WO2007027118A1

WO2007027118A1 - Dermatological composition

Info

Publication number: WO2007027118A1
Application number: PCT/RU2005/000439
Authority: WO
Inventors: Victor Stanislavovich Polyakov; Anatoli Pavlovich Gorshkov; Natalia Aleksandrovna Vorotyagina
Original assignee: Victor Stanislavovich Polyakov
Priority date: 2005-08-29
Filing date: 2005-08-29
Publication date: 2007-03-08

Abstract

The invention relates to pharmaceutical agents for protecting the skin from chemical and biological damage effects, from bacterial and fungus infections, for preventing occupational skin diseases, contact dermatitis including allergic dermatitis, for rendering first predoctor aid and for subsequently treating traumatic skin, soft tissue and mucous coat defects. Said invention can be used in industry, building, agriculture, medicine and at home. The inventive therapeutic and remedial dermatological composition for local application contains an active principle in the form of complex compounds of rare-earth element salts and a pharmaceutically acceptable carrier. Said pharmaceutical composition based on complex compounds of rare-earth compositions and polyhydroxy compounds in the form of a liquid or soft dosage form exhibits an expressed protective and preventive, dermoprotective and curative effect, the absence of side reactions, is easily tolerant and rapidly repairs the skin.

Description

Dermatological composition

The invention relates to pharmaceuticals used to protect the skin from damaging factors of a chemical and biological nature, bacterial and fungal infections, to prevent the occurrence of occupational skin diseases, to prevent contact dermatitis, including allergic nature, as well as to provide first aid and further healing of wound defects of the skin, soft tissues, mucous membranes and can be used as labor protection organs in industry, construction ie, agriculture, and medicine, and everyday life.

Skin is a “borderline” organ that acts as a protective barrier between the environment and the body. Natural protective and barrier functions of the skin are aimed at compensating for the negative effects of environmental factors. However, the adaptability of the skin to the effects of external factors is not unlimited, and if you overcome the highest threshold of resistance, local or extensive skin damage develops, which ultimately leads to impaired various functions of the body. In real conditions in production, the skin, as a rule, is subjected to the combined effects of chemical, biological and mechanical factors, resulting in a sharp degreasing and drying of the stratum corneum of the epidermis, and, consequently, a violation of the normal function of the skin and the natural self-healing mechanism, which leads to the development occupational skin diseases. An external manifestation of a decrease in protective and barrier properties is the occurrence dermatitis, peeling of the skin, erythema, as well as cuts, abrasions, abrasions, etc. This can be observed not only when working with harmful substances, but also when using detergents, with prolonged wearing of rubber gloves, with a sharp change in temperature and humidity. To protect the skin and reduce its self-healing time, various cosmetic, hygienic and pharmacological agents are used.

Skin protective agents are known. In the monograph by Bagnova M. D., “Professional dermatoses”, M., Medicine, 1984, pp. 262-269 [1], hydrophilic ointments and pastes XIOT-6 and Mikolan are described that protect the skin from fats, oils, petroleum products, organic solvents. There are also links to hydrophobic ointments and pastes IEP-2, silicone cream and ointments based on tylose, which protect the skin from the harmful effects of water and aqueous solutions of various substances.

The purpose of these protective agents is only to prevent the contact of harmful substances with the surface of the skin, but their protective effect is small, since in the process they are easily washed or washed off. Film-forming protective agents that remain on the skin for a long time (the so-called “Biological prints”) interfere with natural perspiration and have a negative effect on the functional state of the skin.

Known cosmetic cream for care and protection of the skin from the harmful effects of organophosphorus pesticides in agriculture, chemical industry and household (see patent RU 2038072) [2]. The cream contains glycerin, ethyl alcohol, polyethylene glycol, alkali metal hydroxide, lanthanum salt, or cerium, or praseodymium, or neodymium and water at a certain ratio of components. The use of this cosmetic product is limited and is used only when working with specific hazardous organophosphorus substances. In relation to other toxicants of a chemical nature, this tool may not be effective, because it contains ethyl alcohol, which, as you know, negatively affects the natural protective and barrier properties of the skin due to delipidization of the epidermis, which significantly increases the permeability of the skin and the absorption of the toxicant. An additional introduction to this cream of succinic and hyaluronic acids according to the patent RU 2159105 [3] does not lead to the manifestation of universal protective properties, make it expensive and less competitive.

Known biologically active composition based on complexes of deprotonated hyaluronic acid with metal ions, used as a pharmaceutical to accelerate the process of epithelialization of skin areas, healing of femoral ulcers, pressure sores, burns, effects of radiation and heat exposure (see patent HU 891/89 [4] and patent RU 2021304 [5]). This tool exhibits only reparative properties.

A complex compound of ferrocene with nitrogen-containing components is also known for the treatment of diseases of the skin and mucous membranes by applying a finely divided composition in a safe carrier to the lesion site 1-3 times a day (see patent RU 2132187) [6]. This complex compound has bactericidal activity and contributes to the regulation of blood and lymph microcirculation, but these properties are not enough to create a protective, prophylactic and dermatoprotective therapeutic composition. A complex chelate compound of the antibiotic azithromycin with a salt of a divalent and / or trivalent metal, in particular lanthanum, is known to have bactericidal activity and is used to obtain an antiulcer drug in the form of a gel (see patent RU2039061) [7]. It is used only for internal use.

Known therapeutic and prophylactic agent for protecting the skin from adverse environmental factors, which is a cream containing nitrate or hydrochloride of lanthanum or cerium in an amount of 0.4-0.8% of the total mass, analgin, vitamins and a base including glycerin, PEG, ethylene glycol, alcohol, potassium hydroxide, water and oil (see patent RU2210356) [8]. This tool does not provide the necessary antiseptic effect, which limits the possibility of its use in a number of skin lesions. It practically does not have bacteriostatic and fungistatic effects, because it has a small “buffering capacity” and maintains a neutral skin pH for a short time (up to 3 hours). At the same time, for the destruction of pathogenic fungi and microorganisms, it is necessary for a long time to maintain a neutral pH value on the skin, which creates the conditions for stopping the development of colonies of microorganisms.

The closest technical solution to the invention is a pharmaceutical composition for topical treatment of a wound process, comprising a complex compound of podands with rare earth elements of the general formula Me (NO ₃ ) ₃ L mH ₂ 0 or a mixture thereof, or an auxiliary solution and a pharmaceutically acceptable carrier. The latter is selected from biologically inert water-soluble hydrophilic compounds, mainly organic solvents. The pharmaceutical composition is used for external treatment of a wound defect of the skin or mucous membrane of various localization, regardless of etiology at all stages of the wound process and exhibits reparative properties that encompass antimicrobial, osmotic, dehydrating, analgesic and regenerating activities (see patent RU 2221802) [9]. This decision does not disclose the possibility of using to protect against chemical and toxic skin lesions. In addition, the tool does not show a sufficiently effective fungicidal effect, as well as a therapeutic effect in relation to contact dermatitis.

To prevent the development of occupational skin diseases, it is preferable that the protective agent not only protects the skin from the penetration of exogenous substances, but also inactivates them, and also promotes skin self-healing processes.

Thus, the objective of the present invention is to provide a pharmaceutical composition exhibiting a complex effect with a wider range of lesions of the skin and mucous membranes, due to protective and preventive, dermatoprotective, antiseptic and wound healing properties and meeting the following requirements:

- possess a wide range of preventive actions to protect the skin from exposure to various harmful and sensitizing substances, as well as pathogenic microorganisms, fungi;

- inactivate various classes of chemicals and pathogens; - contribute to the processes of self-healing of the skin;

- do not disturb the water-lipid balance of the skin;

- not significantly change the metabolism;

- do not disturb the physiological functions of the skin: gas and heat transfer, vapor through the skin;

- have a neutral or slightly acid reaction and maintain the acid-base indicator of the skin;

- possess an osmotic effect and contribute to the natural rejection of non-functional elements; - do not cause irritation; not have a sensitizing effect;

- be harmless;

- easy to wash off with normal soap and water. The technical result is achieved through the development of the claimed therapeutic and prophylactic and protective agent that meets the above requirements, and can be obtained on the basis of new complex compounds of rare earth elements and polyoxy compounds.

The object of the present invention is a therapeutic and prophylactic dermatological composition for topical application, which contains the active principle in the form of complex compounds of salts of rare earth elements of the general formula: Ln (X,) (X ₂ ) ₂ (L) _p . m H ₂ O (1) where: Ln is the cation of the rare-earth element of the cerium subgroup, which includes lanthanum, cerium, praseodymium, neodymium, or mixtures thereof; Xi - denotes the residue of a compound having basic properties selected from the group: —OH, —O — Ci. _b- alkyl, -amine of the formula NHR ₂ where R ₂ represents hydrogen or a Ci- ₄ alkoxy group;

X ₂ is nitrate or chloride;

L - denotes the ligand of the complex compound {R0 [(CHR,) m ₂ O] m, R} _p , in which

R - is H, C _{] -8} alkyl, linear or branched R _{1 -} is H, methyl, ethyl, propyl or isopropyl, fields - (- CH2-CH2-OH) mi - is an integer, the number is 1 or 2, m ₂ - is an integer equal to 1, 2 or 3 p - is an integer equal to 1 or 2 m - is an integer equal to 1, 2 or 3 in an effective amount and a pharmaceutical acceptable carrier.

The ligand of the complex compound is preferably selected from the group of polyoxy compounds and is preferably triethylene glycol, propylene glycol, ethyl carbitol,

1, 3-butyl glycol, polypropylene glycol, polyethylene glycol or mixtures thereof.

Complex compounds of salts of rare-earth elements form a chemical group with a certain stoichiometry and are crystalline substances. Their structures are established by the usual methods of elemental and X-ray diffraction analysis. Complexes having the general formula (1) are used as exhibiting dermatoprotective, inactivating, and wound healing properties that promote processes self-healing skin, and exhibiting desensitizing effect.

The complex compounds of mixtures of salts of rare-earth elements, as a rule, include homogeneous ligands

which are polyoxy compounds, such as triethylene glycol, propylene glycol, diethylene glycol mono- and diesters, 1,3-butylene glycol, as well as polyethylene, polypropylene oxides and hydroxypropyl cellulose with different molecular weights. Said pharmaceutically acceptable carrier is preferably selected from the group of polyoxy compounds, including predominantly glycerol, triethylene glycol, diethylene glycol mono- and diesters, polypropylene glycol, polyethylene glycol, hydroxypropyl cellulose, or mixtures thereof. The pharmaceutical composition is expediently performed in the form of a liquid dosage form, such as a solution, emulsion, or in the form of a soft dosage form, such as an ointment, gel, paste, liniment, which may contain acceptable excipients, for example, effective solvents, surfactants, emulsifiers, perfumes.

The amount of active substance varies depending on the degree and nature of the lesion, the age, gender and weight of the patient. In the composition of the composition, the active substance is administered in an effective amount, which, as a rule, is 3-8% of the total weight of the composition.

The composition of the pharmaceutical composition, it is advisable to additionally introduce substances of natural or synthetic origin, performing the role of a potentiator and increasing the effectiveness of the pharmaceutical composition.

As such potentiating agents, for example, glycerin, mono- and diesters of glycols, sea buckthorn, mink and other oils, fats, waxes, surfactants, both ionic and nonionic, drugs, in particular antimicrobial and / or fungicidal, such as miramistin, urotropin, salicylic acid, etc., herbal extracts that have a daily exposure in a safe and effective amount at the site of exposure to harmful exogenous factors on the skin. Examples of such extracts are oil extracts of chamomile, sea buckthorn, potentiating wound healing effect, water-alcohol solution of rose hips, potentiating effectiveness in the treatment of dermatitis, etc. An effective and safe amount of potentizing agent refers to such an amount that is sufficient to create the desired result without side effects such as toxicity, irritation, allergic reactions commensurate with a reasonable benefit / risk ratio when used in Compliant with the present invention. It changes due to factors such as the specific type of exogenous substance, condition of the skin, predisposition to allergic reactions. As a rule, these funds are used in doses generally accepted for certain pathologies.

One of the preferred options is the combination of the compounds of formula (1) and miramistin, which is added in an amount of 0.5-1% by weight of the composition. This combination allows significantly increase antimicrobial activity, the effectiveness of the treatment of mycoses, acne, as well as the wound healing effect.

The application of the pharmaceutical composition to the skin and mucous membranes is carried out mainly in the form of applications of a liquid or thickened form using hands, spatula, tampons, turunda or by irrigation.

When applied topically, the claimed composition is applied, as a rule, at the rate of 0.2-0.5 g / dm ² . However, with severe lesions, the dosage can be increased, and vice versa, for example, for cosmetic purposes, reduced.

The pharmaceutical composition can be obtained by introducing a pre-prepared crystalline active substance using methods known in the art of pharmacy into a pharmaceutical acceptable carrier and, optionally, additionally containing excipients, depending on the dosage form.

The pharmaceutical composition can also be obtained without additional isolation of a crystalline substance, by obtaining a solution of the complex compound in excess of ligand (auxiliary solution). This method is more appropriate.

A salting-out method was used to prove the formation of a solution of the complex compound of the general formula (1) in excess of the ligand: acetonitrile or dichloroethane was carefully added to the solution of the complex compound, and a complex compound crystallized at the phase boundary, identical to that obtained by the first method, using the same reagents. A method of obtaining complex compounds of General formula (I). A -0.01 M solution of a water-soluble salt of the rare-earth elements of the cerium subgroup is prepared (for example, nitrate hexahydrate or lanthanum, cerium, praseodymium or neodymium hydrochloride hexahydrate) in acetonitrile. Slowly, dropwise with vigorous stirring and room temperature add an equimolar amount of alkaline agent to the first jump according to the potentiometer. (Alkolates, aqueous solutions of alkalis, monoethanolamine, etc. can be used as the alkaline agent.) A solution of ligand in acetonitrile is immediately added to the resulting solution in the ratio: per 1 mol of REE salt, 1 mol of a ligand containing more than 2 oxygen atoms (for example, triethylene glycol, ethyl carbitol, tetraethylene glycol); or per 1 mol of REE salt, 2 moles of a ligand containing 2 oxygen atoms (e.g. 1, 2-propylene glycol,

1,3-propyl glycol, 1,3-butylene glycol). The reaction mass is maintained with stirring for 0.5-1 hours. The crystalline precipitate of the complex compound is filtered off, washed with acetonitrile and dried in vacuum at a temperature not exceeding 50 ° C to constant weight.

The resulting complex compound is dissolved in the excess of the ligand used to obtain an auxiliary solution of the complex compound, which is used to prepare the pharmaceutical composition.

In the table. l shows the composition of some complex compounds.

Table 1 The composition of some complex compounds

According to x-ray analysis, the complex compounds shown in table. l, have a similar structure: Complex compound 1.

Six oxygen atoms: 4 - from the ligand (triethylene glycol), 1 - from the hydroxo group and 1 - from the water molecule form a distorted hexagon, in the center of the plane of which (with a slight deviation of ~ 0.73 angstroms) there is a lanthanum atom. Both nitrate groups are flat, bidentantly bonded to the lanthanum atom. One NO3 group is located above the ligand plane, and the second is located below the ligand plane. The coordination number of the lanthanum atom is 10. Complex compound 2.

Six oxygen atoms: 4 - from two ligand molecules (1, 3-propylene glycol), 1 - from ethyl carbitolate ion and 1 - from a water molecule form a distorted hexagon, in the center of the plane of which there is a neodymium atom with a slight deviation. Chlorine molecules are bonded to the central atom of neodymium. One chlorine atom and one water molecule are located above the ligand plane, a second chlorine atom and a water molecule are located under the ligand plane. The coordination number of the neodymium atom is 10. Complex compound 3.

Six oxygen atoms: 4 - from two ligand molecules (1, 2-propylene glycol), 1 - from the isobutylate ion and 1 - from the water molecule form a distorted hexagon, in the center of the plane of which there is a lanthanum atom with a slight deviation. One chlorine atom and one water molecule are located above the ligand plane, a second chlorine atom and a water molecule are located under the ligand plane. The coordination number of the lanthanum atom is 10. Complex compound 4. Six oxygen atoms: 4 - from two ligand molecules (1, 3-butylene glycol), 1 - from a hydroxo-ion and 1 - from a water molecule form a distorted hexagon, in the center of the plane of which there is a praseodymium atom with a slight deviation. Molecules of nitrate groups are bound bidentantly to the central atom of praseodymium. One NO3 group is located above the ligand plane, and the second is located under the ligand plane. The coordination number of the praseodymium atom is 10. Complex compound 5.

Six oxygen atoms: 4 - from a ligand molecule (triethylene glycol), 1 - from monoethanolamine and 1 - from a water molecule form a distorted hexagon, in the center of the plane of which there is a cerium (III) atom with a slight deviation. Molecules of nitrate groups are bound bidentantly to the central atom of cerium. One NO ₃ group is located above the ligand plane, and the second under the ligand plane. The coordination number of the cerium atom is 10. Complex compound 6.

Six oxygen atoms: 3 - from the ligand molecule (ethyl carbitol), 1 - from the ethyl carbitolate ion and 2 - from the water molecule form a distorted hexagon, in the center of the plane of which there is a lanthanum atom with a slight deviation. Molecules of nitrate groups are bound bidentantly to the central atom of lanthanum. One NO ₃ group is located above the ligand plane, and the second under the ligand plane. The coordination number of the lanthanum atom is 10.

Complex compound 7. Six oxygen atoms: 5 - from the ligand molecule

(tetraethylene glycol) and 1 - from the hydroxo-ion form a distorted hexagon, in the center of the plane of which there is a lanthanum atom with a slight deviation. Above the ligand plane is one a chlorine atom and one water molecule, under the plane of the ligand - a second chlorine atom and a water molecule. The coordination number of the lanthanum atom is 10.

General method for preparing auxiliary solutions (BP)

(without isolation of the complex compound).

Prepare a 25-27% (in terms of the rare earth cation) aqueous solution of a water-soluble salt of the rare-earth element of the cerium subgroup (for example, nitrate hexahydrate or hydrochloride hexahydrate of lanthanum, cerium, praseodymium or neodymium, or mixtures thereof). To 5-10 g of the resulting solution, 30-50 g of a ligand (triethylene glycol, or tetraethylene glycol, or 1,2-propylene glycol, or 1,3-propylene glycol, or ethylcarbitol, or 1, 3-butyl glycol) are added with stirring and kept at a temperature 40-50 ⁰ C for 2 hours until a homogeneous clear solution is formed. To the resulting solution, an equimolar amount of an alkaline agent is added with stirring and room temperature, the end of the addition is before the first jump according to the potentiometer. Get the auxiliary solution of the complex compounds used for the preparation of the pharmaceutical composition.

Pharmaceutical compositions (FCs) containing complex compounds of the general formula (I) are prepared from an auxiliary solution (BP), which is a solution of the complex compound in excess of the ligand (see Table 2).

Table 2 The composition of auxiliary solutions

The auxiliary solution containing complex compounds according to the formula (I) has a combination of the following properties and qualities:

- bacteriostatic; - fungistaticity;

- osmotic activity;

- the ability to form complex compounds with salts of heavy metals;

- the ability to catalytic decomposition of phosphorus, chlorine, sulfur containing organic compounds;

- the ability to optimize reparative processes;

- It is a harmless, low-toxic composition, does not have an allergenic, irritating, mutagenic effect;

The auxiliary solution as such can be used as a protective, prophylactic, dermatoprotective agent, and can serve as the basis for the creation of pharmaceutical compositions

(FC), in which one of the properties is most pronounced. For this, the composition

FC can be additionally introduced substances of natural or synthetic origin, acting as a potentiator and increasing its effectiveness. For example, to increase antimicrobial activity to the auxiliary solution JSГ "1 add a potentiating agent, for example, bactericidal preparations, to the auxiliary solution N ° 2 - extracts of medicinal plants. To enhance the osmotic activity of JNs3 auxiliary solution, polyethylene oxides of various molecular weights used in the pharmacopeia are added. For stronger bonding of heavy metals, effective complexing agents (oxy compounds with a sufficiently high pK _α value) are introduced into the JN ° 4 auxiliary solution. To enhance the catalytic effect of the decomposition of chemicals, activators (polyhydric alcohols, glycerin, sorbitol, glucose, etc.) are introduced into the composition of auxiliary solution N ° 5 and optimize the viscosity of the medium; in order to impart hydrophobic properties to the pharmaceutical composition, silicones and polyfluorinated compounds are introduced. To maximize the manifestation of skin-regenerating properties, hyaluronic acid, ascorbic acid, and biological active additives can be added to any composition. Glycerin, mono- and diesters of glycols, sea buckthorn, mink and other oils, fats, waxes, surfactants, both ionic and nonionic, drugs can also be used as potentiators.

The following are specific examples of the invention.

The compositions of the pharmaceutical compositions (FC) are given in table.Z. Table 3

The composition of some pharmaceutical compositions

Example 1. Obtaining an auxiliary solution.

5.5 g of La (NO ₃ ) ₃ -6 H ₂ O are dissolved in 2 ml of water when heated, 45 g of triethylene glycol are added and stirred at a temperature of 40-50 ^° C until a clear, homogeneous solution is formed. A 50% aqueous solution of caustic soda (~ Ir) is slowly added to the resulting solution with vigorous stirring, the end of the addition is before the first jump according to the potentiometer. Get about 50 g of an auxiliary solution containing -10% of the complex compounds - La (NO ₃ ) ₂ (OH) -C ₆ H ₁₄ O ₄ .H ₂ O.

The data of IR spectroscopy prove the formation of the indicated complex compound: the absorption band at 415 cm ^"is observed on the spectrogram, which refers to La-O stretching vibrations; the bands at 670-680 cm ^{" 1} , which are characteristic for OH deformation vibrations in La-OH planes; in the region of 1730-1770 cm ^"1 , several bands appear confirming the existence of a bidendant nitrate ion. Using a salting out method, a complex compound of the indicated composition was isolated from the resulting solution. IR spectrum of the complex compound isolated from the auxiliary solution, RG spectrum of the solution after dissolving of the complex compound in triethylene glycol and the RJ spectrum of the auxiliary solution are identical. The structure of this complex is proved by X-ray diffraction analysis. Coordination polyhedron lan the tana is an irregular 16-faceted atom.The lanthanum atom coordinates 10 oxygen atoms: 4 from two bidendant nitrate ions; 4 from a triethylene glycol molecule; 1 from a hydroxo group; 1 from water.

Example 2. Obtaining the drug in the form of a solution (hereinafter - “Lantaderm solution”) 25 g of ethylcarbitol are poured into 75 g of the auxiliary solution (obtained from the recipe of Example 1) and stirred at a temperature of 40-50 ⁰ C.

Example 3. Preparation of the preparation in the form of a gel (hereinafter referred to as “Lantaderm gel”) ~ 100 g of hydroxypropyl cellulose is added to 100 g of Lantaderm solution (obtained from the recipe of Example 2), intensively stirred at a temperature not exceeding 5O ⁰ C until formation homogeneous mass and cool.

Example 4. Obtaining the drug in the form of an ointment (hereinafter - “Lantaderm-ointment)

85 g of the Lantaderm-solution preparation (obtained from the recipe of Example 2) are heated to 4O ⁰ C, 15 g of PEO-4000 are added, stirred until complete dissolution and cooled with stirring.

Examples 5 to 11 illustrate the harmlessness of FC. They are not toxic, do not affect the indicators of the general condition of the body, do not have a sensitizing and mutagenic effect. Example 5. Assessment of acute toxicity

It was carried out on 4 types of laboratory animals with oral, intraperitoneal and cutaneous application. The results of toxicometry, presented in Table 4, allow us to attribute different forms of FA (solution, gel, ointment) to safe non-toxic substances for skin application.

Table 4 Acute toxicity of FC

Example 6. Chronic toxicity

In subacute and chronic experiments, we studied the effect of the drug “Lantaderm” (solution, gel, ointment) when applied to damaged skin. The back skin of experimental animals was scarified once a week. In the experiments of animals (rats, dogs), harmlessness was shown when applied over the skin for 30 days with the Lantaderm-solution and 90 days with the Lantaderm-oil and

"Lantaderm-gel." No negative effects were found on the functions of the cardiovascular and endocrine systems, the activity of the kidneys and liver, the hematopoiesis system, and the fluctuations in the weight coefficients of internal organs. Clinical and biochemical studies of blood and urine, anatomical and histological studies of the liver, spleen, kidneys, organs of the cardiovascular and nervous systems, respiratory and digestive systems showed that the drug does not cause any pathological changes.

In addition, in the chronic experiment, it was shown that all forms of the Lantaderm drug do not violate the physiological functions of the skin (water-lipid balance, gas and heat transfer, metabolism) and contribute to skin self-healing processes: The scarified skin of laboratory animals was completely restored within 3-5 days.

Example 7. Assessment of irritant action

Irritation of the skin of rabbits when applying FK-4, FK-6, FK-5 and the drug "Lantaderm" (solution, gel, ointment) for 10 days with an exposure of 6 hours is absent. Irritation of rabbits' eyes was characterized by short-term blindness of their eyes for (35 + 21) seconds, slight hyperimia passing through 1 - 4 hours, and in some cases - lacrimation. After 4 hours and the following days, no changes in the eyes were observed. Example 8. Allergenicity

The study of the possible allergenic effect of the Lantaderm drug (solution, ointment, gel) was carried out by the reaction of general anaphylaxis (guinea pigs), the reaction of immune complexes (guinea pigs), the indirect mast cell degranulation reaction (white rats), and the conjunctival test (guinea pigs). It is shown that the drug does not have allergenic properties. Example 9. Mutagenicity

The mutagenicity of the Lantaderm preparations (solution, gel, ointment) and FK-9 was studied by the method of accounting for chromosomal aberrations in a human whole blood culture. Found that the drug

Lantaderm (solution, gel, ointment) and FK-9 do not have a damaging cytogenetic effect on human blood cells in vitro.

Example 10. Tolerance. Tests of tolerability of the Lantaderm-solution in experiments on healthy volunteers (2 groups of 20 people) included clinical observation, examination of a dermatologist, studies of clinical blood and urine tests, blood biochemistry, determination prothrombin index and fibrinogen concentration in the blood, the study of detailed electrocoagulograms. The results showed that repeated application of the drug does not have a general and local toxic effect on humans, including the blood coagulation process.

Example 11. The effect on the skin

Studies of the effect of the drug “Lantaderm-solution” on the functional properties of the skin of volunteers showed that its repeated application to the skin does not adversely affect the skin’s natural protective functions and the buffer system, does not change the pH of the skin, positively affects microcirculation, the state of epidermal cell membranes , softens and moisturizes the skin, promotes the rapid healing of minor scratches, abrasions, scuffs, reduces pain, including insect bites.

Examples 12-18 show that FCs exhibit antimicrobial and fungicidal activity, have a fairly wide range of prophylactic effects, inactivate various classes of chemicals, protecting the skin from exposure to harmful substances.

Example 12. The study of the bactericidal and bacteriostatic properties of the drugs "Lantaderm" (solution, ointment) and FC-6 was carried out in relation to clinical strains of pathogenic staphylococcus, Escherichia coli and Pseudomonas aeruginosa, Proteus according to standard methods. The high bacteriostatic and bactericidal properties of “Lantaderm” preparations (solution, ointment) before a dilution of 1: 8 and FC-6 to a dilution of 1: 32 with respect to the gram-positive spore-forming bacillus Vasillus serius, the yeast fungus Sapdida albisaps, and pathogenic bacteria sem. Epterobastereasae, Starhulossossus aureus, Pseudomopas aeschipos.

Example 13. The study of microbial contamination of the hands was carried out on volunteers. The drug “Lantaderm-solution” was applied to the skin of the hands with a flow rate of 0.3-0.5 g / dm ^{2 of} the skin surface, the excess of the drug was removed with a paper towel in blotting movements. 6 hours after application of the drug, hygienic washings were carried out, in which the presence of microorganisms was determined. It was established that 6 hours after the start of the experiment, the skin surface remains sterile, no bacteria of the E. coli group and other microorganisms were found in hygienic washings. According to the subjective assessment of the subjects, the drug "Lantaderm-solution" has a softening effect.

Example 14. The study of the fungistaticity of the preparations “Landerderm-gel”, “Lantaderm-oil” and FC-5 was carried out according to standard methods for Fusarium solapi, Fusarium pivella, Vutrutis siperia,

Asrergillus piger, as well as in relation to pathogenic fungi that cause fungal skin diseases: corynebacteria, Malassesia

Furfiir, Trishorhutop rubrum, yeast-like genus Sapdida. Comparison drug was Lamisin, widely used to treat fungal diseases. The data obtained indicate a high fungistaticity of pharmaceutical compositions based on complex compounds of the general formula (I), which are not inferior in their effectiveness and, in some cases, superior to the reference drug.

Example 15. Complexation with salts of heavy metals. The drug “Lantaderm-solution”, FK-4, FK-9 contain up to 85% (total) acidic solvents (triethylene glycol, ethylcarbitol, glycerin, propylene glycol, tetraethylene glycol), which have quite a lot of active centers (oxygen atoms with lone electron pairs) and are able to enter into a complexation reaction with salts of heavy metals. According to IR and UV spectroscopy, when the aqueous solutions of nickel, chromium, cobalt and lead salts are added to the PC, the absorption bands shift in the spectra. The study of the IR and UV spectra of specially prepared complex compounds of nickel, chromium, cobalt, lead, triethylene glycol, propylene glycol, tetraethylene glycol nitrates, and a comparison of the characteristic absorption frequencies of these spectra with the spectra of solutions of these heavy metal salts in the FC prove the formation of chelate complex compounds. Thus, the solvents in the FC in relation to salts of heavy metals perform the function of inactivation. The development of occupational skin diseases when working with heavy metals is associated with the ability of the latter to interact with amino acids and skin proteins. When applying FA in advance to the skin, heavy metals are bound into complexes, which prevents their interaction with amino acids and skin proteins and thereby ensures the prevention of skin diseases.

Experiments on the prevention of heavy metal poisoning through the skin were performed on guinea pigs. In the control group, a toxicant was applied to the clipped area of the skin of laboratory animals; after an hour of exposure, the area was washed with water. In the experimental group, the skin of laboratory animals was pretreated with FC, a toxicant was applied, after 1 hour, washed off with water and treated with FC. The results are presented in table. 5. Table 5

Heavy Metal Poisoning Prevention

Example 16

Skin protection from fats, oils, petroleum products, hydrophobic organic solvents, hydrocarbons. The indicated classes of chemical compounds are fat soluble. They disrupt the water-lipid balance of the skin, "washing out" lipids from the epidermis, easily penetrate the skin and can cause a number of pathological processes in the skin. The composition of the FC includes hydrophilic solvents that are not miscible with fat-soluble substances. Thus, the preliminary application of Lantaderm preparations to the skin increases the lyophilicity of the skin, prevents direct contact of hydrophobic substances with the skin and significantly reduces their negative impact. Application of Lantaderm preparations to the skin after removal of the exogenous substance promotes skin self-healing processes and ensures the prevention of skin diseases.

In experiments on laboratory animals (white mice), data were obtained that testify to the positive effect of the Lantaderm solution in protecting the skin from the effects of petroleum products and preventing skin diseases. In the experimental group of laboratory animals, they were treated with Lantaderm-solution at the rate of 1 g / dm ² , gasoline or oil were applied, which were removed with alcohol after 4 hours of exposure, and then Lantaderm-solution was again applied in the same dose. In the control group, gasoline and oil was applied to unprotected skin for 4 hours. During the experiment (30 days) in the control group, the development of dryness, keratosis, and an inflammatory reaction were observed in animals. In individual animals, baldness, turning into persistent hyperemia, the appearance of cracks, crusts, was noted. The animals of the experimental group looked neat, visually the skin was without significant changes. The slight hyperemia that occurs after a 4-hour exposure completely disappeared within 1-2 hours after removal of the stimulus. According to the results of morphological and histological studies conducted after the end of the experiment, the skin of animals of the experimental group without significant changes. Example 17

Inactivation of organophosphorus compounds. The skin-resorptive toxicity of organophosphorus compounds (including insecticides) for warm-blooded animals varies widely. An important property of substances of this group is the cumulative effect. Therefore, even substances with sufficiently low toxicity (for example, isopropylurethane phosphoric acid dimethyl ether, LD _5O more than 5000 mg / kg for white mice) can cause severe poisoning. One of the most characteristic manifestations of the biological effect of organophosphorus compounds is the inactivation of blood cholinesterase.

By experiments on white rats, it was found that the Lantaderm solution applied to the skin of laboratory animals (at a dose of 120 mg / cm) increases the activity of acetylcholinesterase around the hair follicles and in the epidermis. The effectiveness of the protective properties of the drug "Lantaderm-solution" in relation to esters of dithiophosphoric acid - phosphamide and anti, widely used in as pesticides, determined on white rats (infection area - 10 cm ² ; drug consumption - 1.0 g / dm ² ). The resulting protection coefficient is 4.8 and 5.2 for phosphamide and anti, respectively. The protection coefficient (K ₃ ) was calculated from the ratio of LD ₅₀ values in experiments on animals whose skin was pretreated with the drug and LD _5O when skin-resorptive exposure to unprotected animal skin: K ₃ = LD _5O (protected skin) / LD ₅ O (unprotected skin).

Example 18. Protection of the skin from aqueous solutions of acids and alkalis. Lantaderm preparations (solution, gel, ointment) are a buffer system with a neutral value of the conditional pH. 10 ml of the Lantaderm-solution preparation completely neutralizes ~ 15 g of a 10% aqueous solution of caustic soda and ~ 18 g of a 10% aqueous solution of sulfuric acid, while the conditional pH of the preparation remains almost constant. Thus, preliminary application of the drug to the skin due to the neutralization reaction provides effective prevention of chemical burns in case of accidental contact with drops of caustic alkalis and strong acids.

Examples 19-21 indicate the ability of FCs to optimize skin self-healing processes and confirm efficacy in the treatment of chemical burns, professional contact dermatitis of an allergic and non-allergic form, damage to the skin and soft tissues.

Example 19. The skin is the only self-healing organ. A special mechanism for self-healing and reorganization is activated immediately after any damage. Depending on the exposure factor, the response of the body is, first of all, a change in the condition of the skin, expressed in the form of inflammation and aimed at reducing the degree of this effect. Inflammation of the skin occurs as a result of damage to its tissues by a wide variety of agents: mechanical (injuries, bruises, injuries), physical (burns, frostbite, irradiation), chemical (damage by strong acids, alkalis, ADHD, toxic chemicals, surface-active substances), biological ( the introduction of bacteria, fungi, viruses). In case of overcoming the higher threshold of resistance, local or generalized skin damage develops. Therefore, one of the main tasks of a topical pharmaceutical product is to create optimal conditions for the manifestation of the regenerative abilities of tissues and the body as a whole.

Optimization of skin self-healing processes is considered on the example of damage to the skin by toxic chemicals (dichlorodiethyl sulfide, chlorovinyl dichlorarsin), which have a skin-invasive effect. The experiments were carried out on rabbits. The toxicant was applied to a clipped area of the skin with an infection density of 1 g / m ² (droplet mass 1 mg), exposure to the toxicant was 4 hours. The developed skin lesion is characterized by extensive exudative edema with a funnel-shaped depression and molten tissues (necrosis) at the sites of application of the drops of the toxicant. After the developed skin lesion in the first group of animals, they were treated with the Lantaderm-Maz drug in a dose of 0.5 g / dm ² (4 hours after the toxicant was applied, then 1 time per day for 10 days); in the second group of animals - the preparation of the prototype [9] at a dose of 0.5 g / dm ² (4 hours after application of the toxicant, further 1 time per day for 10 days); in the third (control) group - without treatment.

The first group. On the second day, the edema is insignificant, localized in places where the toxicant was applied, there is no redness of the skin. After 5 days, the condition of the skin significantly improved: the thickness of the skin fold began to approach normal, hyperemia and swelling of the skin were not observed, in the places where the toxicant was applied, there was a soft scab under which growing granulations are visible. After 7-10 days, the skin is completely restored. The second group. On the second day, edema decreased significantly.

Areas of damaged skin (at the places where the toxicant is applied) are slightly hyperemic. You can fold the skin with your fingers. In places where the toxicant was applied, swelling of small follicles was observed. On the 5th day, the appearance of single crusts was recorded in places where the toxicant was applied. Full restoration of the skin - after 10-15 days.

The third group (control). In the first three days after exposure to a toxicant, a maximum level of damage develops, which is characterized by ulceration and areas of necrosis that capture the deep layers of the skin. In places where the toxicant drops are applied, there are coarse crusts, in some cases intense melting of skin tissues. On day 5, ulcers with purulent hemorrhagic effusion formed on the skin of animals.

Example 20. The treatment of chemical burns with the drug "Lantaderm-maz" and FC-8. The experiments were carried out on white rats. The first group - a chemical burn of 3 degrees when exposed to concentrated sulfuric acid; treatment under dressings with the drug "Lantaderm-maz"; dressing change 1 time per day. The second group - a chemical burn of 2 degrees with exposure to 50% aqueous sodium hydroxide solution; treatment under dressings FK-8; dressing change 1 time per day. The third group (control) - treatment of a chemical burn of the 2nd degree under dressings with the drug Dermazin, traditionally used to treat burns. In all three groups, before applying dressings, the skin of the animals was treated with a 2% aqueous solution of soda (when exposed to sulfuric acid) or a 2% aqueous solution of boric acid (when exposed to alkali), and then with water. The objectivity of the research results was achieved identical for all animals, the conditions of their maintenance, treatment, as well as a unified methodology for evaluating the data obtained and the histological monitoring of the healing process. The data are presented in tables 6, 7.

Table 6 The terms of healing of burn wounds in rats (day)

Table 7

The percentage of fully epithelialized wounds

From tables 6 and 7 it is seen that the therapeutic effectiveness of the tested drugs in terms of complete healing of chemical burns exceeds the comparison drug. The results were confirmed by pathomorphological data. In addition, seeding of wound surfaces was sown on blood agar, Chistovich medium, Saburo, Endo and meat and peptone agar, and staphylococci and grams of negative rods were detected. The results are summarized in table 8, where the following notation is used:

+++ - continuous growth, ++ - growth within 100 colonies, + - growth of single colonies, - lack of growth.

Table 8 Microbial contamination of a burn wound

Example 21. Prevention and treatment of contact dermatitis. A big problem is professional contact dermatitis that occurs when direct contact with aggressive chemicals (solutions of salts of acids and alkalis, gasoline and organic solvents, fuels and lubricants, cement, detergents and cleaners, etc.). As a rule, with contact dermatitis, the hands and forearms are affected, as are most often exposed to damaging factors. The effectiveness of the treatment of professional contact dermatitis is considered on the example of contact latex dermatitis (allergic and non-allergic forms) when using the drug “Lantadermaz”.

56 patients aged 23 to 65 years were treated (45 men and 11 women). Of these, 27 patients with contact allergic dermatitis (including 8 people with atopic status), 29 patients with simple non-allergic contact dermatitis. It was shown that the use of the drug increases the average rate of regression of skin manifestations (from the moment of skin manifestation to its complete disappearance) by 2.5 times. The treatment results were evaluated according to a standard method using the following criteria: clinical cure, significant improvement and slight improvement, as well as the dynamics of clinical symptoms (dry skin, itching, erythema, swelling, skin rashes). The data obtained, presented in tables 9 and 10, indicate that the drug "Lantaderm-maz" is an effective drug for the treatment of contact latex dermatitis. In addition, the experience of using the drug “Lantaderm-maz” showed the feasibility of its use for the prevention of possible relapses. Table 9

The dynamics of clinical symptoms on the background of treatment with the drug "Lantaderm-maz" of medical personnel in contact with latex gloves (n = 56)

Table 10

Evaluation of the effectiveness of the drug “Lantaderm-maz” in the treatment of patients in contact with latex gloves (n = 56)

Example 22. The effectiveness of the drug in the treatment of damage to the skin and soft tissues. “Lantaderm” preparations (solution, ointment) were used in high altitude conditions (1800-3200 m above sea level), where reparative processes are significantly reduced due to oxygen deficiency and wounds are infected. In the treatment of injuries to the skin and soft tissues of various sizes and depths (foot wear, abrasions, sunburns, chipped and cut wounds) marked a decrease in the healing time of wounds, the absence of infection and the manifestation of allergic reactions.

Thus, the above examples show that in all cases of the use of a pharmaceutical composition based on complexes of rare-earth compounds with polyoxy compounds according to the general formula (I) in the form of a liquid or soft dosage form, a pronounced protective, prophylactic, dermatoprotective and therapeutic effect, as well as the absence of reactions, good tolerance and quick healing of a skin defect.

Claims

Claim

1. A therapeutic and prophylactic dermatological composition for topical application, containing the active principle in the form of complex compounds of rare earth salts and a pharmaceutically acceptable carrier, characterized in that it contains an effective amount of a complex compound of rare earth salts of the general formula (1)

Ln (X ₁ ) (Xz) ₂ (L) _p . m H ₂ O where: Ln - denotes the cation of the rare-earth element of the cerium subgroup, which includes lanthanum, cerium, praseodymium, neodymium, or mixtures thereof; X ₁ - denotes the remainder of the compounds having basic properties selected from the group: —OH, —O — Si. _b- alkyl, -amine of the formula NHR ₂ where R ₂ represents hydrogen or C |. ₄ alkoxy group; X ₂ is nitrate or chloride; L - denotes a ligand of the complex compounds

{RO [(CHR,) m ₂ O] In ₁ R} _p in which R - is H, Cj.s alkyl, linear or branched Ri - is H, methyl, ethyl, propyl or isopropyl, fields - (- CH2- CH2-OH) mi - is an integer equal to 1 or 2, m ₂ - is an integer equal to 1, 2 or 3, p - is an integer equal to 1 or 2, m - is an integer equal to 1, 2 or 3 however, an effective amount is from 3 to 8 percent of the total weight of the composition, depending on the degree and nature of the lesion, age, gender and weight of the patient.

2. The therapeutic and dermatological composition according to claim 1, characterized in that the ligand of the complex compound is selected from the group consisting of triethylene glycol, propylene glycol, ethyl carbitol, 1,3-butylene glycol, polypropylene glycol, polyethylene glycol or mixtures thereof.

3. The therapeutic and dermatological composition according to claim 1 or claim 2, wherein said pharmaceutically acceptable carrier is selected from the group consisting of glycerol, triethylene glycol, diethylene glycol mono- and diesters, polypropylene glycol, polyethylene glycol, hydroxypropyl cellulose or mixtures thereof.

4. The therapeutic and prophylactic dermatological composition according to claim 1 or claim 2, characterized in that it further comprises an effective amount of a potentiator of natural or synthetic origin from the group: urotropin, miramistin, plant extract, while the effective amount is from 0.5 up to 1 percent of the weight of the composition.

5. The therapeutic and prophylactic dermatological composition according to claim 4, characterized in that it contains, as a potentiating agent, miramistin in an amount of 0.5-1% by weight of the composition.

6. The therapeutic and prophylactic dermatological composition according to claim 1, characterized in that it is made in the form of a liquid dosage form, such as a solution, emulsion, or in the form of a soft dosage form, such as an ointment, gel, paste.