OPHTHALMOLOGICAL IMPLANT COMPRISING AN ACTIVE INGREDIENT RELEASE SYSTEM AND METHOD FOR PRODUCING AN OPHTHALMOLOGICAL IMPLANT OF THIS TYPE

Abstract

Provided are ophthalmological implants comprising an active ingredient release system which, when the ophthalmological implant is implanted, delivers at least one pharmacological active ingredient, the active ingredient release system comprising at least one hydrogel as a matrix, the hydrogel forming a layer on an optical portion of the implant, binding covalently to the optical portion and being charged with the at least one active ingredient. Also provided are methods for producing the ophthalmological implant comprising the active ingredient release system.

Claims

1. An ophthalmological implant, comprising: at least one hydrogel as a matrix, and at least one optical component, wherein the at least one hydrogel forms a layer on the optical component of the implant, is covalently bonded to the optical component, and is laden with at least one pharmacologically active ingredient, and wherein the at least one pharmacologically active ingredient is released when the ophthalmological implant is implanted into a tissue of a subject.

2. The ophthalmological implant as claimed in claim 1, wherein the ophthalmological implant is an intraocular lens.

3. The ophthalmological implant as claimed in claim 1, wherein the at least one hydrogel is degradable.

4. The ophthalmological implant as claimed in claim 1, wherein the hydrogel is comprised of any one or more of: poly(N-isopropylacrylamide), polyvinylalcohol, polyethyleneglycol, polylactic acid, polyethyleneimine, cellulose, cellulose ethers having methyl and/or ethyl and/or propyl groups, especially hydroxypropyl methylcellulose, hydroxyethyl methylcellulose and/or methylcellulose, glycosaminoglycans, especially hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, keratan sulfate, alginic acid, polymannuronic acid, polyguluronic acid, polyglucuronic acid, amylose, amylopectin, callose, chitosan, polygalactomannan, dextran, xanthan, a mixture, and/or a physiologically acceptable salt thereof.

5. The ophthalmological implant as claimed in claim 1, wherein the at least one active ingredient is: covalently bonded to the hydrogel via a biodegradable bond, covalently bonded to a monomer, and/or oligomer, distributed in the at least one hydrogel, and/or resides in polymer nanoparticles distributed within the at least one hydrogel that are biodegradable.

6. The ophthalmological implant as claimed in claim 1, wherein hydrogel comprises at least one surface region, and wherein the at least one pharmacologically active ingredient is covalently bonded to the at least one surface region of the at least one hydrogel.

7. The ophthalmological implant as claimed in claim 1, wherein the at least one pharmacologically active ingredient is one or more of a steroidal inflammation inhibitor, a non-steroidal inflammation inhibitor, a prostaglandin, a prostamide, an antibiotic, and a beta-blocker.

8. The ophthalmological implant as claimed in claim 1, wherein the ophthalmological implant is stored in a saturated solution of the at least one active ingredient.

9. A process for producing an ophthalmological implant, which comprises: providing an active ingredient release system, wherein the active ingredient release system releases at least one pharmacologically active ingredient when the ophthalmological implant is implanted into a subject, providing an optical component, coating the optical component with at least one hydrogel as matrix of the active ingredient release system, and covalently binding the at least one hydrogel to the optical component, wherein the at least one hydrogel is laden with the at least one active ingredient.

10. The process as claimed in claim 9, wherein covalently binding comprises: generating surface hydroxyl groups on the optical component; graft polymerizing at least one reactive silane compound comprising at least one functional group and a silane group onto the surface hydroxyl groups; and covalently binding the at least one hydrogel onto the at least one functional group of the grafted silane compound.

11. The ophthalmological implant as claimed in claim 2, wherein the intraocular lens is an accommodating intraocular lens, ring, or tube.

12. The ophthalmological implant as claimed in claim 11, wherein the intraocular lens is an accommodating ring, and wherein the ring is a capsular tension ring.

13. The ophthalmological implant as claimed in claim 1, wherein the hydrogel is biodegradable.

14. The ophthalmological implant as claimed in claim 1, wherein the at least one pharmacologically active ingredient is a COX-2 inhibitor.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The invention will now be described with reference to the drawings, wherein:

[0024] FIG. 1 is a schematic diagram of an active ingredient release system comprising a matrix composed of a biodegradable hydrogel with intercalated active ingredient molecules that are released by degradation of the hydrogel;

[0025] FIG. 2 is a schematic diagram of the active ingredient release system comprising a matrix composed of a non-degradable hydrogel with intercalated active ingredient molecules that are released from the hydrogel by diffusion;

[0026] FIG. 3 is a schematic of the progression of a coupling reaction of the biodegradable hydrogel onto an optical component of an ophthalmological implant and loading of the hydrogel with an active pharmacological ingredient;

[0027] FIG. 4 is a schematic of the progression of a coupling reaction of the non-degradable hydrogel onto an optical component of an ophthalmological implant, where the hydrogel is coupled to the active pharmacological ingredient via degradable bonds;

[0028] FIG. 5 is a schematic of the progression of release of the active ingredient present in the degradable hydrogel by biodegradation of the hydrogel; and,

[0029] FIG. 6 is a schematic of the progression of release of the active ingredient present in the non-degradable hydrogel.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] FIG. 1 shows a schematic diagram of an active ingredient release system 1 comprising a matrix composed of a biodegradable hydrogel 2 with intercalated active ingredient molecules 3 that are released into the environment by degradation of the hydrogel 2. The hydrogel 2 is selected, for example, from the group of poly(N-isopropylacrylamide), poly(vinyl alcohol), poly(ethylene glycol), hyaluronic acid, cellulose, poly(lactic acid) and the like. Such hydrophilic long-chain polymers are converted to hydrogels 2, for example, by simple crosslinking reactions. Owing to the large amount of hydrophilic groups, the hydrogel 2 can subsequently absorb a large amount of water, often several times its own starting weight or dry weight. The same interactions are utilized in order to physically “trap” active ingredient molecules 3 within the hydrogel system 2. In the present case, the hydrogel 2 is biodegraded, for example by enzymes that occur in the eye. This releases the previously “trapped” active ingredient molecules 3.

[0031] FIG. 2 shows a schematic diagram of the active ingredient release system 1 comprising a matrix composed of a non-degradable hydrogel 2 with intercalated active ingredient molecules 3 that, by contrast with FIG. 1, are released from the hydrogel 2 by diffusion. It can be seen that the hydrogel 2 swells as a result of absorption of additional water, which increases the pore size of the polymer network and facilitates or actually enables the diffusion of the active ingredient molecules 3. For long-lasting controlled release of the active ingredient molecules 3, it is possible to use hydrophilic active ingredient molecules 3 of maximum volume, since they only diffuse slowly out of the hydrogel 2 and hence reduce the likelihood of a burst release a short time after the implantation of an assigned ophthalmological implant 4 (see FIG. 3) into an eye. Small hydrophobic active ingredient molecules 3 are alternatively successfully incorporated into such polymer networks, for example by copolymerization with other monomers and oligomers, or by manipulation of the surface of the hydrogel 2. Alternatively, the active ingredient molecules 3 are also covalently bonded to the hydrogel 2 by bonds that are biodegradable or degradable in some other way. The speed of degradation of these degradable bonds are then used in some embodiments to essentially control the release of the active ingredient molecules 3. All the materials and techniques mentioned for production of medicament-laden hydrogels 2 are used in certain embodiments to appropriately modify the surfaces of optical components 5 and optionally also of tactile components (not shown) of ophthalmological implants 4.

[0032] In order to achieve covalent crosslinking of a hydrogel 2 with the surface of the implant 4 via a chemical reaction, it is possible to use various techniques. In an embodiment, reactive groups are grafted by, for example epoxides or thiols, onto the surface of the implant 4. During polymerization of the hydrogel 2 or of the hydrogel precursor 6, parts of the polymer network react with the modified surface, which achieves the immobilization of the hydrogel 2.

[0033] This is effected, in an example, via the use of what is called click chemistry on a chemically modified surface of the implant 4. In this way, the target surface of the implant 4 that is to be provided with the hydrogel layer is exposed to a plasma, which forms hydroxyl groups. These can readily react, for example, with triethoxysilanes having different reactive groups, which essentially gives rise to a surface covered completely or predominantly with such reactive groups. According to the type of reaction used, these groups then react directly with the polymers during the hydrogel synthesis. If, for example, an EDC/NHS-mediated amide coupling reaction is used for crosslinking of the hydrogel 2, the grafting of either carboxyl groups or amine groups would allow simultaneous formation of the hydrogel 2 and immobilization thereof on the surface of the implant 4. If, alternatively, a Michael-type thiol reaction is used, the grafting of thiols onto the surface would allow immobilization of the hydrogel 2. Graft reactions with triethoxysilanes allow for the introduction of a multitude of reactive groups on the surface of the implant 4 and allow controlled immobilization in relation to the types of reaction used in the production of the hydrogel 2, and hence high flexibility for preparation of immobilized medicament-eluting hydrogels 2. This offers a wide range of options by which intraocular lenses and other ophthalmological implants 4 modified with hydrogels 2 that release an active ingredient 3 can be produced.

[0034] FIG. 3 shows a schematic of the progression of a coupling reaction of the biodegradable hydrogel 2 onto an optical component 5 of an ophthalmological implant 4 and loading of the hydrogel 2 with an active pharmacological ingredient 3. In the example shown, the active ingredient molecules 3 are physically incorporated within the hydrogel 2 during formation. This is achieved in that the implant 4 is first provided in step a) and, in step b), the surface of the optical component 5 of the implant 4 in the region to be coated is provided by plasma activation with hydroxyl groups. These hydroxyl groups are subsequently exposed to reactive silanes, with use in the present case of 3-(triethoxysilyl)propan-1-amine by way of example. In this embodiment, amino groups are grafted therewith. It is generally possible also to use other silanes and other functional groups, provided that the types of reaction required are compatible with one another.

[0035] In a next step c), a mixture of a polymer skeleton or precursor 6 of the hydrogel 2 having amino groups, a crosslinker 7 having two (or more) carboxyl groups and optionally at least one degradable bond 8, the active ingredient 3 and EDC/NHS is applied to the surface of the optical component 5. This initiates peptide formation between the crosslinker 7, the precursor 6 and the surface-fixed amino groups, which forms the immobilized hydrogel 2 as the active ingredient release system 1 incorporating the active ingredient molecules 3. For the polymer or precursor 6 itself, it is possible to use any suitable polymer skeleton (for example, poly(ethylene glycol), hyaluronic acid, cellulose, alginate, et cetera), provided that they bear the reactive group(s) required or can be correspondingly modified to bear the reactive group(s) required. If, for example, a carbohydrate is used, it is possible to use a similar EDC/NHS-mediated peptide coupling for this purpose. Alternatively, functional groups may be reversed, in that, for example, carboxyl functions are grafted on and a crosslinker 7 having two (or more) amino groups is used.

[0036] The optional degradable bond 8 from the crosslinker 7 is degraded by hydrolysis, for example. For this purpose, in an embodiment, active ester bonds are provided. Alternatively, an enzymatic degradation is used, for example by the use of hyaluronic acid in the polymer skeleton of the hydrogel 2, which is degraded by hyaluronidase in the implanted state of the implant 4. Alternatively or additionally, it is possible to provide peptide bonds that are cleaved by peptidases.

[0037] FIG. 4 shows a schematic of the progression of a coupling reaction of the non-degradable hydrogel 2 onto the optical component 5 of the ophthalmological implant 4, where the hydrogel 2 is coupled to the active pharmacological ingredient 3 via degradable bonds 8. In other words, what is used in this embodiment is a non-(bio)degradable hydrogel 2. After plasma activation in step b), this is accomplished by a first grafting of alkene groups onto the surface of the optical component 5 in step c) by the silanization that has already been described. The silane used by way of example is triethoxy(hex-5-enyl)silane. In a next step d), a mixture of thiol-containing polymers or precursors 6 and crosslinkers 7 having two (or more) alkene groups is applied to the modified surface. This induces a Michael-type thiol reaction between the alkenes and thiol groups that leads to the active ingredient release system 1 having the crosslinked surface-immobilized hydrogel 2 and the intercalated active ingredients 3. While the active ingredients 3 in the example shown are physically incorporated within the hydrogel 2 and are subsequently released by diffusion over time, in an alternative embodiment provided are biodegradable bonds 8 in order to covalently bond the active ingredient molecules 3 to the polymer skeleton of the hydrogel 2. This allows for better control over the release profile of the active ingredient 3 via the rate of degradation of these bonds 8. In this way, it is also possible to release relatively small active ingredient molecules 3 over a prolonged period without initial burst release. The (biological/hydrolytic) degradation of the bond 8 between the hydrogel 2 and the active ingredient 3 is significant in determining the release profile.

[0038] Similarly to the embodiment described above, any suitable polymer or any suitable precursor 6 is substitutable that is biocompatible and modifiable with the desired chemical groups and is capable of forming hydrogels 2. It is especially possible to use alternative configurations of click chemistry to obtain an immobilized hydrogel 2 with intercalated active ingredient 3. Both embodiments are merely examples of ways in which medicament-eluting hydrogels 2 can be produced as active ingredient release system 1 on surfaces of ophthalmological implants 4, and are not limited to the types of reaction shown in these examples.

[0039] FIG. 5 shows a schematic of the progression of release of the active ingredient 3 present in the degradable hydrogel 2 by biodegradation of the degradable bonds 8 of the hydrogel 2. The rate of degradation of the hydrogel 2 defines the rate of active ingredient release of the active ingredient release system 1.

[0040] FIG. 6 shows a schematic of the progression of release of the active ingredient 3 present in the non-degradable hydrogel 2. The active ingredient molecules 3 are bonded to the nondegradable polymer skeleton of the hydrogel 2 via degradable bonds 8. After the degradation of the bonds 8, the active ingredients 3 are released in a diffusion-based manner, which enables particularly long-lasting, uniform release.

[0041] What is thus permitted by the use of the active ingredient release systems 1 described for coating of a portion or the entire surface area of the optical component 5 of an ophthalmological implant 4, by comparison with an exclusive arrangement on a tactile component (not shown), is the provision of a great amount of active ingredient without limiting the optical and tactile functionality of the implant 4.

[0042] A further advantage relates to reduced tackiness of the surface of the implant 4. A problem with some hydrophobic IOL materials is that their surface is comparatively tacky. The effect of this can be that IOL unfolding can be unfavorable after surgical introduction into the eye. In the extreme case, one or both tactile surfaces can get stuck to the IOL surface of the optical component 5, which requires additional manipulation of the IOL by the doctor. This tack can be avoided by the surface being coated with multiple heparin and polymin layers. However, there are a number of problems with this approach. The use of the active ingredient release system 1 of the invention for partial or complete coating of the optical component 5 also solves the problem of tack and some of the problems with other established coatings.

[0043] A further advantageous aspect of the active ingredient release system 1 is improved lubrication. For surgical insertion, intraocular lenses 4 are folded and injected into the eye with an injector. In order to prevent possible damage to the cornea by reduction of the incision size, it is desirable to keep the injection tips as small as possible. This leads to a certain physical force that has to be expended in order to force the folded IOL 4 through the injector. These forces are generally reduced by glide coating of the inner wall of the injector. The immobilized hydrogel 2 of the active ingredient release system 1 may offer (additional) lubrication and either improve the injection process or completely replace the lubrication at the injector wall that has been needed to date.

[0044] The active ingredient release system 1 is also used in some embodiments for PCO prevention. A common post-operative complication for cataract operations is “post-operative capsular opacification” (PCO): Cells grow on the surface 5 of the capsular bag and IOL, and cause occlusion of the capsular bag with time. Although this can be treated by application of laser, it is nevertheless desirable to delay the commencement of PCO as far as possible or prevent it completely. The above-described surface modification of an IOL 4 with an immobilized hydrogel 2 that releases active ingredients 3 can slow or completely prevent PCO development. Furthermore, the surface of the hydrogel 2 can optionally be modified in such a way that PCO prevention is additionally assisted, for example, by the grafting of additional functional groups onto the surface of the hydrogel 2. For example, COX-2-blocking NSAIDs can help in the prevention of PCO. Such NSAIDs are used for the treatment of inflammation and can also prevent or considerably slow the development of PCO by being incorporated into the hydrogel 2.

[0045] The active ingredient release system 1 is additionally used in some embodiments as a platform for different medicaments and active ingredients 3. As well as the use of inflammation inhibitors as active ingredient 3, it is entirely possible to use the active ingredient release system 1 for uptake and release of other medicament types. This embodiment includes antibiotics for prevention of bacterial infection or medicaments for reduction of intraocular pressure to counter the commencement of glaucoma inter alia. If the hydrogel 2 offers a sufficiently large reservoir, it is also possible to use two or more active ingredients 3 for simultaneous prolonged release.

[0046] With regard to hydrophilic IOLs and other hydrophilic ophthalmological implants 4 that are stored in water until implantation, there are various possible strategies for achieving a high storage stability. For example, an implant 4 that has been coated with a non-(bio)degradable hydrogel 2 can be stored in a saturated active ingredient solution. In this way, the active ingredient concentration remains constant during storage within the active ingredient release system 1.

[0047] Alternatively or additionally, degradable bonds 8 are incorporated that are not hydrolysis-sensitive. In one example, active ingredients 3 are bound to the hydrogel 2 via degradable peptide bonds 8. Alternatively or additionally, crosslinkers 7 are incorporated that contain peptide bonds and/or generate peptide bonds. Peptidase enzymes in the environment of the eye, after implantation, can then degrade the hydrogel 2 and/or separate the active ingredients 3 from the polymer skeleton of the hydrogel 2. No enzymes are present during storage, which means that the active ingredient release system 1 is storage-stable.

[0048] A further variant involves the production or use of a hydrogel 2 that greatly limits the diffusion of the intercalated active ingredients 3, for example via small pore size and large active ingredient molecules 3. The hydrogel 2 is, in an embodiment, produced from an enzymatically degradable component, for example, hyaluronic acid. The active ingredient release system 1 is stable during storage since it is only in the implanted state in the environment of the eye that it is degraded with hyaluronidase (or a comparable enzyme), and the intercalated active ingredients 3 are released.

[0049] The parameter values specified in the documents to define process and measurement conditions for the characterization of specific properties of the subject matter described herein are also considered to be encompassed by the scope of the description in the context of deviations—for example due to measurement errors, system errors, weighing errors, DIN tolerances and the like.

[0050] It is understood that the foregoing description is that of the preferred embodiments and that various changes and modifications may be made thereto without departing from the spirit and scope of the invention as defined in the appended claims.

LIST OF REFERENCE NUMERALS

[0051] 1 Active ingredient release system [0052] 2 Hydrogel [0053] 3 Active ingredient [0054] 4 Implant [0055] 5 Optical component [0056] 6 Precursor [0057] 7 Crosslinker [0058] 8 Degradable bond