RU2705392C1 - Eye ointment based on 6-methyl-3-(thietan-3-yl)uracil with wound-healing effect - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, namely to ophthalmology, and aims at treating a thermal burn of the cornea. Ointment contains biologically active substance 6-methyl-3-(thietan-3-yl)uracil, wherein as an ointment base contains Vaseline and lanolin, taken in ratio 9:1. Components are used in claimed amounts.EFFECT: use of the invention provides higher clinical effectiveness in thermal burns of the cornea.1 cl, 4 dwg, 1 ex

Description

The invention relates to medicine, in particular to ophthalmology, and can be used in the treatment of thermal burn, postoperative corneal edema with phacoemulsification of cataracts and traumatic corneal erosion.

According to the World Health Organization (WHO), around 253 million people worldwide suffer from visual impairment, 36 million of them are blind. According to Rosstat, the number of operations on the organ of vision in the hospital in 2016 amounted to 821.6 thousand, which is 46% more than in 2005 - 534 thousand operations [Healthcare in Russia. 2017: Stat. Sat / Rosstat. - M., Z-46 2017. - 170 p.]. 81% of people with blindness are in the age group of 50 years and older, and they have a widespread pathology of the organ of vision: age-related cataracts and glaucoma.

Postoperative corneal edema is one of the most significant problems in the rehabilitation of patients operated on for complicated cataracts. In most cases, a high probability of corneal edema can be assumed at the stage of diagnostic examination. Factors such as high cataract density, subluxation of the lens, weakness of the zinc cords in the pseudoexfoliation syndrome, small anterior chamber, adhesions, initial corneal pathology can complicate the operation and increase the duration of the surgery.

A modern approach to the surgical treatment of cataracts includes possible measures for the prevention of postoperative complications.

Methyluracil (2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine) - improves trophism, enhances cell growth and reproduction, stimulates the regeneration process in damaged tissues, accelerates healing of wounds, burns, increases the body's resistance to infections . It is also described that methyluracil has an anti-inflammatory effect.

A known method of treating eye burns by installing on the cornea of the drug "Adgelon" -6-KD polypeptide, 3-6 times a day for 14 days. As a result of treatment, corneal epithelization and relief of signs of inflammation occur on the 5-7th day [RF application 94008009, published on 06/20/1996]. The disadvantages of the method are repeated instillation of the drug, which causes inconvenience in use, and the difficulty of obtaining active components.

Known eye drops containing a solvent in the form of purified water and an active substance, which use the natural mineral bischofite. An aqueous 5-20% bischofite solution is purified from mechanical impurities of calcium and iron and, after sterilization and visual inspection, is used for instillation. Eye drops provide anti-inflammatory, absorbable, antiseptic effect and contribute to gentle scarring of the cornea tissue [RF patent 2112473, 1998]. The disadvantages of the composition are the difficulty of extraction of the bischofite mineral and lower efficiency due to the liquid composition.

There is a method of treating postoperative corneal edema in surgery for age-related cataracts, characterized in that from the first day after surgery, a 0.25% solution of derinate is instilled 3 times within 1 minute. Immediately after the last installation, the cornea is exposed to the running pulsed magnetic field of the AMO-ATOS apparatus, the emitter head of which is located at a distance of 3 mm from the outer surface of the cornea. At the same time carry out exposure to laser radiation. In this case, the laser beam from the LAST-01 apparatus is induced through an axial hole in the head of the field emitter. The emitter frequency is 5-10 Hz, the position of the diaphragm is 4, the exposure time is 5 minutes, for a course of 2-3 sessions. The method provides an improvement in the outcome of the operation and a decrease in the duration of treatment of gerontological patients with the declared pathology by reducing the recovery time of the normal anatomical and morphological and optical state of the cornea, reducing the incidence of chronic bullous keratopathy, restoring the development of mechanisms that determine energy and metabolic reserves of the cell [RF patent No. 2476194 , 2013]. The disadvantage of this method is its complexity.

Known eye ointment containing, as a biologically active substance, high molecular weight hyaluronic acid (0.3-0.5 g) isolated from human umbilical cords and an ointment base (petrolatum - lanolin in a ratio of 6: 4) - the rest [RF Patent No. 2173136, 2001 g.]. The disadvantages of the ointment are the complexity of the technology for producing the main component - hyaluronic acid from human umbilical cords, which is inaccessible and technically difficult to perform, as well as repeated use of the drug up to 3-4 times a day to increase the efficiency and long term healing of eye wounds (30 days).

The closest analogue of the invention is the known 2% betamecil ointment (crystalline form of 6-methiuratsil) for stimulating reparative regeneration of corneal tissue, containing 2 grams of betametsil, anhydrous lanolin - 39.2 grams, petroleum jelly - 58.8 grams per 100 grams of drug substance, treatment continues until the elimination of inflammatory phenomena and the full restoration of the corneal epithelium. The disadvantage of the prototype is the low content of the active substance in the composition, which leads to low therapeutic efficacy and the need for long-term use. [Jafarali T.B. A new stimulator of the regeneration of the cornea-betamecil ointment 2% ophthalmic in the treatment of diseases of the anterior eye: Abstract. ... dis. Cand. honey. sciences. - Moscow, 1996. - 22 p.].

The task of the invention is to expand the arsenal of drugs for the treatment of thermal burns of the eye, postoperative corneal edema.

The technical result when using the invention is to obtain a new eye ointment with a high wound healing effect.

The inventive eye ointment contains as a biologically active substance 6-methyl-3- (thietan-3-yl) uracil, and as an ointment base contains petrolatum and lanolin taken in a ratio of 9: 1, with the following components, wt. %:

6-methyl-3- (thietan-3-yl) uracil 10 petrolatum-lanolin base 90

The invention is illustrated by the following figures: in FIG. 1 shows a histological preparation of the cornea of the right eye, characterizing the view on the first day after a thermal burn of the eyes; in FIG. 2 - a histological preparation of the cornea of the left eye, characterizing the appearance on the first day after a thermal burn of the eyes; in FIG. 3 - histological preparation of the cornea of the right eye on the 3rd day; in FIG. 4 - histological preparation of the cornea of the left eye on the 3rd day;

6-Methyl-3- (thietan-3-yl) uracil is synthesized according to the procedure described in patent RU 2485118, 2013.

It is known that 6-methyl-3- (thietan-3-yl) uracil stimulates the protective activity of phagocytes [RF patent 2485118] and has antimicrobial activity [S.A. Meshcheryakova, V.A. Kataev, I.Ya. Fattakhova [et al.] Synthesis and antimicrobial activity of acetanilides and acetylhydrazones of thietanylpyrimidin-2,4 (1H, 3H) -dione series // Chemical and Pharmaceutical Journal, 2015. - V. 49, No. 9. - S. 28-31].

At the first stage of the ointment preparation technology, the preparation of the main technological raw material is carried out - the substance 6-Methyl-3- (thietan-3-yl) uracil, as a basis for the preparation of the ointment, vaseline varieties for eye ointments (additionally purified with activated carbon) and lanolin are used anhydrous in a ratio of 9: 1. The ointment base is obtained by fusing the above components, followed by sterilization in an oven-sterilization cabinet at a temperature of 180 ° C. The substance is sieved through a No. 1 sieve to free from mechanical impurities and dried in an oven at a temperature of + 40-45 ° С. The dry material is homogenized in a ball mill or coffee grinder. The degree of dispersion is controlled using a microscope, which should be no more than 25 microns. Particles larger than 90 microns are not allowed. The resulting powder is used as one of the main components of the anti-burn ointment.

расплавленной мазевой основы от навески субстанции.The technological process of preparing the ointment is as follows. Since the substance is not soluble in oils and water, it is introduced into the composition of the ointment as a suspension. For this, a substance is introduced into a reactor equipped with a combined stirrer, a jacket for heating (cooling) and an external homogenizer and triturated with

molten ointment base from a sample of substance.

Then the substances are thoroughly crushed and dispersed to a high degree of dispersion. The process proceeds at a temperature of 40-50 ° C. The residue of the ointment base is added to the resulting mass of ointment base and substance with continuous stirring and homogenized until a homogeneous mass is obtained.

The degree of homogenization is evaluated visually and using a microscope. The ointment should be visually homogeneous, the presence of particles larger than 90 microns is not allowed. The ointment is packaged on a filling machine in sterile jars with screw-on plastic lids and with sterilized parchment pads weighing no more than 10 g.

Production safety is stipulated by the relevant sections of the regulation and safety instructions. To ensure sanitary standards, the premises where the ointment is manufactured, packaged, and packaged are equipped with supply and exhaust ventilation, an air conditioning system, and bactericidal UV lamps. According to the degree of fire and explosion hazard, the production of ointment belongs to the category “B”, according to sanitary design standards - non-toxic, according to the rules of electrical installations - non-explosive. By-products, wastewater, and air emissions from the production of ointment are absent.

The proposed eye ointment is placed in the conjunctival cavity 2-3 times a day for 7-14 days.

The use of ophthalmic ointment improves functional outcomes, shortens treatment time, is well tolerated by patients, economical and convenient to use. An indicator of clinical recovery is the restoration of the epithelial-stromal layer of the cornea.

For experimental verification of the claimed medicine, the following samples of ointments were prepared using various bases and their ratios. With an increase or decrease in the number of components from this interval, the ointment exfoliates and does not meet the requirements of the GF-XIV edition. Ready ointment of yellow color with a characteristic odor, uniform consistency. The ointment is recommended to be stored in a cool, dark place. Example.

The proposed thietanylmethyluracil ointment was tested in an experiment on 6 chinchilla rabbits, divided into 2 groups: right eyes made up the main group, left eyes - control. A thermal burn of a cornea with hot water of 80 degrees Celsius was experimentally caused. The right eye was treated with the proposed ointment, and the left eye (control) with 20% solcoseryl gel. The treatment was carried out 3 times a day. The therapeutic effectiveness of the treatment was evaluated according to the following criteria: terms of reduction and disappearance of the phenomena of irritation, edema, mucopurulent discharge.

Checking the effectiveness of the ointment for a mild burn. Thermal burn modeling was carried out by preliminary instillation of eye drops of 0.4% inocaine twice, then hot water was dripped 80 degrees 30 drops in the exposure for 20 seconds. The experiment was completed by instillation of an antibiotic tobramycin 0.3% and thietanylmethyluracy ointment (the proposed drug) was placed in the right eye, 20% solcoseryl gel (the known drug) was placed in the left eye. Method of application: for an eyelid 3 times a day an ointment was laid with a glass rod. After 10-15 minutes, lacrimation, conjunctival injection, and mild photophobia were observed in animals with a thermal burn of the cornea. On the first day of treatment, conjunctival hyperemia, injection of scleral vessels, and corneal epithelial edema in the optical zone were observed in both groups (main and control). The area of the damaged surface of the cornea was the same in both groups, since the burn was applied to all rabbits in exactly the same way. On examination, there were no visible signs of primary infection. During the first days after the burn in the experimental group, vascular injection and conjunctival hyperemia persisted, positive dynamics was noted for 2-3 days - the inflammatory response of the conjunctiva significantly decreased. Edema of the corneal epithelium was absent. While in the control group, vascular injection and conjunctival hyperemia persisted during the first 5 days and decreased only by the 7th day with moderate corneal edema.

Clinical changes are confirmed by histological studies.

Histologically, it was found that thermal burn injury - the 1st day after thermal burn (main group) in the number 1 animal on the right eye during treatment with thietanylmethyluracil ointment was manifested by a change in the damaged corneal epithelium in the form of edema due to the appearance of a clear fluid in the intercellular space. The deep layers of the cornea: the Bowman membrane, the stroma, the descemet membrane and the posterior corneal epithelium remained unchanged (Fig. 1).

In the left (control) eye of rabbit 1, the first day after thermal burn (control) during treatment with solcoseryl gel, the changes were accompanied by pronounced desquamation of the epithelium, in some areas relatively narrow gaps were found between the cells and the extracellular matrix. The gaps were filled with an optically bright homogeneous fluid (edema) (Fig. 2).

In an experimental study, when taken as a prototype (betamecil ointment 2% ophthalmic), the first clinical signs of improvement were observed in 3.8 days, in the proposed ointment on the next day after the start of treatment, which is associated with the content of the titanium fragment in the proposed eye ointment.

Against the background of treatment, positive dynamics was observed in both groups. On the right eye of rabbit 2 (main group), on the 3rd day of treatment, a decrease in edema between the cells was observed, to compensate for the defect, mitotic division of young cells was observed (Fig. 3).

In the control group, the above changes were also observed, with the exception of some areas where a relatively late closure of the defect was observed (Fig. 4, arrow).

Claims (2)

An ointment for the treatment of thermal burns of the cornea, containing methyluracil and petrolatum-lanolin ointment base, characterized in that it contains 6-methyl-3- (thietan-3-yl) uracil as methyluracil, and petrolatum and lanolin contain 9: 1 at the following content of components, wt.%: 6-methyl-3- (thietan-3-yl) uracil 10 petrolatum-lanolin base in a ratio of 9: 1 90

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