OPHTHALMOLOGICAL IMPLANT, METHOD FOR PRODUCING AN OPHTHALMOLOGICAL IMPLANT, AND USE OF A LIGAND FOR PRODUCING AN OPHTHALMOLOGICAL IMPLANT

Abstract

The disclosure relates to an ophthalmological instrument with a main body and at least one ligand (L) immobilized on the main body. In the implanted state of the ophthalmological implant, the ligand (L) binds and/or deactivates at least one fibrinogen and/or cytokine. The disclosure further relates to a method for producing an ophthalmological implant, and to a use of a ligand (L), via which at least one fibrinogen and/or cytokine is to be bound and/or deactivated in the implanted state of the ophthalmological implant, for producing an ophthalmological implant.

Claims

1. An ophthalmological implant, which comprises: a main body, and at least one ligand immobilized on the main body, wherein the at least one ligand binds and/or deactivates at least one fibrinogen and/or cytokine when contacted with the at least one ligand and when the ophthalmological implant is implanted.

2. The ophthalmological implant of claim 1, wherein the ligand is embedded in a matrix and/or the ligand is covalently bonded to at least one polymer.

3. The ophthalmological implant of claim 2, wherein the at least one ligand is covalently coupled to the at least one polymer via a spacer.

4. The ophthalmological implant of claim 2, wherein the at least one polymer is a polysaccharide selected from of cellulose, a cellulose ether, a glycosaminoglycan, chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, keratan sulfate, alginic acid, polymannuronic acid, polyguluronic acid, polyglucuronic acid, amylose, amylopectin, callose, chitosan, polygalactomannan, dextran, xanthan gum, and/or a mixture thereof, and/or a physiologically acceptable salt thereof.

5. The ophthalmological implant of claim 1, wherein the main body further comprises at least one haptic part and at least one optical part.

6. The ophthalmological implant of claim 1, wherein the main body further comprises an accommodation region, and wherein the immobilized ligand is attached to the accommodation region.

7. The ophthalmological implant of claim 1, wherein at least part of a surface of the main body is coated with a layer system which comprises the immobilized ligand.

8. The ophthalmological implant of claim 7, wherein the layer system comprises at least two layers, wherein at least one of the at least two layers comprises the immobilized ligand and at least one of the at least two layers comprises a polymer selected from polyethylenimines, polyamines, and polyallylamines.

9. The ophthalmological implant of claim 1, wherein the at least one ligand further binds and/or deactivates TGF-β, TNF-α, and/or interleukin-1.

10. The ophthalmological implant of claim 1, wherein the at least one ligand is selected from antibodies, Fab fragments, single-chain variable fragments (scFv), and multivalent antibody fragments.

11. A method for producing an ophthalmological implant, which comprises: immobilizing at least one ligand on a main body, wherein at least one fibrinogen and/or cytokine is bound and/or deactivated on contacting the at least one ligand when the ophthalmological implant is implanted.

12. The method of claim 11, wherein the at least one ligand (L) is covalently coupled to a polysaccharide (P.

13. The method of claim 11, further comprising: generating a layer system comprising at least two layers on a surface region of the main body, wherein at least one of the at least two layers comprises the immobilized ligand and at least one of the at least two layers comprises a polymer selected from polyethylenimines, polyamines, and polyallylamines.

14. The method of claim 11, wherein the main body further comprises an active-substance delivery system designed to deliver alkali metal ions selected from Li.sup.+, K.sup.+, Rb.sup.+, and/or Cs.sup.+, when the ophthalmological implant is implanted.

15. The ophthalmological implant of claim 2, wherein the at least one polymer is at least one biopolymer.

16. The ophthalmological implant of claim 4, wherein the at least one polymer is the cellulose ether substituted with methyl and/or ethyl and/or propyl groups.

17. The ophthalmological implant of claim 16, wherein the cellulose ether substituted with methyl and/or ethyl and/or propyl groups is hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, and/or methylcellulose.

18. The ophthalmological implant of claim 4, wherein the polysaccharide is glycosaminoglycan, and wherein the glycosaminoglycan is hyaluronic acid.

19. The ophthalmological implant of claim 4, wherein the physiologically acceptable salt is an alkali metal salt.

20. The ophthalmological implant of claim 5, wherein the ligand is at least attached to the haptic part.

21. The ophthalmological implant of claim 6, wherein the ligand is covalently bonded to the main body.

22. The ophthalmological implant of claim 10, wherein the ligand is an antibody, and wherein the antibody is an anti-TGF-β antibody, anti-TGFα antibody, and/or anti-interleukin-1 antibody.

23. The method of claim 12, wherein the covalent coupling is performed by: providing the ligand, wherein the ligand comprises at least one amino group; providing the polysaccharide, wherein the polysaccharide comprises at least one carboxylic acid group; activating, at least partially, the carboxylic acid group of the polysaccharide; and coupling the activated carboxylic acid group with the at least one amino group of the ligand.

24. A method of treating and/or reducing the occurrence of posterior capsule opacification or cataracta secundaria, which comprises: implanting the ophthalmological implant of claim 1 into an eye of a subject in need thereof.

25. The method of claim 24, wherein the subject has had one or more cataract operations in the eye.

26. The method of claim 24, wherein the subject is human.

27. The method of claim 24, wherein the ligand is embedded in a matrix and/or the ligand is covalently bonded to at least one polymer.

28. The method of claim 27, wherein the at least one ligand is covalently coupled to the at least one polymer via a spacer.

29. The method of claim 27, wherein the at least one polymer is a polysaccharide selected from of cellulose, a cellulose ether comprising methyl and/or ethyl and/or propyl groups, a glycosaminoglycan, chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, keratan sulfate, alginic acid, polymannuronic acid, polyguluronic acid, polyglucuronic acid, amylose, amylopectin, callose, chitosan, polygalactomannan, dextran, xanthan gum, and/or a mixture thereof, and/or a physiologically acceptable salt thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The invention will now be described with reference to the drawings wherein:

[0027] FIG. 1 shows a schematic side view of part of an ophthalmological implant known from the prior art;

[0028] FIG. 2 shows an enlarged depiction of the detailed area II shown in FIG. 1;

[0029] FIG. 3 shows an enlarged depiction of the detailed area III shown in FIG. 1;

[0030] FIG. 4 shows a depiction of the principle of a reaction for covalently coupling a ligand to a polysaccharide;

[0031] FIG. 5 shows a chemical formula of the polysaccharide coupled with the ligand;

[0032] FIG. 6 shows a schematic lateral sectional view of one embodiment of an ophthalmological implant according to the invention; and,

[0033] FIG. 7 shows a schematic view of part of the ophthalmological implant according to the invention, which has immobilized thereon the polysaccharide coupled with the ligand.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] FIG. 1 shows a schematic side view of part of an ophthalmological implant 1 known from the prior art that, in the present case, is configured as an intraocular lens. The implant 1 comprises, in a manner known per se, a haptic part 2 and an optical part 3. For better understanding, FIG. 2 shows an enlarged depiction of the detailed area II shown in FIG. 1, whereas FIG. 3 shows an enlarged depiction of the detailed area III shown in FIG. 1. It can be seen that the implant 1, in particular in the region of the haptic part 2, does not lie continuously flush against the posterior capsular bag 4, since the capsular bag 4 forms folds and cavities. As schematically depicted in FIG. 2, the result of this is that so-called E cells 5, which are located in the equatorial region of the capsular bag 4, are mitotically active and normally form a cobblestone-like monolayer, progressively dissociate away from one other under the influence of transforming growth factor beta (TGF-β) and assume various elongated spindle shapes 6. Furthermore, the spindle-shaped cells 6 expressed α-SMA (alpha-actin-2, alpha smooth muscle actin) to a considerable extent, which leads to the development of posterior capsule opacification (PCO, cataracta secundaria). It can be seen in FIG. 3 that the spindle-shaped cells 6, which lead to fibrosis and wrinkling, also infiltrate the optical part 3 of the implant 1. What sometimes form are so-called Wedl cells 7, which form inflated, irregularly shaped fibers, tear and spread cell debris. These aberrant Wedl cells 7 and fragments thereof also collect in a disordered manner on the optical part 3 and form sites of clouding. Histopathologically, the Wedl cells 7 correspond to the clinically visible Hirschberg-Elschnig pearls, which are also responsible for the formation of the so-called Soemmering ring, which was first described in connection with eye trauma.

[0035] FIG. 4 shows a depiction of the principle of a reaction for covalently coupling a ligand L to a polymer or biopolymer, which, in the present case and by way of example, is a polysaccharide P, namely hyaluronic acid HA or carboxymethylcellulose CMC. The ligand L is, in some embodiments, also coupled with other polymers instead of the polysaccharide P. Hyaluronic acid belongs to the group of glycosaminoglycans, which are polysaccharides consisting of repetitive, linearly constructed and acidic disaccharide units. The disaccharide units of glycosaminoglycans generally include esters of a uronic acid. It is glucuronic acid in most cases, less frequently iduronic acid. The disaccharide units are linked to an amino sugar (for example, N-acetylglucosamine) via a 1,3-glycosidic bond. The formation of a chain of disaccharide units is achieved via 1,4-glycosidic bonds. Owing to relevant side groups (hydroxyl, carboxy or sulfate groups), the glycosaminoglycans are negatively charged. Glycosaminoglycans are divisible into sulfated and nonsulfated glycosaminoglycans. Hyaluronic acid (hyaluronan) is the only nonsulfated glycosaminoglycan and has free carboxy groups which, as a result of activation with the aid of N-hydroxysulfosuccinimide (NHS/sulfo-NHS) and subsequent carbodiimide-mediated (for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride/EDC and/or N′,N′-dicyclohexylcarbodiimide/DCC) reaction, can be covalently coupled with the ligand L. If necessary, 4-(dimethylamino)pyridine (4-DMAP) can be used as a nucleophilic catalyst in order to couple sterically demanding ligands L under mild conditions. Covalent coupling is in some embodiments analogously carried out with acid groups of carboxymethylcellulose.

[0036] In the embodiment shown in FIG. 4, the ligand L used is, by way of example, an anti-TGF-β antibody which is coupled to the polysaccharide P via a free amino group. Alternatively, in other embodiments, the ligand L is, for example, an anti-TGF-α antibody, an anti-interleukin-1 antibody, a Fab fragment, a single-chain variable fragment (scFv), or a multivalent antibody fragment (scFv multimer), and any combinations thereof, and it can be coupled with the polysaccharide P.

[0037] The resulting polysaccharide P coupled with the ligand L is shown schematically in FIG. 5, with an exemplary depiction of hyaluronic acid as polysaccharide P and an antibody, for example anti-TGF-β and/or anti-IL-1α, as ligand L. The polysaccharide-ligand compound PL is used in some embodiment for removal and/or biological deactivation of fibrinogens and/or cytokines with which an ophthalmological implant 10 comes or can come into contact when it has been implanted. The polysaccharide-ligand compound PL is in some embodiments present as a physiologically acceptable salt, in particular as a lithium salt. To this end, lithium hyaluronate, in an embodiment, is used as reactant and coupled with the ligand L. Alternatively, the polysaccharide-ligand compound PL is, in another embodiment, after production, converted into a physiologically acceptable salt, for example a lithium salt.

[0038] Without wishing to be bound by theory, it is assumed that topically administered alkali metal ions from the group consisting of Li.sup.+, K.sup.+, Rb.sup.+, and Cs.sup.+, can considerably slow down or even completely prevent the development of PCO and fibrosis, efficacy generally being the highest for Li.sup.+. The ions prevent the conversion of equatorial epithelial cells which were not removed during an eye operation into fibroblasts, fibroblasts being the main cause of PCO and fibrosis. The effect is presumably based on the ability of alkali metal ions of the group mentioned to stabilize the quiescent, polarized phenotype of lens epithelial cells. The epithelial cells in question therefore maintain the apical-basolateral polarity and cobblestone-like arrangement that are characteristic of lens epithelial cells. When applied locally, the alkali metal ions of the group mentioned also block the potent epithelial mesenchymal transition (EMT)-promoting effect of transforming growth factor beta (TGF-β) on lens epithelial cells. Experiments have shown that cells in TGF-β-treated explants progressively dissociated away from one another and assumed various elongated spindle shapes. Furthermore, the cells expressed α-SMA (apha-actin-2, alpha smooth muscle actin) to a considerable extent. These features are characteristic of the development of PCO. As a result of treatment with alkali metal ions of the group mentioned, it was possible to block the formation of α-SMA effectively and to stabilize the cells in the polarized, adherent, cobblestone-like monolayer. The counterions (anion) which can be used in relation to the alkali metal ion(s) (cation) used are in principle all suitable or pharmaceutically acceptable anions formed from atoms and/or molecules. Particular preference is given to chloride ions (Cl.sup.−). The active-substance delivery system can in general exclusively consist of a compound containing alkali metal ions of the group mentioned. Alternatively, further components can be provided, for example components for adjusting delivery of active-substance alkali metal ions or components in the form of binding or release agents.

[0039] FIG. 6 shows a schematic lateral sectional view of one embodiment of an ophthalmological implant 10 that has been implanted in a capsular bag 4 of a patient. In the present case, the implant 10 is configured as an accommodating intraocular lens (IOL) and comprises a main body 12 having a haptic part 2 and an optical part 3 which has a lens body 8. Furthermore, the implant 10 comprises a hollow, centrally arranged cylinder 14 which, when implanted, applies a force to a spring-mounted membrane 16 in an axial manner with respect to a central axis of the implant 10. The membrane 16 is part of a wall of a gas-filled cavity 18 and delimits the cavity 18 in the direction of the cylinder 14, whereas the optical part 3 delimits the side of the cavity 18 that is facing away from the cylinder 14.

[0040] It can be seen that the haptic part 2 and the edge of the cylinder 14 have situated therebetween, in the axial direction, an encircling accommodation region, marked with a circle VI, into which equatorial lens epithelial cells (E cells) 5 can penetrate and can, as a result of secretion of cytokines and/or fibrinogens, for example of TGF-β, interleukin-1 and the like, cause cell proliferation, cell differentiation and infiltration of the implant 10 with fibroblasts and the like, which can consequently lead to PCO and fibrosis.

[0041] In order to prevent the occurrence of PCO and fibrosis, the polysaccharide-ligand compound PL is immobilized on the ophthalmological implant 10. In relation to this, FIG. 7 shows a schematic view of part of the ophthalmological implant 10, with immobilization of the polysaccharide-ligand compound PL in the accommodation region VI in order to bind and/or biologically deactivate cytokines and/or fibrinogens in the aqueous humor. The polysaccharide-ligand compound PL has been arranged in such a way that the accommodation ability of the implant 10 is not hindered. The polysaccharide-ligand compound PL has preferably been arranged in an encircling manner on the outer circumference of the cylinder 14 and thus in the vicinity of the E cells 5 in order to ensure particularly reliable and long-lasting protection. Alternatively, the polysaccharide-ligand compound PL has been arranged at one or more discrete sites on the outside of the implant 10. It is likewise conceivable that the implant 10 has been partially or completely coated with the polysaccharide-ligand compound PL.

[0042] In some embodiments, a layer system (not shown) having two or more layers is also provided. Irrespective of this, it is also possible to form the implant 10 from the polysaccharide-ligand compound PL at least in part. In addition to the polysaccharide-ligand compound PL, one or more further compounds are optionally provided, for example in order to achieve additional medical effects, to adjust chemical and/or mechanical properties and/or to bring about or assist immobilization on the implant 10.

[0043] For example, the polysaccharide P is in some embodiments bonded to the material of the implant 10 via 1,4-butanediol diglycidyl ether as a crosslinker. The crosslinking rate can be used to control or adjust the amount of ligands and thus to control the theoretically bindable and/or deactivatable amount of fibrinogens/cytokines and to control the biodegradability of the polysaccharide P (for example, by hyaluronidase)

[0044] In the nonimplanted state, the polysaccharide-ligand compound PL is in some embodiments nonhydrated or anhydrous, in particular lyophilized, in order to be able to compress the implant 10 as much as possible and to implant it through an appropriately small incision. Both polysaccharides P or other polymers and ligands L such as, for instance, antibodies are obtainable in anhydrous form, for example by lyophilization, and also storable for a long time as a covalent conjugate in this form. Hydration with a corresponding increase in volume then takes place automatically after implantation as a result of contact with aqueous humor. The covalent bonding of the ligand L and the immobilization of the polysaccharide P on the implant 10 prevent the aqueous humor from washing out the ligand L or the polysaccharide-ligand compound PL.

[0045] Alternatively or additionally, in an embodiment, the polysaccharide and/or another type of polymer, optionally in the form of a hydrogel or a foam, forms a matrix—in particular biodegradable matrix—in which the ligand L or multiple different ligands L are embedded and thereby immobilized in the matrix. The other type of polymer is, in some embodiments, a homopolymer or copolymer that has been optionally crosslinked. For example, the other type of polymer is an alginate. Alternatively or additionally, the matrix contains or consists of an alkali metal salt, for example lithium hyaluronate. As a result, what can be realized in addition to the immobilized ligand L is a kind of active-substance delivery system which can bind and/or deactivate cytokines and/or fibrinogens from the aqueous humor over an adjustable period of time. Furthermore, the ligand L immobilized in the matrix can also be released over time as a result of degradation of the matrix.

[0046] The parameter values specified in the documents to define process and measurement conditions for the characterization of specific properties of the subject matter of the described embodiments should also be considered to be encompassed herein in the context of deviations—for example due to measurement errors, system errors, weighing errors, DIN tolerances, and the like.

[0047] It is understood that the foregoing description is that of various embodiments and that various changes and modifications may be made thereto without departing from the spirit and scope as defined in the appended claims.

LIST OF REFERENCE SIGNS

[0048] 1 Implant (prior art) [0049] 2 Haptic part [0050] 3 Optical part [0051] 4 Capsular bag [0052] 5 E cells [0053] 6 Cells [0054] 7 Wedl cells [0055] 10 Implant according to the invention [0056] 12 Main body [0057] 14 Cylinder [0058] 16 Membrane [0059] 18 Cavity [0060] VI Accommodation region [0061] P Polysaccharide [0062] L Ligand [0063] PL Polysaccharide-ligand compound [0064] HA Hyaluronic acid [0065] CMC Carboxymethylcellulose