RU2412707C1 - Cross-linking ophthalmic agent - Google Patents

Abstract

FIELD: medicine. ^ SUBSTANCE: invention refers to medicine, namely to medical products used as an ophthalmic agent, containing riboflavin and pharmaceutical aids applied for a cross-linking procedure in corneal ectasias. The agent contains riboflavin mononucleotide, dextran, sodium chloride, tris-(hydroxymethyl)-methylamine, nipagin, trilon and purified distilled water in a certain relation of components. ^ EFFECT: invention provides prolonged action of the ophthalmic agent, improves its chemical and bacteriological stability in a solution. ^ 1 ex

Description

The invention relates to medicine, namely to medical devices used as an ophthalmic agent containing riboflavin and excipients used for the cross-linking procedure for corneal ectasia.

Known means for corneal collagen crosslinking provide strengthening of the cornea due to the photopolymerization of stromal fibers, due to the combined effects of photosensitizing substances (riboflavin) and ultraviolet radiation (A.Caporossi, C. Mazzotta, S. Baiocchi. Technological Innovations in Corneal Collagen Cross-Linking // Ophthalmology Times Europe. Sept. 2007).

The prototype of the invention is an ophthalmic agent for corneal collagen cross-linking containing riboflavin phosphate, dextran, sodium chloride, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate and distilled water (ibid.). However, these funds do not provide a sufficient degree of stability of the active substance, and therefore can limit the duration of its use.

The objective of the invention is to develop an effective tool for collagen crosslinking with a long shelf life.

The technical result when using the invention is the prolonged action of the agent, increasing its chemical and bacteriological stability in solution.

The specified technical result is achieved by the fact that an ophthalmic crosslinking agent containing riboflavin mononucleotide, dextran, sodium chloride and distilled purified water according to the invention additionally contains tris- (hydroxymethyl) methylamine, nipagin, trilon B in the following ratio of components, wt.% :

Riboflavin Mononucleotide 0.14-0.15 Dextran 18.0-22.0 Tris- (hydroxymethyl) methylamine 0.08-0.12 Nipagin 0.0075-0.0125 Trilon B 0.005-0.01 Sodium chloride 0.8-0.9 Distilled purified water rest.

Characteristics of the components.

Riboflavin mononucleotide (riboflavin-5'-sodium monophosphate) is a crystalline powder of yellow-orange color. The aqueous solution has a yellowish-orange color, intensively fluoresces in ultraviolet light. Introduced into the composition of the proposed funds in a concentration of 0.15 wt.%. It is important to note that the solubility of riboflavin sodium mononucleotide is significantly higher than riboflavin.

Dextran is a glucose polymer, a white amorphous powder, soluble in water. Molecular Weight, 450-550 Yes. In an ophthalmic agent, dextran is introduced in a concentration of 20 wt.% In order to give it viscosity, prolong the therapeutic effect, and provide an anti-edematous effect. In addition, viscous polymers allow better tolerance of installations and provide long-term contact of drugs with the mucosa.

Tris- (hydroxymethyl) methylamine, Tris is a white crystalline powder, it is soluble in water. Introduced into the composition of the proposed funds as a buffer at a concentration of 0.1 wt.%.

Trilon B (disodium salt of ethylenediaminetetraacetic acid) is an odorless white crystalline powder, readily soluble in water (FS 42-1173-78 or GOST 10652-73). Trilon B binds heavy metal ions, it is used as a stabilizer for the preparation of injection solutions and eye drops. Trilon B is introduced into the ophthalmic agent as a stabilizing component at a concentration of 0.075 wt.%.

Nipagin is a methyl ester of n-hydroxybenzoic acid, a white crystalline powder, poorly soluble in water (FS 42-1460-80). It is widely used as a preservative in the preparation of injection solutions, eye drops. Nipagin is introduced into an ophthalmic agent as a preservative, which helps preserve the sterility of the agent during storage and during its use. The content of nipagin in the solution is 0.01, since the optimal concentrations in which it exhibits an antimicrobial effect are 0.01-0.05 wt.%.

Sodium chloride is a white crystalline powder, soluble in water. Sodium chloride is introduced into the composition of the proposed solution as a means of providing physiological osmotic pressure of the solution.

The proposed tool is obtained as follows. 0.15 g of riboflavin mononucleotide is dissolved by heating in 100 ml of freshly prepared distilled water. Then 0.85 g of sodium chloride and 0.1 g of tris- (hydroxymethyl) methylamine are placed. Next, nipagin 0.01 g and Trilon B 0.075 g are sequentially dissolved. Upon heating and constant stirring, 20.0 g of dextran is added in portions to the solution surface until complete dissolution. The resulting solution is filtered through a membrane filter, packaged in bottles that are sealed with rubber stoppers, rolled in aluminum caps and then autoclaved at 0.5 atm and 110 ° C for 30 minutes. It is stored in a dark place. Shelf life 2 years.

When performing experimental studies, biomicroscopy and ophthalmoscopy were performed after daily instillations of the proposed agent to 8 rabbits (group 1) for 14 days. The pair eye served as a control.

In the second group of animals (8 rabbits), a cross-linking procedure was carried out - instillations of the proposed ophthalmic agent were accompanied by simultaneous ultraviolet irradiation of the rabbit’s cornea with the UVlink device (registration certificate No. ФСР 2009/05489) for 30 minutes (6 intervals of 5 minutes, at a wavelength 370 nm).

In the third experimental group (8 rabbits), the indicated irradiation procedure with the UVlink device was carried out after deepithelization of the cornea with a diameter of 4 mm under local anesthesia (inocaine 0.4%).

In the 3rd group, unexpressed corneal edema was observed during the first day after the procedure. Subsequently, it was found that the use of the proposed ophthalmic agent in all experimental groups did not reveal any toxic or irritating effect during biomicroscopy and ophthalmoscopy for 2 weeks, which was confirmed by morphological studies of enucleated animal eyes.

The clinical observations included 6 patients (6 eyes) aged 19 to 44 years old with a diagnosis of stage II-III keratoconus (Amsler classification). In addition to traditional ophthalmic research methods, confocal biomicroscopy (HRT-III, Heidelberg, Germany), and optic coherence tomography (OCT) (Vizante-OCT, Carl Zeiss, USA) were performed.

Edema of the outer layers of the corneal stroma was observed in 57.2% of patients, which took place 2-3 days before the end of epithelization. After a month, these patients showed an increase in corrected visual acuity to 0.49 ± 1.09 (p <0.05). The value of corneal astigmatism decreased by 2.14 ± 1.25 D (p <0.05). The value of the refractive power of the cornea initially decreased from 52.01 ± 0.39 to 49.12 ± 0.24 D, and for the period of the last examinations (6-12 months) it was 50.03 ± 1.29 D (p <0.05 ) The radius of curvature increased to 6.85 ± 0.15 mm. In the period from 1 to 3 months, a gradual decrease in the thickness of the cornea to 30.02 ± 0.12 microns was observed. During confocal microscopy, after 1 month, moderate apoptosis of keratocytes was detected in the anterior stroma, which was determined as a highly reflective mesh structure, the posterior and middle portions of the stroma were preserved without significant changes.

During the observation period (12 months), no complications associated with the use of this ophthalmic agent were noted.

The invention is illustrated by the following clinical example. Patient R., 35 years old, was admitted with a diagnosis of stage II keratoconus. Survey data: visual acuity - 0.3. The value of corneal astigmatism is 5.2 D, the radius of curvature of the cornea is 6.52 mm, the thickness of the cornea in the center is 445 μm according to optical coherence tomography (OCT).

Crosslinking procedure was carried out in the operating room. Under local anesthesia (2% lidocaine hydrochloride solution), after de-epithelialization of the cornea with a diameter of 7 mm, the proposed ophthalmic agent was instilled for 15 minutes, then the cornea was irradiated six times (5 minutes) using the UVlink device with simultaneous installations of the proposed ophthalmic agent. In the postoperative period, local antibacterial and dehydration therapy was used.

On the first day after the cross-linking procedure, the patient observed minor edema of the outer layers of the cornea, which passed by the time epithelization was completed. After 30 days, there was an increase in corrected visual acuity to 0.4. Corneal astigmatism decreased by 2.0 D, the radius of curvature of the cornea was 6.70 mm, and the thickness of the cornea in the center was 440 μm (on OCT).

Thus, the composition of the main and active substances included in the proposed ophthalmic agent provides an effective and safe cross-linking procedure used in the treatment of the initial stages of corneal ectasia. The product has a long shelf life, during which it remains sterile.

Claims (1)

Ophthalmic crosslinking agent containing riboflavin mononucleotide, dextran, sodium chloride and purified distilled water, characterized in that it additionally contains tris (hydroxymethyl) methylamine, nipagin, trilon B in the following ratio, wt.%:
Riboflavin Mononucleotide 0.14-0.15 Dextran 18.0-22.0 Tris- (hydroxymethyl) methylamine 0.08-0.12 Nipagin 0.0075-0.0125 Trilon B 0.005-0.01 Sodium chloride 0.8-0.9 Distilled purified water Rest