OPHTHALMOLOGICAL IMPLANT WITH AN ACTIVE SUBSTANCE DELIVERY SYSTEM AND METHOD FOR PRODUCING SUCH AN OPHTHALMOLOGICAL IMPLANT

Description

Technical area

[0001] The invention relates to an ophthalmic implant with a drug delivery system designed to deliver at least one pharmacologically active ingredient in the implanted state of the ophthalmic implant. The invention further relates to a method for producing such an ophthalmic implant. State of the art

[0002] Fibrosis (also known as fibrosis in technical terms) is the pathological proliferation of connective tissue in human and animal tissue, the main component of which is collagen fibers. This causes the tissue of the affected organ to harden, resulting in scarring which, in advanced stages, can limit the function of the organ in question. When using ophthalmic implants, such as intraocular lenses (IOLs), various complications can arise due to interactions between the implant and adjacent biological tissue, of which fibrosis is particularly problematic. For example, after cataract surgery, a condition known as posterior capsule opacification (PCO, secondary cataract) sometimes occurs. PCO is a postoperative clouding of the lens capsule following the surgical extraction of a natural lens.The remaining lens epithelial cells (E cells) in the equatorial region of the capsular bag are mitotically active and can transform into fibroblasts. These then trigger a type of wound healing, forming collagen-containing connective tissue. Since some fibroblast subtypes not only migrate to the inner surface of the capsular bag but can also contract, wrinkling occurs within the capsular bag. The clouding of the capsule is thus the result of a wound healing process and associated scarring. Since the resulting lens clouding has different causes than the original cataract, it is referred to as a "secondary cataract." A clinically significant secondary cataract can lead to reduced visual acuity, color perception, and contrast sensitivity, as well as increased glare.

[0003] Secondary cataracts are a common complication following extracapsular cataract surgery (ECCE) and subsequent intraocular lens (IOL) implantation into the capsular bag. Without IOL implantation into the empty capsular bag, the risk of secondary cataracts is significantly increased, as unimpeded cell migration to the posterior surface of the capsular bag is possible.

[0004] The incidence of secondary cataracts increases over time after surgery. A meta-analysis of cases of secondary cataracts for all existing types of IOLs showed an approximate average increase of 12% after one year and an approximate average increase of 30% after five years. The age of the patient also appears to be a crucial factor, so it must be expected that almost all treated children and adolescents could suffer from postoperative secondary cataracts after a certain period of time.

[0005] Another common postoperative complication of cataract surgery is eye inflammation. This is caused by the wound in the cornea created by the corneal incision required to replace the natural lens with an artificial implant. This physical trauma can trigger an inflammatory response by releasing inflammatory mediators such as prostaglandins and leukotrienes, which subsequently trigger an immune response within the eye. In the short term, this can cause pain and discomfort for the patient. If not properly managed, persistent inflammation can lead to serious side effects such as posterior synechia, uveitis, and secondary glaucoma. It is therefore important to manage the postoperative process as well as possible.

[0006] Postoperative inflammation management is typically performed with medication. Currently, there are two recognized drug classes: one based on corticosteroids and one based on so-called "non-steroidal anti-inflammatory drugs" (NSAIDS). Steroidal medications are generally considered more effective but have side effects such as increased intraocular pressure. NSAIDs cause fewer complications but are generally less effective, although research on this topic is still ongoing.

[0007] The need for patient compliance also poses a certain problem. Anti-inflammatory medications are usually prescribed for 4-6 weeks and must be administered by the patient themselves via eye drops during this time. However, patients sometimes do not adhere to their medication regimen. This can be due to, for example, not recognizing the need for treatment, not wanting or being able to afford the cost of the medication, not being physically able to administer the medication correctly themselves, or forgetting to administer it. This lack of adherence to the medication schedule is often observed in more than half of patients. Even with regular examinations, however, this lack of adherence to the medication schedule is often not detectable by a doctor.In addition, there are some areas where patients do not regularly attend a practice for examinations, for example, due to long travel times. These omissions can lead to problems with postoperative treatment and discomfort for the patient. Therefore, it is highly desirable to avoid active patient participation in the implementation of a postoperative medication plan whenever possible and to find a way to ensure correct medication administration. This should preferably be done in such a way that such a solution is, or can be, integrated into the normal course of eye surgery.

[0008] WO 2008 / 113043 A1 discloses an ophthalmic implant designed as an intraocular lens with an optical part and two haptic parts. A drug delivery system is arranged on at least one of the haptic parts to deliver a pharmacologically active agent when the implant is in place.

[0009] WO 1995 / 03783 A1 describes an intraocular polymer device and a method for its manufacture and use, wherein the polymer device comprises a polymer and at least one cytotoxic agent, in particular an immunotoxin for the prevention and treatment of secondary cataracts.

[0010] DE 197 00 082 A1 discloses a method for producing cell proliferation-inhibiting, covalently fixed coatings on the surface of substrates for the medical field. This involves radiation-induced graft polymerization.

[0011] A disadvantage of the known ophthalmic implant is the fact that the amount of deliverable drug is comparatively small, since only the thin haptic parts are used, unless the delivery system itself is relatively bulky. However, this would increase the required incision size during implantation and make the lens less safe for surgical use. Furthermore, it would increase the likelihood of impairing the functionality of the haptic parts and thus also of the optical part. Description of the invention

[0012] The object of the present invention is to create an ophthalmic implant that enables improved and longer-lasting drug delivery. A further object of the invention is to enable the production of such an ophthalmic implant.

[0013] The objects are achieved according to the invention by an ophthalmic implant having the features of patent claim 1 and by a method having the features of patent claim 9. Advantageous embodiments with expedient developments of the invention are specified in the respective subclaims, wherein advantageous embodiments of each aspect of the invention are to be regarded as advantageous embodiments of the respective other aspect of the invention.

[0014] A first aspect of the invention relates to an ophthalmic implant according to claim 1 with a drug delivery system which is designed to deliver at least one pharmacologically active ingredient in the implanted state of the ophthalmic implant. According to the invention, the drug delivery system is present in polymer nanoparticles distributed in the hydrogel. An improved and longer-lasting drug delivery is made possible by the drug delivery system comprising at least one hydrogel as a matrix, wherein the hydrogel forms a layer on an optical part of the implant, is covalently bound to the optical part, and is loaded with the at least one drug. In other words,that the drug delivery system is arranged as a coating on the optical part of the implant and immobilized by covalently bonding the hydrogel to the optical part. The hydrogel generally acts as a matrix for the drug to be delivered, with which the hydrogel is loaded. This makes it possible, in contrast to an arrangement on a haptic part, to use a significantly larger area of ​​the implant for the drug delivery system with a correspondingly higher amount of drug, without having to accept restrictions regarding the space requirements, implantability, and functionality of the implant. Since hydrogels, by definition, contain a comparatively large amount of water in the hydrated state and can often absorb several times their own weight in water upon contact with water,Their refractive index in the implanted and hydrated state is comparable to that of the environment around the eye. Therefore, hydrogels are practically invisible to the human and animal eye. This allows the hydrogel, as the matrix of the drug delivery system, to be applied in a layered manner, i.e., across the entire surface and not in the form of isolated particles or the like, to the optical surface of the implant, as it does not impair the optical properties of the optical part. Furthermore, in this way, implants can be equipped with the drug delivery system independently of a haptic part, for example, implants with only one haptic part or implants without haptic parts. If the implant has one or more haptic parts, it can be providedthat the haptic part or parts is / are formed without an active ingredient delivery system. Alternatively, the active ingredient delivery system can also be formed on one or more haptic parts in addition to the optical part, although this is generally less preferred. The active ingredient delivery system can in principle be arranged on one or more surface areas of the optical part or on the entire surface of the optical part. For example, the hydrogel can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62 %, 63 %, 64 %, 65 %, 66 %, 67 %, 68 %, 69 %, 70 %, 71 %, 72 %, 73 %, 74 %, 75 %, 76 %, 77 %, 78 %, 79 %, 80 %, 81 %, 82 %, 83 %, 84 %,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the surface of the optical part. Furthermore, the drug delivery system can form a single layer or be multi-layered, i.e. be made up of two or more layers, with a single layer generally being preferred. In the case of multiple layers, these can each have the same composition or different compositions, be of the same or different thicknesses, and contain the same or different active ingredients or combinations of active ingredients. The two or more layers can also be covalently coupled to one another in order to ensure a particularly reliable connection of the entire layer system to the optical part. The total thickness of the hydrogel layer(s) can be up to 200 µm in certain applications, for example 1 µm, 2 µm, 3 µm, 4 µm, 5 µm, 6 µm, 7 µm, 8 µm, 9 µm, 10 µm, 11 µm, 12 µm, 13 µm, 14 µm, 15 µm, 16 µm,17 µm, 18 µm, 19 µm, 20 µm, 21 µm, 22 µm, 23 µm, 24 µm, 25 µm, 26 µm, 27 µm, 28 µm, 29 µm, 30 µm, 31 µm, 32 µm, 33 µm, 34 µm, 35 µm, 36 µm, 37 µm, 38 µm, 39 µm, 40 µm, 41 µm, 42 µm, 43 µm, 44 µm, 45 µm, 46 µm, 47 µm, 48 µm, 49 µm, 50 µm, 51 µm, 52 µm, 53 µm, 54 µm, 55 µm, 56 µm, 57 µm, 58 µm, 59 µm, 60 µm, 61 µm, 62 µm, 63 µm, 64 µm, 65 µm, 66 µm, 67 µm, 68 µm, 69 µm, 70 µm, 71 µm, 72 µm, 73 µm, 74 µm, 75 µm, 76 µm, 77 µm, 78 µm, 79 µm, 80 µm, 81 µm, 82 µm, 83 µm, 84 µm, 85 µm, 86 µm, 87 µm, 88 µm, 89 µm, 90 µm, 91 µm, 92 µm, 93 µm, 94 µm, 95 µm, 96 µm, 97 µm, 98 µm, 99 µm, 100 µm, 101 µm, 102 µm, 103 µm, 104 µm, 105 µm, 106 µm, 107 µm, 108 µm, 109 µm, 110 µm, 111 µm, 112 µm, 113 µm, 114 µm, 115 µm, 116 µm, 117 µm, 118 µm, 119 µm, 120 µm, 121 µm, 122 µm, 123 µm, 124 µm, 125 µm, 126 µm, 127 µm, 128 µm, 129 µm, 130 µm, 131 µm, 132 µm, 133 µm, 134 µm, 135 µm, 136 µm, 137 µm, 138 µm, 139 µm, 140 µm, 141 µm, 142 µm, 143 µm, 144 µm, 145 µm, 146 µm, 147 µm, 148 µm, 149 µm, 150 µm, 151 µm,152 µm, 153 µm, 154 µm, 155 µm, 156 µm, 157 µm, 158 µm, 159 µm, 160 µm, 161 µm, 162 µm, 163 µm, 164 µm, 165 µm, 166 µm, 167 µm, 168 µm, 169 µm, 170 µm, 171 µm, 172 µm, 173 µm, 174 µm, 175 µm, 176 µm, 177 µm, 178 µm, 179 µm, 180 µm, 181 µm, 182 µm, 183 µm, 184 µm, 185 µm, 186 µm, 187 µm, 188 µm, 189 µm, 190 µm, 191 µm, 192 µm, 193 µm, 194 µm, 195 µm, 196 µm, 197 µm, 198 µm, 199 µm or 200 µm. In principle, however, larger layer thicknesses, for example 200 µm, 250 µm, 300 µm, 350 µm, 400 µm, 450 µm, 500 µm or more, can also be provided, whereby corresponding intermediate values ​​are to be considered as co-disclosed. An active ingredient within the meaning of the present disclosure can generally be a pharmacologically active substance, optionally in the form of its salt, as a conjugate, etc., and / or a precursor substance ("prodrug").which only becomes active after metabolism. The polymer nanoparticles themselves can consist of a hydrogel. This allows the release rate of the active ingredient to be adjusted very precisely. Furthermore, the active ingredient can be protected from undesirable reactions during the formation of the hydrogel network. Generally, "a" / "an" are to be read as indefinite articles in this disclosure, i.e., unless expressly stated otherwise, always as "at least one." Conversely, "a" / "an" can also be understood as "only one."

[0015] In an advantageous embodiment of the invention, the implant is designed as an intraocular lens, in particular an accommodating intraocular lens. This allows the advantages realizable according to the invention to be realized in the context of various eye surgeries and implant types. This applies particularly to an implant designed as an accommodating intraocular lens, since in such an IOL, inflammatory reactions, fibrosis, and the like could impair or completely prevent the accommodative capacity of the IOL. For surgical insertion, intraocular lenses are usually folded and injected into the eye using an injector. To limit potential damage to the cornea, it is desirable to reduce the incision size as much as possible and keep the injector's injection tips as small as possible. This means that a certain amount of force is required to push the folded IOL through the injector.These forces are typically reduced by a lubricating coating on the inner wall of the injector. Since the implant according to the invention is coated with a hydrogel, the drug-releasing hydrogel of the drug delivery system advantageously provides additional lubrication, thereby either improving the existing injection process or even completely replacing or eliminating the existing lubricating coating on the injector wall.

[0016] In a further advantageous embodiment of the invention, it is provided that the hydrogel is degradable, in particular biodegradable. This enables a particularly well-controllable release of the at least one active ingredient stored in the hydrogel, whereby undesired release peaks are particularly reliably prevented and the active ingredient can be released continuously over a period of several weeks. The degradation of the hydrogel can occur, for example, if the hydrogel has hydrolyzable polymer bonds and / or hydrolyzable chemical bonds to the active ingredient molecules. Alternatively or additionally, the hydrogel can have enzymatically degradable polymer bonds and / or enzymatically degradable bonds to the active ingredient molecules. For example, peptide bonds can be provided that are cleaved by peptidases after implantation.The release of the active ingredient can be designed in such a way that the active ingredient can be released exclusively through degradation of the hydrogel, for example, by binding the active ingredient to the hydrogel and / or by sterically "trapped" in the lattice of the hydrogel matrix. Alternatively, it can be provided that, in addition to release through degradation of the hydrogel, the active ingredient can also be released through diffusion out of the hydrogel, which generally allows for a higher release rate.

[0017] In a further advantageous embodiment of the invention, the hydrogel is selected from a group comprising poly(N-isopropylacrylamide), polyvinyl alcohol, polyethylene glycol, polylactic acid, polyethyleneimine, cellulose, cellulose ethers with methyl and / or ethyl and / or propyl groups, in particular hydroxypropylmethylcellulose, hydroxyethylmethylcellulose and / or methylcellulose, glycosaminoglycans, in particular 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, and / or a mixture and / or a physiologically acceptable salt thereof. This allows the properties of the hydrogel, for example its viscoelasticity and degradability, to be optimally adapted to the respective application and intended use of the implant.Hydrophilic long-chain polymers, for example, can be converted into hydrogels through simple cross-linking reactions. Due to the large number of hydrophilic groups, the gel can then absorb a correspondingly large amount of water, often several times its own weight. These same interactions can be used to physically entrap drug molecules within the hydrogel network. For slow and sustained release, hydrophilic and comparatively large or sterically demanding drug molecules are preferred because they do not diffuse out of the hydrogel as quickly and reduce the likelihood of a so-called burst release of a large portion of the drug shortly after implantation. However, small hydrophobic drugs could also be successfully entrapped in such networks, for example, by copolymerization with other monomers or by manipulating the surface of the polymer.Alternatively, such drug molecules can be covalently linked to the polymer via a degradable bond. The degradation rate then controls the release of the drugs rather than the diffusion of these molecules.

[0018] Polysaccharides, also known as glycans, generally represent a subclass of carbohydrates and are complex sugars made up of monosaccharide units (e.g., glucose, fructose, galactose, etc.) that form a chain. Each monosaccharide, also known as a simple sugar, consists of a chain of carbon atoms. Depending on the number of carbon atoms, they are classified as trioses (3), tetroses (4), pentoses (5), hexoses (6), heptoses (7), etc. Polysaccharides can be divided according to the type of saccharide units into homoglycans with only one type of simple sugar and heteroglycans with two or more different types of individual sugars. Furthermore, polysaccharides can be unsubstituted or substituted and can carry one or more side groups such as hydroxy, carboxyl, amino, or sulfate groups.

[0019] In a further advantageous embodiment of the invention, it is provided that the at least one active ingredient is covalently bound to the hydrogel via a preferably biodegradable bond type. This also enables a particularly well-controllable release of the active ingredient bound to the hydrogel, whereby undesired release peaks can be particularly reliably prevented and the active ingredient can be released continuously over a period of several weeks. The controlled release of the active ingredient can also be achieved in conjunction with a non- or poorly degradable hydrogel. In this case, too, the degradation of the covalent bond and the release of the active ingredient can occur, for example, by the active ingredient having hydrolyzable chemical bonds to the hydrogel network. Alternatively or additionally, the active ingredient can have enzymatically degradable bonds to the hydrogel network.For example, peptide bonds can be provided which are cleaved by peptidases after implantation. Alternatively or additionally, the active ingredient can be covalently bound to a monomer and / or oligomer. This can increase the space required by the active ingredient, so that even small active ingredient molecules cannot diffuse out of the hydrogel network or can only diffuse at low rates due to steric hindrance. Preferably, the monomer or oligomer does not impair the pharmacological effect of the active ingredient. Alternatively, the bond between the active ingredient and the monomer / oligomer can be degradable, so that the active ingredient is present in its physiological active form before and / or after diffusion from the hydrogel network. Furthermore, the active ingredient can be distributed throughout the hydrogel. This can be achieved by polymerizing the active ingredient during the polymerization of the hydrogel starting materials or oligomers.

[0020] Precursors are present in the reaction mixture and are "trapped" in the formed network, and / or the hydrogel is introduced into a preferably saturated solution of the active ingredient, so that the active ingredient diffuses into the hydrogel. According to the invention, the active ingredient is present in, in particular, biodegradable polymer nanoparticles distributed within the hydrogel. The polymer nanoparticles can themselves consist of a hydrogel and are biodegradable. This allows the release rate of the active ingredient to be adjusted particularly precisely. Furthermore, the active ingredient can be protected from undesirable reactions during the formation of the hydrogel network.

[0021] In a further advantageous embodiment of the invention, at least one pharmacologically active ingredient is covalently bound to at least one surface area of ​​the hydrogel. This allows the desired pharmacological effect to be achieved directly on the surface of the implant. For example, the active ingredient can be an antibody that captures and binds unwanted target structures, such as inflammatory mediators, fibrogens, or the like, directly on the surface of the implant. This allows impairment of the optical properties of the implant to be particularly reliably prevented.

[0022] In a further advantageous embodiment of the invention, the at least one active ingredient is selected from a group comprising steroidal and non-steroidal anti-inflammatory drugs, in particular COX-2 inhibitors, prostaglandins and / or prostamides, antibiotics, and beta-blockers. This allows the pharmacological effect of the implant to be optimally adapted to various expected endogenous reactions and potential complications, for example, inflammatory reactions and / or PCOS.

[0023] In a further advantageous embodiment of the invention, the implant is stored in a saturated solution of the at least one active ingredient. This ensures that the concentration of the active ingredient in the drug delivery system remains constant during storage of the implant, particularly in cases where the active ingredient is not firmly bound to the hydrogel or otherwise "trapped" in the hydrogel, but is to be released, for example, by diffusion.

[0024] A second aspect of the invention relates to a method according to claim 9 for producing an ophthalmic implant with a drug delivery system which is designed to deliver at least one pharmacologically active ingredient in the implanted state of the ophthalmic implant. Improved and longer-lasting drug delivery is made possible by coating an optical part of the implant with at least one hydrogel as the matrix of the drug delivery system and covalently bonding the at least one hydrogel to the optical part, wherein the hydrogel is loaded with the at least one drug. According to the invention, the at least one drug is present in polymer nanoparticles which are distributed in the hydrogel. In other words, it is provided that the drug delivery system is arranged as a coating on the optical part of the implant and is immobilized by covalently bonding the hydrogel to the optical part.The hydrogel generally acts as a matrix for the drug to be delivered, with which the hydrogel is loaded. This makes it possible, in contrast to an arrangement on a haptic part, to use a significantly larger area of ​​the implant for the arrangement of the drug delivery system with a correspondingly higher amount of drug, without having to accept restrictions in terms of space requirements, implantability, or functionality of the implant. Since hydrogels, by definition, contain a comparatively large amount of water in the hydrated state and can often absorb several times their own weight in water upon contact with water, their refractive index in the implanted and hydrated state is comparable to that of the environment surrounding the eye. Therefore, hydrogels are practically invisible to the human and animal eye.The hydrogel can generally be loaded with the active ingredient or active ingredient combination before coating the optical part with the hydrogel, during coating the optical part with the hydrogel, and / or after covalently bonding the hydrogel to the optical part. Furthermore, the hydrogel can first be applied to the optical part in a partially or fully dehydrated state, covalently bonded, and then hydrated by contacting it with water. The covalent bonding of the hydrogel can be carried out using any suitable chemical method, for example, so-called click chemistry. The polymer nanoparticles themselves can consist of a hydrogel. This allows the release rate of the active ingredient to be adjusted very precisely. In addition, the active ingredient can be protected from undesirable reactions during the formation of the hydrogel network.Further features and advantages can be found in the descriptions of the first aspect of the invention, whereby advantageous embodiments of the first aspect of the invention are to be regarded as advantageous embodiments of the second aspect of the invention. Conversely, advantageous embodiments of the second aspect of the invention are to be regarded as advantageous embodiments of the first aspect of the invention.

[0025] In an advantageous embodiment of the invention, the covalent bonding of the at least one hydrogel to the optical part of the implant comprises the steps of generating surface hydroxyl groups on the optical part of the implant, grafting at least one reactive silane compound, which carries at least one further functional group in addition to a silane group, onto the surface hydroxyl groups of the implant, and covalently bonding the at least one hydrogel to the further functional group of the grafted silane compound. The generation of surface hydroxyl groups on the optical part of the implant is generally only necessary if the optical part itself has no or too few free hydroxyl groups. The hydroxyl groups are preferably generated by plasma activation, although other suitable techniques can generally also be used.Trialkoxysilanes of the general formula (I) are particularly suitable as silane compounds. where G denotes the functional group and the parameters n can be chosen independently of one another, i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more. G can be, for example, an amino group or an ethenyl group, although other functional groups, such as carboxyl groups, epoxy groups, phosphate groups, anhydrides, hydroxy groups, thiol groups, and the like, as well as corresponding combinations, are also possible, allowing the covalent coupling of the hydrogel to the optical part. For example, the silane compound can be 3-(triethoxysilyl)propan-1-amine or triethoxy(hex-5-enyl)silane. In the case of an amino-group-bearing silane and an amino-group-bearing hydrogel, crosslinkers bearing two or more carboxyl groups and optionally additionally containing one or more (biodegradable) bonds can be used for covalent coupling.Using a known EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) / NHS (1-hydroxy-2,5-pyrrolidinedione) coupling reaction, the hydrogel can then be covalently coupled to the optical part via peptide bonds. The functional groups can, of course, also be interchanged, meaning that the hydrogel carries carboxyl groups and the crosslinker carries amino groups. Alternatively, the silane can carry a functional alkenyl group, which is coupled to a hydrogel bearing thiol groups via a crosslinker (diene, triene, etc.) bearing at least two alkenyl groups in a thiol-Michael-type reaction. Depending on the functional groups present, other suitable crosslinking reactions are also conceivable.

[0026] Further features of the invention emerge from the claims, the figures, and the description of the figures. The features and combinations of features mentioned above in the description, as well as the features and combinations of features mentioned below in the description of the figures and / or shown alone in the figures can be used not only in the respective combination specified, but also in other combinations. Thus, embodiments are also to be regarded as disclosed that are not explicitly shown and explained in the figures, but which emerge and can be produced by separate combinations of features from the explained embodiments. Embodiments and combinations of features are also to be regarded as disclosed that therefore do not have all the features of an originally formulated independent claim.Furthermore, embodiments and combinations of features are to be considered disclosed, in particular by the embodiments presented above, which go beyond or deviate from the combinations of features presented in the claims. This shows: . Fig. 1 shows a schematic representation of a drug delivery system comprising a matrix of a biodegradable hydrogel with embedded drug molecules that are released by degradation of the hydrogel; Fig. 2 shows a schematic representation of the drug delivery system comprising a matrix of a non-degradable hydrogel with embedded drug molecules that are released from the hydrogel by diffusion; Fig. 3 shows a schematic representation of the coupling reaction of the biodegradable hydrogel to an optical part of an ophthalmic implant and a loading of the hydrogel with a pharmacological active ingredient; Fig. 4 shows a schematic representation of the coupling reaction of the non-degradable hydrogel to an optical part of an ophthalmic implant, wherein the hydrogel is coupled to the pharmacological active ingredient via degradable bonds; Fig.Fig. 5 schematically shows the release process of the active ingredient contained in the degradable hydrogel through biological degradation of the hydrogel; and Fig. 6 schematically shows the release process of the active ingredient contained in the non-degradable hydrogel. Preferred embodiment of the invention

[0027] Fig. 1shows a schematic representation of a drug delivery system 1 comprising a matrix of a biodegradable hydrogel 2 with embedded drug molecules 3, which are released into the environment upon degradation of the hydrogel 2. The hydrogel 2 can, for example, be selected from the group consisting of poly(N-isopropylacrylamide), poly(vinyl alcohol), poly(ethylene glycol), hyaluronic acid, cellulose, poly(lactic acid), and the like. Such hydrophilic long-chain polymers can, for example, be converted into hydrogels 2 through simple crosslinking reactions. Due to the large number of hydrophilic groups, the hydrogel 2 can subsequently absorb a large amount of water, often several times its own initial or dry weight. The same interactions can be used to physically "capture" drug molecules 3 within the hydrogel system 2.In this case, the hydrogel 2 is biodegraded, for example, by enzymes found in the eye. This releases the previously "captured" active ingredient molecules 3.

[0028] Fig. 2 shows a schematic representation of the drug delivery system 1, which comprises a matrix of a non-degradable hydrogel 2 with embedded drug molecules 3, which, in contrast to Fig. 1released from the hydrogel 2 by diffusion. It can be seen that the hydrogel 2 swells by absorbing additional water, thereby increasing the pore size of the polymer network and facilitating or even enabling the diffusion of the active ingredient molecules 3. For a long-lasting, controlled release of the active ingredient molecules 3, hydrophilic and, if possible, voluminous active ingredient molecules 3 can be used, since they diffuse only slowly from the hydrogel 2 and thus reduce the likelihood of a burst release shortly after the implantation of an associated ophthalmic implant 4 (see Fig. 3) into an eye. However, small hydrophobic drug molecules 3 can also be successfully enclosed in such polymer networks, for example by copolymerization with other monomers or oligomers or by manipulating the surface of the hydrogel 2. Alternatively, the drug molecules 3 can also be covalently linked to the hydrogel 2 via biologically or otherwise degradable bonds. The release of the drug molecules 3 can then be significantly controlled via the rate of degradation of these degradable bonds. All of the materials and techniques mentioned for producing drug-loaded hydrogels 2 can be used to modify the surfaces of optical parts 5 and optionally also of haptic parts (not shown) of ophthalmic implants 4 accordingly.

[0029] Various techniques can be used to achieve covalent crosslinking of a hydrogel 2 with the surface of the implant 4 via a chemical reaction. A preferred option is the grafting of reactive groups, e.g., epoxides or thiols, onto the surface of the implant 4. During polymerization of the hydrogel 2 or the hydrogel precursor 6, parts of the polymer network react with the modified surface, thereby immobilizing the hydrogel 2.

[0030] This can be achieved, for example, by using so-called click chemistry on a chemically modified surface of the implant 4. Here, the target surface of the implant 4, which is to be coated with the hydrogel layer, is exposed to a plasma, thereby forming hydroxyl groups. These can easily react, for example, with triethoxysilanes containing different reactive groups, essentially creating a surface completely or predominantly covered with such reactive groups. Depending on the reaction type used, these groups can then react directly with the polymers during hydrogel synthesis. For example, if an EDC / NHS-mediated amide coupling reaction is used to crosslink the hydrogel 2, the grafting of either carboxyl groups or amine groups would allow the hydrogel 2 to be formed simultaneously and immobilized on the surface of the implant 4.Alternatively, if a thiol-Michael reaction is used, grafting thiols onto the surface would enable immobilization of the hydrogel 2. Grafting reactions with triethoxysilanes allow the introduction of a variety of reactive groups onto the surface of the implant 4 and enable controlled immobilization with respect to the reaction types used in the preparation of the hydrogel 2, thus providing high flexibility for the preparation of immobilized, drug-eluting hydrogels 2. This offers a wide range of possibilities for producing intraocular lenses and other ophthalmic implants 4 modified with drug-releasing hydrogels 2.

[0031] Fig. 3schematically shows the sequence of a coupling reaction of the biodegradable hydrogel 2 to an optical part 5 of an ophthalmic implant 4 and a loading of the hydrogel 2 with a pharmacological active ingredient 3. In the example shown, the active ingredient molecules 3 are physically enclosed in the hydrogel 2 during formation. This is achieved by first providing the implant 4 in step a) and, in step b), providing the surface of the optical part 5 of the implant 4 in the area to be coated with hydroxyl groups by plasma activation. These hydroxyl groups are then exposed to reactive silanes, with 3-(triethoxysilyl)propan-1-amine being used as an example here. In this embodiment, amino groups are grafted on. It should be emphasized that, in general, other silanes and other functional groups can also be used, as long as the required reaction types are compatible with each other.

[0032] In a next step c), a mixture of a polymer backbone or precursor 6 of the hydrogel 2 with amino groups, a crosslinker 7 with 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 part 5. This initiates peptide formation between the crosslinker 7, the precursor 6, and the surface-fixed amino groups, whereby the immobilized hydrogel 2 is formed as the drug delivery system 1 and the drug molecules 3 are enclosed therein. Any suitable polymer backbone (e.g., poly(ethylene glycol), hyaluronic acid, cellulose, alginate, etc.) can be used for the polymer or precursor 6 itself, provided they carry the required reactive group(s) or can be modified accordingly to carry the required reactive group(s).For example, if a carbohydrate is used, a similar EDC / NHS-mediated peptide coupling can be used for this purpose. Alternatively, the functional groups can be reversed, for example, by grafting carboxyl functions and using a crosslinker 7 with two (or more) amino groups.

[0033] The degradation of the optional degradable bond 8 from the crosslinker 7 can occur, for example, by hydrolysis. Active ester bonds can be provided for this purpose. Alternatively, enzymatic degradation can be used, for example, by using hyaluronic acid in the polymer framework of the hydrogel 2, which can be degraded by hyaluronidase in the implanted state of the implant 4. Alternatively or additionally, peptide bonds that can be cleaved by peptidases can be provided.

[0034] Fig. 4shows a schematic representation of the coupling reaction between the non-degradable hydrogel 2 and the optical part 5 of the ophthalmic implant 4, wherein the hydrogel 2 is coupled to the pharmacologically active ingredient 3 via degradable bonds 8. In other words, in this exemplary embodiment, a non-(bio)degradable hydrogel 2 is used. This occurs after plasma activation in step b) by a first grafting of alkene groups onto the surface of the optical part 5 in step c) by the silanization already described. Triethoxy(hex-5-enyl)silane is used as the silane. In a next step d), a mixture of thiol-containing polymers or prescursors 6 and crosslinkers 7 with two (or more) alkene groups is applied to the modified surface.This initiates a thiol-Michael reaction between the alkenes and thiol groups, resulting in the drug delivery system 1 comprising the cross-linked, surface-immobilized hydrogel 2 and the encapsulated active ingredients 3. While the active ingredients 3 in the example shown are physically enclosed within the hydrogel 2 and subsequently released over time by diffusion, an alternative embodiment can provide biodegradable bonds 8 to covalently link the active ingredient molecules 3 to the polymer backbone of the hydrogel 2. This allows for better control over the release profile of the active ingredient 3 via the degradation rate of these bonds 8. This allows even smaller active ingredient molecules 3 to be released over a longer period of time without an initial burst release. The (biological / hydrolytic) degradation of the bonds 8 between the hydrogel 2 and the active ingredient 3 significantly determines the release profile.

[0035] Similar to the embodiment described above, in principle any suitable polymer or precursor 6 can be used that is biocompatible, modifiable with the desired chemical groups, and capable of forming hydrogels 2. In particular, alternative click chemistry configurations can be used to obtain an immobilized hydrogel 2 with an incorporated active ingredient 3. Both embodiments are only examples of how drug-eluting hydrogels 2 can be produced as a drug delivery system 1 on surfaces of ophthalmic implants 4 and are not limited to the reaction types shown in these examples.

[0036] Fig. 5shows schematically the process of release of the active ingredient 3 contained in the degradable hydrogel 2 by biological degradation of the degradable compounds 8 of the hydrogel 2. The degradation rate of the hydrogel 2 defines the rate of active ingredient release of the active ingredient delivery system 1.

[0037] Fig. 6 shows a schematic representation of the release process of the active ingredient 3 contained in the non-degradable hydrogel 2. The active ingredient molecules 3 are bound to the non-degradable polymer framework of the hydrogel 2 via degradable compounds 8. After the degradation of the compounds 8, a diffusion-based release of the active ingredients 3 occurs, enabling a particularly long-lasting, uniform release.

[0038] The use of the described drug delivery systems 1 for coating part or the entire surface of the optical part 5 of an ophthalmic implant 4 thus allows the provision of a larger amount of drug compared to an exclusive arrangement on a haptic part (not shown), without restricting the optical and haptic functionality of the implant 4.

[0039] A further advantage relates to reduced stickiness of the surface of the implant 4. Some hydrophobic IOL materials have the problem that their surface is comparatively sticky. This can lead to unfavorable IOL deployment after surgical insertion into the eye. In extreme cases, one or both haptics may adhere to the IOL surface of the optical part 5, requiring additional manipulation of the IOL by the physician. This stickiness can be avoided by coating the surface with multiple layers of heparin and polymine. However, there are several problems with this approach. Using the drug delivery system 1 to partially or completely coat the optical part 5 also solves the stickiness problem, as well as some of the problems of other established coatings.

[0040] Another advantageous aspect of the drug delivery system 1 is improved lubrication. For surgical insertion, intraocular lenses 4 are folded and injected into the eye using an injector. To prevent potential corneal damage by reducing the incision size, it is desirable to keep the injection tips as small as possible. This results in a certain physical force that must be applied to push the folded IOL 4 through the injector. These forces are typically reduced by a lubricating coating on the inner wall of the injector. The immobilized hydrogel 2 of the drug delivery system 1 can provide (additional) lubrication and either improve the injection process or completely replace the previously necessary lubrication on the injector wall.

[0041] The drug delivery system 1 can also be used for PCO prevention. A common postoperative complication of cataract surgery is postoperative capsular opacification (PCO): cells grow on the capsular bag and IOL surface 5 and, over time, cause closure of the capsular bag. Although this can be treated by laser application, it is still desirable to delay the onset of PCO as much as possible or prevent it altogether. The surface modification of an IOL 4 with an immobilized, drug-releasing hydrogel 2, as described above, can slow or completely prevent PCO development. Furthermore, the surface of the hydrogel 2 can optionally be modified to further support PCO prevention, e.g., by grafting additional functional groups to the surface of the hydrogel 2. For example, COX-2 blocking NSAIDS can help prevent PCO.Such NSAIDs are used to treat inflammation and, through their incorporation into the hydrogel 2, can also prevent or significantly slow down the development of PCOS.

[0042] The drug delivery system 1 can also be used as a platform for various medications and active ingredients 3. In addition to using anti-inflammatory drugs as the active ingredient 3, it is quite possible to use the drug delivery system 1 to absorb and release other types of medications. These could include, among others, antibiotics to prevent bacterial infections or medications to reduce intraocular pressure against the onset of glaucoma. If the hydrogel 2 provides a sufficiently large reservoir, two or more active ingredients 3 can also be used for simultaneous sustained release.

[0043] With regard to hydrophilic IOLs and other hydrophilic ophthalmic implants 4 that are stored in water until implantation, various strategies are available to achieve high storage stability. For example, an implant 4 coated with a non-(bio)degradable hydrogel 2 can be stored in a saturated drug solution. In this way, the drug concentration within the drug delivery system 1 remains constant during storage.

[0044] Alternatively or additionally, degradable bonds 8 that are not sensitive to hydrolysis can be used. For example, active ingredients 3 can be bound to the hydrogel 2 via degradable peptide bonds 8. Alternatively or additionally, crosslinkers 7 that contain and / or generate peptide bonds can also be used. Peptidase enzymes in the ocular environment can then degrade the hydrogel 2 after implantation and / or separate the active ingredients 3 from the polymer backbone of the hydrogel 2. No enzymes are present during storage, making the drug delivery system 1 storage-stable.

[0045] Another variant involves the production or use of a hydrogel 2 that severely restricts the diffusion of the embedded active ingredients 3, e.g., through small pore size and large active ingredient molecules 3. The hydrogel 2 can be made from an enzymatically degradable component, e.g., hyaluronic acid. During storage, the drug delivery system 1 is stable because it is only degraded by hyaluronidase (or a comparable enzyme) in the ocular environment once implanted, releasing the embedded active ingredients 3.

[0046] The parameter values ​​specified in the documents for defining process and measurement conditions for characterizing specific properties of the subject matter of the invention are to be considered as being included within the scope of the invention, even in the case of deviations - for example due to measurement errors, system errors, weighing errors, DIN tolerances and the like. List of reference symbols

[0047] 1Drug delivery system 2Hydrogel 3Drug 4Implant 5Optical part 6Precursor 7Crosslinker 8Degradable bond

Claims

1. Ophthalmological implant (4) having an active ingredient release system (1) designed to release at least one pharmacologically active ingredient (3) in the implanted state of the ophthalmological implant (4), where the active ingredient release system (1) comprises at least one hydrogel (2) as matrix, where the hydrogel (2) forms a layer on an optical component (5) of the implant (4), is covalently bonded to the optical component (5) and is laden with the at least one active ingredient (3), characterized in that the at least one active ingredient (3) is in the form of polymer nanoparticles distributed within the hydrogel (2) .

2. Ophthalmological implant (4) according to Claim 1, characterized in that it takes the form of an intraocular lens, especially an accommodating intraocular lens.

3. Ophthalmological implant (4) according to Claim 1 or 2, characterized in that the hydrogel (2) is degradable, especially biodegradable.

4. Ophthalmological implant (4) according to any of Claims 1 to 3, characterized in that the hydrogel (2) is selected from a group comprising 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 and / or a mixture and / or a physiologically acceptable salt thereof.

5. Ophthalmological implant (4) according to any of Claims 1 to 4, characterized in that the at least one active ingredient (3) is covalently bonded to the hydrogel (2) via a preferably biodegradable type of bond (8) and / or is covalently bonded to a monomer and / or oligomer and / or is distributed in the hydrogel (2) and / or is in the form of biodegradable polymer nanoparticles distributed within the hydrogel (2).

6. Ophthalmological implant (4) according to any of Claims 1 to 5, characterized in that at least one pharmacologically active ingredient (3) is covalently bonded to at least one surface region of the hydrogel (2).

7. Ophthalmological implant (4) according to any of Claims 1 to 6, characterized in that the at least one active ingredient (3) is selected from a group comprising steroidal and non-steroidal inflammation inhibitors, especially COX-2 inhibitors, prostaglandins and / or prostamides, antibiotics and beta-blockers.

8. Ophthalmological implant (4) according to any of Claims 1 to 7, characterized in that it is stored in a saturated solution of the at least one active ingredient (3).

9. Process for producing an ophthalmological implant (4) having an active ingredient release system (1) designed to release at least one pharmacologically active ingredient (3) in the implanted state of the ophthalmological implant (4), where an optical component (5) of the implant (4) is coated with at least one hydrogel (2) as matrix of the active ingredient release system (1), and the at least one hydrogel (2) is covalently bonded to the optical component (5), where the hydrogel (2) is laden with the at least one active ingredient (3), characterized in that the at least one active ingredient (3) is in the form of polymer nanoparticles distributed within the hydrogel (2) .

10. Process according to Claim 9, characterized in that the covalent binding of the at least one hydrogel (2) to the optical component (5) of the implant (4) comprises the steps of - generating surface hydroxyl groups on the optical component (5) of the implant (4); - graft polymerizing at least one reactive silane compound bearing at least one further functional group as well as a silane group onto the surface hydroxyl groups of the implant (4); and - covalently binding the at least one hydrogel (2) to the further functional group of the grafted silane compound.