Ophthalmic viscoelastic device and kit for use in eye surgery

Abstract

The invention relates to an ophthalmic viscoelastic device which comprises at least one viscoelastic polymer (10) that can be split into polymer chains (12) with a low molecular weight. The viscoelastic polymer (10) comprises at least two polymer chains (12) which are connected together via at least one nucleobase conjugate (14). The invention additionally relates to a kit for use in eye surgery.

Description

[0001] Ophthalmic viscoelastic device and kit for use in ophthalmic surgery

[0002] Technical area

[0003] The invention relates to a degradable ophthalmic viscoelastic device and a kit for use in eye surgery with 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 their 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 and the anterior chamber of the eye. Disperse OVDs contain polymer chains with lower molecular weights compared to cohesive OVDs.

[0010] While a longer-chain, cohesive OVD can be easily washed out by flushing the anterior chamber with irrigating solution, shorter-chain, dispersive OVDs are significantly more difficult to remove or aspirate after surgery. At the end of cataract surgery, the surgeon is often confronted with a layer of OVD covering the cornea and extending to the corner of the eye. An additional challenge is that the dispersive OVD material is usually located directly on the endothelium, where it is generally difficult to aspirate, and in the corner of the eye, where it is also difficult to detect.

[0011] Residual OVD remaining in the eye after surgery can be gradually washed out by the aqueous humor and transported away via the trabecular meshwork. However, polymer chains that are too long can partially clog the trabecular meshwork and delay or completely prevent its removal. This can then lead to increased intraocular pressure (IOP) after surgery. However, increased intraocular pressure poses a risk to the patient, as it can lead to glaucoma.

[0012] Description of the Invention The object of the present invention is to provide an ophthalmic viscoelastic device for use in eye surgery that reduces the risk of increased intraocular pressure after eye surgery. A further object of the invention is to create a correspondingly advantageous kit with an ophthalmic viscoelastic device.

[0013] This object is achieved according to the invention by an ophthalmic viscoelastic device according to claim 1 and by a kit according to claim 9 for use in eye surgery. Advantageous embodiments with expedient modifications of the invention are specified in the subclaims, wherein advantageous modifications of each aspect of the invention are to be regarded as advantageous modifications of the respective other aspect of the invention.

[0014] A first aspect of the invention relates to an ophthalmic viscoelastic device comprising at least one viscoelastic polymer that can be cleaved into polymer chains of lower molecular weight. According to the invention, the risk of an increase in intraocular pressure after eye surgery is reduced by the viscoelastic polymer comprising at least two polymer chains that are linked to one another via at least one nucleic base conjugate. In other words, the invention provides that the at least one viscoelastic polymer consists of two or more polymer chains, wherein at least two of these polymer chains, and preferably the majority or all of the polymer chains, are each linked to one another via at least one nucleic base conjugate.In the context of the present disclosure, a nucleic base conjugate is understood to mean a coupling in which at least one nucleic base is arranged on one of the polymer chains and is connected to at least one nucleic base of the other polymer chain. The connection between the nucleic bases preferably occurs via weak molecular interactions, in particular via one, two, or three hydrogen bonds per nucleic base pair. This bonding is also referred to as "hybridization." A specific nucleic base or sequence of nucleic bases preferentially binds to another nucleic base or sequence of nucleic bases that has exactly the complementary set of bases. Furthermore, nucleic bases are versatile molecules that can be conjugated relatively easily and efficiently with other chemical substances, in particular with viscoelastic polymers or their formation blocks or repeating units.The invention also utilizes the "programmability" of nucleic bases due to the specificity of the respective nucleic base pair complementarity to create an OVD that can degrade into smaller polymer chains or fragments, particularly in vivo, i.e., in the patient's eye, depending on various chemical and / or physical stimuli, and therefore does not need to be removed from the eye at the end of the operation. The resulting polymer chains are preferably small enough to be completely or at least essentially completely removed from the eye quickly, i.e., preferably within a few hours, via natural drainage pathways, particularly through the trabecular meshwork or the pores of Schlemn's canal. Each nucleic base conjugate can be adjusted so that the viscoelastic polymer coupled via such double-stranded (ds) nucleic bases exhibits specific properties.In particular, the nucleic base conjugates can separate (melt) and, upon a specific trigger event or chemical and / or physical stimulus, decompose back into their single-stranded (es) form, whereby the polymer also decomposes into its corresponding polymer chains or formation blocks. The "melting" or decomposition of such a ds-conjugate can be very precisely "programmed"—i.e., adjusted and predetermined—by changing the sequence length and composition of the nucleic base(s) used. Since the OVD according to the invention can dissolve or decompose in the eye and be naturally removed and disposed of by the body, the OVD no longer needs to be removed after surgery. This saves time for physicians and operating room staff and enables a higher number of procedures to be performed within a given time.Finally, such an OVD increases patient safety by reducing the likelihood of postoperative intraocular pressure increases or problems with the trabecular meshwork. Generally, "a" / "an" should be read as an indefinite article throughout this disclosure, meaning, unless expressly stated otherwise, "at least one" / "at least one." Conversely, "a" / "an" can also be understood as "only one."

[0015] In an advantageous embodiment of the invention, it is provided that the polymer chains have a molecular mass of between 70 kDa and 200 kDa, in particular between 76 kDa and 190 kDa, and / or that the viscoelastic polymer comprises between 10 and 40, in particular between 15 and 38 polymer chains, which are preferably each linked to one another via at least one nucleic base conjugate, and / or that the polymer chains have an average particle size of between 600 nm at the most, in particular an average particle size of between 200 nm and 500 nm. All of the measures and properties mentioned, individually or in any combination, result in the polymer chains, particles or fragments resulting from the dissolution or disintegration of the nucleic base conjugates having a sufficiently small size to be able to pass particularly reliably and at least substantially completely or entirely through the trabecular meshwork orto pass through the pores of Schlemm's canal and be removed from the eye.

[0016] In a further advantageous embodiment of the invention, it is provided that the at least one nucleic base conjugate comprises at least one nucleic base from the group adenine (A), guanine (G), cytosine (C), thymine (T), uracil (U), hypoxanthine (HX), xanthine (X), 7-methylguanine, 5-methylcytosine, 5-hydroxymethylcytosine and 5,6-dihydrouracil. Alternatively or additionally, it is provided that the at least one nucleic base conjugate comprises at least 3 and preferably between 3 and 30 nucleic base pairs. Furthermore, it can be alternatively or additionally provided that the nucleic base conjugate comprises at least one nucleotide from DNA (deoxyribonucleic acid), RNA (ribonucleic acid) and PNA (peptide nucleic acid). As a result, the properties of the at least one nucleic base conjugate can be adjusted by suitable selection of the nucleic bases orThe base pairs and, if applicable, their molecular backbone can be precisely adjusted and adapted to the desired property profile of the OVD. The nucleic bases can be present as oligonucleotides. PNA (peptide nucleic acid) refers to peptide nucleic acids, which are analogues of the nucleic acids RNA and DNA, in which the sugar-phosphate backbone of RNA or DNA is replaced by a pseudopeptide. A corresponding nucleic base is then bound to this pseudopeptide backbone or basic structure. Compared to DNA and RNA, PNA enables a higher hybridization temperature and salt-independent hybridization at low ionic strengths.

[0017] Further advantages arise from the fact that the at least one nucleic base conjugate consists of two nucleic base strands with the same or different numbers of nucleic bases. In other words, the nucleic bases or nucleic base strands of the bound polymer chains hybridized in the initial state of the viscoelastic polymer can have the same number of nucleic bases, for example, three nucleic bases each, or a different number, for example, one polymer chain can have two or four nucleic bases and the other polymer chain can have three nucleic bases. This allows the binding properties of the respective nucleic base conjugate to be precisely adjusted, allowing the disintegration properties to be optimally adapted to the desired application profile of the OVD.Alternatively or additionally, the at least one nucleic base conjugate consists of two nucleic base strands, wherein the nucleic base strands comprise complementary nucleic base pairs and / or non-complementary nucleic base pairs. Complementary nucleic base pairs are understood to be nucleic base pairs within the meaning of the biological base pairing rules, each forming the same number of hydrogen bonds. Depending on the choice of nucleic base pairs, this also includes reverse Watson-Crick pairings, Hoogsteen pairings, reverse Hoogsteen pairings, or non-Watson-Crick pairings with Watson-Crick-like geometry. For example, guanine (G) and cytosine (C) form a complementary nucleic base pair via three hydrogen bonds, while adenine (A) can form a complementary base pair with thymine (T) or uracil (U) via two hydrogen bonds.Complementary nucleic base pairs are therefore generally more stable than non-complementary nucleic base pairs, in which base pairs are conjugated with each other that do not fit together optimally, for example GA, CT, etc., which leads to a correspondingly weaker bond and easier cleavage.

[0018] 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, chondroitin sulfate, collagen, and gelatin. Corresponding derivatives and salts of the aforementioned formation blocks, such as hyaluronates, alginates, chitosan salts, etc., are generally 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 shorter polymer chains, which in turn consist of these formation blocks.Furthermore, it can be provided that the viscoelastic polymer, apart from the nucleic bases, consists exclusively of one of the aforementioned building blocks, for example, exclusively of hyaluronic acid blocks that are cross-linked indirectly, i.e., via spacers or other derivatizations, or directly via one or more nucleic bases, forming the viscoelastic polymer. Conversely, it can also be provided that the viscoelastic polymer consists of two or more different building blocks.

[0019] Further advantages arise from the fact that the at least one viscoelastic polymer comprises polymer chains that are linked end-to-end via the at least one nucleic base conjugate and are preferably linked via at least one further, non-terminal nucleic base conjugate. 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 nucleic bases. This allows the size of the polymer chains to be predetermined with particular precision after cleavage of the nucleic base conjugates, thereby enabling particularly reliable removal of the polymer fragments via the aqueous humor and the trabecular meshwork. In principle, the individual polymer chains can be linked to one another alternatively or additionally via non-terminal nucleic base conjugates.This allows the formation of a three-dimensional network, which allows for the adjustment of both the degradability and the rheological properties of the viscoelastic polymer. Furthermore, the individual polymer chains can be cross-linked via other functional groups, as long as the degradability and transportability after cleavage of the nucleobase conjugates are sufficiently ensured. This also allows the viscoelastic properties to be adjusted with particular precision.

[0020] Further advantages arise from the fact that the at least one viscoelastic polymer has a melting temperature (Tm) between 30 °C and 35 °C, at which the nucleic bases of the at least one nucleic base conjugate separate from one another. This makes it possible to provide OVDs whose viscoelastic polymer is stable at room temperature, i.e. between approximately 20 °C and 25 °C, but automatically “melts” in the patient’s eye due to the increased temperature or decomposes into the short-chain polymer chains because the nucleic base conjugates separate. Alternatively or additionally, it is provided that the nucleic bases of the at least one nucleic base conjugate separate from one another depending on the ion concentration of the surrounding medium. For example, the nucleic base conjugate can separate at high salt or ion concentrations, for example in an environment whose osmolarity is higher than that of an isotonic solution orthe ion concentration typically prevailing in the eye, is stable and splits at the ion concentration typically prevailing in the patient's eye.

[0021] In a further advantageous embodiment, the ophthalmic viscoelastic device is designed as a dispersive ophthalmic viscoelastic device. This allows for the particularly reliable creation of an adherent polymer barrier 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 also possess the aforementioned properties at different temperatures and / or pressures.

[0022] 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. When used in the kit according to the second aspect of the invention, the type and amount of the cleaving agent should be adjusted accordingly.

[0023] 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 not covalently bound to the at least one viscoelastic polymer. This enables a preferably controlled release of the therapeutic agent, which can optionally be controlled by the degradation rate of the viscoelastic polymer, thereby further facilitating eye surgery. The therapeutic agent is preferably not covalently bound to the at least one viscoelastic polymer, but rather embedded in the polymer and / or dissolved in the OVD.

[0024] A second aspect of the invention relates to a kit for use in eye surgery, comprising an ophthalmic viscoelastic device comprising at least one viscoelastic polymer, and at least one cleaving agent by means of which the viscoelastic polymer can be cleaved into polymer chains of lower molecular weight. According to the invention, the viscoelastic polymer consists of at least two polymer chains linked to one another via at least one nucleic base conjugate, and the cleaving agent is designed to cleave the at least one nucleic base conjugate.In other words, the kit comprises an OVD according to the first aspect of the invention and a cleaving agent, by means of which at least one nucleic base conjugate, and preferably the majority or all of the nucleic base conjugates, are cleaved, particularly in vivo, i.e., in the patient's eye, resulting in shorter-chain polymer or oligomer chains with correspondingly lower molecular weights and different rheological properties. These shorter-chain degradation products can then be easily washed out of the anterior chamber via natural processes without clogging the trabecular meshwork. The cleavage or decomposition of the OVD can be controlled particularly precisely by appropriately selecting the type and amount of cleaving agent, as well as by the time of its addition to the OVD. This mechanism can, of course, also be used for in vitro methods.The viscoelastic polymer can also be referred to as a transitional viscoelastic, which the surgeon can leave in the eye in comparatively significant quantities, where it is broken down by the cleavage agent and transported away and eliminated through the body's natural processes without causing a dangerous increase in intraocular pressure. A further advantage is that the previously required, lengthy, and complicated step of suctioning out the viscoelastic after eye surgery can be completely eliminated. The kit according to the invention can be used in various eye surgeries, particularly those where there is a risk of postoperatively increased intraocular pressure. This applies, for example, to operations on the anterior segment of the eye, such as cataract surgery, corneal transplants, and glaucoma surgery.The cleavage agent can generally be added before the OVD, together with the OVD, and / or after the OVD, or at the conclusion of the eye surgery. 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 considered advantageous embodiments of the other aspect of the invention.

[0025] In an advantageous embodiment of the invention, the viscoelastic polymer and the cleaving agent are coordinated such that the cleaving agent cleaves at least 70%, in particular at least 80%, of all nucleic base conjugates of the viscoelastic polymer in vivo within a maximum of 9 hours, in particular within a maximum of 6 hours, particularly preferably within a maximum of 4.5 hours. This ensures that the viscoelastic polymer degrades sufficiently quickly into sufficiently small polymer fragments to ensure gradual washing out of the polymer fragments via the aqueous humor and the trabecular meshwork without leading to increased intraocular pressure. Conversely, the degradation of the viscoelastic polymer is not too rapid, which would complicate the use of the kit in eye surgery due to excessively rapid decomposition.Alternatively or additionally, the cleaving agent comprises nucleic bases that are complementary to the nucleic bases of the nucleic base conjugate. This allows the nucleic base conjugates to be cleaved by competitive binding of the added nucleic bases of the cleaving agent. The added nucleic bases of the cleaving agent are preferably not bound to a polymer, but rather have the lowest possible molecular weight. The added nucleic bases can, for example, be components of nucleosides, nucleotides, nucleic acids, or peptides or pseudopeptides. Alternatively or additionally, the cleaving agent can comprise at least one enzyme, in particular DNase and / or RNase, by means of which the at least one nucleic base conjugate is to be cleaved and / or degraded. In this way, the viscoelastic polymer can be "digested" and broken down into its components by, if appropriate, endogenous or nature-identical enzymes.Alternatively or additionally, the cleaving agent may be a buffer solution and / or Mg. 2+ -ions and / or Ca 2+-ions. This also allows the cleavage time and rate of the nucleobase conjugate to be controlled. In addition, a favorable environment for naturally occurring enzymes and / or enzymes added as cleavage agents can be created. 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 specified combination, but also in other combinations without departing from the scope of the invention.Thus, embodiments of the invention are also to be considered encompassed and disclosed that are not explicitly shown and explained in the figures, but which arise and can be generated through separate combinations of features from the explained embodiments. Embodiments and combinations of features are also to be considered 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 through the embodiments presented above, that go beyond or deviate from the combinations of features presented in the backreferences to the claims. Here, it shows:

[0026] Fig. 1 is a schematic representation 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 a viscoelastic polymer of an ophthalmic viscoelastic device according to the invention, which is cleaved in a temperature-dependent manner;

[0028] Fig. 3 is a schematic representation of a viscoelastic polymer of an ophthalmic viscoelastic device according to the invention, which is cleaved by changing the ion concentration of a surrounding medium;

[0029] Fig. 4 is a schematic representation of a viscoelastic polymer of an ophthalmic viscoelastic device according to the invention, which is cleaved by adding a nucleic base cleaving agent; Fig. 5 is a schematic representation of a viscoelastic polymer of an ophthalmic viscoelastic device according to the invention, which is cleaved by adding an enzyme cleaving agent;

[0030] Fig. 6 is a schematic representation of a disaccharide repeating unit of hyaluronic acid;

[0031] Fig. 7 shows a reaction scheme of an alkynyl functionalization of hyaluronic acid; and

[0032] Fig. 8 shows a reaction scheme for coupling an azide-functionalized DNA oligonucleotide to the alkynyl-functionalized hyaluronic acid by “click chemistry”.

[0033] Preferred embodiment of the invention

[0034] Fig. 1 shows a schematic, partial representation of a viscoelastic polymer 10 of an ophthalmic viscoelastic device (OVD) according to an embodiment of the invention. The viscoelastic polymer 10 comprises approximately 15 to 38 polymer chains 12, which in this case consist of hyaluronic acid (HA) polymers and each have a molecular weight between approximately 76 and 190 kDa or consist of approximately 200 to approximately 500 disaccharide repeat units. However, it should be emphasized that in addition to or instead of hyaluronic acid, other starting materials or blocks suitable for producing viscoelastic polymers can also be used. In the embodiment shown, the individual polymer chains 12 form fragments or particles in the isolated state with an average size between approximately 200 nm and 500 nm, whereby they can, for example, pass through the pores of Schlemm's canal (SC) to be disposed of naturally by the body.

[0035] The polymer chains 12 are connected end-to-end via nucleic base conjugates 14. Alternatively or in addition to the end-to-end connections shown, the nucleic base or nucleic acid strands can also be linked head-to-tail or attached at locations other than the end of the polymer chains 12, for example, in the middle of the respective polymer chain 12. In the present example, the nucleic base conjugates 14 consist of short DNA strands with sequences of four complementary nucleic bases C, G, A, and T each. The sequences are designed such that the short DNA strands hybridize and connect the HA polymer chains 12 to form a long chain. The number, sequence, and arrangement of the nucleic base conjugates 14 can be used to control, among other things, the molecular weight of the resulting viscoelastic polymer 10 and thus its physical properties.In addition to the nucleic acids that are specifically bound to the reductive end of each HA polymer chain 12, one or more nucleic acids are optionally provided at other locations, for example in the middle region of one or more HA polymer chains 12, whereby further nucleic base conjugates 14 are possible and three-dimensional cross-linking between the individual polymer chains 12 is achieved, which, among other things, changes the rheological properties of the viscoelastic polymer 10. In principle, it can be provided that the hybridization of the nucleic base conjugates 14 is reversible, i.e. that the individual polymer chains 12 hybridize or separate depending on a chemical and / or physical stimulus. Furthermore, the individual nucleic base conjugates 14 can each consist of the same nucleic bases or nucleic base sequences or different nucleic bases ornucleic base sequences, which opens up further possibilities for the combinatorics of different formation blocks.

[0036] The respective nucleic base conjugates 14 can be designed such that the double-stranded (ds) viscoelastic polymer 10 of the OVD exhibits specific properties. In particular, it can separate (melt) and return to its single-stranded (es) form upon a specific triggering event. The melting of the ds polymer 10 can be very precisely "programmed" or adjusted by changing the sequence length and composition of the nucleic base conjugates 14. According to the present invention, this programmability is utilized such that, after the OVD is injected into a patient's eye, the conjugates 14 melt or separate, allowing the OVD to decompose into its small HA strands or polymer chains 12.Since the isolated polymer chains 12 are small enough to be quickly removed from the eye through the trabecular meshwork or other natural drainage pathways, such OVDs do not need to be removed from the eye by the surgeon at the end of an eye operation, for example, cataract surgery. This saves the surgeon considerable time and increases patient safety. Fig. 2 shows a schematic representation of a viscoelastic polymer 10 of an ophthalmic viscoelastic device according to the invention, which is cleaved in a temperature-dependent manner. It can be seen that the nucleic bases CGGT-GCCA of the viscoelastic polymer 10, which are exemplary in number and type, are present as a double-stranded conjugate 14 at temperatures below 30°C, i.e., at room temperature, but the sequences "melt" or "split" as temperatures rise above 30°C.separate, whereby the viscoelastic polymer 10 is degraded automatically after application to the eye of a patient and the associated heating without the addition of a cleaving agent 16 (Fig. 4). Alternatively, a cleaving agent 16 can also be added to accelerate the degradation of the polymer 10. The OVD and the cleaving agent 16 can be present as a kit. The released polymer chains 12 separate during this degradation and, due to their small size, can be naturally removed and degraded by the patient's body. The melting temperature Tm, at which the conjugates 14 separate, can be adjusted to a desired value or range of values ​​by varying the type, number, and sequence of the nucleic bases. The value of the melting temperature Tm can be precisely adjusted by selecting the type, number, and sequence of the nucleic bases. For example, CG pairs melt at a higher temperature than AT pairs.Likewise, longer sequences melt at higher temperatures than shorter sequences. By introducing mismatches, i.e., non-complementary nucleic base pairings (e.g., CA, GT, etc.), the melting temperature Tm can also be controlled, particularly by lowering it relatively.

[0037] Fig. 3 shows a schematic representation of a viscoelastic polymer 10 of an ophthalmic viscoelastic device according to the invention, which is cleaved by changing the ion concentration of an ambient medium. The melting of the ds sequence of the conjugate 14 is triggered by a change in the ion concentration of the medium surrounding the polymer 10. The lower the ion concentration, the more likely the ds sequences of the conjugates 14, for example, dsDNA, break down into single strands. By adjusting the corresponding nucleic base sequences, a sequence can be selected that is stable at high salt concentrations, i.e., at a salt concentration higher than in drinking water, for example, in aqueous humor, in isotonic saline solution (0.9% NaCl), etc., and can cleave at the lower ion concentration prevailing in the patient's eye.This allows the viscoelastic polymer 10, consisting for example of DNA-HA, and thus the OVD, to dissolve automatically and without the addition of a cleaving agent when injected into the patient's eye.

[0038] Fig. 4 shows a schematic representation of a viscoelastic polymer 10 of an ophthalmic viscoelastic device according to the invention, which is cleaved from nucleic bases or nucleic acids by adding a cleaving agent 16. The cleaving agent 16 thus competes with the nucleic bases of the conjugate 14. In the present embodiment, at least one base pair of the conjugate 14 is non-complementary (CGGT-GCGA instead of the complementary conjugate CGCT-GCGA), which weakens the bond between the polymer chains 12. The short, freely diffusing nucleic base sequence CGCT of the cleaving agent 16, on the other hand, is completely complementary to the nucleic bases of one polymer chain 12 and therefore competes with the less well-binding nucleic bases CGGT of the other polymer chain 12. The viscoelastic polymer 10, which can be, for example, an HA polymer linked by ds-nucleic acids, thereby disintegrates into small fragments orPolymer chains 12, which, as already described, can then be removed and broken down by the body itself.

[0039] Fig. 5 shows a schematic representation of a viscoelastic polymer 10 of an ophthalmic viscoelastic device according to the invention, which is enzymatically digested and thereby cleaved by adding a cleaving agent 16 consisting of enzymes. Nucleic bases present as nucleic acids can be naturally digested by the body's own enzymes, for example, by DNase and RNase. To melt the dsDNA / dsRNA of the viscoelastic polymer 10 in vivo, i.e., in the patient's eye, so that the OVD can be degraded, enzymes such as DNase or RNase can be injected as cleaving agents 16 at the end of the eye surgery, depending on the nucleic base conjugates 14 used. It is understood that this mechanism can also be used for in vitro methods.The enzymes 16 are then cleaved into their individual nucleic acids 18, thereby cleaving the long chains of the viscoelastic polymer 10 into correspondingly smaller fragments consisting of the polymer chains 12. DNase I, for example, can be used as an enzyme. DNase I preferentially cleaves DNA at phosphodiester bonds adjacent to a pyrimidine nucleotide, releasing di-, tri-, and oligonucleotide products (on average, tetranucleotides are formed) with 5'-phosphorylated and 3'-hydroxylated ends. It acts on both single-stranded and double-stranded DNA. DNase I requires divalent cations (Mg) for maximum activity. 2+ and Ca 2+ ), which can be added to the buffer with the DNase.

[0040] Fig. 6 shows a schematic representation of a disaccharide repeat unit of hyaluronic acid. Such a D-glucuronic acid-N-acetyl-D-glucosamine disaccharide has a size of approximately 1 nm. Arrows V1a-V1g indicate various reactive functional groups and potential reaction centers for derivatization of hyaluronic acid (HA). Via denotes a carboxyl group, V1b a primary hydroxyl group, Vic the reductive end group of HA, V1d an N-acetyl group, and Vie, Vif, and V1g secondary hydroxyl groups. Nucleic bases, for example in the form of nucleic acids, can be bound to the HA backbone in various ways via these functional groups.

[0041] Fig. 7 shows a reaction scheme for the alkynyl functionalization of hyaluronic acid. The reaction is part of a synthetic method known as "click chemistry," which can be used for the modular construction of complex molecules from "simpler" building blocks. The click reaction involves the chemical coupling of an azide-functionalized molecule and an alkynyl-functionalized molecule to form a "bifunctional" conjugate. The major advantage of click chemistry is that it is very efficient and selective and occurs under mild conditions. Therefore, click chemistry can help accelerate and simplify the synthesis of complex molecules. Another important advantage of the click reaction is its bioorthogonality, meaning it is compatible with biological systems. The azide and alkyne groups do not occur naturally in systems, making the click reaction a very useful method for synthesizing molecules such asTo bind nucleic bases or acids to polymers or oligomers such as HA and other viscoelastic polymers, or to the corresponding building blocks of such viscoelastic polymers. Nucleic bases, which here are present in the form of nucleic acids, are versatile molecules and can be conjugated relatively easily and efficiently with various chemical compounds. In the illustrated example, ethyldiamine is first bound to the reductive end of the HA via reductive amination using NaCNBH (sodium cyanoborohydride, Borch reagent). The free amino group of the ethyldiamine then reacts with the carboxyl group of a modified dibenzocyclooctyl acid to form an amide bond.

[0042] Fig. 8 shows a reaction scheme for coupling an azide-functionalized DNA oligonucleotide to alkynyl-functionalized hyaluronic acid using "click chemistry." Here, the ethynyl group of the modified dibenzocyclooctic acid reacts with a DNA-azide conjugate (DNA-N3) through a cycloaddition reaction to link the nucleic bases, which here are present as DNA, but can also be present as RNA (RNA-N3) or PNA (PNA-N3), to the HA. In this way, tailor-made synthetic nucleic bases or oligonucleotides can be linked to polymer chains 12 to construct the viscoelastic polymer 10.

[0043] In general, nucleic bases or nucleic base sequences can be bound to any group of the HA polymer (or other polymers) by such standard reactions. However, they are preferably bound only in small amounts per polymer chain 12, so that on average, only about one further polymer chain 12 is bound per modified polymer chain 12. For example, the carboxyl group of D-glucuronic acid can react with a diamine to form an amide bond. This is comparable to the terminal bond without reduction by NaCNBH3 (Fig. 2), but in the presence of EDC and HOBt (Fig. 3). Finally, a DNA-azide conjugate can also be bound to the dibenzocyclooctyne by cycloaddition (Fig.).

[0044] Nucleic bases can also be linked to polysaccharides other than HA to produce nucleotide-based OVDs with tailored properties, for example with alginate, chitosan, methylcellulose or mixtures thereof.

[0045] The content of the nucleic base sequences, i.e. how many and which nucleic bases (e.g.

[0046] The number of nucleic bases (e.g., AT and CG pairs or other nucleic bases and nucleic base pairs per conjugate), as well as the length of the individual nucleic base sequences, can be varied. The sequence can be any of the possible combinations; the length per nucleic base sequence can preferably be at least 3 nucleic bases and a maximum of approximately 30 nucleic bases. The melting temperature and / or salt concentration required for separation can cover various ranges, but must be adapted to each sequence variant. The match of the nucleic base pairs does not have to be exact. The strength of the bond between the sense and antisense nucleic acids can be modulated, for example, by the number of matching or corresponding base pairs.

[0047] The invention saves the time the physician spends removing OVD from the eye during cataract surgery or other eye surgeries. This increases the efficiency of the operation and the patient's safety. Typically, OVD remnants remain in the eye after surgery and cannot be completely removed, which can lead to an increase in intraocular pressure. Eyes with glaucoma damage that are sensitive to increased intraocular pressure could be further damaged or further damaged by such an increase in intraocular pressure. The dissociation of the polymer fragments 12 linked by nucleic bases facilitates the outflow of the viscoelastic polymer 10 and prevents clogging of Schlemm's canals or the trabecular meshwork, thus reliably preventing a harmful increase in IOP.

[0048] 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.

[0049] 10 polymers

[0050] 12 Polymer chain 14 Conjugate

[0051] 16 splitting agents

[0052] 18 nucleic acids

[0053] Vla-IVg functional groups

[0054] C, G, T, A nucleic bases

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 nucleic base conjugate (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) comprises between 10 and 40, in particular between 15 and 38 polymer chains (12), which are preferably each connected to one another via at least one nucleic base conjugate (14), and / or that the polymer chains (12) have an average particle size of between 600 nm at the most, in particular an average particle size of between 200 nm and 500 nm.

3. The ophthalmic viscoelastic device according to claim 1 or 2, characterized in that the at least one nucleic base conjugate (14) comprises at least one nucleic base from the group consisting of adenine, guanine, cytosine, thymine, uracil, hypoxanthine, xanthine, 7-methylguanine, 5-methylcytosine, 5-hydroxymethylcytosine, and 5,6-dihydrouracil; and / or that the at least one nucleic base conjugate (14) comprises at least 3, and preferably between 3 and 30, nucleic base pairs; and / or that the nucleic base conjugate (14) comprises at least one nucleotide from DNA, RNA, and PNA.

4. Ophthalmic viscoelastic device according to one of claims 1 to 3, characterized in that that the at least one nucleic base conjugate (14) consists of two nucleic base strands with the same or different number of nucleic bases; and / or that the at least one nucleic base conjugate (14) consists of two nucleic base strands, wherein the nucleic base strands comprise complementary nucleic base pairs and / or non-complementary nucleic base pairs.

5. Ophthalmic viscoelastic device according to one of claims 1 to 4, characterized in that the at least one viscoelastic polymer (10) comprises at least one forming block from the group consisting of hyaluronic acid, alginate, chitosan, methylcellulose, hydroxypropylmethylcellulose, chondroitin sulfate, collagen and gelatin.

6. Ophthalmic viscoelastic device according to one of claims 1 to 5, characterized in that the at least one viscoelastic polymer (10) comprises polymer chains (12) which are linked end-to-end to one another via the at least one nucleic base conjugate (14) and are preferably linked to one another via at least one further, non-terminal nucleic base conjugate (14).

7. An ophthalmic viscoelastic device according to any one of claims 1 to 6, characterized in that the at least one viscoelastic polymer (10) has a melting temperature (Tm) between 30°C and 35°C, at which the nucleic bases of the at least one nucleic base conjugate (14) separate from one another; and / or that the nucleic bases of the at least one nucleic base conjugate (14) separate from one another depending on an ion concentration of a surrounding medium.

8. Ophthalmic viscoelastic device according to one of claims 1 to 7, characterized in that it is designed as a 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 not covalently bound to the at least one viscoelastic polymer (10).

9. A kit for use in eye surgery, comprising an ophthalmic viscoelastic device comprising at least one viscoelastic polymer (10) and at least one cleaving agent (16) by means of which the viscoelastic polymer (10) can be cleaved into polymer chains (12) of lower molecular weight, characterized in that the viscoelastic polymer (10) consists of at least two polymer chains (12) which are linked to one another via at least one nucleic base conjugate (14), and in that the cleaving agent (16) is designed to cleave the at least one nucleic base conjugate (14).

10. Kit according to claim 9, characterized in that the viscoelastic polymer (10) and the cleaving agent (16) are matched to one another such that the cleaving agent (16) cleaves in vivo at least 70%, in particular at least 80%, of all nucleic base conjugates (14) of the viscoelastic polymer (10) within a maximum of 9 hours, in particular of a maximum of 6 hours, particularly preferably of a maximum of 4.5 hours; and / or that the cleaving agent (16) comprises nucleic bases which are complementary to the nucleic bases of the nucleic base conjugate (14); and / or that the cleaving agent (16) comprises at least one enzyme, in particular DNase and / or RNase, by means of which the at least one nucleic base conjugate (14) is to be cleaved and / or degraded; and / or that the cleaving agent (16) comprises a buffer solution and / or Mg 2+ -ions and / or Ca 2+ -ions.

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