GB2246353A - Cornea-protecting compositions - Google Patents

Abstract

Cornea-protecting compositions for use in ophthalmic surgery are disclosed such as for the extraction of cataracts of assorted aetiology, for implanting an intraocular lens, or for keratoplasty. The compositions comprise methyl cellulose, are easily eliminated and do not give rise to increased intraocular pressure. The preferred form of methyl cellulose is Tylose (RTM).

Description

CORNEA-PROTECTING COMPOSITIONS AND PROCESSES FOR THEIR PRODUCTION The

present invention relates generally to medicine 0 and more specifically to a corneal protector and to a process for producing same, and can find application in ophthalmosurgerjr for extraction of cataracts of diverse etiology, implantazion of intraocular lens, or keratoplasty.

At present use is made of some viscous substances as a corneal protector, one of such substances being a cellulose derivative, viz., methyloellulose.

Known in the present state of the art are a corneal protector and a process for producing same (cf. British Journal of Ophthalmology,1983, 67, pp. 250-2063), said D. 0 corneal protector being essentially a 2-percent solution of methyloellulose in a 0.85-percent aqueous sodium chl-)ride or in 'Ringer's solution, free from a preservative.

The process for producinZ said corneal protector resides in that methy1cellulose is dissolved in a boiling solvent, the resultant solution is let to cool, some glacial solvent is added thereto an,] the solution is frozen and left over night at from minus 101 to OOC. Next the solution is pas sed throLiZh a filter having a pore size from 16 Itm to 0.5 ji4mg filled and sterilized. The aforediscussed corneal protector ' however, is characterised by too high a concentration of the methyleellulose solution, which hampers its withdraryal from the eye after su.-,o..ery and co.-it:cJ-butes to prolonged hjpertension (for 24 hours or lonjer) and to iridocyclitis as a result of lon-time persi.tence (over six days) of the D - residual preparation in the anterior eye chamber, thus necessitatinS its po:itoperctive vinshing-out.

In addition, said corneal protector has ;'lobules larger than phisiolog.ical pores (0.67 Pm)9 - L ,hich impedes elicination. of the protector from the ore,anism by the natural route.

It is an obect of the present invention to provide a corneal protector capable of reducing the degree oil injury to the cornea, decreasing intraand postoperative complications, and eliminable from the eye at a hiCher rate bi the natural route.

It is another object of the present invention to pro- ej - vide a -:)-,ocess for p-roducin-7 the corneal protector propo- sed herein.

We have now discovered that it is possible to provide cornea-protecting compositions for use in ophthalmosurgery, such as for the extraction of cataracts of assorted aetiology, for implanting an intraocular lens, or for keratoplasty, which overcome the problems of the art. These compositions comprise Tylose (registered Trade Mark) and are not easily eliminated and do not give rise to increased intraocular pressure.

Accordingly, in a first aspect, the present invention provides a cornea-protection composition comprising a physiologically acceptable, aqueous solution of Tylose, the amount of Ty-lQse being sufficient that the viscosity of the solution is great enough to allow mechanical support, but not so great as to cause a substantive increase in intraocular pressure, in situ.

c 1 4 i i 1 i i i -J- By physiologically acceptable is meant any composition which can be used in ophthalmosurgery without substantial adverse affect. Thus, it is preferred that the solution should have a comparable pH to the eye and should not cause an increase in intraocular pressure in use.

Advantageously, the compositions of the invention have a concentration of Tylose between about 0.7% and about 0.8% in dispersed solution. It is preferred that the Tylose has a maximum globule size of 0.4Lm, to allow elimination through physiological channels.

it is preferred to use a saline solution, particularly containing about 0. 85% sodium chloride.

For comfort, it is advantageous for the composition to further comprise a buffer having a pH value of from about 7.2 to about 7.4.

The present invention also provides a process for producing a composition as defined above, comprising preparing a solution of the ingredients, subjecting the resulting solution to centrifugation, decanting and collecting the supernatant solution, and filtering and isolating the fraction having a maximum globule size of 0. 4Lm.

In an alternative aspect, there is provided a corneal protector based on a cellulose derivative, comprising thyllose as said cellulos.e.derivative and consisting of a 0.7-to 0.8-percent dispersed Tylose solution having a globule size not in excess of o.4 M, in a mixture with a 0.85-percent aqueous sodium chloride and a buffer having the pH value of from 7.2 to 7.4.

There is further provided a process for producing the here-in proposed corneal protector, incorporating preparation of a solution of the cellulose derivative, and filtration of the resultant solution, accordia:S to the invention, used as saiQ s -re-3red cellu.1ose derivative _s Tylose and there its 0.7 to 0.8-percent solution in a mixture -,,ith a C.85-percent aqueous sodium chloride and a buffer havinS the pH value of from 7.2 to 7.4, -whereupon. the resultant Tylose solution is subjected to centrifugation, follo-,-,,ed by SeD8r8Lion oJ_ the supernatant liquid and isolation a fraction tharefrom, cont-ainin-, Tylose vith.3 maximum :,,lz)bule size off 0.4 m.

The -roposed corneal protector features lower conoentration of the ce'Llulose derivative, i.e., Tylose, than the hereto'Lore-known protector, uhich promotes its accelernted elizaination from t'e eye after sur-gery. 3esiles, the -lobule s4ze (not exceedin- 0.4 pm) is below _D U D -the phjsiolo.;-ical pore size,.vliich c,)n- Jbutes to natural V filtr:ition and hastens elimination of the protector from the eye by the natural route. Use of the proposed corneal protector enables one to reduce the deSree of injury to the cornea and dec2ease postoperative complications.

The proposed corneal protector has been tested in experiments on test animals and clinic,-illy on patients.

The pro-Dosed corneal protector comprises the cellulose derivative i.e., ' Tylose, as the basic component.

Both cellul-)se ethers 3nd esters are known to have 1 i 1 1 1 1 i i i been studied SCrU-UlOUSlY from the tOXiCO10'iC81 7ie'" point anJ are now in videspxead use in pharmaceutical practice. To obtain toxicoh,79ienic claaracteristics of the proposed co::neal protector, there h3s been studied its possible effect on the ocular tissues under the conditions of its intended clinical uses. Special emphasis has been placed on topical effect and immuno.,Senicity of the proposed corneal protector, since such an effect miSht manifest itself in nontoxic doses.

Investizrations h3ve been carried out according to :D a programme underlaid with standards used for toxicohy--ienic CD regulations of polymer materials for inturaocular applica- I - tions.

-al of 25 test rabbits we--e subjecided to experi- A tot ments, five of them servin.- as the control. Nine runs of experi. jents 7.ere carried out.

Some particular char3cteristics of the propose,"' corneal protector (pH value, ability to be brominated, oxidability and Fourier-transform infrared spectroscopy) prove to be at a nontoxic level. The proposed corneal protector is featured by a slight3y increased oxidability level, which is concerned -.-,,I'uh the ph,,vsicochemical properties of the preparation and therefore cannot produce anny toxic effect upon its IV.-. sient stay in the nnterior eye chamber folloied by was"hin3-out of the corneal protector.

Zero toxicity of the Proposed DrOtCCtOZ is co-n-fi.-j----d by the results of the "living cells" tes-%i, that is, no effect is produced bY the present protector on the metabolism of bull's spermatozoa, while the survival time of the 13tter cells in the experiment differs in nothing from that of control.

Three test rabbits were subjected to instillation of the proposed corneal protector (undiluted) in a dose of one drop three ti-mes a day for three days, which complied fully with the requirement to study into a substance intended for single use. No inflammatory reaction nor any sisns of irritation were observed. The conjunctiva remained cuiet, Ygitl-,out injection of the vessels of the conjunctival sec and of the episclera. The cornea appeared transparent, lustrous, and reflecting. The subjacent portions of the anterior eye chamber exhibited no changes.

The test rabbit eyes,,;.ere subjected to biomicroscopy, a total of 12 eyes were examined in 7 test rabbits.

Examination time: one hour, one day, two days, three days, seven days, one month. The biomic.roscopic picture was assessed according to the following classification of the reaction stases elaborated by the authors: Degree 0 - nonreactive coursin-,: the eye quiet, intra- U ocular fluids transparent, the iris prominent, the imp13nted matter intact; i I 1 1 1 i 1; i 1 1 1 i i I l j - -7 - DeSree ill-defined reaction: edema of the corneal epithelium in the anterior eye chamber, presence of fibrin or precipitation on the implant, general edema, hjperemia of the pupillary margin of the iris, or sliSht irritation'of the entire iris; Degree IImoderately severe reaction: epithelial edema in half the corneal area, sporadic folds of the 71.

Descemet's membrane, presence of fibrin in the aqueous humor of the anterior eye chamber, exudate on the crystalline lens, pronounced Seneral -0 the iridal vessels; edema, dilatation ol De-:,ree III - markedly pronounced reaction: edema of the entire co-rnea; thickening of the stroma, severe descemetitis, exudate, hypopyon, hyphema! in the anterior eye chamber, prcnounced exudation on the implant synechine occurring till sealing the implant, exudate on the iris, newly induced blood vessels.

Zero corneal reaction ras observed in all instances unexceptionally as for the biomicroscopic picture, iacluding that of endothelium, aqueous humor of the anterior eye chamber, and the iris, which agreed fully zith the nontoxic nature of the proposed corneal protector injected into the anterior eye chamber in a dose of 0.1 ml,,ihich vas equal to the therapeutic dose of the preparation administered durimS its clinical aDplioation.

i5 - The corneal endothelium, after having been subjected to silvering according to -Smolin, was studied with. the aid of the classification developed by the authors beforehand:

Degrees I and 2 - nonuniform colouration of the cells, retained shape and size of the cells, arrangement of their rows, the presence of zonal location of the lesion, remained density of the cells in the centre and at the periphery, the state of intercelluinr bridges - the changes of the aforelisted Darameters occur on a corneal area of up to 50 percent.

Degrees 3 and 4 - coarse lesion of the cells of the type of paranecrosis (drastic increase in permeability of the protoplasm, its diffuse colouration, impa-ired structure) and necrosis (shrinkiaS, deoomposition, resorption of the nuclei, and lysis of the whole cell) on corneal 1 L :!ren exceedin,3 2J De2:Cent, or affection of degrees I a-ad 2 on a corneal area exceedirg 51 percent.

In all cases under study used as the control was the reaction below degree 11 iihile in experiments within all 0 the specified periods, including the one-month oneq there than 15 per- vas observed a degree 1-2 reaction on an area less -U cent of the whole co--nea, -,-,hich gave evidence that the nro- 0 - -cosed corneal protector exhibited zero.toxicity in a given particul3-- test.

Pathohi-5tol--gical examination was carried out on four i i 1 i i 1 i test and four control eyes itithin the period:s of 2, 3, and 7 dayeg a but-fer and the Hank-91 solution servin, as the control.

The state of the eyes uader test.:as the same within all exrerimental time. No affection of the cornea an,"' i.-is vias noted apart from the prickinG point of the injection needle for ad-ministerin.3 the proposed corneal protector. The anterior chamber aqueous humor remained transparent and more eosinoplailic at an earlier stage than in the control. The subjacent humors were also transparent, the chor.-id, the retina, and the optic nerve exhibited no changes. Examinazion of the proposed corneal protector ZD - for i,.,.munogenicity yielded a negative result.

Th I.-us, experimental studies of the proposed protector for both systemic and tcpical injurious effect, as well as for i--imuno-3enicity have demonst.-ated its indifference and therefore suitability for a shoxttirae use in ophthalmosurgery on the front eyeball portion.

Clinical studies of the proposed corneal protector 'were performed in more than ten thousand patients during ophthalmosurgery for extraction of cataracts of diverse etiology, implantazion of intraocular lenses, and for keratoplasty.

The proposed corneal protector is applied - r- as follovgs.

In the case of cataract extraction a 3-mm corneoscieral inclsion is made and the aqueous humor is let out of the anterior eye chamber. Then a Tylose solution havin.,; a i maximum globule size of 0.4,pm is syrin-e-injected into ID 1j the anterior eye chamber, the aaterior crystalline capsule U is destructedt usin.-,r a cystotome, 'whereupon the nucleus and lenticular masses are removed. The corneal protector is not taken o--.at of the anterior eye chamber, while a number of sutures are applied to the corneoscleral incision.

In the case of keratotomy, prior to surgery a 0.7- or 0.8-percent Tylose solution having a maximum globule size of 0.4 cm is aPPlied to the central optical zone -he cornea, whereupon a surgical procedure is performed.

o f -'U, The clinical studies thus effected have demonstrated that neither intraoperatively nor postoperatively (,Aithin a period from 24 hours to six days) the patients operated upon. Lave developed any increase in the intraocular pressure; besides, no complications have been observed.

The process for producia, the proposed co--neal protector is carried into effect as follovs.

In a preferred embodiment there is prepared a 0.7- or 0.8-jercent Tylose as a solution in a mixture with a 0.85-percent sodium chloride solution and a buffer having the pH value of from ?.2 to 7.4.

The ' Tylose concentration should tot be belovw 0.7 percent, viscosity of the solution less than 1JJ0 eSt may give the result that any mechanical deepening of the anterior eye chamber during intraocular surgery is no longer possible. On the other hand, a- Tylose concentration exceedin, 0.8 percent m.i,ht result in too hiSh viscosity of the solution and hence in an increased intraocular pressure.

i z 1 i 1 i i i 1 i i 1 j 1 i 1: i 1 -hin 7.2 The DH value of the buffer solution kept,i-vV and 7.4 is an important factor for retention of a normal buffer system in the anterior eye chamber and normal functioning of the endothelium. A pH value belovi 7.2 may lead to overacidulation of the aqueous t I., e humor of the anterior chamber and to acidosis of endothelium; on the o-.Ijher hand, a pH value above 7.4 may result in alkalosis and in a shift in the cell metabolism.

Tylose dissolution and all the subsequent stares are preferably effected at 40C, since higher temperatures impair the quality of the corneal protector. - Tylose is dissolved -or 24 hours,.,,,hereupon the resultant solution is stirred for at least 10 minutes to let the entire mass render into solution.."Text -rhe mass is centrifugated to let coarse -hich the supernatant Tylose particles settle dovvn, after solution is decant-d and stirred so as to establish unifc.rm concentration of the particles throughout the entire volume of the solution, the stirring period beinS at least one hour. Thereupon the solution is exposed to consecutive filtration on membranes through filters. featuring the maximum oore diameter of 0.4 m, since a greater par- P -0 ticle size is frauG-ht vith obstruction of the Schlemm's canal of the anterior eye chamber. Finally the thusobtained solution is sterilized.

1 To promote understanding of the present invention, given below are the follo7in3 examples of producing the proposed corneal protector and of its clinical trials# Example I

IJJ ml of a mixture of a 0.85-percent a'queous sodium chloride and a phosphate buffer havinG the pH value of from 7.2 to 7.4 is doped rith I.of dry powdery Tylose, %,hereupon the thus-obtained Tylose solution is alloTed to dissolve in a coo ler at +4'0 for 24 hours and is stirred for another hour to brinz, the concentration of the solu- 0 tion to 0.7 -.,ei;ht percent. The resultant Tylose solution is then placed in a centrifuge and subjected to ceatrifuZa tion for one hour at a speed of 28.JJO rpm. Next the super solution is decanted in the cold at +4 v natant Tylose 0"1 and stirred for 10 to 1,-) minutes, whereupon some Tylose solution is dravn in a syringe and filtered on a membrane havin3 a pore diameter of 0.4 P mo The thus-produced corneal protector has been tested clinically.

Male patient A-, 34 was under observation for a mature cataract of the left eye, the visual acuity of the ajofeoted eye before surgery beinS li:-ht pexception with correct projection. The Datient underwent surgery for extracapsular cataract extraction accompanied by implantation of an. intraocular leas. Used as the corneal protector was a 0.7-percent Tylose solution having a -,lobule size of' from 0.2 i j 1 i 1 i i 1 1 1 i 1 i 1 1 i i i i 1 to 4 9m. Postoperative visual acuity.0.7. -i4 nor -oost-oDerative complications -f.eie obse:rved. Example 2 Iii ml of a mixture of a 0.85- percent aqueous sodium chl-',ride and a phosphate buffer having the pH value of from 7.2 to 7.4 is doped 'with I of drT powdery Tylose, - whereupon the thus-obtained Tylose solution is allowed to dissolve in a cooler at +40C for 24 hours and is stirred X for another hour to brin, the concentration of the solu tion to 0.75 zei;ht percent. The resultaat Tylose solu- tion is then placed in a centrifuge and subjected to centrifuation for one hour at a speed of 28,)JU rpm. Next the supernatant Tylose e solution is decan-.ed and sti--red in the colCli (at +400) for 10 to 15 minutes. The resultant Tylose solution is drawn in a syringe and filtered on a membrane havin,,-,, a pore diameter of 0.4pm. The thus obtained corneal protector has been trialled clinically.

Ila" e patient Sh. 9 60 v.,as under observation for a mature a3e-related cataract of the right eye. Visual acuity of the affected eye before surgery - li,ht perception with coriect projection. The patient was subjected to surgery for extracapsular cataract extraction accompanied by imn .lantation of an intraocular lens. Used as the corneal DTotector was a 0.75-percent Tylose solution havin,3 a -=,13bule size of fron, 0.2 to 0.4 -was left 0 pm. The protector in the anterior eye chamber. Postoperative visual acuity 0.5. No preoperative and postoperative complications were observed.

:';XaMDle 3 0 a mixture of a 0-85 m 1 Of -Dercent aqueous sodium chloride and a phosphate buffer having the pH value of from 7.2 to 7.4 is doped with 1 g of dry powdery Tylose, 7hereupon the thus-obtained Tylose solution is allowed to dissolve in a cooler at +400 for 24 hours and is stirred for another hour to bring the concentration of the solu tion to 0.8 7ei-,bLt percent. The resultant Tylose - solution is then Dlaced in a centrifuze and sub-'ected to centrifuva tion for one hou-- at a speed of 2800J rpm. Next the super natant solution is decanted in the cold and stirred for 10 to 15 minutes, dravn in a syrinSe, and passed throu,-:-,h a membrane filter havin, a ore dia.-eter of 0.4 jam.

The thus-Droduced corneal Dxotector has been trialled clinically.

Female patient V-, 59 was under observation for a;ipe age-dependent cataract of the left eye, visual acaity Z) of the affected eye beia,, light perception vith correct projection. The patient 'T.as subjected to surgery for extracapsular cataract extraction accompanie d by implantation of an intraocular lens. Used as the corneal protector was a 0.8-percent Tylose. solution having a.3lobule size of from 0.2 to 0.4 m. The corneal protector was,left in the anterior eye chamber. Pos-tt-Poperative visual acuity 0.2. No intra- or postoperati-;e complications vere observed.

1 1 z:

1 i 1 -i,S- The herein-proposed corneal protector features lo-w Tylose concentration, which pxomo-Ves its accelerated elimination from the eye within the postoperative period. Besides, the c3lobule size (not exceeding 0.4. Atm) is below the phrsiological poze size, whicli contributes to natural filtration and hastens elimination of the protector from the eye by the natural route. Use of the proposed corneal protector enables one to reduce the degree of injury to the cornea an,,', decrease postoperative complications.

i 1 Cl ai ms - i 6 - 1. A cornea-protection composition comprising a physiologically acceptable, aqueous solution of Tylose, the amount of Tylose - being sufficient that the viscosity of the solution is great enough to allow mechanical support, but not so great as to cause a substantive increase in intraocular pressure, in situ.

2. A composition according to claim 1, wherein the concentration Of Tylose, is between about 0. 7% and about 0.8% in dispersed solution.

3. A composition according to claim 1 or 2, wherein the Tylose has a maximum globule size of 0. 4Lm.

4. A composition according to any preceding claim, wherein the solution is a saline solution.

5. A composition according to claim 4, wherein the saline solution contains about 0.85-percent aqueous sodium chloride.

6. A composition according to any preceding claim, further comprising a buffer having a pH value of from about 7.2 to about 7.4.

7. A corneal protector which is essentially a 0.7% to 0. 8% dispersed Tylose solution having a maximum globule size of 0.4Vm, in a mixture with 0.85% aqueous sodium chloride and a buffer having a pH value of from 7.2 to 7.4, said protector optionally further comprising any one or more suitable features as defined in any preceding 1 i i 1 1 1 1 i i i 1 1 1 1 j i 1 1! 1 i 1 claim, in any suitable combination.

8. A cornea -protection composition comprising Tylose, substantially as hereinbefore described, with particular reference to the accompanying Examples.

9. A process for producing a composition as defined in any preceding claim, comprising preparing a solution of the ingredients, subjecting the resulting solution to centrifugation, decanting and collecting the supernatan solution, and filtering and isolating the fraction having a maximum globule size of 0.4gm.

10. A process according to claim 9, wherein dissolution of Tylose is carried out between about OC and about 4C.

11. A process for producing a cornea-protection composition comprising Tylose, said process being substantially as hereinbefore described, with particular reference to the accompanying Examples.

Published 1992 at The Patent Office. Concept House. Cardiff Road. Newport. Gwent NP9 I RH Further copies may be obtained from Sales Branch. Unit 6. Nine Mile, Point. Cwrinfelinfach. Cros:i Keys. Newport. NPI 7HZ. Printed by Multiplex techniques ltd- St Mary Cray. Kent.