RU2560669C1 - Ophthalmic agent for transepithelial ultraviolet corneal collagen crosslinking - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: agent contains riboflavin mononucleotide, hydroxypropyl methylcellulose, sodium chloride, tris-(hydroxymethyl)-methylamine, Nipagin, Trilon B in a certain ratio, wt %: 0.24-0.26, 0.4-0.6, 0.8-0.9, 0.08-0.12, 0.0075-0.0125, 0.005-0.01 and purified distilled water up to 100 respectively.

EFFECT: using the invention enables increasing the transepithelial penetration of riboflavin ensured by increasing its concentration, and preventing the corneal thinning.

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Description

The invention relates to medicine, in particular to ophthalmology, and in particular to medical devices used as an ophthalmic solution containing riboflavin and excipients used in the process of ultraviolet (UV) crosslinking (cross-linking) of collagen during corneal ectasia.

Known means for collagen cross-linking, which provides strengthening of the cornea of the eye due to the photopolymerization of stromal fibers, due to the combined effects of photosensitizing substances (riboflavin) and ultraviolet radiation with a wavelength of 370 nm [A. Caporossi, S. Mazzotta, S. Baiocchi. Technological Innovations in Corneal Collagen Cross-Linking // Ophthalmology Times Europe. Sept. 2007].

Known means for ultraviolet crosslinking containing riboflavin-mononucleotide, chitosan succinate, sodium chloride, tris- (hydroxymethyl) methylamine, nipagin, trilon B and distilled water [M.M. Bikbov, A.R. Halimov, G.M. Bikbova // Patent for the invention RU No. 2475248 of 02.20.2013].

The prototype was an ophthalmic solution for crosslinking containing riboflavin mononucleotide, dextran with a molecular weight of 450-550 kDa, sodium chloride, tris- (hydroxymethyl) methylamine, nipagin, trilon B and distilled purified water [M.M. Bikbov, A.R. Halimov, G.M. Bikbova // Patent for invention RU No. 2412707 of 02.27.2011].

It should be noted that the above funds are used to perform the standard UV cross-linking procedure, in which saturation of the stroma with riboflavin is ensured by de-epithelialization of the cornea in the ectasia zone. However, in this case, removal of the epithelium can lead to the development of corneal syndrome in the postoperative period. Another factor limiting the use of such solutions is their dehydrating effect, leading to a decrease in the thickness of the cornea during the procedure. In a number of cases, this circumstance serves as a contraindication to crosslinking, since the additional thinning of the de-epithelized cornea significantly complicates the course of the pathological process during corneoectasias.

A new modified (transepithelial) method of corneal crosslinking with preservation of the epithelium is known, in which the stroma is saturated with riboflavin by electrophoresis [M.M. Bikbov et al. // Patent for the invention RU No. 2510258 of 03/27/2014]. The advantage of this method is the absence of postoperative pain syndrome caused by de-epithelialization, and the possibility of crosslinking in patients with corneal thickness less than 400 microns.

However, when using this method of crosslinking, the preserved epithelium makes it difficult to fully and quickly saturate the corneal stroma with a photosensitizer due to the insufficient concentration of riboflavin.

To this we add that the price of dextran and chitosan used in the previously declared ophthalmic solutions exceeds the cost of the proposed polymer - hydroxypropyl methylcellulose (HPMC).

The objective of the invention is to develop a new ophthalmic solution for transepithelial ultraviolet crosslinking of collagen of the cornea of the eye, expanding the arsenal of means for crosslinking.

The technical result of the invention is to prevent the dehydrating effect and accordingly reducing the thickness of the cornea when performing the UV crosslinking procedure, increasing the penetration of riboflavin through the epithelium by increasing its concentration.

The proposed ophthalmic agent according to the invention contains riboflavin mononucleotide, hydroxypropyl methylcellulose, sodium chloride, tris (hydroxymethyl) methylamine, nipagin, trilon B and distilled purified water in the following ratio, wt.%:

Riboflavin Mononucleotide 0.24-0.26 Hydroxypropyl methylcellulose 0.4-0.6 Sodium chloride 0.8-0.9 Tris- (hydroxymethyl) methylamine 0.08-0.12 Nipagin 0.0075-0.0125 Trilon B 0.005-0.01 Distilled purified water rest

Component Feature

Riboflavin mononucleotide (riboflavin-5′-sodium monophosphate) is a yellow-orange crystalline powder. 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 0.25 wt.% As a photosensitizer.

Hydroxypropylmethyl cellulose is a natural polymer that dissolves in cold water to form a clear, viscous solution. Used as a hydrophilic base for the creation of drugs and cosmetics, does not have a toxic effect. Introduced into the composition of the proposed funds in a concentration of 0.4-0.6 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.

Tris- (hydroxymethyl) -methylamine, (Tris) is a white crystalline powder, soluble in water. Introduced into the composition of the proposed funds as a buffer at a concentration of 0.08-0.12 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 0.0075-0.0125 wt.%, Since the optimal concentrations in which it exhibits an antimicrobial effect are 0.01-0.05 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. Into an ophthalmic agent is introduced as a stabilizing component in a concentration of 0.005-0.01 wt.%.

The proposed tool is obtained as follows. 0.25 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 successively dissolved. 0.5 g of hydroxypropylmethyl cellulose is added in portions when heated to 30-40 ° C and continuously stirred in portions until it is completely dissolved. The resulting viscous 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.

The inventive tool was tested in the experiment. Laboratory animals were divided into four groups of 2 rabbits (4 eyes) in each.

In the first group, the proposed solution was used to perform the standard UV crosslinking procedure after deepithelization of the cornea with a diameter of 4 mm under local anesthesia (inocaine 0.4%). After the cornea was saturated with a photosensitizer, it was subjected to ultraviolet irradiation with the UVlink device (registration certificate No. FSR 2009/05489) with a wavelength of 370 nm for 30 minutes (6 intervals of 5 minutes).

The second group also used the standard crosslinking method with 0.1% riboflavin mononucleotide with 20% dextran m.m. 450-550 kDa.

In the third group, the proposed transepithelial crosslinking solution was used, in which saturation was carried out by electrophoresis with a current strength of 1.0 mA using a galvanizer (GE-50-2 "Potok-1", Russia).

In the fourth group, as in the third, transepithelial crosslinking was used only with the use of a solution of 0.1% riboflavin mononucleotide with 20% dextran m.m. 450-550 kDa.

The use of the developed ophthalmic agent did not reveal a toxic or irritating effect during daily biomicroscopy and animal ophthalmoscopy for 18 days, which was subsequently confirmed by morphological studies. To determine the thickness of the cornea, all animals underwent pachymetry.

The use of the proposed solution to saturate the cornea in a standard way (group 1) was traditional and did not reveal any inconvenience or side effects. At the same time, the penetration rate of the photosensitizer was significantly higher than in the second group, due to the higher concentration of riboflavin. When using the developed product, the corneal thickness slightly increased (7 ± 2%), which is a positive factor for the pathologically thinned, de-epithelized cornea, while in the second group, a decrease in the corneal thickness due to the dehydrating action of dextran was observed.

When performing crosslinking using transepithelial saturation of the cornea with the proposed solution (group 3), rapid penetration of riboflavin was also observed, it should be noted that the thickness of the cornea of the animals after this procedure remained stable, in the fourth group it was 15 ± 3% less.

The clinical observations included 6 patients (6 eyes) aged 24 to 34 years old with a diagnosis of stage II-III keratoconus (Amsler classification). Traditional ophthalmic research methods were used, in addition optic coherence tomography (Vizante-OCT, Carl Zeiss, USA) and confocal biomicroscopy (HRT-III, Heidelberg, Germany).

Edema of the outer layers of the corneal stroma after crosslinking was not observed. The postoperative period was calm, pain was absent in patients.

After a month, these patients showed an increase in corrected visual acuity. The value of corneal astigmatism decreased by 1.85 ± 0.2 D. The radius of curvature of the cornea increased to 6.92 ± 0.12 mm.

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

The invention is illustrated by the following clinical example.

Patient K., 30 years old, was admitted with a diagnosis of stage II keratoconus. Examination data: visual acuity - OD 0.7; OS 0.4 (operated eye). The thickness of the cornea in the center is 468 microns. The radius of curvature of the cornea is up to 6.80 mm.

Prior to crosslinking, the patient underwent a bath electrophoresis with a solution of 0.25% riboflavin mononucleotide and 0.5% HPMC with a maximum current of 1 mA for 10 min. Corneal saturation was determined by yellow glow in the anterior chamber of the eye using a slit lamp (blue - cobalt filter).

The UV crosslinking procedure was carried out in the operating room, ultraviolet irradiation of the cornea was performed with the UVlink device at a wavelength of 370 nm with a radiation power of 3 mW / cm ² , lasting 30 minutes (6 cycles of 5 minutes) with simultaneous installation of a solution containing 0.25% riboflavin mononucleotide and 0.5% HPMC. At the end of the procedure, the cornea was washed with physiological saline, Normax eye drops (3 mg / ml norfloxacin) were instilled. 1 day after surgery, the eye is calm, pain was absent, visual acuity without correction was 0.6. Corneal astigmatism decreased by 2.0 D, the thickness of the cornea in the center - 460 microns. The radius of curvature of the cornea is up to 6.88 mm.

Biomicroscopically, the cornea is transparent. There were no complications during and after the transepithelial corneal collagen cross-linking procedure. 12 months after surgery, the visual acuity of the left eye is 0.6.

Thus, the proposed composition of the base and active components of the ophthalmic agent provides an effective and safe conduct of ultraviolet transepithelial crosslinking used in the treatment of corneal ectasia. The agent quickly penetrates the stroma, creates a prolonged contact of the active substance with the shell of the eye, during the procedure, one of the pathogenetically determined criteria for this disease, the thickness of the cornea, is stable.

Claims (1)

Ophthalmic agent for transepithelial ultraviolet crosslinking of corneal collagen, containing riboflavin mononucleotide, base, as excipients, wt. %: sodium chloride 0.8-0.9, tris- (hydroxymethyl) methylamine 0.08-0.12, nipagin 0.0075-0.0125, Trilon B 0.005-0.01 and distilled purified water to 100, characterized in that it as a basis contains hydroxypropylmethyl cellulose in an amount of 0.4-0.6 wt. %, and riboflavin-mononucleotide contains in an amount of 0.24-0.26 wt. %