RU2704354C1 - Method for preventing development of corneal opacity in case of mechanical injuries - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to medicine, specifically to ophthalmology. To prevent development of corneal opacity in case of mechanical injuries, solution of the following ingredients is used, wt%: oxyethylammonium methylphenoxyacetate powder – 5, water for injections – 95. Ingredients are mixed ex tempore until complete dissolution of oxyethylammonium methylphenoxyacetate powder. Subconjunctival injections are 0.5 ml once a day daily, applications – 2 drops 2 times day – 1 time in morning and 1 time in the evening, course of 7 days.EFFECT: method provides prevention of corneal opacity in case of mechanical injuries by stimulating proliferative-reparative processes in the cornea.1 cl, 1 dwg, 1 tbl, 1 ex

Description

The invention relates to pharmacology and can be used to prevent corneal disorders arising from its mechanical damage.

Corneal diseases account for at least 25% of all ocular pathology. The constant presence of microflora in the conjunctival cavity is often dangerous even with minimal damage to the cornea. The first place (up to 70-80%) belongs to viral keratitis. Keratitis is more common in immunocompromised patients (regardless of age and gender).

The consequences of corneal diseases: up to 50% of persistent visual impairment (which requires surgical treatment to restore the optical function of the cornea) and even blindness (Clinical recommendations. Ophthalmology, n / a L.K. Moshetova et al., 12.05.2006, p. 45- 71).

For the prevention of complications, including clouding of the cornea, it is necessary to timely contact a specialist, rejection of the uncontrolled use of drugs that contribute to the spread of the pathogen, and observance of the rules of personal and public hygiene.

A known method for correcting regeneration processes during thermal skin burns. This is achieved by the fact that for the stimulation of proliferative-reparative processes, the one developed under the guidance of M.G. Voronkov at the Irkutsk Institute of Chemistry SB RAS [see Voronkov M.G., Dyakov V.M., Semenova N.V. and others A.S. No. 515742 of the USSR.] The drug trekrezan, the active substance of which is hydroxyethylammonium methylphenoxyacetate, and its analogues [see Rasulov M.M., Motorina I.G., Yushkov G.G., et al. - J. Pathogenesis, 2017; Rasulov P.M., Motorina I.G., Demanova I.F., et al. - Sat: Science today: theoretical and practical aspects. Vologda, 2015; Yakhkind M.I., Rasulov M.M., Abzaeva K.A., et al. - RF Patent No. 2645115].

The above literature data allowed us to hypothesize that hydroxyethylammonium methylphenoxyacetate can, in principle, stimulate reparative processes in traumatic lesions of the cornea, preventing its clouding, despite very large differences in the structure and function of the skin and cornea. In particular, the cornea is a thinner tissue, which, unlike the skin, has greater light transmission, other blood and lymph supply (its capillaries do not "pass" red blood cells), more pronounced and sensitive innervation, a different structure of the protein skeleton (the prevalence of glycosaminoglycans) and etc. These factors create fundamentally different conditions for the normal healing of the cornea compared with the skin during mechanical injuries.

Earlier, such studies of the effects of hydroxyethylammonium methylphenoxyacetate have not been carried out, despite the urgency of the problem of stimulating proliferative and reparative processes and preventing complications in ophthalmic practice.

Accordingly, a positive result of the study would allow the use of the specified substance for a new purpose - to prevent the development of opacification with mechanical injuries of the cornea.

Oxyethylammonium methylphenoxyacetate is the basis of the well-known drug trekrezan used in the form of tablets. Another name for this compound is tris- (2-hydroxyethyl) -ammonium-o-cresoxyacetate.

A method of producing trekrezan in the form of a crystalline form is known, for example, from SU 515742, 06/22/1976.

The use of trekrezan in medicine in the form of a powder and other acceptable dosage forms is known from RU 2429832 C1, 09.27.2011, Rasulov M.M., p. 4, lines 38-42.

In addition, aqueous solutions of trekrezan prepared by ex tempore are known for administration intramuscularly in animal experiments (Bobkova S.N. Use of hydroxyethylammonium methylphenoxyacetate (trekrezan) for the correction and control of the course of hyperlipoproteinemia and coronary heart disease, diss. MD, M., 2015, pp. 6 and 31), as well as intraperitoneally - 1 ml of 0.5% aqueous solution (M. G. Voronkov, M. M. Rasulov. Trekrezan - the founder of a new class of adaptogens and immunomodulators (review) // Chemical and Pharmaceutical Journal, 2007, v. 41, No. 1, p. 3-7).

In the State Register of Medicines, registration number FS 001854 dated January 29, 2019 also contains hydroxyethylammonium methylphenoxyacetate, which is produced as a powder substance in jars - pure for analysis (PSA). The registration certificate was issued by Pharmcorp LLC, and the substance is produced by the Federal State Unitary Enterprise Special Design and Technological Bureau Technologist (FSUE SKTB Technolog) in St. Petersburg (http://grls.rosminzdrav.ru/Grls_viewFS_v2.aspx?routingGuid = 731a3fb9-bdc6-4668-9a04-8d81ea0141c4 & t =, circulation date 05/31/2019).

общего количества случаев. Помимо этого, использование целого комплекса лекарственных средств удорожает такое лечение и профилактику осложнений.As the closest analogue of the invention, a method for the prevention of complications, in particular, clouding of the cornea with its mechanical injuries, is considered. A complex of drugs is used, in particular, for installations (applications) and subconjunctival administration (Clinical recommendations. Ophthalmology, p / r L.K. Moshetova et al., 12.05.2006, p. 45-52). Namely, in the specified prototype, solutions of antibiotics, antiseptics (sulfacetamide 10-20% solution, chloramphenicol 0.25%, etc.) are used, in particular, for application (installation) to the corneal wound (3-4 times a day) and subconjunctival injection. ), agents that contribute to the regeneration of the cornea (methylethylpyridinol 1% solution of 1 ml 1 time per day), sometimes glucocorticosteroids in the form of eye drops. At the same time, these measures, even against the background of the use of systemic treatment with the introduction of detoxification agents, antibiotics, with a long course of drug administration from 14 to 30 days (2-4 weeks), do not provide complete healing of the cornea, in particular, prevention of its clouding. Complications, in particular in the form of corneal opacity, range from 1/3 to

total number of cases. In addition, the use of a whole range of medicines makes such treatment and prevention of complications more expensive.

The task was to find out the effectiveness of the use of hydroxyethylammonium methylphenoxyacetate in a new form, suitable for subconjunctival injections and eye drops for applications to prevent the development of corneal opacity due to mechanical injuries.

The technical result is the prevention of clouding of the cornea with its mechanical injuries in more than 90% of cases with the introduction of a course of 7 days.

This is achieved by the fact that in case of mechanical injury to the cornea, hydroxyethylammonium methylphenoxyacetate (the basis of the drug trekrezan) is used in the form of a pure for analysis (PSA) powder, which is dissolved ex tempore in sterile water for injection. The resulting solution is administered subconjunctively and by local application in the form of drops on the corneal wound.

Thus, a method for preventing the development of clouding of the cornea after its mechanical injuries is proposed, which consists in conducting subconjunctival injections and external applications in the form of drops on the corneal wound of the solution. For the manufacture of the solution using the following ingredients, mass%:

oxyethylammonium methylphenoxyacetate powder - 5

water for injection - 95;

which are mixed ex tempore until the hydroxyethylammonium methylphenoxyacetate powder is completely dissolved, with subconjunctival injections being 0.5 ml once a day, applications - 2 drops 2 times a day - 1 time in the morning and 1 time in the evening, for 7 days.

Oxyethylammonium methylphenoxyacetate - a white crystalline substance, readily soluble in water with a _{mp of} 80-81 ° C, has the formula:

and the following view:

Methods of synthesis of a substance and its physicochemical properties are described in detail in the monograph [see Rasulov M.M., Storozhenko P.A., Zhigacheva I.V. - Bassin, 2018, 276 pp.].

To obtain the claimed funds in the form of a solution, use PSA powder of hydroxyethylammonium methylphenoxyacetate and sterile water for injection. The composition is prepared ex tempore, mixing the ingredients until the powder is completely dissolved in the ratio, mass%:

oxyethylammonium powder methylphenoxyacetate - 5,

sterile water for injection - 95.

The resulting solution is used in the form of subconjunctival injections and external applications in the form of drops on the corneal wound for 7 days. Injections are carried out 1 time per day, 0.5 ml each solution, applications - 2 drops 2 times a day: 1 time in the morning and 1 time in the evening.

Confirmation of the effectiveness of the use of hydroxyethylammonium methylphenoxyacetate in the practice of ophthalmology to prevent the development of corneal opacities during its mechanical injuries, in comparison with the prototype, demonstrate the following data.

The object of the study is male Chinchilla rabbits with a body weight of 2.5-3 kg. The experiments are carried out on 40 rabbits (80 eyes) in accordance with the "Rules of Laboratory Practice in the Russian Federation" approved by order of the Ministry of Health of the Russian Federation dated 06.06.2003 No. 267 (Rules of laboratory practice in the Russian Federation Ministry of Health of the Russian Federation Order No. 267 of June 19, 2003 http: //www.kodeks.ru (April 24, 2010)). Animals are kept in accordance with the rules of the European Convention for the Protection of Vertebrate Animals, used for experimental and other scientific purposes. At the end of the experiment, animals are euthanized with a cervical dislocation of 5 vertebrae, following the rules of the “European Convention for the Protection of Vertebrate Animals that are Used for Experimental and Other Scientific Purposes” (Strasbourg, 1986).

Animals are divided into the following groups:

A - control group, 20 individuals, which are injected daily under the conjunctiva of 0.5 ml of physiological saline;

B - a group of experiment, 20 individuals, who are injected daily with 0.5 ml of the cornea under the conjunctiva of the claimed ex tempore solution, followed by instillation of the same solution on the cornea 2 drops twice a day - 1 time in the morning and 1 time in the evening. The exposure is carried out in a course of 7 days.

It should be noted that previously, the authors conducted studies of dose effects (solution concentration from 0.5% to 10%, the number of applications for 2 drops of the solution varied from 1 to 4 per day, the volume of the solution with subconjunctival administration varied from 0.1 to 0.5 ml, for 5 to 10 days) of the use of a solution of hydroxyethylammonium methylphenoxyacetate for mechanical injuries of the cornea. A greater number of subconjunctival injections was not performed, due to the extreme pain and limited administration area.

As a result, it was found that to solve the problem, the optimal concentration of the inventive hydroxyethylammonium methylphenoxyacetate solution is 5%, the volume of the solution with subconjunctival administration of 0.5 ml, the number of applications of the same solution is 2 times a day (1 time in the morning and 1 time in the evening) course 7 days

Statistical data processing is carried out by the student method. The data are presented as mean and standard error values - M and m, respectively.

Reliable are considered differences at p≤0.05 (see Petri A., Sabin K, 2009].

Example.

At the beginning of the experiment, animals from groups A and B after a 3-fold irrigation of the eye with a 0.5% aqueous solution of dicaine are mechanically injured in the central part of the cornea at half its thickness with a trepan with an opening diameter of 4 mm. The material for histological examination is taken after slaughtering the animals on the 1st, 7th, 15th, 25th and 60th days, 4 heads (8 eyes) for each period and treated with conventional histological methods. Stained sections with hematoxylin-eosin. The data obtained are presented in table 1.

Thus, statistical analysis reveals that the above morphological changes, indicating a faster regeneration of the damaged cornea in rabbits of the experimental group (group A, received the claimed solution), are reliable.

At the same time, by the 25th day of observation, restoration processes and restructuring of the tissue components of the cornea in control group rabbits (group A) are still ongoing, and 9 individuals (about 50%) show signs of corneal opacity, which persisted even in long-term observation periods (up to 60 days). No new complications arose.

At the same time, only one rabbit (5%) of the experimental group (group B) on the 25th day continued the processes of differentiation of the cornea, which allows one to detect subtle clouding in the central part of the cornea (Figure 1).

In the long-term follow-up (up to 60 days), no complications were noted in the experience group.

A positive effect - subconjunctival injection and instillation of the claimed solution after applying a mechanical injury to the cornea for 7 days activate the processes of early elimination of necrotic tissue at the site of the defect. The claimed solution containing hydroxyethylammonium methylphenoxyacetate limits the spread of the pathological process, accelerates the epithelization of the wound by 13-14 days after injury during treatment for the specified period, ensuring the histotypicity of the epithelial layer, leads to an ordered arrangement of the fibers of the cornea's own substance in the wound defect. At the same time, there are no signs of corneal opacity even in the long term after its healing.

Given that in the prototype discussed above, the healing of the damaged cornea proceeded with complications in 1 / 3-1 / 2 of cases, even when using a complex of drugs of various kinds (antibiotics, hormones, regenerating agents, etc.), the advantages of using hydroxyethylammonium methylphenoxyacetate in the form of the proposed A 5% aqueous solution for preventing the development of corneal opacities during mechanical injury in more than 90% of cases is considered proven.

Thus, it becomes clear that oxyethylammonium methylphenoxyacetate (the active substance of the drug trekrezan), when injected under the conjunctiva, together with its applications in the form of eye drops of the claimed 5% aqueous solution, reliably prevents the development of corneal opacity in rabbits when used for 7 days. . This is the result of effective stimulation of proliferative and reparative processes in the cornea with its mechanical lesions and indicates the fundamental possibility of its use in ophthalmic practice, expanding in the future the scope of hydroxyethylammonium methylphenoxyacetate. The use of a solution of hydroxyethylammonium methylphenoxyacetate in clinical practice is possible only after conducting studies established in accordance with orders of the Ministry of Health of the Russian Federation.

Claims (4)

A way to prevent the development of clouding of the cornea after mechanical injuries, which consists in conducting subconjunctival injections and external applications in the form of drops on the wound of the cornea of the solution, characterized in that the following ingredients are used to make the solution, wt.%: oxyethylammonium methylphenoxyacetate powder - 5; water for injection - 95, which are mixed ex tempore until the hydroxyethylammonium methylphenoxyacetate powder is completely dissolved, with subconjunctival injections being 0.5 ml once a day, applications - 2 drops 2 times a day - 1 time in the morning and 1 time in the evening, for 7 days.

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