WO2014204357A2 - Drug for the treatment of keratoconus and other degenerative disorders of the cornea and pharmaceutical preparations on the basis thereof - Google Patents

Abstract

The invention relates to medicine, in particular to ophthalmology, and is intended for the treatment of degenerative disorders of the cornea such as keratoconus and other keratectasias. One of the aspects of the invention is a drug for the treatment of keratoconus and other degenerative diseases of the cornea, which drug comprises, as active ingredient, an effective quantity of amine with functional groups in salt form or in the composition of a complex compound of a transition metal or mixtures thereof. Other aspects of the present invention comprise pharmaceutical preparations in which said drug is used, namely: 1) a pharmaceutical preparation which comprises an aqueous solution of a drug intended for administration into the conjunctival sac by means of installation; 2) a pharmaceutical preparation in the form of an eye gel containing, in its composition, a drug intended for insertion behind the lower eyelid; 3) a pharmaceutical preparation in the form of a medicinal film which contains, in its composition, a drug intended for insertion behind the lower eyelid; 4) a pharmaceutical preparation in the form of medicinal contact lenses which contain, in their composition, a drug which is intended to be placed on the surface of the cornea.

Description

 A drug for the treatment of keratoconus and other degenerative diseases of the cornea and pharmaceutical preparations based on it

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 most 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: // wA ^ ov.sfe.ru/infomation/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 MJ C. "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, N ° l 1, 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 light used 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, in the form of an eye gel or 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 derived from such products and, accordingly, they 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, 3-hydroxy-2-methylpyridine derivatives, 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 the 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 B, L-mixture (racemate) of the indicated 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-, b- (natural) optical isomers or their B, L-mixture (racemate) of the indicated amino acids can be used.

 As the esters of the above amino acids, ethyl ether, 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, 1,3-butylene glycol ether, 1,4-butylene glycol ether, glycerol ether, or a mixture thereof. In this case, lactams of D-, b- (natural) optical isomers or their D, L-CMecb (racemate) of the indicated amino acids can be used.

Heteromeric oligopeptides having at least one L-ornithine, L-lysine or L- unit are used as oligopeptides. hydroxylysine, for example, dipeptides: L-alanine-L-lysine, L-arginine-L-lysine, L-valine-L-lysine, L-hydroxylysine-L-lysine, L-hydroxyproline-L-lysine, L-histidine- B-lysine, glycine-lysine, b-isoleucine-b-lysine, b-leucine-b-lysine, L-methionine-b-lysine, b-proline-b-lysine, b-serine-b-lysine, b- tyrosine-b-lysine, L-threonine-b-lysine, b-tryptophan-b-lysine, b-phenylalanine-b-lysine, b-cysteine-b-lysine, or a mixture thereof, or tripeptides: b-alanine-b- histidine-L-lysine, L-arginine-L-histidine-L-lysine, L-valine-L-histidine ^ -lysine, L-nifl oKcraH3HH-L-histididine-L-lysine, L-hydroxyciproline-L-histididine L-lysine, L-racTHflHH-L-histididine-L-l isine, glycine-L-histidine-L-lysine, L-isoleucine-L-histidine-L-lysine,

L-lysine-L-histididine-L-lysine, L-methionine ^ -hystidine ^ -lysine, L-π-proline-L-histidine-L-lysine, L-cepHH-L-histididine-L-lysine, L-tyrosine- L-histididine-L-lysine, L-TpeoHHH-L-racnmHH-L-lysine, L-τpiptofan-L-histididin-L-lysine, L-phenylalanine-L-histididin-L-lysine, L-UHCTeHH rHCTHflHH-L-nH3HH or a mixture thereof.

 As polypeptides, homomeric compounds obtained on the basis of amino acids containing two amino groups are used: poly ^ -orni in, poly-L-lysine, poly ^ -hydroxylisine, poly ^ -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-diaminbutane), 2-hydroxyputrescin, cadaverine (1,5-pentamethylenediamine), agmatine [1- (4-aminobutyl) guanidine], 1,8-diamino-octane, 1,12-diamino before dean, 2.2'-

(ethylenedioxy) bis (ethylamine), 4,9-dioxo-1, 12-dodecandiamine, 3,6,9-triox-

1,11-undecandiamine; 4,7; 10-trioxa-1,13-tridecandiamine;

-spe idin 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 - dimethylspermidine, 8,8-dimethylspermidine, 2-hydroxy spermidine, homospermidine; spermine and its derivatives: spermine, 1-methylspermine, 6-methylspermine, 1, 12-dimethylspermine, 5,8-dimethylspermine, 1,1,12, 12-tetramethyl spermine, 3,3,10, 10-tetramethyl spermine, norspermin, or a mixture thereof.

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

 As amino saccharides, natural compounds containing the primary primary amino group are used, for example: D-glucosamine (chitosamine) (2-amino-2-deoxy-0-glucose), D-galactosamine (chondrosamine) (2-amino-2-deoxy-B -galactose), D-mannosamine (2-amino-2-deoxy-0-mannose), D-fucosamine (2-amino-2,6-dideoxy-0-galactose), neuraminic acid (5-amino-3,5 -deoxy-0-glycero-B-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, undecylic, lauric, myristic, undecylenic, sorbic, succinic, fumaric, adipic, sebacic, azelaic acid, azelaic acid, malic, tartaric, citric acid, or glutaronic, or glutamic, or pyroglutaminic, or asparaglutamic, or asproglutamino acid, or asproglutamino acid, or asproglutamino, or pelargonic, or capric, or undecyl, or lauric, or myristic, or undecylenic, or sorbic, or pyruvic acid, or succinic, or fumaric, or maleic, or adipic, or pimelic, or se bacic or azelaic acid, or malic, or tartaric, or citric, nicotinic (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 AFH: polyacrylic acid, copolymers of acrylic acid, their partially neutralized salt or a mixture thereof, and methacrylic, maleic, itaconic acid, Ν-vinylpyrrolidone or a mixture thereof are 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 stitched structure it fundamentally cannot penetrate into the cornea through the stratified 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 ligand 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. “Sorreg (P) complexes with 1-lysine and 1-ornithine: is the side-chain involved in the coordination? - A thermodynamic and spectroscopic study. "Thermochimica Acta, 362, N ° 1, 2000, 13-23. - [7];. N. G. Furmanova, J. I. Berdaliev, TC Chernaya, V. F. Resnyansky, NK Shytyeva, KS Sulaymankulov. "Synthesis and crystal structures of coordination compounds of pyridoxine with zinc and cadmium sulfates. Crystallography. 2009, 54, JY" 2, 255-261 - [8]).

 9+ 94-

The indicated transition metals — Cu and Zn cations — 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 installations;

 - 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 embedded over 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 ethanol or in 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 medicinal 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 exceeding 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) functional amine salt and an acid, usually strong, for example, hydrochloric. 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 the polyacrylic acid itself or copolymers of acrylic acid or crosslinked polyacrylic acid and its copolymers with U- 30-alkyl acrylates use their partially neutralized form or a mixture thereof.

 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 amount 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, may be introduced into the drug, or it may initially be used as aqueous medium upon receipt of the solution or to be introduced into the already prepared aqueous solution of the drug in concentrated form.

 A method of producing a gelling agent based on crosslinked polyacrylic acid and its copolymers with C 10-30 alkyl acres having an acidic reaction involves the preliminary dispersion of these polymeric acids in water with stirring and the subsequent neutralization with a base, which uses alkali metal hydroxides (Na, K) or amines: ammonia, primary, secondary, tertiary amines, including APH, or mixtures thereof.

Pharmaceutical preparations for the prevention and treatment of drug-based keratoconus.

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

Solution for installations

 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, hydroxypropylguar, or polyethylene glycol-polypropylene glycol-polyethylene glycol R-18, e.g. ® F 68 and F 127), 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 hardening), which provides the effect of additional prolongation with the introduction.

 After administration of the main components, preservatives, for example, benzalkonium chloride and other additional ingredients, can be added to the solution intended for use in the form of eye drops.

Table 1. The composition of the pharmaceutical preparation in the form of an aqueous solution to strengthen the cornea

 Component Content, wt.% Drug (AFG compound) 0, 10-7.0 gelling agent 0-5.0

isotonic substance 0-5.0 preservative and auxiliary components 0-0.3 distilled water the rest Table 2. The composition of the pharmaceutical preparation in the form of an eye gel for strengthening the cornea

Component Content, wt.% Drug (AFG compound) 0.10-7.0 gelling agent 2.0-25.0 isotonic substance 0-5.0 preservative and auxiliary components 0-0.3 distilled water the rest

The use of the drug using polymer eye contact lenses

 Medical contact lenses are widespread 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 a drug using polymeric ophthalmic medicinal films

 The use of pharmaceuticals 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 medicinal films is preferably 5-50% by weight (table 3).

As a polymer binder for the drug in this technical solution, various synthetic and natural polymers are used: 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 SODI for

 corneal strengthening

 Component Content, wt.% Drug (AFG compound) 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. Most preferred embodiments of the invention

To strengthen the cornea with the help of installations, 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 installations 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 no toxic or inflammatory effects were detected. 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 with 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 indicators of the cornea (breaking load P (N), tensile strength σ (MPa), elongation at break ε (%) and elastic modulus E (MPa) of these tissues with a special knife with 4.0 mm wide standard samples were cut with two cutting surfaces. After measuring their thickness on a PosiTector 6000 apparatus from DeFelsko (USA), the samples were placed in the clamps of an Autograph AGS-PI deformation machine from Shimadzu (Japan) and mechanical tests were performed. The dependence “stress-strain” obtained in the process of stretching the sample (speed 1 mm / min) up to the gap, was continuously recorded in digital and graphic mode by the computer unit of the apparatus.

 The biomechanical test data of the cornea are shown in table 4. Table 4. Mechanical tests of the rabbit cornea after administration of pharmaceutical preparations

 - water solution

 eye gel

 medical contact lens

 GLP

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. So, the increase in tensile strength σ / σ ₀ is 1.13-1.60 times, and the increase in the most important biomechanical criterion - the elastic modulus E / E ₀ 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.

Industrial applicability

 The alleged principle of cross-linking collagen when using the claimed medicinal product and preparations based on it. As you know, collagen fibrils (fibers) are stabilized by a whole system of cross-links (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 ageing of collagen.” Mech. Ag. Dev. 1998, 106, 1-56 - [10]) and during their formation, the stage of formation of al-lysine (an aldehyde derivative of lysine) as a result of the deamination of the side chains of lysine or a guide is especially important of roxylisin under the action of the enzyme lysyl oxidase (a copper-containing enzyme in which pyridoxal acts as a cofactor). Then, spontaneously, without the participation of enzymes, a Schiff base is formed with a spatially close amino group of the lysine residue located in another polypeptide chain. The resulting bond is -N = CH-, being in itself unstable, can be restored to a stable saturated bond, turning into an extremely strong crosslinking - lysinonorleucine.

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 the aldehyde groups of allysine in adjacent peptide chains to form the corresponding Schiff’s 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, which can directly react with the corresponding functional groups in neighboring collagen fibers.

 -aminosacchae ides: in a reactive tautomeric aldose form, in contrast to an inert pyranose ring form, they 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 corneal strengthening effect 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 drug 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 medicinal film and / or therapeutic contact lenses;

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

Application examples:

Example 1. 0.132 g (9.06 * 10 ^'4 mol) of D-lysine, Sigma in 10.0 ml of balanced physiological solution of BBS are dissolved in a glass flask with 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 (M _w 1800), Aldrich in 10.0 ml of distilled water and stirred for 15 minutes. Next, an additional amount of a solution of polyacrylic acid was used to bring the pH to 7, four.

 The prepared 1.0 wt% AFH 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 per within 1 month. During this period and within 1 month after the end of the installation course, the eye condition of 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.% Solution of AFG salt was 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 installations 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 (M _w 1800), Aldrich dissolved in 18.0 ml of distilled water. Further, 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 installations according to the method described in example 1.

Example 4. In a glass flask, while stirring with a magnetic stirrer, 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 mol) of adipic acid dissolved in 30.0 ml of balanced physiological saline, then an additional amount of adipic acid solution was used to adjust the pH to values of 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 installations 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 installations 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 while stirring with a magnetic stirrer, and then the dissolved amine is neutralized 1.78 g (2.54 * 10 ^{" 3} ) polyacrylic acid (M _w 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

installations according to the method described in example 1.

 Example 7. In a glass flask, 2.00 g of D-galactosamine hydrochloride, Sigma was dissolved in 98.0 ml of distilled water with magnetic stirring, 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 installations according to the method described in example 1. Example 8. In a glass flask 2.74 g (1.88 * 10 ^" mol) of 0, L-lysine, Sigma was dissolved in 80.0 ml of distilled water with stirring with a magnetic stir bar, and then 1.26 g was 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 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 installations 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 is dissolved in 60.0 ml of distilled water with stirring with a magnetic stirrer, and then 0 is added to the resulting solution over 5 minutes. 65g (1.62 * 10 ^"2 mole) NaOH, dissolved in 16 ml of distilled water, and then the resulting free amine is added 1,09g (0.812 x ^{10" 2} mole) SiS1 _2, dissolved in 20 ml of distilled water. The resulting 4 , 0 wt.% Solution of the complex compound AFG sterile filtered through a Millipore membrane with pores of 0.22 μm and poured into glass bottles with a volume of 5 m l

 This composition was used to strengthen the cornea by installations 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 stirrer, 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 installations 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 is dissolved in 80.0 ml of distilled water with magnetic stirring, and then 0.571 g (0.422 * 10 ^"2 mol) of ZnCl ₂ dissolved in 18 ml of distilled water are added to the resulting solution. 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 installations according to the method described in example 1.

 Example 12. A gel based on a crosslinked copolymer of acrylic acid and C 10-30 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, turning 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” / Arygodsky A.R., Sanina N.N., Scherbakov V.V., 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 salt L- ornithine and citric acid (in accordance with example 2) and was kept in it for 12 hours. After that, it was put on the cornea and 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 by the method (see RF patent 2352589, 2007/2009. “Method for the preparation of bio-soluble polymers of acrylamide, vinyl pyrrolidone and alkyl acrylate” / Bely 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 of relevant information

 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, Nsl l, 183-200; 4. Wollensak G, Spoerl E, Seiler T. “Riboflavin / ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus”. Am J Ophthalmol. 2003, 135, 620-627;

 5. Yomdina E.H. "Biomechanics of the scleral membrane of the eye with myopia: diagnosis of disorders and their experimental correction." Diss. Doct. biol. sciences. M., 2000, 3 16 s;

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

 7. Conato C; Contino A .; Maccarrone G. .; Magr A .; Remelli M .; Tabb G. “Sorreg (P) complexes with 1-lysine and 1-ornithine: is the side-chain involved in the coordination? “A thermodynamic and spectroscopic study.” Thermochimica Acta, 362, X ° 1, 2000, 13-23 .;

 8. Furmanova N.G., Berdalieva J.I., Chernaya T.C., Resnyansky V.F., Shytieva N.K., Sulaymankulov K.S. "Synthesis and crystal structures of coordination compounds of pyridoxine with zinc and cadmium sulfates." Crystallography. 2009, 54, JV ° 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 of obtaining a bio-soluble polymer of acrylamide, vinylpyrrolidone and alkyl acrylate" / White SI.,

Davydov A.B., Mikhailov S.F., Khromov G.L.

Claims

FORMULA

 1. A medicine 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.

 2. The drug according to p. 1, characterized in that as an amine with functional groups use amino alcohols, or amino acids, or derivatives of amino acids, or oligopeptides, or polypeptides, or polyamines, or derivatives of 3-hydroxy-2-methylpyridine, or amino saccharides or a mixture thereof.

 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-CMecb (racemate) are used as amino acids.

 6. The drug according to claim 2, characterized in that the derivatives of amino acids use the lactam of one of the amino acids according to claims 4 and 5 or a mixture of the amino acid lactams according to claims 4 and 5 ..

 7. The drug according to claim 2, characterized in that the ester of one of the amino acids according to claims 4 and 5 or a mixture of amino acid esters according to claims 4 and 5 are used as derivatives of amino acids.

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 claim 2, characterized in that the oligopeptides use oligopeptides having at least one L-ornithine or L-lysine unit, 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: b-alanine-b-lysine, b-arginine-b-lysine, L-valine-L-lysine, b-hydroxylysine- B-lysine, L-hydroxyproline-b-lysine, b-histidine-b-lysine, glycine-b-lysine, b-isoleucine-b-lysine, b-leucine-b-lysine, b-methionine-b-lysine, B-proline-b-lysine, b-serine-b-lysine, b-tyrosine-b-lysine, b-threonine-b-lysine, b-tryptophan-b-lysine, L-phenylalanine-L-lysine, b- cysteine-b-lysine, or one of the following tripeptides: b-alanine-b-histidine-L-lysine, b-arginine-b-histidine-b-lysine, L-valine-L-gi stydin-L-lysine, L-ranpoKcaiiroHH-L-rHCTHflHH-L ^ H3HH, L-hydroxycyline-L-histidine-L-lysine, L-racTHflHH-L-racTHflHH-L ^ H3HH, glycine ^ -histidine ^ - lysine L-isoleucine-L-histidine-L-lysine, L-leucine-L-histidine-L-lysine, L-methionine ^ -hystidine ^ -lysine, L-π-proline-L-histidine-L-lysine, L-cepHH- L-histididine-L-lysine,

L-TpeoHHH-L-racraunrH-L-lysine, L-τpiptofan-L-histidine-L-lysine, L-phenylalanine-L-histididine-L-lysine,

or a mixture thereof.

 11. The medicine according to claim 2, characterized in that poly ^ -ornithine or poly-L-lysine or poly-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-diaminobutane) 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-diamino to decane, or 2,2 '- (ethylenedioxy) bis (ethylamine), or 4,9-dioxa-1,12-dodecandiamine, or 3.6 , 9-trioxa-1,1 1-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-hydroxyspermidine or homospermidine or spermine or 1-methylspermine or 6-methylspermine or 1,12-dimethyl spermine or 5,8-dimethylspermine or 1,1,12,12-tetramethylspermine or 3 , 3,10,10-tetramethyl spermine, or norspermin or a mixture thereof.

 14. The drug according to claim 2, characterized in that pyridoxine, or pyridoxine-5-phosphate, or pyridoxal, or pyridoxal-5-phosphate, or pyridoxamine, or pyridoxamine-5 are used as derivatives of 3-hydroxy-2-methylpyridine -phosphate or a mixture thereof.

 15. The drug according to claim 2, characterized in that D-glucosamine (chitosamine, 2-amino-2-deoxy-0-glucose), or D-galactosamine (chondrosamine, 2-amino-2-deoxy) is used as amino saccharides -0-galactose), or D-mannosamine (2-amino-2-deoxy-0-mannose), or D-fucosamine (2-amino-2,6-dideoxy-0-galactose), or neuraminic acid (5- amino-3,5-deoxy-0-glycero-O-galactonone l ozone acid) or a mixture thereof.

 16. The drug according to claim 1, characterized in that the salt used is obtained by neutralizing an amine with functional groups with an acid.

 17. The drug according to p. 16, characterized in that the acid used is low molecular weight or polymeric acid or mixtures thereof.

18. The medicine according to claim 17, characterized in that hydrochloric or hydrobromic, or nitric, or sulfuric, or phosphoric, or acetic, or pivalic (trimethylacetic), or glycolic, or milk, or glutamic acid is used as low molecular weight acid, 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, or adipic, or pimelic, or sebacic, or azelaic acid, or malic, or tartaric, or citric acid, or a mixture thereof.

19. The medicine according to claim 17, characterized in that polyacrylic acid or acrylic acid copolymers, crosslinked polyacrylic acid and its copolymers with C 10-30 alkyl acrylates, or a partially neutralized form thereof, or a mixture thereof are used as the polymeric acid.

 20. The drug according to claim 19, characterized in that methacrylic or maleic, or itaconic acid, or Ν-vinylpyrrolidone or a mixture thereof is used as acrylic acid copolymers.

 21. The drug according to claim 19, characterized in that the polymeric acids have a molecular weight of 300-5000000.

22. The drug according to claim 1, characterized in that the Cu ²⁺ and / or Zn ²⁺ cation is used as the transition metal.

 23. A pharmaceutical preparation for the treatment of keratoconus and other degenerative diseases of the cornea, which is an aqueous solution of the drug according to any one of claims 1 to 22, intended for insertion into the conjunctival sac by means of installations.

 24. The drug according to p. 23, characterized in that the concentration of the drug in solution is 0.10-7.0 wt.%.

 25. The preparation according to claim 23, characterized in that distilled water or an isotonic solution or a mixture thereof is used as the aqueous medium for the solution.

 26. The drug according to p. 25, characterized in that the physiological (0.9 wt.% NaCl) or balanced physiological solution of BBS and / or aqueous solutions of nonionic compounds such as glycerol or sorbitol or mannitol or propylene glycol or dextrose.

 27. The drug according to paragraphs. 23-26, characterized in that the aqueous solution of the drug further comprises a gelling agent.

28. The preparation according to p. 27, characterized in that the gelling agent used is hyaluronic acid or polyvinyl alcohol, or methyl cellulose, or hydroxyethyl cellulose, or hydroxypropyl cellulose or hydroxypropyl guar, or polyethylene glycol-polypropylene glycol-polyethylene glycol block copolymer or Na-carboxymethyl, sodium salt polyacrylic acid and its copolymers with C 10-30 alkyl acre boards or a mixture thereof.

29. The drug according to p. 27, characterized in that the content of the gelling agent in the aqueous solution is 0.1-25.0 wt.%.

 30. A pharmaceutical preparation for the treatment of keratoconus and other degenerative diseases of the cornea in the form of an eye gel containing a drug according to any one of claims 1 to 22, intended for laying behind the lower eyelid.

 31. A pharmaceutical preparation for the treatment of keratoconus and other degenerative diseases of the cornea, which is a drug film containing in its composition a drug according to any one of claims 1 to 22, intended for laying behind the lower eyelid.

 32. A pharmaceutical preparation for the treatment of keratoconus and other degenerative diseases of the cornea, which is a therapeutic contact lens containing a drug according to any one of claims 1 to 22, intended for placement on the surface of the cornea.