.

The declared FC based on ABA and the method of its application are devoid of the above disadvantages. The technical solution is a new principle for the creation of FC and the technological process of processing the individual urine of one person by obtaining from it, purifying and concentrating the main ABA for subsequent transdermal use by the same person for therapeutic or restorative purposes.

In accordance with a preferred embodiment of the invention, we disclose the composition of the claimed pharmaceutical composition and the method for its transdermal application.

Individual urine, in a total volume of 1 liter, was sent for processing to the specialized production of the Mediko-Biologicheskie Sistemy LLC, Russian Federation, Izhevsk (MBS LLC), which kindly provided this opportunity. Urine processing included the following operations:

1. Preliminary purification of urine from supramolecular compounds such as corpuscles, bacteria, mucus, denatured protein aggregates, urine salts.

2. Obtaining a hormonal concentrate, purification from unwanted components, concentration.

3. Obtaining proteoglycans and glycosaminoglycans, includes: isolation, purification and concentration.

4. Obtaining a complex of fatty acids, a pool of urinary peptides, a complex of amino acids, adenylmethionine, includes: isolation, purification, concentration.

Ultimately, MBS LLC received three highly purified and concentrated fractions, which were used to obtain an individual pharmaceutical composition. The composition of the fractions is as follows:

1. Fraction 1 (F1) - represented by the ABA group in the form of PG and GAG with a degree of purification, on average, 99.86 ± 6.2%. The total volume of the fraction is 10 ml. The composition of the fraction is shown in Table 2.

The composition of the fractions in the studied samples of the initial product shows the presence of GAGs in the form of chondroitin sulfate C, chondroitin sulfates A + B (I - fraction), keratan sulfate (II - fraction), heparan sulfate, heparin (III - fraction).

The results of studies of samples of the initial product show that the main part of carbohydrate components and their derivatives (amino sugars, di- and monosaccharides, complexes with glucuronic acid) are characteristic of the structural units of proteoglycans, and this is consistent with the data in Table 2, reflecting the qualitative and quantitative composition of GAG ...

2. Fraction 2 (F2). The total volume of the fraction is 10 ml, it includes the following ABA groups:

2.1. FAs are mainly represented by decanoic acid and its derivatives and include at least: decanoic, hydroxydecanoic, oxoundecanoic, 3-hydroxydodecanoic, tetracosodecanoic, hydroxypentadecanoic acids. The total content of fatty acids is up to 87% of the composition of the fraction.

We have studied the quantitative content and qualitative composition of FA in the urine of 22 people. This group included 12 men and 10 women. The objectives of these studies were to establish the stability of the presence of the claimed ABA in different individuals, as well as to establish the boundaries of the range of indicators of the quantitative content and ratio of ABA. The results of the conducted studies allow us to conclude that the quantitative content of the proposed FAs and their ratio between other ABA compositions reflect the natural physiological composition of FAs and the natural physiological ratio inherent in each individual, individual, from whom they are isolated, purified, concentrated and applied. It was found that the regularity of the ratio between the main components studied in all the examined persons remains stable.

2.2. Peptides (up to 11% of the composition of the fraction). The composition of the fraction is represented by small oligopeptides (di-, tri, and tetrapeptides), while selective analysis of the spectra of oligopeptides reveals only homomeric homodetic peptides, however, due to the presence of cysteine and FA amino acid residues, the presence of heterodetic peptides is allowed. The bulk of small peptides are tripeptides, which include at least:

2.2.1. CDY-tripeptidide (cysteine-asparagine-tyrosine).

2.2.2. PTF tripeptide with an arbitrary unknown amino acid sequence (proline, threonine, phenylalanine).

2.2.3. WTM-tripeptide (tryptophan-threonine-methionine).

2.2.4. HKM tripeptide (histidine-lysine-methionine).

2.2.5. GHL tripeptide (glycine-histidine-lysine).

2.3. Amino acids (up to 1.8% of the fraction composition). The composition of the amino acids of the fraction includes at least: cysteine, asparagine, tyrosine, proline, threonine, phenylalanine, tryptophan, histidine, lysine, methionine, glycine.

2.4. Adenosylmethionine (SAM), up to 0.2% of the fraction composition.

Note. The results of the studies presented in paragraphs. 2.1., 2.2, 2.3., 2.4. (except for clause 2.2.5.) were performed and kindly provided by a specialized laboratory of the Advanced Research Foundation, Moscow, Russian Federation.

The biological activity of the isolated components of fractions F1 and F2 was studied in small laboratory animals when simulating acute mechanical and burn injury. The results of experimental studies have shown that the combined use of fractions F1 and F2 contributes to a significant acceleration of regenerative processes, a decrease in the degree of reactive inflammation, and a faster, compared with the control group of animals, a decrease in the size of the wound. Adverse reactions that could accompany the use of fractions F1 F2 under subjective and objective control in experimental animals were not identified.

Fraction 3. Represents ABA, in the form of an autohormonal concentrate, which is based on steroid hormones, includes at least: estradiol, progesterone, testosterone, cortisol, cortisone.

The prerequisite and justification for its use were the data of scientific and technical literature and the results of our research, which showed the presence of the above hormones in human urine, and their content in the concentrate obtained by freezing from urine increased on average by 20-40 times. These data made it possible to reasonably obtain and use the hormonal concentrate to create a targeted effect due to the combination of concentrated hormonal components of urine.

An autohormonal concentrate for research and preparation of PK from individual urine of one person was kindly provided by OOO Mediko-Biologicheskie Sistemy, Izhevsk, RF, in a liquid state, 1 ml in glass ampoules. In the process of isolation and processing of the autohormonal concentrate in order to purify it from unwanted components, pigments, native and denatured proteins, phospholipids, high and low density lipoproteins (HDL and LDL, respectively) were removed. The amount of all the above undesirable components after cleaning decreased to unreported values. This information is presented in table 3.

This is important for the complete elimination of the risk of immunological reactions inherent in analogues and prototype. The optical density of the hormone concentrate (in% of the initial) after purification increased to 92%. The study of the specific gravity of the hormonal concentrate samples showed that the specific gravity of the hormonal concentrate is, on average, 033.8 ± 3.7, with the values of the initial urine, on average, 1010.9 ± 4.8 (p <0.05).

To obtain a dry residue, the resulting hormonal concentrate and the original urine were dried in an oven at 100 ° C for 18 hours to completely remove moisture. Fine weighing of the remaining dry residue was carried out on a digital balance (GF-400, "A&D Corp. Taiwan"). As a result, 1.251 g was obtained from 100 ml of the hormonal concentrate after drying. dry matter, which is in percentage terms - 1.25%. The final weighing of the dry residue from 100 ml of the original urine established 1.116 g. dry residue, which is 1.2% as a percentage. Comparison of the results of weighing the dry residue in terms of comparable values in 1 liter, the weight of the dry residue in the hormonal concentrate corresponds to 0.24 g. In this case, when compared with the weight of the dry residue of the original urine, also in terms of 1 liter, the weight of its dry residue is 11 grams, which is more than 45.8 times more than the weight of the dry residue of the hormonal concentrate obtained from 1 liter of urine. The calculations show that the purification process leads to a significant, almost 46-fold decrease in the proportion of substances that make up undesirable components of the dry residue.

The results of studying the weight and composition of the dry residue in the original urine, which underwent the purification process and the hormonal concentrate, are presented in Table 4.

The main amount of hormonal substances, constituting from 80% to 90% of their total content in the original urine, is in the autohormonal concentrate.

The conducted studies of the content of 4 different steroid hormones in the original urine, as well as in the hormonal concentrate, showed significant differences in their content. The qualitative and quantitative composition of the autohormonal concentrate presented in Table 5 shows that the content of at least four studied hormones in the original urine and after the release of the hormonal concentrate differ in the direction of a significant increase in their concentration, on average by 20-40 times. The level of estradol in the autohormonal concentrate (obtained from normal urine) exceeded 90,000 pg / ml and, at initial values of 5805.1 ± 324.4 pg / ml, was almost 15 times higher than in the initial urine. Similarly, the level of cortisol a, with initial values of 430.9 ± 26.4 μg / day, in the autohormonal concentrate exceeded 8000 μg / day.

The results of the study of the content of other hormones, such as testosterone and progesterone, showed that their concentration in the autohormonal concentrate is also significantly higher than that determined in the original urine.

The isolated and purified autohormonal concentrate from individual human urine was kindly provided by MBS LLC, Izhevsk, RF. The processing time for each 1 liter urine portion is preferably no more than 12 hours. The volume of the autohormonal concentrate obtained from 1 liter of individual urine is preferably 1 ml.

The preferred quantitative composition of ABA in the claimed pharmaceutically acceptable composition (taking into account the added autohormonal concentrate in a volume of 1 ml) per 20 ml of the total volume is as follows:

1. ABK1, representing GHG and GAG - 49%.

2. ABA 2, representing a group of fatty acids - 43.5%.

3. ABA 3, representing a group of peptides - 5.5%.

4. ABA 4, representing a group of amino acids - 1.8%.

5. ABA 5, representing adenosylmethionine - 0.2%.

6. ABA 6, representing the group of steroid hormones - 1%.

The ratio of each ABA in each individual urine sample is different, and depends on many external and internal factors, mainly, such as: individual genetic characteristics of the body's metabolism, age, sex, qualitative and quantitative composition of food, etc.

An essential distinguishing feature and advantage of the claimed composition is that the general regularities of the composition of individual urine ABA isolated from one person reflect the physiological balance of these ABA in this person at the time of isolation, and are the most acceptable physiological composition for use by the same person in insignificant the timing of the time interval.

In this regard, the formation of the FA composition by additional biologically active substances of exogenous or xerogenic origin was not carried out. We used only the natural composition that was present at the time of sampling in the individual urine of a particular person without changes.

The ABA to FA ratio was formed taking into account the ABA ratio in the original urine before purification. Thus, the main ABA criterion was their initial, physiological for a particular person, the ratio, which was retained in FC.

The results of our numerous and versatile studies of the qualitative composition and quantitative ratio of ABA to FA have established a high scatter of individual indicators of most ABA, reaching 37%. In this regard, it was recognized as inappropriate to create FC in a ratio that is the same for all individuals, regardless of the individual characteristics of the ABA ratios in each of them. On the contrary, it turned out to be preferable to prepare FA without any changes, with maximum preservation of the individual, initial physiological composition and the ratio of individual ABA FAs.

It is important to note that despite the fact that each of the claimed ABA pharmaceutical compositions has a proven biological effect, the use of only one component will not be able to provide the claimed effect. This is due to the fact that each ABA individually performs strictly specific biological functions. For example, the introduction of only ABA 5, which includes a group of amino acids, is limited by the fact that it cannot independently pass through the intact stratum corneum of the skin without a conductor (FA) and thereby realize a biological effect due to participation in the synthesis of substrates necessary for the activation of local metabolism in cells. skin or extracellular matrix. On the contrary, administration of only ABA 2, which is a FA group, will also not be able to activate metabolism in skin cells or extracellular matrix, since in a pharmaceutical composition it performs a highly specific function of a conductor and is not intended for other purposes. Thus, it is obvious that the effectiveness of the biological action of the claimed pharmaceutically acceptable composition can be realized only with the combined use of all the claimed ABA, each of which performs highly specific functions that also ensure the implementation of highly specific, but other functions of the ABA of the pharmaceutical composition. It is important to add that only the combination of various functions of ABA makes it possible to obtain the overall total and potentiating effect from the use of the composition of the claimed pharmaceutical composition.

Substantiation of the transdermal route of FC administration.

Currently, the transdermal route of delivery (TPD) of medicinal substances (LP) is widespread and is one of the innovative areas of modern medical pharmaceuticals and cosmetology. (63). TPD provides an alternative route of drug use, since traditional oral or parenteral routes of administration are less effective, primarily due to their instability in the gastrointestinal tract and the likelihood of destruction in the detoxification systems of the liver. Transdermal drug delivery methods are progressively developing, since they are widely used due to their ease of use, high safety and efficiency (8). TDP provides for the delivery of drugs through the skin into the systemic circulation at a therapeutically predictable dose and rate (37). In most cases, TPD uses the principle of passive drug migration through the skin, based on their diffusion in a concentration gradient across a semipermeable membrane, which is skin (15, 23). The TPD process consists in the fact that a drug or a group of substances diffuse through the stratum corneum and epidermis, then gradually reach the dermis, where they remain and / or enter the microcirculation system, which carries the drug into the endocorporeal circulation.

One of the prerequisites for the implementation of TPD is to ensure the effective passage of the drug through intact skin, specifically through the stratum corneum. In the case of TPD, this is solved by the use of substances that have the properties of conductors, which allow free passage through the lipid component of the stratum corneum, both independently and in combination with other, usually hydrophobic substances that do not have a conductive effect. In most cases, drugs intended for TPD are combined into a variety of compositions in which the functions of substances with a conductive effect and substances that directly exert a therapeutic effect in a local segment or scale of the body are clearly provided. To preserve the maximum possible time interval for drug use, various options for their protection have been developed, providing, first of all, resistance to premature evaporation of drugs from the skin surface or their drying. It is known to use for this purpose various film-like carriers (PON) of animal, vegetable or artificial origin. Each of the listed groups of PONs, to a greater or lesser extent, has positive and negative features of use, however, the main criterion of safety and bioavailability belongs to a greater extent to natural substances that are physiological for a particular individual. At the present state of the art, the use of natural PONs is known, such as: collagen, gelatin, elastin, chitosan, as well as some plant substances in the form of pectins, alginates, agar-agar, dextrin. PONs from natural collagen polymers and chitosan, as well as their compositions, are widely used. Known "Kollahit FA" on the basis of a collagen-chitosan complex with the inclusion of antiseptic furagin potassium and anesthetic anilocaine; "Kollahit Sh" - based on a collagen-chitosan complex with the inclusion of a plant-derived antiseptic shikonin (27). Currently, there are many publications on various compositions of TDP, the active components of which are represented by groups with different pharmacological effects, such as: hormones, chemotherapeutic drugs, antimicrobial and antiseptic agents, immunomodulators, antioxidants, etc. Despite the lack of available sources of information about PG and GAG as PON, it is possible to admit their taken place for this purpose, or attempts to use them. In this regard, it should be noted that any xerogenic PON, especially isolated from the products of invertebrate processing, as well as fish, specific organs and tissues of cattle, even with their application, carry a high risk of early and delayed local and general reactions with an immunodominant component. This creates the need for careful selection of drugs for transdermal use. In any case, we did not find information on the use of PG-GAG as autobiocomponents (ABG) isolated from individual urine as a PON for a pharmaceutical composition for use by the same person in the available technical literature or other sources.

TDP of drugs has several advantages, of which the main ones are the rapid onset of drug action, the absence of inactivation or decrease in the activity of drugs as a result of negative effects on them in the gastrointestinal tract and liver. Efficiency is of no less importance, since local application significantly reduces the volume of unused or deactivated drugs, as a rule, at least 100 times (18). This makes it possible to significantly increase the availability of TDP and its cost. The disadvantages of TDP are mainly related to the fact that it takes a relatively longer time to start the implementation of the action of the drug, in comparison with injectable forms. It should be added that the formation of an effective PK is directly related to the choice of an equally effective and safe substance with a conductive effect, which provides free transport of drugs into the skin.

Important morphological and functional aspects of the skin are known and studied from the current state of the art. To substantiate the feasibility of the formation of FC of a specific component composition, it is necessary to dwell on the known information about the structure of the skin. Known classification of the main layers of the skin, which secretes the epidermis, dermis and subcutaneous fat. In turn, the epidermis is the upper outer layer of the skin of mammals, including humans, consists of the basal, prickly, granular, shiny and stratum corneum.

The basal layer (lower) is formed by dividing cells of the prismatic epithelium located on the basement membrane, among which there are pigment cells - melanocytes - containing the pigment melanin, which determines the color of the skin. Through the basement membrane from the vessels of the dermis, nutrition and removal of metabolic products from the epidermis are carried out. The spiny layer is formed by cells with cytoplasmic spine-like outgrowths that separate the cells from each other, creating the intercellular space necessary for nourishing the upper layers of the epidermis. Langerhans cells are present in the spinous layer, which perform secretory and immunomodulatory functions due to the synthesis of many already studied factors. The dividing cells of the prickly and basal layers that make up the germ layer are called skin stem cells. The granular layer is relatively thin, consists of flattened, elongated cells located parallel to the skin surface, in the cytoplasm of which keratohyalin grains are determined. Keratinization reaches its maximum in the granular layer, where cells die and turn into corneocytes.

The shiny layer is formed by flat, nuclear-free cells filled with the protein eleidin, which is an intermediate product of the conversion of keratohyalin into the stratum corneum - keratin. The glossy layer forms a dense and effective hydrophobic barrier with the stratum corneum. The outer stratum corneum is formed by a stratified keratinizing epithelium, consisting of dead flattened corneocytes firmly connected to each other. Inside these cells are corneodesmosomes, which are high molecular weight protein structures that connect keratinocytes into a network. Also present, a few long-chain molecules called ceramides, provide strong binding of the lipid layers located between corneocytes. These structures provide high stability of the properties of the components and the entire stratum corneum. Metabolism in the stratum corneum of the skin plays an important role in the biological defense of the body due to the action of various enzymes, including hydrolases, which hydrolyze triglycerides into di- and monoglycerides, as well as glycerol and fatty acids. Proteases, provide the supply of amino acids to maintain the composition of the so-called. a natural moisturizing factor that is an effective natural free radical scavenger.

For TDP, the stratum corneum is the focal surface, where the conductive effect is realized, the efficiency of which determines the degree of saturation of the underlying layers of the skin with medicinal substances.

Lipophilic substances penetrate into the deeper layers of the skin mainly through the intracellular lipid bilayer and structures of the corneodesmosome. Lipophilic substances with a molecular weight of up to 500 kDa have the highest penetrating ability. For example, steroid hormones related to lipophilic compounds independently penetrate through the stratum corneum and have a local effect on the intracellular structures of the skin. This does not apply to amino acids, short peptides or ceramides, most of which are hydrophobic substances. With the help of liposomes derived from phosphatidylcholine, drugs or cosmetics are transferred through the epidermis into the deeper layers of the skin. Similarly, lipophilic nanodispersions accelerate the penetration of lipophilic agents (24).

There is a patent (20), which describes a titratable system for transdermal drug delivery, including an effective dose of an antithrombotic agent such as tirofiban, or a pharmaceutically acceptable salt thereof. The dose of the drug delivered is proportional to the size of the patch used and reaches 60-85% platelet inhibition. The system allows for individualized treatment of patients. Also provided are methods of treating various disorders where platelet inhibition is desired. The transdermal delivery system can deliver a drug to a patient over an extended period of time. The disadvantages are that the pharmaceutical composition is not able to passively diffuse through the flexible base, for which an enhancer is additionally included for permeation or penetration into the skin. In addition, the composition of the pharmaceutical composition is not intended for use in dermatology or cosmetology.

TDP studies of estrogen use are known. It has been shown that percutaneous administration of estrogens is not associated with an increased risk of breast cancer, thrombophilia and is associated with a much lower risk from the gastrointestinal tract. The gel form of percutaneous HRT does not lead to skin irritation typical of the use of patches.

It has been proven that transdermal hormone replacement therapy with monoestrogens in the climacteric period has a greater safety profile compared to oral administration when used for a long time. At the same time, the effectiveness of therapy is comparable. This allows the authors to argue that in women of reproductive age who need a short course of therapy, estrogen treatment by transdermal administration will be effective and safe, as with long-term therapy (7).

Known patent (12), which describes the use of a pharmacological agent, namely a patch for transdermal administration. The essence of the invention lies in the fact that the transdermal patch is a matrix system and includes a lining layer, a matrix layer and an opaque protective coating in the following ratio of components; 6.72 wt. % hypoxene substance, 15.11 wt. % solution of sodium metabisulfite in propylene glycol, of which 0.067 wt. % falls on sodium metabisulfite, as well as 56.0 wt. % ethyl alcohol 95% and 22.17 wt. % PVP K30. The patch is intended for percutaneous administration of hypoxene. The area of the patch is 25 cm ² . The proposed patch, used for the treatment and prevention of chronic diseases, avoids problems associated with oral administration, improves patient compliance, allows maintaining a constant hypoxene concentration for a long time, and is convenient for use in combination therapy. The disadvantages are that the method is not designed for use in dermatology or cosmetology, requires industrial production of a patch. Provides for the use of chemically active substances.

The biological effect of autologous blood on the stimulation of the defenses of the human body is known. In this regard, there is a known method of autohemotherapy, which provides for the subcutaneous or intramuscular administration of the patient's own blood taken from a vein. Autohemotherapy was used in dermatological practice in the early 1900s. Classical autohemotherapy involves the subcutaneous or intramuscular administration of the patient's own fresh venous blood, which is not exposed to any influences and is not mixed with any substances. The implementation of the method consists in the fact that blood from a vein is injected deeply intramuscularly into the upper outer quadrant of the buttock.

Along with classical autohemotherapy, there are options for introducing autoblood subjected to various chemical or physical influences. In particular, it is known to use preliminary freezing of blood before administration, irradiation with X-rays or ultraviolet rays. Autohemotherapy with pre-ozonized blood was used as a type of autohemotherapy (31).

Based on the known results indicating the immunomodulatory efficacy after the use of ozonation and ultraviolet autohemotherapy, it can be considered that this method has a certain clinical significance, but at present the mechanism of its action is still insufficiently understood. It is also likely that the various changes in metabolism caused by ozone and ultraviolet light are unlikely to act specifically only on the desired target molecules, which means that there are risks of side complications (67).

The disadvantage of this method is that dermatologists have stopped using autohemotherapy due to the lack of any evidence of its effectiveness. Conducted systematic reviews of the use of autohemotherapy for such manifestations as urticaria and eczema have shown that autohemotherapy does not have any serious side effects, and minor side effects are short-lived and similar to placebo injections. The effectiveness of autohemotherapy in general is not statistically different from placebo injections or no treatment. The results of studies of the clinical efficacy of autohemotherapy in the treatment of dermatological diseases such as urticaria, acne and eczema suggest that autohemotherapy is no more effective than injections of saline (33).

The known method of mesotherapy. The term mesotherapy was coined by the French physician Michel Pistor, who proposed intradermal injections of procaine into the mesoderm. A noticeable improvement in the condition of the skin after a course of injections served as the basis for widespread use in cosmetology for skin rejuvenation. Mesotherapy is widely used in the treatment of the vascular, immune and nervous systems, in the restoration of the musculoskeletal system.

The component mixture, administered intradermally during mesotherapy, consists of vitamins, various drugs, organic acids, extracts of plant or animal origin, mineral components, as well as trace amounts of hyaluronic acid (1-2 mg once a day). The action of this composition is aimed at restoring the cellular matrix.

There is a known method of one of the varieties of mesotherapy - biorevitalization, which was proposed by the Italian doctor A. Di Pietro, who discovered the stimulation of the reparative processes of the skin after intradermal administration of hyaluronic acid. Currently, this method has found application in cosmetology to create the effect of skin rejuvenation. The method involves the use of gels with a high content of hyaluronic acid, which is the active and main component of the administered drug in combination with a minimum amount of excipients. It is believed that biorevitalization creates a quick but not lasting effect of skin hydration, promotes the activation of the synthesis of its own hyaluronic acid, thereby increasing the volume of filling the intercellular space of the dermis.

The known method of plasmolifing, which provides for the stimulation of regeneration processes in tissues by injection of a drug produced from the patient's own blood. This method can be considered as a variant of biomesotherapy, in which the patient's own biomaterials are used for treatment. The method is said to provide biocompatibility and virtually eliminate the possibility of allergic reactions. The manufacturer also claims that plasma lifting is the most non-toxic and safest way to control the process of tissue regeneration, based solely on the internal resources of the body. According to the description, the procedure is carried out by taking venous blood from the patient in a volume of 10-20 ml. The blood is placed in a test tube containing an anticoagulant and a separation gel. Further, in a laboratory centrifuge, the blood is divided into fractions: the cellular component (erythrocytes, leukocytes), platelet-rich plasma (about 1 million / μl), and platelet-poor plasma (less than 150 thousand / μl). For safety reasons, it is forbidden to add any other components, vitamins or otherwise modify it into the received preparation. The skin is treated with an antiseptic and in case of hypersensitivity, anesthetized with a cream. Platelet-rich plasma is injected into the problem areas using the microinjection method. The density of the injections is approximately one injection for every 2 sq. see skin. At the end of the procedure, problem areas are re-treated with an antiseptic. The duration of the procedure is 40-50 minutes. The course is from two to four procedures with intervals of two to three weeks.

Disadvantages of mesotherapy, biorevitalization and plasma lifting:

1. All three methods are invasive with associated possible complications.

2. The procedure is painful and causes psychological discomfort for patients.

3. All three methods have an age limit. The age of patients for mesotherapy is recommended from 25 years. When carrying out biorevitalization from 35 years old.

4. The change in the skin condition after mesotherapy occurs rather slowly. Wrinkles, acne and age spots disappear gradually and for a period not exceeding 3 months. Frequent relapses with acne. The effect after a full course of procedures is observed mainly with early wrinkles. For hyperpigmentation, the visible positive effect is no more than six months.

5. Mesotherapy is carried out by hardware and manual methods.

6. Mesotherapy is carried out by a course of procedures, on average it is 8-10 sessions every 5-7 days. After the main course, supportive procedures are prescribed with a frequency of first 2, and then 1 time per month.

7. Biorevitalization involves a deeper injection of the drug, swelling remains at the injection sites.

8. Biorevitalization involves 3-4 sessions of procedures with a time interval of 6 to 9 months. The effect is largely related to the specific drug, its quality and the amount of hyaluronic acid administered.

Closest to the claimed invention, taken as a prototype, is Plasmolifting ^™ cream serum and its method of application. The Plasmolifting ™ serum cream is based on the CellularFriendlyTech® technology, which provides for the preliminary obtaining of venous blood, its processing to obtain individual platelet autoplasma, on the basis of which a composition of other, additional components is created. The composition of the components includes:

1. Short peptides that provide penetration of substances into various layers of the skin and activate the extracellular matrix.

2. Growth factors that stimulate tissue regeneration processes.

3. Amino acids, which penetrate into the dermis, stimulate metabolic processes and the production of proteins necessary for the body.

According to the advertising description, the biological action of the serum cream contributes to: increasing skin turgor; stimulation of physiological regeneration processes; activation of cellular metabolism; normalization of water and oxygen metabolism; increasing the local immunity of the skin and the resistance of cells to the effects of toxins; regulation of tissue and cell metabolism.

Also according to the advertising description, the clinical results show: a reduction in the depth of superficial wrinkles; improvement of complexion; decrease in the severity of hyperpigmentation; a decrease in the severity of rosacea and a decrease in skin hypersensitivity, primarily due to a low immune status; reduction of puffiness under the eyes; elimination of dry lips, characteristic of chronic cheilitis; reduced reactivity and itching of the skin. The results of using Plasmolifting ^™ cream are an improvement in complexion, an increase in hydration, elasticity and tissue turgor, the disappearance of small scars formed as a result of various skin diseases, a reduction in the number and depth of wrinkles.

The disadvantages of the above described prototype are as follows.

1. Inconsistency in the description of the action of additional components of the cream. Specifically, according to the available scientific and technical information, the possibility of independent penetration of amino acids through the intact layers of the skin has not been proven.

2. Lack of data on the source of origin of additional components of the cream and the method of obtaining them. This is extremely important, since information about the source of origin is associated with the possibility of banning their use as a medicinal product.

3. The use of Plasmolifting ^™ serum cream as a medicinal product is not permitted on the territory of the Russian Federation, and is due to the fact that the cream contains additional biocomponents, the use of which for medicinal purposes requires obtaining a Registration Certificate, which, in turn, cannot be issued without conducting mandatory preclinical and clinical trials.

4. Invasiveness of the method, requiring intravenous access and sampling of autoplasma.

5. The risk of infection when taking plasma from a patient, processing it outside the body and intradermal administration (in the case of using the plasma-lifting method).

6. Selective mention of the effect of growth factors present in the preparation is incorrect, since it does not affect more than 150 basic, already known biologically active substances and factors that are released during the destruction of platelets in the process of plasma-lifting and have, among other things, a significant negative effect ( 37, 39, 40, 42, 55, 56).

7. The main significant disadvantage of using plasmolifting or cream - serum Plasmolifting ^™ is the currently established immunosuppressive effect of the products of destroyed auto platelets on the state of the body's immune system. In works (40, 55, 56), it was shown that after activation, platelets degranulate, releasing numerous factors and biologically active lipids into the bloodstream. On the one hand, this process facilitates skin regeneration, but on the other hand, it suppresses platelet-mediated immune recognition and elimination of cancer cells, which creates the possibility of their fixation in the endothelium, contributes to their survival and spread, as well as the development of secondary lesions and metastasis. Substantial evidence supporting this opinion is based on the fact that P-selectin from granules of destroyed platelets mediates tumor metastasis (37, 39, 42). Thus, the effect of the products of artificial destruction of autothrombocytes poses a real danger of oncological manifestations in the long-term period, and at present, the use of plasma-lifting or Plasmolifting ^™ serum cream seems undesirable and dangerous until full-fledged versatile research is carried out.

Analysis of the above data allows us to conclude that there is undoubted promise and potentially high efficiency of TDP for creating a targeted local therapeutic or cosmetic effect. Almost all existing methods of using TDP are based on the use of chemicals of non-biological origin to create a conductive and therapeutic effect. There is no information on the safe use of ABA for TDP in the patent and technical literature available to us. Meanwhile, in our opinion, the use of ABA brings TDP to a qualitatively new level of application of these substances or a group of substances, for a significant increase in the level of metabolism in specific skin structures for therapeutic or cosmetic purposes.

The inventive method for transdermal administration of a pharmaceutical composition based on ABA is as follows.

Individual human urine, obtained within no more than 12 hours from the moment of collection, is transferred for processing to specialized production facilities, where it is purified from urine salts, medium and large molecular weight undesirable substances, as well as supramolecular compounds, including bacteria, corpuscles, mucus, aggregates denatured proteins, etc. Before processing, at least 10 ml of urine is taken to determine the main steroid hormones. After that, the urine is processed to precipitate the main claimed components, such as PG-GAG, fatty acids, peptides, steroid hormones, adenosylmethionine, amino acids. These components are purified, concentrated and sterilized. After the final operations, the components are packed in the form of a gel in a sterile container, specifically in glass penicillin vials with a volume of at least 40 ml. Other disposable containers are allowed for filling, which ensure sterility, safety of storage and transportation, as well as easy to use. The finished components are packaged in a natural, physiological ratio (as in the original urine) and in the following composition: PG-GAG, fatty acids, peptides, amino acids and adenosylmethionine, as well as an autohormonal concentrate in an amount of 5 ml (from 1 liter of the original urine). The bottle is hermetically packed, labeled and handed over to the customer. The customer is supposed to be a specific person, from whose urine ABA was obtained. For this person, these ABA will be applied directly only to him for medical or cosmetic purposes.

The medical or cosmetic procedure is carried out no more than 12 hours after the final production of the FC. For an individual FC made from ABC, a TDP is provided for its use, preferably in a specialized institution designed to carry out and apply this method. It is also preferable to use additional technical means that promote the active process of TDP by using ultrasonic, laser, light or other safe sources to stimulate or potentiate the transdermal transfer of substances. The TDP procedure is performed preferably with an interval of 5 days, preferably in a course of 5 procedures.

The essential distinguishing features of the claimed invention are:

1. The use of biologically active ABA with proven action in a ratio and composition that are individual and physiological for each specific person, from whose urine they are isolated, purified, concentrated and transdermally administered to the same person for therapeutic or cosmetic purposes.

2. Application of highly purified ABA.

3. Application of concentrated ABA.

4. The use of urinary purified, concentrated autopeptides to stimulate metabolism in the dermis.

5. The use of purified, concentrated steroid autohormones to stimulate metabolism in the dermis.

6. The use of FA in various combinations to obtain the maximum therapeutic or restorative effect and at the same time to prevent the risk of an undesirable effect by reducing the concentration or completely removing one or more ABA from the pharmaceutical composition.

7. Complete exclusion of the risk of autoimmunosensitization, immunosuppression.

8. Complete elimination of the risk of complications caused by bacterial flora and (or) viral infection.

9. Non-invasiveness of the method due to the transdermal application of ABA FA to the internal structures of the skin requiring correction to obtain the maximum therapeutic or restorative effect.

10. Obtaining a combined and potentiating effect when using ABA of the claimed FC.

11. Reducing the age barrier for the application of the method.

12. Safety and almost constant availability of raw materials for the production of ABK FK.

Bioadaptive PK based on natural PG-GAGs, oligopeptides, adenosylmethionine, autohormones, amino acids and fatty acids promotes skin regeneration, tissue renewal by activating the metabolism of skin cells and extracellular matrix, as well as microvessels.

The transdermal application of FA is provided through the use of ABA, some of which are natural conductors of biologically active ABA through the intact stratum corneum of the skin, while the latter directly affect the metabolism of skin cells and the intercellular matrix.

Based on the composition of the FA components and the known properties of each of its components, its use is indicated for various disorders of skin and tissue metabolism, and will be effective for any skin type, as well as for such skin types as: oily skin, sensitive skin, eyelid skin, aging skin, combination skin, dry skin, normal skin, body skin, problem skin.

Examples of implementation of the invention

Example 1.

Woman M., 52 years old, asked to isolate ABA from her urine, purify and concentrate them, and transfer them back to her in a sterile form. Urine in the amount of 1 liter, frozen up to -10C, is received and transferred to a specialized company for order fulfillment. After urine processing, including the stages of preliminary purification and further fractionation under aseptic conditions, in order to isolate ABA, their composition was obtained in the following percentage ratio: PG-GAG (51%); FA, represented mainly by decanoic acid and its derivatives, including at least: decanoic, hydroxydecanoic, oxoundecanoic, 3-hydroxydodecanoic, tetracosodecanoic, hydroxypentadecanoic acids, the total content of which was (38%); oligopeptides, including at least tripeptides with the amino acid sequence: CDY, WTM, HKM, PTF and GHL (9%); adenosine methionine (0.1%); amino acids including at least: cysteine, asparagine, tyrosine, proline, threonine, phenylalanine, tryptophan, histidine, lysine, methionine, glycine (1.9%). In addition to these ABA, an autohormonal concentrate was added, the amount of which was 1% of the total volume of the above ABA. In the autohormonal concentrate itself, the quantitative composition of individual hormones is presented in Table 6 as follows:

The consistency of the isolated ABA differed in physical properties, namely:

1. PG-GAG represented a concentrated translucent, with a matte shade biogel, odorless.

2. FA, oligopeptides, amino acids, and adenosylmethionine were a white, odorless pasty product.

3. The autohormonal concentrate was a light brown liquid with a faint smell of ethyl alcohol.

After mixing all ABA, the FA in consistency was a concentrated, thick white biogel with a creamy, slightly yellowish tinge, odorless, and the pH value of this FA was in the range of 6-5.7. Purified and concentrated end product isolated from individual urine under aseptic conditions, in an amount of 20 g. packaged in a sterile 50 ml glass container and handed over to the customer. The time spent on the preparation of FC from individual urine on an individual order was 24 hours. Later, Mrs. M. turned to a specialized beauty salon with a request to carry out transdermal administration of the individual FC provided by her, from her ABA. In a beauty salon, transdermal ABA was injected on the skin of the face and neck in a uniform layer with exposure for 30 minutes and subsequent rinsing of the ABA residues with warm water and drying the face with a hairdryer without the use of napkins. In total, 4 procedures were carried out over the next 4 days. In the above example, the transdermal administration of ABA was passive, without the use of physical methods that accelerate the process of their delivery through the stratum corneum into the deeper layers of the skin. FK applied to the skin spreads easily, liquefies, without causing a sticky or rolling sensation.

A subjective survey immediately during and after the transdermal administration of ABA did not reveal any complaints indicating discomfort or undesirable sensations at the sites of the procedure. Comparative comparison of the data of examination of the skin of the face and neck before and 14 days after the application of FA from ABA showed an improvement in complexion and an increase in the degree of moisture. The hyperpigmentation has noticeably decreased, the elasticity, volumetric density and firmness of the skin have improved, the number of fine lines and the depth of fine wrinkles have decreased. The skin on the neck is tighter.

Example 2.

The use of ABA FA for stimulating the collagen-synthetic function of rat skin fibroblasts. The aim of the research was to study the ratio of type I and type III collagen in the skin of rats without and after transdermal application of FC components.

Material and methods. The studied groups of 24 animals were divided into 2 groups: 12 rats made up the first, control group. The remaining 12 rats were combined into a group that received FC transdermal application. For this purpose, FC in the claimed composition and the ratio of the components in the form of 1 ml of concentrated gel was applied to the previously shaved frontal-occipital region of the head in a diameter of 20 mm in fixed animals. After exposing the gel for 30 minutes, the gel was washed off with warm saline and the animals were freed from fixation. Similarly, the procedures were repeated on days 2, 3, 4 and 5. The biopsy was performed on the 7th day after the start of the PK application.

The study of the ratio of collagen types I and III in the skin of rats of both groups was carried out using polarizing microscopy. Sections were stained with PicroSirius Red, followed by use of an Altami Polar 2 polarizing microscope at × 250 and × 400 magnifications. Slides were photographed using an Altami 3 Mpx digital eyepiece camera. Determination of the ratio of types I and III of collagen (CI / III TC) was carried out on the basis of known data on differences in color perception, specifically for type I collagen red, and for type III collagen - green. For an objective assessment of the CI / III TC, the Altami Studio 3.0 and ImageJ 1.47a software was used. The obtained absolute values of the red and green colors of the histogram were converted into relative values.

Statistical analysis was performed using Microsoft Excel 2010. After checking the sample for normal distribution, the arithmetic mean (M) and standard deviation of the arithmetic mean (m) were calculated. Data were expressed as M ± m indicating the number of experiments (N). The reliability of the differences was checked according to the Student's test (t-test). Mathematical processing of morphometric data of histological sections was carried out using the method of nonparametric statistics (Mann-Whitney U-test for small samples).

In the study of histological preparations of skin in rats of group 1, it was found that the average content of collagen types I and III is, respectively, 53.74 ± 1.64% and 46.26 ± 1.72%. CI / III MC in the skin of rats of this group was 1.16 ± 0.1. The study of collagen types I and III in the skin of animals in the second group established the values, respectively, 69.3 ± 1.54% and 39.7 ± 1.52%, and CI / III TC - 2.25 ± 0.27. The research results showed that the use of FA components in the claimed ratio and composition has a stimulating effect on the collagen-synthesizing function of rat skin fibroblasts, which is manifested in a significant change in the MC mass due to an increase in type I collagen (p <0.05). Microscopy in the second group showed thin, few collagen bundles along fibroblast membranes with a predominance of colored type I collagen fibers. At the same time, the shape of fibroblast membranes and the number of teeth on them did not change. In the control group, these features were not noted.

The alleged invention has been explained in the above description in accordance with the above examples, not limiting the scope of the present invention. It should be considered that all variations including the following claims are within the scope of the present invention.

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Claims (5)

1. A pharmaceutical composition of biologically active substances for a targeted action on the structure of human skin, selected to suspend the course of processes that contribute to skin aging, and to accelerate the healing of wounds caused by trauma or surgery, characterized in that it consists of isolated, purified and concentrated from individual urine of one person at least six pharmacologically acceptable autocomponents such as proteoglycans and glycosaminoglycans selected from chondroitin sulfates, heparan sulfates and keratan sulfates; peptides selected from homomeric homodetic tripeptides with amino acid sequence: CDY, WTM, NKM, PTF and GHL; sulfonated fatty acids selected from decanoic, hydroxydecanoic, oxoundecanoic, 3-hydroxydodecanoic, tetracosodecanoic, hydroxypentadecanoic acids; steroid hormones selected from estradiol, cortisol, cortisone, testosterone, progesterone; adenosylmethionine; amino acids selected from cysteine, asparagine, tyrosine, tryptophan, histidine, lysine, methionine, proline, phenylalanine, and threonine. 2. A pharmaceutical composition of biologically active substances according to claim 1, characterized in that the pharmaceutical composition consists of isolated, purified and concentrated at least six pharmacologically acceptable autocomponents from the individual urine of one person in the ratios existing in the original urine before purification. 3. A pharmaceutical composition of biologically active substances according to claim 1, characterized in that the pharmaceutical composition consists of isolated, purified and concentrated at least six pharmacologically acceptable autocomponents from the individual urine of one person, is a gel, or a suspension, or a cream, or ointment, or lotion, or any other liquid form, the consistency of which provides the claimed therapeutic or cosmetic effect. 4. A pharmaceutical composition of biologically active substances according to claim 1, characterized in that the pharmaceutical composition consists of isolated, purified and concentrated at least six pharmacologically acceptable autocomponents from the individual urine of one person, each of which performs a specific function, the combination of which contributes to the therapeutic or a cosmetic effect. 5. The use of biological active autocomponents isolated, purified and concentrated from the individual urine of one person according to claim 1 for a targeted action on the structure of the human skin, selected to stop the course of processes that contribute to skin aging, and accelerate wound healing by transdermal administration to the same person ...