RU2683651C2 - Medicine for treatment of keraticonus and other degenerative diseases of cornea and pharmaceutical agents based thereon - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to the field of medicine, namely to ophthalmology, and is intended for the treatment of keratoconus and other degenerative diseases of the cornea. Drug for the treatment of keratoconus and other degenerative diseases of the cornea contains, as an active component, providing therapeutic crosslinking, an effective amount of a primary or secondary amine with functional groups in the form of a salt or as part of a transition metal complex compound or a mixture thereof.EFFECT: use of the invention allows to increase the effectiveness of the treatment of keratoconus and other degenerative diseases of the cornea by improving the nutrition of the cornea and increasing its elastic-strength characteristics.21 cl, 4 tbl, 15 ex

Description

Technical field

The invention relates to medicine, in particular to ophthalmology, and is intended for the treatment of degenerative diseases of the cornea, such as keratoconus and other keratectasias.

State of the art

Degenerative (dystrophic) diseases of the cornea are caused by a violation of metabolic processes and are characterized by a progressive violation of the tissue structure of the cornea and irreversible loss of vision.

One of the most common diseases resulting from dystrophy and destruction of the structure of the cornea is keratoconus, which is a non-inflammatory progressive ectasia of the central part of the cornea under normal intraocular pressure and is one of the serious ophthalmic diseases. The frequency of keratoconus in recent years has grown significantly and amounts to at least 1 per 1000 people (Yu.B. Slonimsky, A.Yu. Slonimsky. “Keratoconus. Modern ideas about the disease, management tactics, radical surgery.” Http: // www. sfe.ru/information/articles/keratokonus.html - [2]). It has now been established that one of the main causes of this pathology of the connective tissue of the cornea of the eye is a decrease in the level of collagen cross-linking (Harding JJ, Crabbe MJC "Cross-linking sites of corneal and sclera collagens and their relationship to keratoconus and degenerative myopia" // Ophtalmic Res., 1980, 12, 139-142 - [1]).

In addition to primary progressive keratoconus, malnutrition and destruction of corneal tissue occurs with keratectasia of a different origin, namely, with iatrogenic keratectasia after LASIK, as well as pellucidal marginal dystrophy and keratomalacia.

Targeted biomechanical studies have shown that the elastic-strength parameters and, in particular, the modulus of elasticity of the cornea with keratoconus are significantly lower than the corresponding indicators of the cornea of healthy eyes (Iomdina EN "Mechanical properties of human eye tissue. Modern problems of biomechanics, Publishing House Moscow State University, 2006, No. 11, 183-200 - [3]).

Recently, an effective method has been proposed for treating keratoconus that involves increasing the biomechanical stability of the cornea by increasing the cross-linking of collagen — cross-linking (Wollensak G, Spoerl E, Seiler T. “Riboflavin / ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus ". Am. J. Ophthal. Mol. 2003, 135, 620-627 - [4]). The cross-linking procedure involves irradiating the corneal stroma with a specific wavelength (365 nm) against the background of periodic installations of a photosensitizer - riboflavin.

The disadvantage of this intervention is the need for it in an outpatient operating room, as well as the need for instrumental removal of the epithelium (without de-epithelialization, riboflavin diffusion through the surface layer of the cornea does not occur), which leads to temporary disability of the patient and carries the risk of subsequent complications. In addition, with developed keratoconus, cross-linking is not shown, because due to the thinness of the cornea, ultraviolet radiation can penetrate beyond the corneal stroma and lead to the death of endothelial cells.

SUMMARY OF THE INVENTION

The objective of the invention is to create a medicinal product that helps to improve the nutrition of the cornea and increase its elastic strength characteristics. An additional objective is the development of a pharmaceutical preparation for strengthening the cornea when it is non-invasively introduced into the conjunctival cavity, for example, using conventional installations or in the form of an ophthalmic drug film (hereinafter - HLP). Another objective is the creation of a medicinal product, the main components of which would preferably be products of natural origin or obtained on the basis of such products and, accordingly, would be characterized by a minimal immune response of the body and a lower likelihood of side effects than the known analogues.

The technical result is to strengthen the corneal tissue and improve its nutrition in degenerative diseases of the cornea and, in particular, with keratoconus, by using the proposed drug.

The technical result is achieved through the creation and use of a medicinal product for the treatment of keratoconus and other degenerative diseases of the cornea, containing as an active component an effective amount of an amine with functional groups in the form of a salt or as part of a transition metal complex compound or a mixture thereof. The amine contained in the claimed drug with functional groups of various nature helps to strengthen the cornea of the eye and increase its biomechanical stability due to the effective cross-linking of collagen chains.

Used amines with functional groups (hereinafter also AFG) in accordance with the present invention comprise primary and / or secondary and / or tertiary amino groups, as well as guanidine and / or hydroxyl and / or aldehyde groups. All these functional groups, with the exception of tertiary amino groups, are potentially reactive and can participate in the processes of crosslinking of collagen molecules. Moreover, in the amine molecule with functional groups, which acts as a crosslinking agent, there should be at least two of them.

A special criterion in choosing these materials is their non-toxicity or minimal toxicity, so most of the compounds used are of natural origin.

In accordance with the present invention, amino alcohols, amino acids, derivatives of these amino acids, oligopeptides, polypeptides, polyamines, derivatives of 3-hydroxy-2-methylpyridine, amino saccharides or a mixture thereof can be used as amines with functional groups.

Synthetic primary amines containing two or more hydroxymethyl groups are used as amino alcohols, for example: 2-amino-2-methyl-1,3-propanediol, tris (hydroxymethyl) aminomethane or a mixture thereof.

As amino acids, known natural and synthetic amino acids are used that contain the main amino or guanidine groups, for example: 2,4-diaminobutanoic acid, ornithine (2,5-diaminopentanoic acid), lysine (2,6-diaminohexanoic acid), hydroxylisine (2 , 6-diamino-5-hydroxyhexanoic acid), 2,7-diaminoheptanoic acid, 2,8-diamino-octanoic acid, 2,9-diaminononanoic acid, 2,10-diaminodecanoic acid, 2,12-diaminododecanoic acid, arginine (2- amino-5-guanidinovaleric acid) or a mixture thereof. In this case, D-, L- (natural) optical isomers or their D, L-mixture (racemate) of these amino acids can be used.

As derivatives of the above amino acids, their lactams and esters (containing esterified amino acid carboxyl groups) are used.

The lactams used are the lactams of 2,4-diaminobutanoic acid, ornithine (2,5-diaminopentanoic acid), lysine (2,6-diaminohexanoic acid), hydroxylisine (2,6-diamino-5-hydroxyhexanoic acid), 2,7- diaminoheptanoic acid, 2,8-diamino-octanoic acid, 2,9-diaminononanoic acid, 2,10-diaminodecanoic acid, 2,12-diaminododecanoic acid or a mixture thereof. In this case, lactams of D-, L- (natural) optical isomers or their D, L-mixture (racemate) of these amino acids can be used.

Ethyl esters, propyl ether, isopropyl ether, tert-butyl ether, caprylic ether, undecyl ether, lauryl ether, myristyl ether, oleyl ether, stearyl ether, 1,2-propylene glycol ether are used as esters of the above amino acids. 1,3-butylene glycol ether, 1,4-butylene glycol ether, glycerol ether or a mixture thereof. In this case, lactams of D-, L- (natural) optical isomers or their D, L-mixture (racemate) of these amino acids can be used.

As oligopeptides, heteromeric oligopeptides are used having at least one L-ornithine, L-lysine or L-hydroxylisine unit, for example, dipeptides: L-alanine-L-lysine, L-arginine-L-lysine, L-valine -L-lysine, L-hydroxylisine-L-lysine, L-hydroxyproline-L-lysine, L-histidine-L-lysine, glycine-lysine, L-isoleucine-L-lysine, L-leucine-L-lysine, L -methionine-L-lysine, L-proline-L-lysine, L-serine-L-lysine, L-tyrosine-L-lysine, L-threonine-L-lysine, L-tryptophan-L-lysine, L-phenylalanine -L-lysine, L-cysteine-L-lysine or a mixture thereof, or tripeptides: L-alanine-L-histidine-L-lysine, L-arginine-L-histidine-L-lysine, L-Valine-L- Histidine-L-Lysine, L-Hydroxylysine-L-Histidine-L-Lysine, L-Hydroxyproline-L-Histidine-L-Lysine, L-Histidine-L-Histidine-L-Lysine, Glycine- L-histidine-L-lysine, L-isoleucine-L-histidine-L-lysine, L-leucine-L-histidine-L-lysine, L-lysine-L-histidine-L-lysine, L-methionine-L- histidine-L-lysine, L-proline-L-histidine-L-lysine, L-serine-L-histidine-L-lysine, L-tyrosine-L-histidine-L-lysine, L-threonine-L-histidine- L-lysine, L-tryptophan-L-histidine-L-lysine, L-phenylalanine-L-histidine-L-lysine, L-cysteine-L-histidine-L-lysine, or a mixture thereof.

As polypeptides, homomeric compounds derived from amino acids containing two amino groups are used: poly-L-ornithine, poly-L-lysine, poly-L-hydroxylisine, poly-L-arginine, or a mixture thereof. In this case, compounds having a molecular weight of from 300 (corresponding to a dimer) to 30,000 are used.

As polyamines, natural or modified natural compounds containing 2-4 basic amino groups or guanidine groups can be used, in particular:

- diamines or aminoguanidines: putrescine (1,4-diaminebutane), 2-hydroxyputrescine, cadaverine (1,5-pentamethylenediamine), agmatine [1- (4-aminobutyl) guanidine], 1,8-diamino octane, 1,12-diaminododecane 2,2 '- (ethylenedioxy) bis (ethylamine), 4,9-dioxa-1,12-dodecandiamine, 3,6,9-trioxa-1,11-undecandiamine, 4,7,10-trioxa-1, 13-tridecandiamine;

- spermidine and its derivatives: 1-methylspermidine, 2-methylspermidine, 3-methylspermidine, 8-methylspermidine, 1,1-dimethylspermidine, 2,2-dimethylspermidine, 3,3-dimethylspermidine, 5,5-dimethylspermidine, 5.8- dimethyl spermidine, 8,8-dimethyl spermidine, 2-hydroxy spermidine, homospermidine;

- spermine and its derivatives: spermine, 1-methylspermine, 6-methylspermine, 1,12-dimethylspermine, 5,8-dimethylspermine, 1,1,12,12-tetramethylspermine, 3,3,10,10-tetramethylspermine, norspermine, or a mixture thereof.

Natural compounds of various structures containing a basic tertiary amino group are used as derivatives of 3-hydroxy-2-methylpyridine, for example: pyridoxine, pyridoxine-5-phosphate, pyridoxal, pyridoxal-5-phosphate, pyridoxamine, pyridoxamine-5-phosphate or a mixture thereof.

As amino saccharides, natural compounds containing a basic primary amino group are used, for example: D-glucosamine (chitosamine) (2-amino-2-deoxy-B-glucose), D-galactosamine (chondrosamine) (2-amino-2-deoxy-D -galactose), D-mannosamine (2-amino-2-deoxy-D-mannose), D-fucosamine (2-amino-2,6-dideoxy-D-galactose), neuraminic acid (5-amino-3,5 -deoxy-D-glycero-D-galactononulosonic acid) or a mixture thereof.

The above oligopeptides and polypeptides, as well as polyamines, due to their high efficiency, can be used as a medicine in concentrations lower than the claimed concentration ranges given below for different types of pharmaceutical preparations. This concentration may be 0.05-0.3 wt.%. However, it is preferable to use them in combination with other APH, for example, with amino acids, so that the total concentration of both types of crosslinkers is in the claimed range.

AFGs incorporate basic amino groups and their aqueous solutions have an alkaline reaction. Therefore, their use is possible only in a neutralized form - in the form of a salt or complex compound with a transition metal cation. This kind of salt can be obtained by neutralizing an amine with functional groups with an acid.

As the acids for neutralizing APH in accordance with the present invention, low molecular weight acids of synthetic or natural origin are used, having one or more acid groups and forming non-toxic or low toxic salts, for example: inorganic - hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acid or organic acids - acetic, dichloroacetic, pivalic (trimethylacetic acid), glycolic, lactic, ascorbic, pelargonic, capric, undecyl, lauric, mi ristic, undecylenic, sorbic, succinic, fumaric, adipic, sebacic, azelaic acid, azelaic acid, malic, tartaric, citric acid, or glutaronic, or glutamic, or pyroglutamic, or aspartic, or ascorbic, or Valerian or Valerian undecylic, or lauric, or myristic, or undecylenic, or sorbic, or pyruvic acid, or succinic, or fumaric, or maleic, or adipic, or pimelic, or sebacic, or azelaic acid, or malic, or tartaric, or citric, nicotine (vitamin PP), salicylic, 2 - [(2,6-dichlorophenyl) amino] benzeneacetic (Diclofenac), gallic (3,4,5-trioxybenzoic acid), pantoenoic, pantothenic (vitamin B3), folic (vitamin B9), asiatic, madecassonic acid, or a mixture thereof.

Low molecular weight acids can also be used in partially neutralized form, which is obtained by neutralizing them with a base to a degree of neutralization of not more than 0.8. In this case, alkali and alkaline earth metal hydroxides (Na, K, Ca, Mg), amines: ammonia, primary, secondary, tertiary organic amines or mixtures thereof are used as the base.

In addition to low molecular weight acids, polymeric acids can be used to neutralize APH: polyacrylic acid, copolymers of acrylic acid, their partially neutralized salt or a mixture thereof, and methacrylic, maleic, itaconic acid, N-vinylpyrrolidone or a mixture thereof can be used as copolymers of acrylic acid.

These polymeric acids have a molecular weight of 300-5000000, preferably a relatively small molecular weight of 1000-30000. Due to such a relatively low molecular weight, these polymers easily penetrate the cornea through the epithelium, and are also easily excreted from the body.

On the other hand, in accordance with the present invention, crosslinked polyacrylic acid and its copolymers with C10-30 -alkyl acrylates (Carbopol®, Noveon, Inc.) or its partially neutralized form, which simultaneously act as a neutralizing agent for AFG and gelling agent, are used as the polymeric acid. Due to the crosslinked structure, it cannot fundamentally penetrate into the cornea through the multilayer epithelium and the anterior border membrane. At the same time, AFH immobilized in the form of cations on a polymer gel can be released as a result of hydrolysis, penetrate the cornea and have a corresponding strengthening effect.

Based on the used polymeric acids and organic amines containing two or more amino groups, with a stoichiometric ratio of the components or close to it, supramolecular systems, respectively, of a ladder or lattice structure, are obtained. Sustained action can be expected from ordered systems due to the multicenter binding of polyamines and the reduced diffusion mobility of this supramolecular system as a whole.

It is known that metals such as zinc, copper, iron take part in the metabolism of connective tissue, in particular, in the process of formation of stabilizing cross-bonds in collagen fiber, as well as in the functioning of the antioxidant protective system of the body (see E.N. Iomdina. " Biomechanics of the scleral membrane of the eye in myopia: diagnosis of disorders and their experimental correction. "Diss. Doctor of Biological Sciences. M., 2000, 316 pp. - [5]). Therefore, the introduction into the drug of compounds of transition metals (copper and zinc) to solve the problem of strengthening corneal tissue is physiologically appropriate.

In addition, the presence of these metals in the composition of eye drops is also justified, since drugs - copper sulfate and zinc sulfate in the form of 0.25-1.0% solutions are used as an antiseptic and astringent for conjunctivitis, blepharitis, keratitis.

The best form of using these transition metals in accordance with the present invention is their use in immobilized form - in the form of complex compounds with amines used. These transition metal cations interact with basic amines, as well as amino acids, giving stable neutral complexes (coordination compounds) (see. “Coordination chemistry” Skopenko VV, Tsivadze A.Yu., Savransky L.I., Garnovsky A.D. M .: ICC "Akademkniga", 2007, 487 pp. - [6]).

As is known, in complex compounds, the central atom (complexing agent) binds one or more ligand molecules depending on the coordination number of the complexing agent and the ligand's identity (the number of functional groups in it - binding centers).

Amines with functional groups when interacting with transition metal cations usually act as bident ligands. At the same time, Cu ²⁺ and Zn ²⁺ cations have a coordination number of 4, therefore, when amines interact with functional groups, they form stable complex compounds with two molecules of these ligands. (see Conato C .; Contino A .; Maccarrone G .; Magr A .; Remelli M .; Tabb G. “Copper (II) complexes with 1-lysine and 1-omithine: is the side-chain involved in the coordination ? - A thermodynamic and spectroscopic study. "Thermochimica Acta, 362, No. 1, 2000, 13-23. - [7] ;. N.G. Furmanova, Zh.I. Berdalieva, T. S. Chernaya, V. F. Resnyansky, NK Shytyeva, KS Sulaymankulov. “Synthesis and crystalline structures of coordination compounds of pyridoxine with zinc and cadmium sulfates. Crystallography. 2009, 54, No. 2, 255-261- [8]).

These transition metals - cations CU ²⁺ and Zn ²⁺ are used in salts with the following anions: chloride, bromide, nitrate, sulfate, acetate, glycolate, lactate, or a mixture thereof.

All of the listed compounds AFG (crosslinking compounds) are varieties of the claimed medicinal product used to strengthen the cornea.

This technical solution provides for the use of a medicinal product in various dosage forms:

- in the form of an aqueous solution for instillations;

- in the form of an ophthalmic gel (differs from the solution in a higher concentration of gelling agent), laid for the lower eyelid;

- on polymeric carriers: as part of an ophthalmic medicinal film placed behind the lower eyelid, and therapeutic contact lenses placed on the surface of the cornea.

Receiving a drug

The claimed drug (compound AFG) can be obtained in an aqueous medium and used without isolation in the form of a solution. The drug can be obtained in an environment of ethanol or a mixture of water-ethanol, preferably in concentrated form, and can be used without isolation, for example, to obtain medicinal films or contact lenses.

The drug can be isolated after receiving in a dry form by removing the used solvents and then be used to prepare the appropriate solutions. It should also be noted that some AFH compounds are available as a reagent.

In addition, AFG compounds, when melted, can be processed together with the polymer binder into ophthalmic drug films, for example, by extrusion.

Medicines consisting of an APH salt are prepared by neutralizing the initial main AFG with an appropriate acid taken in stoichiometric amount or close to it, which is determined by the required final pH value. Since the acids used to neutralize the APH in accordance with the present invention are mostly weak, they must be used in amounts greater than stoichiometric in order to achieve neutral pH values. The reaction of the production of the AFG salt is carried out in distilled water, isotonic solution, ethanol, or a mixture thereof.

A similar composition can also be obtained by dissolving in an aqueous medium an existing (previously obtained) amine salt with functional groups and an acid, usually strong, for example, a related hydrochloride. In this case, the pH can be adjusted to the desired value by adding appropriate amounts of a base, preferably an amine, for example, Tris (hydroxymethyl) aminomethane, L-lysine or pyridoxine.

To neutralize AFG compounds, low molecular weight and polymeric acids are used. In addition to polyacrylic acid itself or copolymers of acrylic acid or crosslinked polyacrylic acid and its copolymers with C10-30 alkyl acrylates, their partially neutralized form or a mixture thereof is used.

A partially neutralized form of polymeric acids is obtained by neutralizing a polymeric acid with a base to a degree of neutralization of not more than 0.7. In this case, alkali metal hydroxides (Na, K), amines: ammonia, primary, secondary, tertiary amines or mixtures thereof are used as the base.

As you know, the pH value has a great influence on the comfort of eye drops. Most eye drops have a pH in the range of 5.0-9.0. At pH values> 9 and <5.0, eye drops cause a negative reaction when instilled (severe lacrimation and burning sensation).

The inventive drug intended to strengthen the cornea should have a pH of 5.5-8.0, preferably 7.0-7.4.

Medicines based on the transition metal complex compound are prepared by reacting AFH with a salt of the corresponding transition metal (Cu ²⁺ or Zn ²⁺ ) taken in stoichiometric amounts or close to it, which is determined by the required final pH value. The reaction is carried out in an aqueous medium or ethanol. A similar composition can also be obtained by dissolving in an aqueous medium an existing (previously obtained) complex compound based on AFH and the corresponding transition metal salt.

An aqueous solution of the drug may be prepared based on distilled water, an isotonic solution, or a mixture thereof.

As the isotonic solution, physiological (0.9 wt.% NaCl), balanced physiological saline BBS (Hanks solution) or aqueous solutions of nonionic compounds such as glycerin, sorbitol, mannitol, propylene glycol or dextrose are used, the concentration of which, preferably, is not more than 5 the weight.%. When receiving in distilled water a solution of an AFG compound with a concentration lower than isotonic, it is desirable to isotonize it by introducing an appropriate amount of an isotonic additive (in dry form).

A polymer gelling agent, usually neutral, can be introduced into the drug, or it can be used initially as the aqueous medium in the preparation of the solution or introduced into the concentrated aqueous solution of the drug in a concentrated form.

A method of producing a gelling agent based on crosslinked polyacrylic acid and its copolymers with C10-30 alkyl acrylates having an acidic reaction involves the preliminary dispersion of these polymeric acids in water with stirring and the subsequent neutralization with a base, which is used as alkali metal hydroxides (Na, K) or amines: ammonia, primary, secondary, tertiary amines, including APH, or mixtures thereof.

Pharmaceutical preparations for the treatment of keratoconus and other degenerative diseases of the cornea based on the drug.

Within the framework of this application, several pharmaceutical preparations are also claimed based on the drug described above.

Solution for instillation

A pharmaceutical preparation in the form of an aqueous solution based on the claimed medicinal product can be obtained on the basis of distilled water, isotonic solution or a mixture thereof.

As an isotonic solution, physiological (0.9 wt.% NaCl), balanced physiological saline BBS (Hanks solution) or aqueous solutions of nonionic compounds such as glycerin, sorbitol, mannitol, propylene glycol or dextrose are used. When a drug solution is obtained in distilled water with a concentration lower than isotonic, it is desirable to isotonize it by introducing an appropriate amount of an isotonic additive (in dry form).

In accordance with this technical solution, the concentration of the drug in the solution for strengthening the cornea is preferably 0.10-7.0 wt.%. At high concentrations, unwanted side effects, such as irritation of adjacent tissues, are possible. At lower concentrations, the effect of using the drug is negligible.

To prolong the action, the claimed preparation in the form of a solution may contain a polymeric gelling agent: hyaluronic acid, chondroitin sulfate, polyvinyl alcohol, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl guar, or polyethylene glycol-polypropylene glycol-polyethylene glycol®8, P8, P8, P8, P8, P8, P8, P8, P8 and F127), BASF, Na-carboxymethyl cellulose, salts of crosslinked polyacrylic acid and its copolymers with C10-30 alkyl acrylates (Carbopol®, Noveon, Inc.).

The content of the gelling agent is 0.1-25.0 wt.%. Such a wide range of concentrations makes it possible to obtain pharmaceutical preparations with various properties. So, the drug for the treatment of keratoconus with a low content of gelling agent (see table 1) can be used in the form of eye drops, and with a large (see table 2) - in the form of an eye gel with a prolonged action. It should be noted that the viscosity of the aqueous solution is determined not only by the content of the gelling agent in it, but also by the nature and molecular weight of the latter.

Aqueous solutions of polyethylene glycol-polypropylene glycol-polyethylene glycol block copolymers Kolliphor® P237, P338, P407, used as a gelling agent, at concentrations of 16-25 wt.% At a temperature close to body temperature, become much more viscous (reversible thermal cure), which provides the effect of additional prolongation with the introduction.

In the solution intended for use in the form of eye drops, preservatives and other additional ingredients may be added after the introduction of the main components.

Table 1 The composition of the pharmaceutical preparation in the form of an aqueous solution to strengthen the cornea Component Content, wt.% drug (compound AFG) 0.10-7.0 gelling agent 0-5.0 isotonic substance 0-5.0 preservative and auxiliary components 0-0.3 distilled water rest

table 2 The composition of the pharmaceutical preparation in the form of an eye gel for strengthening the cornea Component Content, wt.% drug (compound AFG) 0.10-7.0 gelling agent 2.0-25.0 isotonic substance 0-5.0 preservative and auxiliary components 0-0.3 distilled water rest

The use of the drug using polymer eye contact lenses

Medical contact lenses are widely used in the treatment of endothelial-epithelial corneal dystrophy, with a number of serious diseases such as long-term non-healing, recurring corneal erosion, corneal ulcers, and injuries caused by thermal and chemical burns. As a rule, highly hydrophilic (water content of more than 50%) soft contact lenses, usually having zero or weak degrees of optical power, are used as medical lenses. The high degree of hydration of the material of the soft contact lens provides high oxygen permeability. A medicinal substance is introduced into therapeutic contact lenses in the process of their production or enters in the process of preliminary saturation with this substance, for example, an antibiotic immediately before use.

In the same way, a pharmaceutical preparation in the form of contact lenses intended to strengthen the cornea in the treatment of keratoconus can be obtained. For this, the drug should be introduced into the composition of contact lenses either once in the process of their preparation or each time before use when holding contact lenses in aqueous solutions of the drug.

In particular, to saturate the active compound, hydrophilic contact lenses are placed in aqueous solutions of the drug. Exposure in these solutions is carried out under normal conditions for 2-10 hours. After that, therapeutic contact lenses containing a sorbed drug as an active compound can be used to treat keratoconus.

The use of the drug using polymer eye drug films

The use of pharmaceutical preparations in the form of ophthalmic medicinal films, as is known, increases the effectiveness of their use and, at the same time, reduces irritating or toxic effects on the eye, because, gradually released from the films, the drug enters the conjunctiva and cornea for a long time and evenly, and its amount diverted to the nose with tear fluid is small.

Important qualities of HFL are also stability, which allows them to be stored for up to two years, high sterility and low risk of infection, the convenience of being packed into the conjunctival sac by both medical personnel and the patient himself.

The following specific requirements are imposed on polymer carriers for ophthalmic medicinal films with various types of therapeutic activity:

- polymers should quickly swell in the lacrimal fluid immediately after placing it in the conjunctival cavity in order to reduce the traumatic effect on the surrounding tissue;

- polymers should completely dissolve in the tear fluid with the formation of viscous solutions that can envelop the tissues of the eye and remain for a long time on their surface;

- polymers must bind the drugs used for a long time, providing a prolonged therapeutic effect.

In the present invention, the claimed drug may be included in the composition of the eye films. Its content in drug films is preferably 5-50% by weight (table 3).

In this technical solution, various synthetic and natural polymers are used as a polymer binder for the preparation: polyacrylamide and its copolymers, polyvinylpyrrolidone and its copolymers, polyvinyl alcohol, Na-carboxymethyl cellulose, hydroxypropyl cellulose, sodium alginate, chitosan.

Table 3. The composition of the pharmaceutical preparation in the form of SOD for strengthening the cornea Component Content, wt.% drug (compound AFG) 5.0-50.0 plasticizer and auxiliary components 1.0-10.0 polymer carrier rest

To obtain the drug in the form of HFL, a joint solution is prepared on the basis of the drug described above and a polymer carrier in an aqueous, aqueous-alcoholic or alcoholic medium. Additionally, plasticizer and auxiliary components (for example, surfactants) can also be added to this solution. After that, the resulting homogeneous solution of the components is poured onto a substrate and dried. Films of the required shape and size are cut out or cut out of the formed polymer tape.

The drug in the form of SOD can also be prepared by co-extrusion processing of the claimed drug and a polymer binder.

When used, a pharmaceutical preparation in the form of HFL containing the drug is placed in the conjunctival sac and, wetted with tear fluid and swelling, passes into an elastic mild state and is retained in the lower conjunctival arch until it is completely dissolved.

Examples of the use of the claimed pharmaceutical preparations

To strengthen the cornea using instillations, the drug was injected daily into the conjunctival sac of the left eye of Chinchilla rabbits, the right intact eye served as a control. The course of treatment consisted of daily instillations 2 times a day, 1-2 drops for 1 month. During this period and within 1 month after the end of the instillation course, the eye condition of the rabbits was monitored by biomicroscopy. No toxic or inflammatory events were found. At the end of the observation period, the eyes were enucleated and used to prepare corneal samples.

To strengthen the cornea with an eye gel, a gel substance weighing 20-25 mg daily for 1 month was put with a spatula for the lower eyelid of the left eye of Chinchilla rabbits, the right intact eye. During this period and within 1 month after the end of the course of treatment by biomicroscopy, the state of the eyes of rabbits was monitored. No toxic or inflammatory events were found. At the end of the observation period, the eyes were enucleated and used to prepare corneal samples.

To strengthen the cornea using a medical contact lens, the lens itself was removed from the aqueous solution of the drug and daily for 6 hours for 1 month were placed on the cornea of the left eye of Chinchilla rabbits, the right intact eye. During this period and within 1 month after the end of the course of treatment by biomicroscopy, the state of the eyes of rabbits was monitored. No toxic or inflammatory events were found. At the end of the observation period, the eyes were enucleated and used to prepare corneal samples.

To strengthen the cornea using an ophthalmic drug film, various types of films weighing 15 mg were laid daily for 1 month in the lower conjunctival arch of the left eye of Chinchilla rabbits, the right intact eye served as a control. During this period and within 1 month after the end of the course of treatment by biomicroscopy, the state of the eyes of rabbits was monitored. No toxic or inflammatory events were found. At the end of the observation period, the eyes were enucleated and used to prepare corneal samples.

Biomechanical indicators of the cornea of a mammal after application of the claimed drug

To determine the biomechanical parameters of the cornea (breaking load P (Н), tensile strength о (MPa), elongation at break ε (%) and elastic modulus E (MPa), standard samples 4 were cut out of these fabrics using a special knife with two cutting surfaces , 0 mm. After measuring their thickness on a PosiTector 6000 apparatus from DeFelsko (USA), the samples were placed in the clamps of an Autograph AGS-H deformation machine from Shimadzu (Japan) and mechanical tests were carried out. ck Height of 1 mm / min) until rupture is continuously recorded in a computer apparatus and a digital unit graphic mode.

Data biomechanical tests of the cornea are shown in table 4.

Table 4 Mechanical tests of rabbit cornea after administration of pharmaceuticals No.exper The concentration of the compound AFG, wt.% Mechanical indicators of the cornea after treatment The ratio of mechanical indicators after and before treatment P, N σ, MPa ε,% E, MPa P / P _o σ / σ _o ε / ε _o E / E _o 1 ¹ 1,0 10.7 5.8 40.7 26.6 1.14 1.19 0.95 1.29 2 ¹ 3.3 8.7 7.0 39.7 19.7 1.20 1.34 0.70 1.55 3 ¹ 2.0 13.1 10.9 58.0 27.3 1.27 1.25 0.79 1.77 4 ¹ 0.5 7.8 8.7 43.0 25,2 1.18 1.26 0.59 1,62 5 ¹ 0.1 6.9 6.5 40.6 35.3 1.10 1.13 0.97 1.20 6 ¹ 6.0 5.2 4.3 47.0 19.5 1.39 1.46 0.57 2,32 7 ¹ 2.0 9.0 5.9 42.6 27.3 1.25 1.27 0.65 1.39 8 ¹ 4.0 13,4 11,2 45.0 33.5 1,59 1,60 0.86 1.86 9 ¹ 4.0 5.9 7.3 43,2 19.2 1.34 1.35 0.62 1.48 10 ¹ 2.0 8.7 8.8 46.5 25.5 1.20 1.24 0.73 1.33 11 ¹ 2.0 9.7 7.9 38,4 22.0 1.35 1.17 0.58 1.26 12 ² 1,0 6.7 7.2 35.9 26.8 1.28 1.25 0.65 1.30 13 ² 1,5 12.0 6.9 45.8 28.7 1.31 1.38 0.69 1.49 14 ³ 1,5 9.6 11.5 52.6 27.9 1.30 1.33 0.84 1.95 15 ⁴ 10.0 8.9 9.8 57.5 30.5 1.43 1.47 0.94 2.25 ¹ - aqueous solution ² - eye gel ³ - therapeutic contact lens ⁴ - HFR

As can be seen from the table, the biomechanical indicators of the cornea into which the claimed drug was introduced in the form of various drugs significantly exceed the corresponding indices of the intact cornea. Thus, an increase in the tensile strength σ / σo is 1.13-1.60 times, and an increase in the most important biomechanical criterion - the elastic modulus E / E _o for the cornea - 1.20-2.32 times. This indicates the high efficiency of the composition used to strengthen the connective tissue of the cornea.

At the same time, for the treatment of keratoconus and other degenerative diseases of the cornea, one can limit oneself to a less pronounced strengthening effect. In this case, the degree of increase in the elastic modulus can be reduced by decreasing the concentration of the introduced components within the claimed range or by reducing the number of instillations or the duration of the instillation course.

The alleged principle of cross-linking collagen when using the claimed drug and drugs based on it

It is known that collagen fibrils (fibers) are stabilized by a whole system of cross-linking (see BaileyA. J. "Intermediate labile intermolecular cross-links in collagen fibrils" // Biochim. Biophys. Acta. 1968. v.160, 447-453 [9 ]; and Bailey AJ, Paul RG, Knott L. “Mechanism of maturation and aging of collagen.” Mech. Ag. Dev. 1998, 106, 1-56 - [10]) and the formation of al -lysine (an aldehyde derivative of lysine) as a result of the deamination of the side chains of lysine or hydroxylisine under the action of the enzyme lysyl oxidase (a copper-containing enzyme in which pyr is a cofactor doksal). Then, spontaneously, without the participation of enzymes, a Schiff base is formed with a spatially approximated amino group of the lysine residue located in another polypeptide chain. The resulting bond -N = CH-, being itself unstable, can be restored to a stable saturated bond, turning into an extremely strong crosslinking - lysinonorleucin.

In this technical solution, as can be assumed, when AFG compounds having primary amino groups are introduced into the corneal tissue, at the first stage of the process, they react with aldehyde groups of al-lysine in adjacent peptide chains with the formation of the corresponding Schiff base with its subsequent restoration to a stable saturated structure.

At the second stage of the process, after covalent immobilization of APH, depending on the nature of the remaining functional groups in its molecule, the following reactions are possible in principle, leading to additional crosslinking of the fibrillar collagen structures of the cornea:

- amino alcohols: free hydroxyl-containing groups in their composition can react with aldehyde groups of al-lysine in neighboring collagen fibers to form acetal groups;

- amino acids, oligo - and polypeptides, as well as polyamines: free amino groups in the composition of these compounds can react with aldehyde groups of al-lysine in neighboring collagen fibers;

- derivatives of 3-hydroxy-2-methylpyridine contain at least two functional groups: aldehyde, primary amino group, alcohol groups that can directly react with the corresponding functional groups in adjacent collagen fibers.

- aminosaccharides: in reactive tautomerism, the aldose form, in contrast to the inert pyranose ring form, can react with amino groups in the side chains of lysine, hydroxylisine or arginine residues in collagen fibers. In addition, the participation of alcohol groups of these compounds in crosslinking processes is possible.

Thus, when using amines with functional groups, it can be assumed that the achieved effect of corneal strengthening is associated with a significant increase in the crosslink density of its constituent fibrillar collagen structures, despite the different nature of the functional groups of these crosslinking agents.

Indications for use of the claimed medicinal product and preparations based on it

Indications for use of the claimed medicinal product and preparations based on it for strengthening the cornea and improving its nutrition, obviously, practically coincide with those when using cross-linking. The main indication is primary progressive keratoconus. However, this method is also indicated for keratectasias of a different origin: with the progression of secondary keratoconus (iatrogenic keratectasia after LASIK), pellucid marginal dystrophy and keratomalization of a different genesis, as well as with other diseases of the cornea of a dystrophic nature. As an additional tool, it can be used for bullous keratopathy of the I-II stage, keratitis and corneal ulcers.

The main advantages of using the claimed technical solutions are:

- high efficiency of the process of strengthening the cornea, which significantly increases its mechanical stability;

- a combination of firming and anti-dystrophic effects on the structure of the cornea;

- Convenience and non-invasiveness of exposure - through conventional instillations, using an eye gel, an ophthalmic drug film and / or therapeutic contact lenses;

- the absence of toxic or inflammatory phenomena throughout the course of treatment.

Industrial applicability

Examples:

Example 1. 0.132 g (9.06 * 10 ^-4 mol) of D-lysine, Sigma in 10.0 ml of balanced physiological saline BBS solution are dissolved in a glass flask while stirring with a magnetic stir bar, and then solution 0 is added to the amine solution as a neutralizing agent. 0652 g (9.06 * 10 ^-4 mol) of polyacrylic acid ( _Mw 1800), Aldrich in 10.0 ml of distilled water and stirred for 15 minutes. Next, an additional amount of polyacrylic acid solution was used to adjust the pH to 7.4.

The prepared 1.0 wt% AFG salt solution is poured into 5 ml glass vials, which are autoclaved at 121 ° C (1.1 atm) for 10 minutes.

This composition was used to strengthen the cornea. To do this, it was introduced daily by instillation into the conjunctival sac of the left eye of the Chinchilla rabbit, the right intact eye served as a control. The course of treatment consisted of daily instillations 2 times a day, 1-2 drops for 1 month. During this period and within 1 month after the end of the instillation course, the eye condition of the rabbits was monitored by biomicroscopy. No toxic or inflammatory events were found. At the end of the observation period, the eyes were enucleated and used to prepare corneal samples.

Example 2. In a glass flask, while stirring with a magnetic stir bar, 2.13 g (1.61 * 10 ^-2 mol) of L-ornithine, Sigma are dissolved in 70.0 ml of distilled water, and then dissolved amine is neutralized with 1.03 g (0.537 * 10 ^-2 mol) of citric acid dissolved in 26.0 ml of distilled water. Next, an additional amount of sebacic acid solution was used to adjust the pH to 7.4. The prepared 3.3 wt% AFG salt solution is sterile filtered through a Durapore® membrane (PVDF), Millipore with 0.22 μm pores and, under sterile conditions, is poured into 5 ml glass vials.

This composition was used to strengthen the cornea by instillation according to the method described in example 1.

Example 3. In a glass flask with stirring with a magnetic stirrer, 0.803 g (0.554 * 10 ^-2 mol) of spermidine, Sigma are dissolved in 80.0 ml of distilled water, and then dissolved amine is neutralized with 1.195 g (1.66 * 10 ^-2 mol) of polyacrylic acid ( _Mw 1800), Aldrich dissolved in 18.0 ml of distilled water. Next, an additional amount of polyacrylic acid solution was used to adjust the pH to 7.4. The prepared 2.0 wt% AFG salt solution is sterile filtered through a 0.22 μm Millipore membrane and poured into 5 ml glass vials.

This composition was used to strengthen the cornea by instillation according to the method described in example 1.

Example 4. In a glass flask, while stirring with a magnetic stir bar, 0.437 g (2.17 * 10 ^-3 mol) of spermine, Sigma, are dissolved in 70.0 ml of balanced saline, and then 0.0633 g (4.34 *) are neutralized with the dissolved amine. 10 ^-3 mol) of adipic acid dissolved in 30.0 ml of balanced saline. Next, an additional amount of adipic acid solution was used to adjust the pH to 7.4. The prepared 0.5 wt% AFG salt solution is sterile filtered through a 0.22 μm Millipore membrane and poured into 5 ml glass vials.

This composition was used to strengthen the cornea by instillation according to the method described in example 1.

Example 5. In a glass flask, 0.10 g of pyridoxamine dihydrochloride, Fluka is dissolved in 100.0 ml of distilled water with stirring with a magnetic stir bar, after which a 5.0 wt.% Aqueous solution of tris (hydroxymethyl) aminomethane is added dropwise to pH 7. 2. The resulting 0.10 wt% AFH salt solution is sterile filtered through a 0.22 μm Millipore membrane and poured into 5 ml glass vials.

This composition was used to strengthen the cornea by instillation according to the method described in example 1.

Example 6. 4.20 g (2.54 * 10 ^-3 mol) of pyridoxine, Sigma in 60.0 ml of distilled water are dissolved in a glass flask with stirring with a magnetic stir bar, and then 1.78 g (2.54 * 10 ^-3 ) polyacrylic acid ( _Mw 1800), Aldrich, dissolved in 28.0 g of distilled water. Further, an additional amount of polyacrylic acid solution was used to adjust the pH to 7.4. The prepared 6.0 wt% AFG salt solution is sterile filtered through a 0.22 μm Millipore membrane and poured into 5 ml glass vials.

This composition was used to strengthen the cornea by instillation according to the method described in example 1.

Example 7. In a glass flask, 2.00 g of D-galactosamine hydrochloride, Sigma, with magnetic stirring, was dissolved in 98.0 ml of distilled water, after which a 50 wt.% Aqueous pyridoxine solution was added dropwise to pH 7.4. The resulting 2.0 wt% AFH salt solution is sterile filtered through a 0.22 μm Millipore membrane and poured into 5 ml glass vials.

This composition was used to strengthen the cornea by instillation according to the method described in example 1.

Example 8. In a glass flask, 2.74 g (1.88 * 10 ^-2 mol) of D, L-lysine, Sigma is dissolved in 80.0 ml of distilled water with magnetic stirring, and then 1.26 g is added to the resulting solution. . (0.94 * 10 ^-2 mol) CuCl ₂ dissolved in 16.0 ml of distilled water. The resulting 4.0 wt.% Solution of the APH complex compound having a pH of 6.8 is sterile filtered through a 0.22 μm Millipore membrane and poured into 5 ml glass vials.

This composition was used to strengthen the cornea by instillation according to the method described in example 1.

Example 9. In a glass flask, 3.49 g (1.62 * 10 ^-2 mol) of D-glucosamine hydrochloride, Sigma are dissolved in 60.0 ml of distilled water with magnetic stirring, and then 0 is added to the resulting solution over 5 minutes 65 g (1.62 * 10 ^-2 mol) of NaOH dissolved in 16 ml of distilled water, and then 1.09 g (0.812 * 10 ^-2 mol) of CuCl ₂ dissolved in 20 ml of distilled water are added to the resulting free amine . The obtained 4.0 wt.% Solution of the APH complex compound is sterile filtered through a 0.22 μm Millipore membrane and poured into 5 ml glass vials.

This composition was used to strengthen the cornea by instillation according to the method described in example 1.

Example 10. In a glass flask of 1.436 g (0.850 * 10 ^-2 mol) of pyridoxine, Sigma is dissolved in 80.0 ml of distilled water with stirring with a magnetic stir bar, and then 0.564 g (0.425 * 10 ^-2 mol) of CuCl is added to the resulting solution. ₂ dissolved in 19.0 ml of distilled water. The resulting 2.0 wt.% Solution of the APH complex compound was sterilely filtered through a 0.22 μm Millipore membrane and poured into 5 ml glass vials.

This composition was used to strengthen the cornea by instillation according to the method described in example 1.

Example 11. In a glass flask, 1.429 g (0.845 * 10 ^-2 mol) of pyridoxine, Sigma was dissolved in 80.0 ml of distilled water with stirring with a magnetic stir bar, and then 0.571 g (0.422 * 10 ^-2 mol) of ZnCl _{2 was} added to the resulting solution. dissolved in 18 ml of distilled water. The resulting 2.0 wt.% Solution of the APH complex compound was sterilely filtered through a 0.22 μm Millipore membrane and poured into 5 ml glass vials.

This composition was used to strengthen the cornea by instillation according to the method described in example 1.

Example 12. A gel based on a crosslinked copolymer of acrylic acid and C10-30 alkyl acrylates.

For preliminary preparation, a 0.5 wt.% Suspension of a polymeric acid (gelling agent) 0.80 g of a crosslinked copolymer of acrylic acid and C10-30 alkyl acrylates (Carbopol Ultrez 20, Noveon, Inc.) is added with vigorous stirring with a mechanical stirrer to 160 g of distilled water and stirred at room temperature for 15 minutes. To the resulting suspension, having a pH of 3.2, a solution of 0.96 g of Tris (hydroxymethyl) aminomethane, Sigma in 14 g of distilled water is added over 5 minutes. As a result of the neutralization reaction, the used polymer acid (gelling agent) gradually dissolves into a salt form, and after holding for 10 minutes, a 1.0 wt.% Transparent viscous gel having a pH of 6.8 is formed. The gel is then autoclaved at 121 ° C (1.1 atm) for 10 minutes. The resulting gel is used directly as an eye gel for the treatment of keratoconus.

Example 13. The gel obtained in accordance with example 12 is used as a gelling agent to prepare a composition additionally containing AFG - 0.875 g (0.5 wt.%) D-galactosamine hydrochloride, Sigma (total concentration of AFG - 1.5 weight. %), which is used as an eye gel for the treatment of keratoconus.

Example 14. Obtaining a pharmaceutical preparation in the form of therapeutic contact lenses.

A soft contact lens based on crosslinked acrylamide was made by a known method (see RF Patent 2104675, 95/98. “Method for producing a soft contact lens” / Korigodsky AR, Sanina NN, Scherbakov VV, Prokofieva L .P., Rozhdestvensky Yu.V. - [11]). A soft contact lens, stored in a balanced solution and having an equilibrium moisture content of 82.0 wt.%, Was placed in a 3.3 wt.% Aqueous solution of L-ornithine salt and citric acid (in accordance with Example 2) and was kept there for 12 hours. After that, she put on the cornea and was used to treat keratoconus.

Example 15. Obtaining a pharmaceutical preparation in the form of an ophthalmic drug film.

95.0 g of ethanol, 180 g of a copolymer of acrylamide, vinylpyrrolidone and alkyl acrylate (50/25/25) (reduced viscosity 1.53 dl / g, water) obtained by known method (see RF patent 2352589, 2007/2009. "Method for the production of bio-soluble polymers of acrylamide, vinyl pyrrolidone and alkyl acrylate" / Belykh SI, Davydov AB, Mikhailov SF, Khromov GL - [12 ]), 4.8 g of glycerol and 544.0 g of distilled water are added over 40 minutes. The temperature in the apparatus is maintained within the range of 50-60 ° C. After 2 hours, the solution was cooled to 25 ° C and 20.0 g of D-glucosamine hydrochloride, Sigma (10.0 wt.%) Was added to the apparatus. Stirring is continued for another 0.5 hours. Then the solution is applied in an even layer on a non-corrosive substrate and dried at a temperature of 40 ° C until a polymer tape or plate is formed, from which oval-shaped films with smooth edges of 9.0 * 4.5 * 0.35 mm in size are cut using a special stamp weighing 15 mg. After this, the films are laid out in individual packages and sterilized by the radiation method. The obtained GLP is used as a treatment for keratoconus, placed in the conjunctival sac.

Sources

1. Harding J.J., Crabbe M.J.C. "Cross-linking sites of corneal and sclera collagens and their relationship to keratoconus and degenerative myopia" // Ophthalmic Res., 1980, 12,139-142;

2. Slonimsky Yu.B., Slonimsky A.YU. “Keratoconus. Modern ideas about the disease, management of patients, radical surgery. " http://www.sfe.ru/information/articles/keratokonus.html;

3. Iomdina E.N. "Mechanical properties of the tissues of the human eye." Modern Problems of Biomechanics, Publishing House of Moscow State University, 2006, No. 11, 183-200;

4. Wollensak G, Spoeri E, Siller T. “Riboflavin / ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus”. Am J Ophthalmol. 2003, 135, 620-627;

5. Iomdina E.N. "Biomechanics of the scleral membrane of the eye with myopia: diagnosis of disorders and their experimental correction." Diss. Doct. biol. sciences. M., 2000, 316 p .;

6. “Coordination chemistry” Skopenko VV, Tsivadze A.Yu., Savransky L.I., Garnovsky A.D. M .: IKC "Akademkniga", 2007, 487 p .;

7. Conato C .; Contino A .; Maccarrone G. .; Magr A .; Remelli M .; Tabb G. “Copper (II) complexes with 1-lysine and 1-ornithine: is the side-chain involved in the coordination? “A thermodynamic and spectroscopic study.” Thermochimica Acta, 362, No. 1,2000, 13-23 .;

8. Furmanova NG, Berdalieva Zh.I., Chernaya TS, Resnyansky VF, Shytieva NK, Sulaymankulov KS “Synthesis and crystal structures of coordination compounds of pyridoxine with zinc and cadmium sulfates ". Crystallography. 2009, 54, No. 2, 255-261;

9. Bailey A. J. "Intermediate labile intermolecular cross-links in collagen fibrils" // Biochim. Biophys. Acta. 1968. v. 160, 447-453;

10. Bailey A. J., Paul R.G., Knott L. "Mechanism of maturation and ageing of collagen". Mech Ag. Dev. 1998, 106, 1-56;

11. RF patent 2104675, 95/98. "A method of obtaining a soft contact lens" / Korigodsky A.R., Sanina N.N., Scherbakov V.V., Prokofieva L.P., Rozhdestvensky Yu.V .;

12. RF patent 2352589, 2007/2009. “A method for producing bio-soluble polymers of acrylamide, vinylpyrrolidone and alkyl acrylate” / Belykh S.I., Davydov A.B., Mikhailov S.F., Khromov G.L.

Claims (21)

1. A medicine for the treatment of keratoconus and other degenerative diseases of the cornea, containing as an active component providing therapeutic crosslinking, an effective amount of a primary or secondary amine with functional groups in the form of a salt or as part of a transition metal complex compound or a mixture thereof. 2. The medicine according to claim 1, characterized in that amino alcohols, or amino acids, or derivatives of amino acids, or oligopeptides, or polypeptides, or polyamines, or amino saccharides or a mixture thereof are used as an amine with functional groups. 3. The drug according to p. 2, characterized in that as amino alcohols use 2-amino-2-methyl-1,3-propanediol or Tris (hydroxymethyl) aminomethane or a mixture thereof. 4. The drug according to claim 2, characterized in that the amino acids used are 2,4-diaminobutanoic acid or ornithine, or lysine, or hydroxylisine, or 2,7-diaminoheptanoic acid, or 2,8-diamino-octanoic acid, or 2 , 9-diaminononanoic acid, or 2,10-diaminodecanoic acid, or 2,12-diaminododecanoic acid, or arginine, or a mixture thereof. 5. The drug according to claim 4, characterized in that the D- or L-optical isomers of the amino acids or their D, L-mixture (racemate) are used as amino acids. 6. The drug according to p. 2, characterized in that the derivatives of amino acids use the lactam of one of the amino acids in paragraphs. 4 and 5 or a mixture of lactams of amino acids in paragraphs. 4 and 5. 7. The drug according to p. 2, characterized in that as the derivatives of amino acids use an ester of one of their amino acids in PP. 4 and 5 or a mixture of esters of amino acids in paragraphs. 4 and 5. 8. The medicine according to claim 7, characterized in that ethyl esters or propyl ether, or isopropyl ether, or tert-butyl ether, or caprylic ether, or undecyl ether, or lauryl ether, or myristyl ether are used as amino acid esters or oleyl ether or stearyl ether or 1,2-propylene glycol ether or 1,3-butylene glycol ether or 1,4-butylene glycol ether or glycerol ether or a mixture thereof. 9. The drug according to p. 2, characterized in that the oligopeptides use oligopeptides having at least one unit of L-ornithine or L-lysine, or L-hydroxylisine or a mixture thereof. 10. The drug according to claim 9, characterized in that one of the following dipeptides is used as oligopeptides: L-alanine-L-lysine, L-arginine-L-lysine, L-valine-L-lysine, L-hydroxylisine- L-lysine, L-hydroxyproline-L-lysine, L-histidine-L-lysine, glycine-L-lysine, L-isoleucine-L-lysine, L-leucine-L-lysine, L-methionine-L-lysine, L-proline-L-lysine, L-serine-L-lysine, L-tyrosine-L-lysine, L-threonine-L-lysine, L-tryptophan-L-lysine, L-phenylalanine-L-lysine, L- cysteine-L-lysine, or one of the following tripeptides: L-alanine-L-histidine-L-lysine, L-arginine-L-histidine-L-lysine, L-valine-L-histidine-L-lysine, L- hydro sylisin-L-histidine-L-lysine, L-hydroxyproline-L-histidine-L-lysine, L-histidine-L-histidine-L-lysine, glycine-L-histidine-L-lysine, L-isoleucine-L- histidine-L-lysine, L-leucine-L-histidine-L-lysine, L-methionine-L-histidine-L-lysine, L-proline-L-histidine-L-lysine, L-serine-L-histidine- L-lysine, L-tyrosine-L-histidine-L-lysine, L-threonine-L-histidine-L-lysine, L-tryptophan-L-histidine-L-lysine, L-phenylalanine-L-histidine-L- lysine, L-cysteine-L-histidine-L-lysine, or a mixture thereof. 11. The drug according to claim 2, characterized in that poly-L-ornithine or poly-L-lysine or L-hydroxylisine or a mixture thereof is used as polypeptides. 12. The drug according to p. 11, characterized in that the polypeptides having a molecular weight of 300-30000 are used. 13. The drug according to claim 2, characterized in that putrescine (1,4-diaminebutane) or 2-hydroxyputrescin, or cadaverine (1,5-pentamethylenediamine), or agmatine [1- (4-aminobutyl) are used as polyamines guanidine], or 1,8-diamino-octane, or 1,12-diaminododecane, or 2,2 '- (ethylenedioxy) bis (ethylamine), or 4,9-dioxa-1,12-dodecandiamine, or 3,6,9 -trioxa-1,11-undecandiamine, or 4,7,10-trioxa-1,13-tridecandiamine, or spermidine, or 1-methylspermidine, or 2-methylspermidine, or 3-methylspermidine, or 8-methylspermidine, or 1, 1-dimethylspermidine, or 2,2-dimethylspermidine, or 3, 3-dimethylspermidine, or 5,5-dimethylspermidine, or 5,8-dimethylspermidine, or 8,8-dimethylspermidine, or 2-hydroxy spermidine, or homospermidine, or spermine, or 1-methylspermine, or 6-methylspermine, or 1, 12-dimethylspermine, or 5.8-dimethylspermine, or 1,1,12,12-tetramethylspermine, or 3,3,10,10-tetramethylspermine, or norspermine, or a mixture thereof. 14. The medicine according to claim 2, characterized in that D-glucosamine (chitosamine, 2-amino-2-deoxy-D-glucose), or D-galactosamine (chondrosamine, 2-amino-2-deoxy) is used as amino saccharides -D-galactose), or D-mannosamine (2-amino-2-deoxy-D-mannose), or D-fucosamine (2-amino-2,6-dideoxy-D-galactose), or neuraminic acid (5- amino-3,5-deoxy-D-glycero-D-galactononulosonic acid) or a mixture thereof. 15. The drug according to claim 1, characterized in that the salt used is obtained by neutralizing an amine with functional groups with an acid. 16. The drug according to p. 15, characterized in that the acid used is low molecular weight or polymeric acid or mixtures thereof. 17. The drug according to p. 16, characterized in that the low molecular weight acid is hydrochloric or hydrobromic, or nitric, or sulfuric, or phosphoric, or acetic, or pivalic (trimethylacetic), or glycolic, or milk, or glutamic or aspartic acid, or ascorbic, or valerianic, or pelargonic, or capric, or undecyl, or lauric, or myristic, or undecylenic, or sorbic, or pyruvic acid, or succinic, or fumaric, or maleic adipic or pimelic acid, or sebacic acid, or azelaic acid, or malic or tartaric or citric acid, or a mixture thereof. 18. The drug according to p. 16, characterized in that the polymeric acid used is polyacrylic acid or acrylic acid copolymers, crosslinked polyacrylic acid and its copolymers with C10-30 alkyl acrylates, or a partially neutralized form thereof, or a mixture thereof. 19. The drug according to claim 18, characterized in that methacrylic or maleic or itaconic acid or N-vinylpyrrolidone or a mixture thereof is used as acrylic acid copolymers. 20. The drug according to p. 18, characterized in that the polymeric acids have a molecular weight of 300-5000000. 21. The drug according to claim 1, characterized in that the cation Cu ²⁺ and / or Zn ^{2+ is} used as a transition metal.