RU2475248C1 - Ophthalmic cross-linking agent-2 - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology. An agent is applicable for a cross-linking procedure accompanying corneal ectasias. The agent contains riboflavin mononucleotide, chitosan succinate, sodium chloride, tris-(hydroxymethyl)-methylamine, Nipagin, disodium dihydrogen ethylenediaminetetraacetate and purified distilled water in certain proportions.

EFFECT: invention provides prolonged action of the agent, improves bacteriological availability for active ingredients, reduces the length and number of instillations for the procedure, provides agent saving.

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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 for cross-linking procedure for corneal ectasia.

Known means for corneal 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 the photosensitizing substance riboflavin and ultraviolet radiation (A.Caporossi, C. Mazzotta, S.Baiocchi. Technological Innovations in Corneal Collagen Cross-Linking // Ophthalmology Times Europe. Sept. 2007).

The prototype was an ophthalmic solution for crosslinking containing riboflavin mononucleotide, dextran with a molecular weight of 450-550 Da, sodium chloride, tris (hydroxymethyl) methylamine, nipagin, Trilon B and distilled purified water [M.M. Bikbov, A.R. .Khalimov, G.M. Bikbova. // Patent for invention RU No. 2412707 of 02.27.2011]. The disadvantages of this tool include the need for more frequent and longer installations to saturate the cornea with riboflavin, which is due to the lower viscosity and bioavailability of the polymer. In addition, the price of dextran exceeds the cost of the proposed chitosan succinate.

The objective of the invention is to develop a new ophthalmic solution of prolonged action, expanding the arsenal of means for cross-linking.

The technical result of the invention is to increase the bioavailability for the active components included in its composition, reducing the duration and number of instillations during the procedure by replacing its polymer base (dextran) with chitosan succinate, reducing the content of riboflavin mononucleotide, which becomes possible due to the fact that the active the substance penetrates into the stroma of the cornea in sufficient quantities, and also increases its solubility in the preparation of the solution.

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

Riboflavin mononucleotide 0.09-0.11 Chitosan succinate 9.5-10.5 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 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 0.1 wt.%. It is important to note that the solubility of riboflavin sodium mononucleotide is significantly higher than riboflavin.

Chitosan (chitosan succinate) - is used as a hydrophilic base for creating drugs, has low toxicity, does not have a cumulative effect and, as an alternative to synthetic polymers, is able to provide a long stay of the active substance in the body, while having its own spectrum of pharmacological activity. Chitosan gels increase the contact time of therapeutic components with the mucosa. The interaction of chitosan with the cell membrane is accompanied by an increase in drug permeability. Introduced into the composition of the proposed funds in a concentration of 10.0 wt.%.

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 0.1 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. 0.1 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. 10.0 g of chitosan succinate is added in portions when heated to 40-50 ° C and continuously stirred in portions until completely dissolved. 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 drug to 6 rabbits (group 1) for 14 days. The pair eye served as a control.

In the 2nd group of animals (6 rabbits), a cross-linking procedure was performed after de-epithelialization of the cornea with a diameter of 4 mm under local anesthesia (0.4% inocaine). The instillations of the proposed ophthalmic solution were accompanied by simultaneous ultraviolet irradiation of the cornea of the rabbit eye with the UVlink device (registration certificate No. FSR 2009/05489) for 30 minutes (6 intervals of 5 minutes, at a wavelength of 370 nm).

In the 3rd experimental group (6 rabbits) the crosslinking procedure was performed similarly to the technique used in the 2nd group. Instillations of an ophthalmic agent containing 20% dextran were performed.

In the second group, a slight corneal edema was observed within 3 hours 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 with daily biomicroscopy and ophthalmoscopy for 14 days, which was also confirmed by further morphological studies of the enucleated eyes of experimental animals.

It is important to note that in those groups of rabbits where the proposed solution was used, less instillations (by 10) and time (4 minutes) were required to saturate the cornea with riboflavin due to the more viscous consistency of the solution and its high bioavailability.

Clinical observations included 8 patients (8 eyes) aged 21 to 32 years old with a diagnosis of stage II-III keratoconus (Amsler classification). Traditional ophthalmic research methods were used. In addition, confocal biomicroscopy (HRT-III, Heidelberg, Germany), and optical coherence tomography (OCT) (Vizante-OCT, Carl Zeiss, USA) were performed.

Edema of the outer layers of the corneal stroma was observed in 45.2% 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 0.53 ± 0.92 (p <0.05). The value of corneal astigmatism decreased by 2.24 ± 0.25 D (p <0.05). The radius of curvature of the cornea increased to 6.88 ± 0.10 mm. During confocal microscopy, after 1 month in the anterior stroma, unexpressed apoptosis of keratocytes was detected, 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 the proposed ophthalmic agent were noted.

The present invention is illustrated by the following clinical example.

Patient R., 28 years old, was admitted with a diagnosis of stage II keratoconus. Examination data: visual acuity - 0.2. The magnitude of corneal astigmatism is 4.8 D, the radius of curvature of the cornea is 6.62 mm, and the thickness of the cornea in the center is 484 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 solution was installed 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.

During the first day after crosslinking, the patient observed a slight swelling of the outer layers of the cornea, which disappeared by the time epithelization was completed. After 28 days, there was an increase in corrected visual acuity to 0.4. Corneal astigmatism decreased by 2.4 D, the radius of curvature of the cornea was 6.70 mm, and the thickness of the cornea in the center was 446 μm (on OCT).

Thus, the proposed composition of the base and the active components of the ophthalmic agent guarantees an effective and safe cross-linking procedure used in the treatment of corneal ectasia. The tool provides long-term contact of the active substance with the shell of the eye, reduces the number of installations and saves the drug.

Claims (1)

Ophthalmic crosslinking agent 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 contains chitosan succinate in the amount of 9.5-10.5 wt.%, And riboflavin mononucleotide contains in the amount of 0, 09-0.11 wt.%.