DE4020623C2 - Corneal protector and method for its production - Google Patents

Description

The present invention relates to a corneal Protector and a process for its manufacture, that in ophthalmic surgery for the extraction of Cataracts of different etiology, during implantation an artificial eye lens and in keratoplasty can be used.

Presently, as a corneal protector, viscous ones are becoming Substances used, one of which is a cellulose derivative, Methyl cellulose.

A corneal protector and a method are known for its production (British Journal of Ophthalmology, 1983, 67, 259-263), which is a 2% methyl cellulose solution in a 0.85% aqueous sodium chloride solution or in the Wrestling solution without preservatives. The process for the production of the named protector exists in that one boils the methyl cellulose in a Dissolves solvent, the resulting solution cools Glacial acetic acid solvent is added, the resulting solution freezes and overnight at a temperature of minus 10 ° C leaves to 0 ° C. Then the solution is filtered off (pore size is from 16 µm to 0.5 µm), filled and sterilized. The protector is characterized by a high concentration of methyl cellulose solution, causing its Elimination from the eye after surgery is difficult and protracted hypertension (24 hours and beyond) and iridocyclitis as a result of one long retention (over 6 days) of product residues in the anterior chamber as well as the need for irrigation conditional after the operation.

The named protector also shows larger globules Dimensions as physiological dimensions of pores (0.67 µm) on what makes its elimination naturally difficult.  

Another cellulose derivative, which is in the form of an aqueous, saline solution is used as a corneal protector, is carboxymethyl cellulose (US Pat. No. 4,819,617). Disadvantageous at the use of this corneal protector is right next to that long time (7 days) that is needed to set up the same natural way out of the eye, one if only brief increase in interocular pressure.

The invention was based on the object the qualitative and quantitative change in the basis of a protector to produce a corneal protector, which reduces the degree of trauma to the cornea, the operative and postoperative complications are reduced and the quickly remove from the eye in a natural way lets develop as well as a process for its production.

The task was solved in that the registered Corneal protector based on a cellulose derivative, according to the invention, contains tylose as the cellulose derivative and from a 0.7 to 0.8% solution of the dispersed Tylose with globule dimensions of maximum 0.4 µm in Mixture with a 0.85% aqueous sodium chloride solution and a buffer solution with a pH of 7.2 to 7.4 put together.

In the process of producing the registered corneal Protector that prepares a solution of cellulose Derivative and the filtration of the solution provided, is used according to the invention as a cellulose derivative tylose. A 0.7 to 0.8% solution is prepared the same in a mixture with a 0.85% aqueous sodium chloride Solution and a buffer solution with a pH from 7.2 to 7.4 and separates from the resulting tylose solution by centrifugation with subsequent separation of the Oversediment solution and its filtration a fraction from the tylose with maximum globule dimensions Contains 0.4 µm.

The registered protector has a lower concentration of cellulose derivative (tylose) than the known one Protector, which is an accelerated excretion of the same promotes from the eye after surgery. The globule dimensions (of maximum 0.4 µm) are also smaller than that physiological pore dimensions, what a natural filtration and an accelerated excretion of the same from the  Encourages the eye in a natural way. The usage of the registered protector enables the degree of trauma reduce the cornea and the operative and postoperative Reduce complications.

The registered protector was tested on animals and tested on people in a clinic.

The registered protector contains tylose as the basis, a cellulose derivative.

Ethers and esters of cellulose have been carefully studied toxicologically examined and are used in pharmaceutical Practice applied extensively. For toxic-hygienic The characteristic of the registered protector became his possible effect on eye tissue under conditions of probable clinical application examined. Here was the local effect and the immunogenicity of the notified Special attention is paid to protectors because the latter can occur with non-toxic doses.

The examinations were carried out according to a program which is based on the criteria for a toxic-hygienic Regulation of polymer materials for intraocular Use was based.

The investigations were carried out on 25 rabbits (5 rabbits of which served as a control). Were carried out 9 test series.

The determination of the characteristic data (pH value, bromizability, Oxidizability and infrared Fourier spectroscopy) of the registered Protectors showed that he had non-toxic indicator standards having. The registered protector draws by a slight increase in the level of oxidizability from what with the physicochemical properties this preparation is related and for a short time Linger in the anterior chamber with subsequent ones Flushing can have no toxic effect.

The results were used to demonstrate the absence of toxicity the test of "living cells": the registered one Protector shows no influence on the metabolism of Bull sperm cells. The survival time of the cells in the experiment does not differ from the control.  

The instillation of the undiluted was carried out registered protector on three rabbits with 1 drop each three times a day within 3 days what the requirement corresponds to the examination of the substance to be used once. There are no inflammatory reactions or any signs of irritation. The conjunctiva remained calmly without injection of the vessels of the conjunctival pouch and the Episklera. The cornea was transparent, shiny and mirror-like. The deeper sections of the anterior chamber are not changed.

Biomicroscopy of the eye was carried out Rabbit. 12 eyes were examined in 7 rabbits.

Duration of the examination: 1 hour, 1 day, 2 days, 3 days, 7 days and 1 month. The biomicroscopic picture was taken according to a classification of the degrees of reaction developed by us rated:

0-degree - area course: eye is calm, media are transparent, iris is relief-shaped, the implanted material is intact;
I grade - weak reaction: edema of the epithelium of the cornea in the area of the anterior chamber, fibrin or precipitation on the implant, edema, hypermia of the pupil edge of the iris or a slight irritation of the entire iris;
II grade - medium severity reaction: edema of the epithelium of half of the cornea, isolated folds of the Descemt membrane, fibrin in the fluid of the anterior chamber, exudate on the lens, pronounced edema, dilation of the vessels of the iris;
III grade - pronounced reaction: edema of the entire cornea, thickening of the stroma, gross descemetitis, exudate, hypopion, hyphema in the anterior chamber, pronounced exudation on the implant, synechia up to soldering, exudate on the iris, newly formed vessels.

In all cases without exception the biomicroscopic Image the corneal zero response, including the Endothelium, the fluid of the anterior chamber, the iris,  observed what completely the non-toxicity of the registered protector corresponds to that in the front chamber in a dose of 0.1 ml, adequate for the introductory dose was introduced in its clinical use.

Examination of the endothelium of the cornea after the silver coloration according to Smolin was based on that of us previously developed classification made: 1st to 2nd Degree - uneven staining of cells, integrity the shape and dimensions, the arrangement of the rows, the Presence of a damaged zone area, integrity the cell density in the center and on the periphery, the State of intracellular connections - changes after these Parameters on an area up to 50%.

3rd to 4th degree: gross damage to type cells paranecrosis (sharp increase in the permeability of protoplasm, their diffuse coloring, structural damage) and Necrosis (shrinkage, decay, resorption of nuclei and Lysis of the entire cell) on an area over 20%, or 1st to 2nd degree - over 50%.

In all cases examined, the control was one Reaction below the 1st degree, in experiments with the above A reaction of the 1st to 2nd Degrees observed in an area under 15% of the cornea, what of lack of toxicity of the registered protector testifies according to this test.

Pathohystological examination was carried out on 4 experimental and performed on 4 control eyes with the following duration: 2, 3 and 7 days. A buffer solution served as a control and Hanks solution.

The condition was independent of the duration of the examinations like the eyes. Except for the injection needle puncture site for the introduction of the registered protector no damage to the cornea and rainbow skin detected. The fluid in the anterior chamber remained transparent and more eosinophilic in the earlier stage than in the Control. The underlying media are also transparent, the choroid, retina and optic nerve are unchanged. Examination of the immunogenicity of the registered Protectors gave a negative result.  

The studies carried out to study the whole and local harmful effects as well as immunogenicity of the registered protector showed that it was inert is, and reaffirmed the possibility of its short-term Use in anterior surgery Section of the eyeball.

Clinical examinations of the registered protector have been applied to more than 10,000 patients in ophthalmic surgery in the extraction of cataracts of different ethiology, when implanting an artificial lens and in performed the keratoplasty.

The registered protector was used as follows.

When extracting cataracts it becomes a carneoscleral Cut with a length of 3 mm, you cut the Fluid from the anterior chamber. Then leads one in the anterior chamber with a syringe a 0.7 to 0.8% tylose solution with maximum globule dimensions 0.4 µm. The anterior is destroyed with a cystotome Capsule of the lens, then you remove the core and the lens mass. The protector is not removed from the front chamber, sutures are placed on the carneoscleral incision.

In the case of keratomy, the operation is performed on the central one optical area of the cornea of the eye drop by drop a 0.7 to 0.8% tylose solution with globule dimensions of maximum 0.4 µm and it will be the surgery carried out.

Clinical studies showed that neither during after the operation (from 24 hours to 6 days) no increase in intraocular pressure in patients No complications were observed.

The process for making the registered protector the cornea is carried out as follows.

A 0.7 to 0.8% tylose solution is prepared in a mixture with a 0.5% sodium chloride solution and one Buffer solution with a pH of 7.2 to 7.4. The concentration of tylose cannot be less than 0.7% because in  in this case the viscosity of the solution is below 1000 centistocks would lose the possibility of the anterior chamber mechanically during intraocular surgery to deepen. A concentration above 0.8% can increase the viscosity of the solution and lead to an increase in intraocular pressure.

The pH of the buffer solution from 7.2 to 7.4 is from Importance for the maintenance of a normal buffer system the anterior chamber of a human being and for the functioning of the endothelium, a pH below 7.2 leads to acidification of the ventricular fluid and acidosis of the endothelium, increasing the pH above 7.4 leads to alkalosis and a shift in cell metabolism. The dissolution of the tylose and all subsequent ones Operations are carried out at a temperature of 4 ° C due to the increase in temperature for deterioration the quality of the protector. The dissolution of tylose is done during 24 hours after which you can additionally mixed within 10 minutes so that the entire mass passes into the dissolved state. Then becomes the mass with the aim of precipitating large tylose aggregates centrifuged. After centrifugation, the Poured over sediment solution and to create a uniform aggregate concentration in the entire volume mixed in the solution. The mixing time is at least 1 hour. After that, the solution is consecutive Filtration on membranes through filters with a Pore diameter of maximum 0.4 µm exposed because of large Dimensions of the aggregates the blockage of the Schlemowschen Channel of the anterior chamber will cause. The Any solution is sterilized.

For a better understanding of the present invention Below are examples of manufacturing the registered Protector and its clinical trials.

Example 1

100 ml of a mixture of 0.85% aqueous sodium chloride Solution and a phosphate buffer solution with a pH of 7.2 to 7.4 is set in 1 g of dry tylose powder to. After 24 hours to dissolve in a refrigerator  at a temperature of plus 4 ° C the tylose Mix the solution within an hour using the Concentration of the solution up to 0.7 wt .-% brings. The accrued Tylose solution is placed in a centrifuge and for 1 hour at a speed of 28 thousand Centrifuged rpm. The oversediment tylose solution is poured in the cold at a temperature of plus 4 ° C and mixed them within 10 to 15 minutes. You take the tylose solution into a syringe and filters through a membrane with a pore diameter of 0.4 µm.

The protector manufactured was tested in a clinic.

Patient A. became 34 years old mature star of the left eye observed, its visual acuity before the operation the sensation of light with correct projection was. An operation was performed on the extracapsular Extraction of the cataract with the implantation of one intraocular lens. One served as the corneal protector 0.7% tylose solution with globule dimensions from 0.2 to 0.4 µm. The visual acuity after the operation was 0.7. Operative and postoperative complications were not observed.

Example 2

100 ml of a mixture of 0.85% aqueous sodium chloride Solution and phosphate buffer solution with a pH A value of 7.2 to 7.4 was set in 1 g of dry tylose powder to. After 24 hours for dissolution in a refrigerator at a temperature of plus 4 ° C the tylose solution to a concentration of within 1 hour 0.75 mass% set. The accrued Tylose solution is placed in a centrifuge and within 1 hour at a speed of 28 thousand Rpm mixed. Then the oversediment solution of the tylose poured off and in the cold (4 ° C) within 10 to 15 Minutes mixed. The tylose solution obtained is taken into a syringe and filters through a membrane with a Pore diameter of 0.4 µm. The manufactured protector was tested in the clinic.

Patient Sch. at the age of 60 it became an occasion of a mature age-related star in the right eye, his visual acuity came before the operation as a sensation of light with correct projection to express.  

An operation of extracapsular extraction was carried out of the cataract with implantation of the intraocular Lens. A 0.75% tylose was used to protect the cornea. Solution with globule dimensions from 0.2 to 0.4 µm. The protector was left in the anterior chamber. The visual acuity of the right eye was after the operation 0.5. There were no operative and postoperative ones Complications observed.

Example 3

100 ml of a mixture of 0.85% aqueous Sodium chloride solution and phosphate buffer solution with one pH from 7.2 to 7.4, 1 g of dry tylose powder is used to. After 24 hours for dissolution in a refrigerator (Temperature is plus 4 ° C) is obtained Tylose solution mixed within 1 hour by changing the concentration the solution is brought to 0.8% by mass. The Any tylose solution is introduced into a centrifuge and within 1 hour at a speed centrifuged at 28 thousand rpm. Then the oversediment solution poured in the cold (plus 4 ° C) and inside mixed from 10 to 15 minutes. You take the Tylose solution into a syringe and filters through a membrane with a pore diameter of 0.4 µm.

The protector thus obtained and manufactured was in the clinic tried.

Patient W. at the age of 59 became an occasion of a mature age-related star in the left eye a visual acuity that turns out to be a sensation of light with proper projection expressed, observed. An operation of the extracapsular was carried out Extraction of the cataract with implantation intraocular lens. One served as the corneal protector 0.8% tylose solution with globule dimensions of 0.2 up to 0.4 µm. The protector was in the anterior chamber calmly. The visual acuity of the left eye was less the operation 0.2. There were no operative and postoperative ones Complications observed.

Claims (2)

1. Corneal protector based on a cellulose derivative, characterized in that it contains 0.7 to 0.8% by weight of tylose with globule dimensions of at most 0.4 µm in 0.85% aqueous, to pH 7.2 to Contains 7.4 buffered NaCl solution dispersed. 2. Process for the production of a corneal protector Claim 1, characterized in that a 0.7 to 0.8% by weight tylose solution in 0.85% aqueous, to pH 7.2 up to 7.4 buffered NaCl solution prepared, the tylose solution centrifuged and the supernatant solution through a membrane filters with a pore diameter of 0.4 µm.