Ophthalmic viscoelastic device and cleaving device

Abstract

The invention relates to an ophthalmic viscoelastic device comprising at least one viscoelastic polymer (10) which can be cleaved into polymer chains (12) with a lower molecular weight. The viscoelastic polymer (10) comprises at least two polymer chains (12) that are connected to one another by at least one thermally and / or photochemically cleavable group (14). The invention also relates to a cleaving device (16) comprising means for cleaving at least one thermally and / or photochemically cleavable group (14) of such an ophthalmic viscoelastic device.

Description

[0001] Ophthalmic viscoelastic device and splitting device

[0002] Technical area

[0003] The invention relates to a degradable ophthalmic viscoelastic device and a splitting device for degrading such an ophthalmic viscoelastic device.

[0004] State of the art

[0005] Cataracts are a common condition, especially among older people, in which the lens of the eye gradually becomes opaque. This clouding of the natural lens leads to a loss of visual acuity. Cataract surgery is required to restore vision. The standard method for removing the cloudy lens nucleus to create a capsular bag for the insertion of an artificial intraocular lens (IOL) is called phacoemulsification, using a device that generates ultrasonic vibrations.

[0006] Immediately before phacoemulsification, the anterior chamber is usually filled with an ophthalmic viscoelastic device (OVD). The viscoelastic OVD is used as a surgical aid to protect intraocular tissue (e.g., the corneal endothelium during phacoemulsification), as a space maintainer (e.g., to maintain the anterior chamber), and to facilitate intraocular procedures, such as performing a controlled capsulorhexis. Such OVDs are also used in other eye surgeries, such as corneal transplants or glaucoma surgery.

[0007] OVDs are typically water-based solutions containing viscoelastic polymers such as hyaluronic acid (HA), chondroitin sulfate (CS), hydroxypropyl methylcellulose (HPMC), or mixtures thereof. The viscoelastic composition can vary depending on the molecular weight of the polysaccharide dissolved in the solution, the concentration of the polysaccharide, and the viscosity of the solution. The rheological properties are highly dependent on the concentration and molecular mass of the polymers.

[0008] Generally, two types of OVDs are distinguished. Highly viscous, cohesive OVDs hold the space and build pressure. They are used, for example, to dilate the pupil before the anterior capsular bag of the lens is opened (capsulorhexis). Cohesive OVDs are made of high-molecular-weight polymers.

[0009] In contrast, less viscous, dispersive OVDs envelop and protect the tissue. One of the most important applications is the creation of an adherent polymer barrier with a layer thickness of approximately 100 μm to approximately 1 mm between the corneal endothelium of the anterior chamber of the eye. Disperse OVDs contain polymer chains with lower molecular weights compared to cohesive OVDs.

[0010] Both types of OVDs are typically injected at the beginning of the procedure. They can be flushed out of the incision during lens fragmentation. For this reason, they are refilled before intraocular lens implantation, as the anterior chamber needs to expand for this step. After surgery, the OVDs must be completely removed from the eye. Degradation and removal of the OVD through natural drainage routes would take too long. During this time, the patient would suffer from severely elevated intraocular pressure. This is not only painful but can also lead to an increased risk of glaucoma.

[0011] Description of the invention

[0012] The object of the present invention is to provide an ophthalmic viscoelastic device for use in eye surgery, which reduces the risk of increased intraocular pressure after the surgery. A further object of the invention is to create a splitting device for such an ophthalmic viscoelastic device. This object is achieved according to the invention by an ophthalmic viscoelastic device according to claim 1 and by a splitting device according to claim 9. Advantageous embodiments with expedient developments of the invention are specified in the subclaims, wherein advantageous embodiments of each aspect of the invention are to be regarded as advantageous embodiments of the other aspect of the invention.

[0013] A first aspect of the invention relates to an ophthalmic viscoelastic device comprising at least one viscoelastic polymer which can be split into polymer chains with a lower molecular weight. According to the invention, the viscoelastic polymer comprises at least two polymer chains which are linked to one another via at least one thermally and / or photochemically cleavable group. In other words, the at least one viscoelastic polymer of the ophthalmic viscoelastic device (OVD) according to the invention consists of two or more shorter-chain polymer chains which are each linked to one another via at least one thermally and / or photochemically cleavable group, whereby predetermined “predetermined breaking points” are realized. In contrast to, for example, hydrolytically cleavable polymers, the viscoelastic polymer of the OVD according to the invention can, under biological conditions, be broken down in the capsular bag orbe designed to be fundamentally stable in the patient's eye and only be specifically fragmented after an external thermal and / or photochemical stimulus. Furthermore, when the viscoelastic polymer is split into shorter-chain polymer chains, pharmaceutically active fragments are preferably not produced. Instead, the viscoelastic polymer can be specifically split by the thermal and / or photochemical stimulus into shorter-chain polymer or oligomer chains with correspondingly lower molecular weight and different rheological properties, which are then small enough to be quickly transported away from the body through the trabecular meshwork or Schlemm's canals and broken down. Since the OVD according to the invention can dissolve or decompose in the eye and be quickly transported away and disposed of by the body via natural drainage routes, the OVD no longer needs to be removed after surgery.This saves time for doctors and operating room staff and allows for a higher number of procedures to be performed in a given time. Finally, such an OVD increases patient safety by reducing the likelihood of post-operative intraocular pressure increases or problems with the trabecular meshwork. In its simplest form, cleavage is possible without additional injections or invasive manipulation, for example, by irradiation with daylight or ambient light or with light of a specific wavelength or wavelength range. In general, "a" / "an" should be read as an indefinite article in this disclosure, i.e., unless expressly stated otherwise, it always also means "at least one / at least one." Conversely, "a" / "an" can also be understood as "only one / only one."

[0014] In an advantageous embodiment of the invention, it is provided that the polymer chains have a molecular weight between 70 kDa and 200 kDa, in particular between 76 kDa and 190 kDa, and / or that the viscoelastic polymer has an average molecular weight of at least 0.5 MDa, in particular of at least 2.5 MDa. All of the above-mentioned measures and properties, individually or in any combination, result in the polymer chains formed after cleavage of the thermally and / or photochemically cleavable group, or their fragments, being sufficiently small to pass particularly reliably and completely, or at least essentially completely, through the trabecular meshwork or through the pores of Schlemn's canal and be removed from the eye.

[0015] Further advantages arise from the fact that the at least one viscoelastic polymer comprises at least one formation block from the group consisting of hyaluronic acid, alginate, chitosan, methylcellulose, hydroxypropylmethylcellulose (HPMC), chondroitin sulfate, collagen, and gelatin. All derivatives and salts of the aforementioned polymers, such as hyaluronates, alginates, etc., are to be considered included. Within the context of the present disclosure, a formation block refers to monomeric, oligomeric, or polymeric structural elements or polymer chains of the viscoelastic polymer. Through the aforementioned cleavage, the viscoelastic polymer can preferably be cleaved back into these original formation blocks or into polymer chains that in turn consist of these formation blocks.Furthermore, it can be provided that the viscoelastic polymer, apart from the thermally and / or photochemically cleavable groups, consists exclusively of one of the aforementioned building blocks, for example, exclusively of hyaluronic acid blocks that are crosslinked indirectly, i.e., via spacers, crosslinkers, or other derivatizations, or directly via the thermally and / or photochemically cleavable group, and form the viscoelastic polymer. Conversely, it can also be provided that the viscoelastic polymer consists of two or more different building blocks, for example, hyaluronic acid blocks and HPMC blocks, etc.

[0016] In a further advantageous embodiment of the invention, the at least one viscoelastic polymer comprises polymer chains that are linked end-to-end via the at least one thermally and / or photochemically cleavable group. In other words, the viscoelastic polymer is formed from two or more shorter-chain polymer chains, wherein the individual polymer chains are linearly cross-linked via terminal thermally and / or photochemically cleavable groups. This allows the size of the polymer chains to be predetermined with particular precision after the cleavage of the cleavable groups, thus enabling particularly reliable removal of the polymer fragments via the aqueous humor and the trabecular meshwork.Conversely, the molecular weight of the viscoelastic polymer can be adjusted particularly easily, and even particularly long polymer chains can be produced, making viscoelastic polymers with unusually high molecular weights easily accessible. Alternatively or additionally, the polymer chains are linked to one another via side chain positions. In other words, the polymer chains have one or more non-terminal thermally and / or photochemically cleavable groups, via which crosslinking with one or more other polymer chains is achieved. A non-terminal side chain position in a polymer chain can also be referred to as an "internal position" or "internal monomer." These are positions between the ends of the chain that are different from the end groups of the polymer. The end groups are the outermost monomers at each end of the chain.The inner monomers generally have a higher mobility than the end groups and can therefore play an important role in the dynamics and properties of the polymer. Furthermore, this can lead to the formation of a three-dimensional network, which allows both the degradability and the rheological properties of the viscoelastic polymer to be adjusted. Furthermore, the individual polymer chains can be cross-linked via other functional groups, as long as degradability and transportability are sufficiently ensured after cleavage of the thermally and / or photochemically labile groups. In this way, the viscoelastic properties of the viscoelastic polymer can also be adjusted with particular precision.

[0017] In a further advantageous embodiment of the invention, the ophthalmic viscoelastic device is designed as a cohesive or dispersive ophthalmic viscoelastic device. A cohesive OVD can be used during eye surgery to fill the space between the lens and the cornea and stabilize the intraocular pressure, offering several advantages that can contribute to improving the safety and effectiveness of eye surgery. Due to the degradability according to the invention, it is not necessary to remove the OVD from the eye after the eye surgery. Furthermore, viscoelastic polymers with a particularly high average molecular weight can be produced according to the invention, which enables particularly good space retention. A dispersive OVD can be used to create an adherent polymer barrier particularly reliably during eye surgery.In this case, the viscoelastic polymer preferably has a molecular weight of at most 2 MDa, in particular of approximately 1 MDa, which in the case of hyaluronic acid corresponds to an average of approximately 1250 monomers. Furthermore, the zero-shear viscosity under standard conditions (25 °C, 1 bar) is at most 100 Pas, in particular at most 50 Pas. It is understood that the definition of standard conditions does not preclude the possibility that the OVD or its ingredients may possess the aforementioned properties even at different temperatures and / or pressures.

[0018] Alternatively or additionally, the concentration of the at least one viscoelastic polymer relative to the total volume of the ophthalmic viscoelastic device is between 0.1 mg / ml and 50 mg / ml. This also allows the properties of the OVD to be optimally adapted to the respective intended use.

[0019] Alternatively or additionally, the ophthalmic viscoelastic device comprises at least one therapeutic agent, in particular an analgesic and / or an antioxidant, wherein the therapeutic agent is preferably covalently bound to the at least one viscoelastic polymer via at least one thermally and / or photochemically cleavable group and / or embedded in the viscoelastic polymer. This enables a release of the therapeutic agent, preferably controlled and optionally controllable by the degradation rate of the viscoelastic polymer, which can further facilitate eye surgery. The therapeutic agent can be covalently bound to the at least one viscoelastic polymer, or embedded in the polymer or dissolved in the OVD.In the case of a covalent bond, the therapeutic agent can also be attached via the same thermally and / or photochemically cleavable group as the polymer chains and released without additional measures using the same thermal and / or photochemical stimulus. Alternatively, the therapeutic agent can be attached via a different group and thus released via a different stimulus. This allows for targeted release of the therapeutic agent without cleavage of the viscoelastic polymer.

[0020] Further advantages arise from the fact that the ophthalmic viscoelastic device comprises a stabilizing agent, in particular a radical scavenger, and / or magnetic particles, in particular microparticles and / or nanoparticles. With the aid of a stabilizing agent, premature, undesired decomposition of the viscoelastic polymer can be reliably prevented and the storage stability of the OVD can be improved. Alternatively or additionally, the viscoelastic polymer can be decomposed or degraded by admixing magnetic particles, in particular microparticles and / or nanoparticles, to the OVD and exposing them to an external magnetic field to decompose the viscoelastic polymer, which can be referred to as magnetic-field-assisted degradation.The basic idea is that the magnetic particles, usually made of magnetite or another ferromagnetic material, are mixed with the viscoelastic polymer, after which an external magnetic field is applied to the mixture. The magnetic field induces an alternating current in the microspheres, which generates heat through magnetic hysteresis. The heat generated by the magnetic microspheres then causes the surrounding viscoelastic polymer to thermally degrade and break down into polymer chains. Alternatively, the heat generated by the magnetic particles can also accelerate the photochemical degradation of the viscoelastic polymer by increasing the rate of chemical reactions.The specific conditions required for magnetic-field-assisted degradation depend on the type of viscoelastic polymer used, the size and concentration of the magnetic particles, and the strength and frequency of the magnetic field. Generally, the magnetic field must be strong enough to induce an alternating current in the magnetic particles, but preferably not so strong that the magnetic particles agglomerate and form clumps, which could prevent uniform degradation of the viscoelastic polymer.

[0021] In a further advantageous embodiment of the invention, at least one thermally and / or photochemically cleavable group is selected from compounds that can be coupled or are coupled by means of a [2+2] cycloaddition and / or click chemistry. In other words, the individual polymer chains are preferably covalently bonded to thermally and / or photochemically cleavable groups, which in turn can be coupled or are coupled to one another by means of a [2+2] cycloaddition and / or click chemistry. The coupling and / or cleavage can, in principle, also be reversible. A [2+2] cycloaddition, also known as a 1,2-cycloaddition, describes the photochemical process in which cyclobutane derivatives are formed from alkenyl groups that have an activated double bond. Compounds suitable for this process include, for example, ketenes, allenes, cinnamic acids, coumarins, and fluoro- and chlorofluoroethylenes.Stereochemistry can be predicted by applying the Woodward-Hoffmann rules based on orbital symmetry. A distinction is made between thermally allowed and photochemically allowed [2+2] cycloadditions. The thermal [2+2] cycloaddition can proceed in three different ways: concerted, radical, or ionic. In contrast to the concerted reaction, orbital symmetry plays no role in radical or ionic processes. Most concerted [2+2] cycloadditions are photochemically allowed, electrocyclic reactions and are described by the Woodward-Hoffmann rules. Click chemistry refers to a class of chemical reactions characterized by a rapid, efficient, and specific reaction between two reactants to form a new compound. The reactions are usually very selective, and the products can be obtained in high yield.Click chemistry is particularly well-suited for the production of functionalized molecules and materials used in biotechnology and medicine. An example of a click chemistry reaction is the Cu(l)-catalyzed azide-alkyne cycloaddition (also known as the "Huisgen cycloaddition"). In this reaction, an azide group is linked to an alkyne group using a catalyst and with the release of nitrogen in a rapid and specific reaction to form a 1,2,3-triazole ring. This reaction is very useful for synthesizing functional molecules and polymers, as the alkyne and azide groups can be introduced into a wide variety of molecules. Click chemistry has proven to be very useful because it offers a simple, efficient, and selective way to chemically link compounds. The major advantage of click chemistry is that it is very efficient and selective and occurs under mild conditions.Another important advantage of the click reaction is its bioorthogonality, meaning it is compatible with biological systems. Azide and alkyne groups do not occur naturally in systems, making the click reaction a very useful method for binding molecules to polymers or oligomers such as hyaluronic acid (HA) and other viscoelastic polymers, or to the corresponding building blocks of such viscoelastic polymers.

[0022] In a further advantageous embodiment of the invention, the ophthalmic viscoelastic device is stored in a thermos flask and / or in a light-protected container. This advantageously increases the shelf life of the OVD and reliably prevents premature or undesired decomposition.

[0023] A second aspect of the invention relates to a cleavage device comprising means for cleaving at least one thermally and / or photochemically cleavable group of an ophthalmic viscoelastic device according to the first aspect of the invention. With the aid of such a cleavage device, a thermal and / or photochemical stimulus can be generated, which leads to the cleavage of the labile groups of the viscoelastic polymer of the OVD, so that the polymer breaks down into the corresponding shorter-chain polymer chains and can be naturally transported out of the patient's eye. Further features and their advantages can be found in the descriptions of the first aspect of the invention, with advantageous embodiments of each aspect of the invention being regarded as advantageous embodiments of the respective other aspect of the invention.

[0024] In an advantageous embodiment of the invention, the splitting device comprises a light source for generating light with a wavelength that photochemically splits the at least one group. Optionally, a light guide can be provided that guides the light generated by the light source to the patient's eye. The splitting device can, for example, be arranged on a surgical microscope or integrated into a surgical microscope and, after completion of the eye surgery, can expose the patient's eye to light of a predetermined wavelength or a predetermined wavelength range over a large area and / or at specific points or along an irradiation path in order to initiate the photochemical decomposition of the group(s) of the viscoelastic polymer.Alternatively or additionally, the cleavage device can be designed as a contact lens, glasses, or, more generally, as a device that can cover at least part of the patient's eye. The light source can be, for example, an LED light source, possibly ring-shaped. The patient can then wear this cleavage device after the operation, for example, during the recovery phase. The light generated by the cleavage device is then transmitted into the anterior chamber of the eye and cleaves the viscoelastic polymer of the OVD. This can advantageously be done without the involvement of a surgeon and is comfortable for the patient if the cleavage of the viscoelastic polymer takes longer than a few seconds.Alternatively or additionally, the cleavage device comprises a magnetic device for generating a magnetic field, by means of which magnetic particles of the ophthalmic viscoelastic device can be heated to cleave the at least one group. Depending on the group used, this can be cleaved purely thermally. Alternatively, the magnetic heating can be used to accelerate the reaction rate of a photochemical cleavage.

[0025] 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 without departing from the scope of the invention. Thus, embodiments are to be regarded as encompassed and disclosed by the invention 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:

[0026] Fig. 1 is a schematic representation of the manufacturing steps of a viscoelastic polymer of an ophthalmic viscoelastic device according to the invention according to an embodiment;

[0027] Fig. 2 is a schematic representation of the manufacturing steps of an alternative viscoelastic polymer of an ophthalmic viscoelastic device according to the invention according to a further embodiment;

[0028] Fig. 3 a [2+2] cycloaddition reaction of coumarin-substituted polymer chains;

[0029] Fig. 4 a [2+2] cycloaddition reaction of cinnamic acid-substituted polymer chains;

[0030] Fig. 5 is a schematic representation of a disaccharide repeating unit of hyaluronic acid;

[0031] Fig. 6 is a schematic diagram of a splitting device according to an embodiment; and

[0032] Fig. 7 is a schematic diagram of a splitting device according to a further embodiment.

[0033] Preferred embodiment of the invention

[0034] Ophthalmic viscoelastic devices (OVDs) are important aids in, among other things, cataract surgery. When the eye 26 (Fig. 6) is incised, the aqueous humor drains from the eye 26. To facilitate cataract surgery, an OVD is inserted into the eye 26 to create space in the anterior chamber 24. OVDs suitable for creating space generally have a relatively high viscosity (cohesive OVD type, viscosity >60,000 mPas). Another function of OVDs is to coat endothelial cells, for which OVDs with a lower viscosity are designed (dispersive OVD type, viscosity <60,000 mPas). Viscosity values ​​can be determined under standard conditions typical for OVDs (25°C, 1 bar).

[0035] Both types of OVDs are injected at the beginning of the procedure. They can be flushed out of the incision during lens fragmentation. For this reason, they are refilled before intraocular lens (IOL) implantation, as the anterior chamber must expand for this step. After surgery, the OVDs must be completely removed from the eye. The body cannot naturally drain conventional OVDs through the trabecular meshwork like aqueous humor. If OVDs remain in the eye after surgery, they block the natural outflow from the eye, which can lead to elevated intraocular pressure (IOP), which is very painful for patients and also carries the risk of glaucoma.

[0036] Fig. 1 shows a schematic representation of the manufacturing steps of a viscoelastic polymer 10 of an ophthalmic viscoelastic device (OVD) according to the invention according to an exemplary embodiment. Polymer chains 12 are first provided, each having a chain length that allows rapid removal in vivo, i.e., in the patient's eye, via natural outflow pathways such as the trabecular meshwork or Schlemm's canals without a significant increase in intraocular pressure (IOP). The polymer chains 12, which can also be referred to as formation blocks, can in principle have the same or different lengths or (average) molecular weights. In a step 1a, the polymer chains 12 are derivatized and provided with functional groups 14. In the exemplary embodiment shown, the functional groups 14 are attached to the two ends of the individual polymer chains 12.In a step 1b, the functional groups 14 are then coupled end-to-end, allowing the production of viscoelastic polymers 10 of virtually any length, depending on the reaction procedure. For example, it is possible to produce viscoelastics with a particularly high molecular weight beyond 3 MDa, which have previously been inaccessible via established production routes. The functional groups 14 at the two ends of each polymer chain 12 can generally be different or identical, as long as they can react with each other in the manner described. Thus, generally, either exclusively head-to-tail linkages or head-to-head, head-to-tail, and tail-to-tail linkages are possible. In the present exemplary embodiment, the head- and tail-side groups 14 differ, so that only head-to-tail linkages are possible.Depending on the type of formation blocks 12 and the functional groups 14, various chemical reaction pathways are possible. Depending on the reaction type, reaction step Ib can be carried out photochemically (h*v) or thermally (A) and is preferably reversible, allowing the polymer 10 to decompose back into the individual polymer chains 12. Photochemical reactions, optionally thermally assisted, are generally preferred. Optionally, in some embodiments, the viscoelastic polymer 10 can be thermally and / or photochemically cleaved according to step Ic, with the functional groups 14 also being irreversibly destroyed, modified, or cleaved off, making this step irreversible. Both scenarios have advantages, among other things, with respect to the manufacturing route and sensitivity to light exposure.In the case of photochemical cleavage, the required wavelength is preferably in a range blocked by the cornea, i.e., below approximately 300 nm. This cleavage or activation wavelength can be varied by appropriate substituents on the molecular structure shown, in particular, increased, e.g., to approximately 400 nm or more. Thus, neither the cornea nor the IOL would represent a barrier. This also applies, for example, to the compound shown in Fig. 4.

[0037] Fig. 2 shows a schematic representation of the manufacturing steps of an alternative viscoelastic polymer 10 of an ophthalmic viscoelastic device according to the invention according to a further exemplary embodiment. In contrast to the previous exemplary embodiment, the polymer chains 12 are first chemically modified in an optional step Ha and cross-linked in step Hb. The cross-linking does not occur terminally or end-to-end, but via side chains of the polymer chains 12. This reaction is mainly concentration-dependent and is preferably controlled such that the number of reactions or cross-links per polymer strand of the viscoelastic polymer 10 is limited to 1, 2, or 3. In order to achieve chain growth that is greater than simply doubling the molecular weight, at least two cross-linking sites should be provided per polymer chain 12, which are located either in the terminal position (Fig.1), in a lateral position (Fig. 2) or in any combination thereof.

[0038] The concept described here is not limited to the use of a specific chemical group for implementation. Structures suitable for [2+2] cycloaddition reactions, such as coumarin or cinnamic acid, can serve as a starting point, as these compounds and reactions are known and can be reliably implemented. In addition, extensive data are available on biocompatibility in the capsular bag, the noninvasive initiation of the reaction through light exposure, as well as chemical modification and modification of the absorption maximum.

[0039] Fig. 3 shows an example of a [2+2] cycloaddition reaction of coumarin-substituted polymer chains 12. Alternatively or in addition to the shown final modification of the polymer chains 12, one or more coumarin groups can also be provided as side groups of the polymer chains 12. Most concerted [2+2] cycloadditions are photochemically allowed, electrocyclic reactions and are described by the Woodward-Hoffmann rules. The stereochemistry can be predicted using these rules. This is a [TT2o+TT2o] cycloaddition, with the ring closure of the orbitals occurring suprafacially. The reaction is initiated, for example, by irradiation with light having a wavelength > 300 nm, whereby the exact wavelength can be varied by derivatization of the coumarin groups. The polymer chains 12 are then linked via the coumarin groups, which act as cross-linkers, thereby correspondingly increasing their molecular weight.The resulting viscoelastic polymer 10 or the entire OVD containing the viscoelastic polymer 10 should then be stored until use, for example, in brown glass vials or in completely light-tight (thermo) containers, in order to reduce or, preferably, completely avoid light exposure and thus the risk of degradation. After application to the patient's eye, the formed cyclobutane rings can then be photochemically cleaved, for example, with light having a wavelength of < 300 nm, causing the polymer 10 to degrade back into its shorter-chain polymer chains 12, which can then be removed from the eye via natural drainage pathways and degraded. The absorption peak can also be tailored here by using appropriate substituents, allowing wavelengths of up to 400 nm longer to be used for cleavage.This is particularly important in the case of an OVD that remains behind an intraocular lens (IOL) during surgery, as this lens may absorb light either in the UV or even partially in the visible range (in yellow IOLs).

[0040] As already mentioned, other chemical structures can also be used to create these reversible bonds between polymer chains 12 and to create a viscoelastic whose viscosity can be changed and adjusted as desired. One of these substance classes is cinnamates or cinnamic acid derivatives. Figure 4 shows a [2+2] cycloaddition reaction of cinnamic acid-substituted polymer chains 12. The general reaction principle corresponds to that of the coumarin groups discussed above. However, a wide range of other light-cleavable chemical groups can also be selected for this purpose and coupled and cleaved according to the described mechanism. To covalently bond these functional groups to the polymer chains 12, various known reaction pathways can be used.

[0041] After the photocleavable viscoelastic polymers 10 have been produced, stabilizing compounds (e.g., radical scavengers) can be added to the OVD, and the viscoelastics can be packaged in a suitable container, protected from light, for storage and transport. During subsequent administration by a surgeon, a distinction must be made between the required activation time, the reaction time for chemical cleavage, and the time for drainage. Since intraocular pressure usually peaks approximately 3-7 hours after surgery, a guideline reaction time is established in order to break down the polymer 10 as quickly as possible after use and to significantly reduce its viscosity for drainage, preferably within minutes or at least within a few hours. Preferably, the reaction is complete or at least largely complete after 2-3 hours.As already mentioned above, the activation time can be set to a few seconds depending on the selected chemical structures. It can also last up to several hours, e.g., if daylight or ambient light is used to initiate the cleavage reaction. The OVD can in principle contain one or more therapeutic agents (e.g., antibiotics), which are also released, for example, into the capsular bag upon cleavage of the polymer 10. The therapeutic agent(s) can be embedded in the polymer 10 or covalently bonded to it. In the latter case, the covalent bonds are preferably achieved with the same groups 14 as the crosslinking of the polymer chains 12, so that the release of the therapeutic agent occurs simultaneously with the cleavage of the polymer 10 or via the same mechanism and trigger as the cleavage of the polymer 10.

[0042] Fig. 5 shows a schematic representation of a disaccharide repeating unit of hyaluronic acid, which can be used as a formation block or as a polymer chain 12 for the polymer 10. Such a D-glucuronic acid-N-acetyl-D-glucosamine disaccharide has a size of approximately 1 nm. Arrows Va-Vg mark various reactive functional groups and potential reaction centers for derivatization of hyaluronic acid (HA). Va denotes a carboxyl group, Vb a primary hydroxyl group, Vc the reductive end group of HA, Vd an N-acetyl group, and Ve, Vf, and Vg secondary hydroxyl groups. Functional groups 14 or crosslinkers can be attached to the HA backbone in various ways via these groups Va-Vg. In addition to the modification of hyaluronic acid for potentially drug-releasing hydrogels, other chemical modifications are also known for a wide range of applications.Regarding the preferred terminal attachment of functional groups, ring-opening reactions or coupling reactions using the reducing end of hyaluronic acid are known. However, the inventive concept is not limited to hyaluronic acid; other viscoelastic polymers 10 or their forming blocks or polymer chains 12 can also be modified accordingly, leading to a wide spectrum of different application scenarios and possibilities.

[0043] Fig. 6 shows a schematic diagram of a splitting device 16 according to an embodiment. In this case, the splitting device 16 is integrated into a surgical microscope 18 (OPMI) and comprises a light source 20, an optional light guide 22, and optionally a video camera (not shown). Splitting of the viscoelastic polymer 10 can then occur either by fully illuminating the anterior chamber 24 of the eye 26 (left-hand illustration) or by local scanning according to arrow VI along an irradiation path around the capsule in order not to overexpose the retina (right-hand illustration). Instead of light, the stimulus for splitting can also be a magnetic field or another, possibly thermal, energy source to initiate the splitting.

[0044] Alternatively or additionally, the cleavage device 16 can be configured to generate a magnetic field (not shown). This allows the polymer 10 of the OVD to be cleaved by additionally loading the OVD with magnetic microspheres or nanospheres that resonate with the magnetic field and thereby generate heat in the OVD (magnetic field-assisted degradation). The polymer 10 can then be thermally cleaved. Alternatively, the generated heat can also be used to assist photochemical cleavage.

[0045] Fig. 7 shows a schematic diagram of a cleavage device 16 according to another embodiment. The cleavage device 16 is generally designed as a device that can partially or completely cover the eye 26, for example in the form of a contact lens, in the form of glasses, or the like. The cleavage device 16 makes it possible to create a controlled, long-term irradiation environment. The patient can wear the optionally individually adapted cleavage device 16 with a built-in light source 20 (e.g., an annular LED, multiple LEDs, or the like) to degrade the viscoelastic polymer 10 in the manner described above. The patient wears this cleavage device 16, for example, after the operation during the recovery phase.The cleaving light of a predetermined wavelength is then transmitted into the anterior chamber 24 of the eye 26 and cleaves the viscoelastic polymer 10 into its short-chain polymer chains 12. This can be done without surgical intervention. Furthermore, the cleaving device 16 can be worn for as long as necessary for the polymer 10 to be substantially or completely degraded.

[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 included within the scope of the invention, even in the case of deviations—for example, due to measurement errors, system errors, DIN tolerances, and the like.

[0047] 10 polymers

[0048] 12 polymer chain 14 group

[0049] 16 Splitting device

[0050] 18 surgical microscope

[0051] 20 light source

[0052] 22 Light guide 24 Anterior chamber

[0053] 26 Eye

[0054] Va-Vg functional group

[0055] VI Exposure path

Claims

Patent claims 1. An ophthalmic viscoelastic device comprising at least one viscoelastic polymer (10) which is cleavable into polymer chains (12) of lower molecular weight, characterized in that the viscoelastic polymer (10) comprises at least two polymer chains (12) which are linked to one another via at least one thermally and / or photochemically cleavable group (14).

2. Ophthalmic viscoelastic device according to claim 1, characterized in that the polymer chains (12) have a molecular mass between 70 kDa and 200 kDa, in particular between 76 kDa and 190 kDa, and / or that the viscoelastic polymer (10) has an average molecular weight of at least 0.5 MDa, in particular of at least 2.5 MDa.

3. Ophthalmic viscoelastic device according to claim 1 or 2, characterized in that the at least one viscoelastic polymer (10) comprises at least one forming block from the group (14) hyaluronic acid, alginate, chitosan, methylcellulose, hydroxypropylmethylcellulose, chondroitin sulfate, collagen and gelatin.

4. Ophthalmic viscoelastic device according to one of claims 1 to 3, characterized in that the at least one viscoelastic polymer (10) comprises polymer chains (12) which are linked to one another end-to-end and / or via side chain positions via the at least one thermally and / or photochemically cleavable group (14).

5. Ophthalmic viscoelastic device according to one of claims 1 to 4, characterized in that it is designed as a cohesive or dispersive ophthalmic viscoelastic device and / or that a concentration of the at least one viscoelastic polymer (10) based on the total volume of the ophthalmic viscoelastic device is between 0.1 mg / ml and 50 mg / ml and / or that it comprises at least one therapeutic agent, in particular an analgesic and / or an antioxidant, wherein the therapeutic agent is preferably covalently bound to the at least one viscoelastic polymer (10) via at least one thermally and / or photochemically cleavable group (14) and / or is embedded in the viscoelastic polymer (10).

6. Ophthalmic viscoelastic device according to one of claims 1 to 5, characterized in that it comprises a stabilizing agent, in particular a radical scavenger, and / or magnetic particles, in particular microparticles and / or nanoparticles.

7. Ophthalmic viscoelastic device according to one of claims 1 to 6, characterized in that at least one thermally and / or photochemically cleavable group (14) is selected from compounds which can be coupled by means of a [2+2] cycloaddition and / or by click chemistry.

8. Ophthalmic viscoelastic device according to one of claims 1 to 7, characterized in that it is stored in a thermos container and / or in a light-protected container.

9. A cleavage device (16) comprising means for cleaving at least one thermally and / or photochemically cleavable group (14) of an ophthalmic viscoelastic device according to any one of claims 1 to 8.

10. Cleavage device (16) according to claim 9, characterized in that it comprises as means a light source (20) for generating light with a wavelength that photochemically splits the at least one group (14) and / or that it comprises as means a magnet device for generating a magnetic field, by means of which magnetic particles of the ophthalmic viscoelastic device can be heated to cleave the at least one thermally and / or photochemically cleavable group (14).

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