Kit for use in eye surgery, and ophthalmic viscoelastic device

Abstract

The invention relates to a kit for use in eye surgery, said kit comprising: an ophthalmic viscoelastic device that has at least one viscoelastic polymer; and at least one cleaving agent by means of which the viscoelastic polymer can be cleaved into polymer chains with a lower molecular weight, wherein the viscoelastic polymer can be cleaved in vivo by means of the cleaving agent into polymer chains which have an average molecular weight of at most 4 MDa. The at least one viscoelastic polymer of the ophthalmic viscoelastic device comprises disulfide bridges, while the cleaving agent is designed to cleave at least a portion of said disulfide bridges. The invention also relates to an ophthalmic viscoelastic device comprising at least one viscoelastic polymer which has disulfide bridges and can be cleaved into polymer chains with a lower molecular weight by means of a cleaving agent, wherein the viscoelastic polymer can be cleaved in vivo by means of the cleaving agent into polymer chains which have an average molecular weight of at most 4 MDa.

Description

[0001] Kit for use in eye surgery and ophthalmic viscoelastic device

[0002] Technical area

[0003] The invention relates to a kit for use in eye surgery and a degradable 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.

[0012] What is needed, therefore, is a biocompatible ophthalmic viscoelastic device that can be degraded after surgery, allowing natural removal through water flow and drainage via the trabecular meshwork. US Pat. No. 6,745,776 B2 discloses an ophthalmic surgical procedure using a kit consisting of an OVD with hyaluronic acid as the viscoelastic polymer and hyaluronidase as the cleaving agent. During the surgical procedure, appropriate amounts of hyaluronidase are simultaneously added to the OVD to degrade the hyaluronic acid over time, thereby preventing a postoperative increase in intraocular pressure.

[0013] A disadvantage of this well-known kit is the fact that it can lead to the uncontrolled dissolution of the body's own hyaluronic acid, which can lead to corresponding problems.

[0014] Description of the invention

[0015] The object of the present invention is to provide a kit for use in eye surgery that reduces the risk of increased intraocular pressure after eye surgery without having to accept problems caused by uncontrolled dissolution of the body's own hyaluronic acid. A further object of the invention is to create a correspondingly advantageous ophthalmic viscoelastic device.

[0016] The object is achieved according to the invention by a kit according to claim 1 for use in eye surgery and by an ophthalmic viscoelastic device according to claim 4. 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 respective other aspect of the invention.

[0017] A first aspect of the invention relates to a kit for use in eye surgery, comprising an ophthalmic viscoelastic device which comprises at least one viscoelastic polymer, and at least one cleaving agent by means of which the viscoelastic polymer can be cleaved into polymer chains with a lower molecular weight. According to the invention, the at least one viscoelastic polymer of the ophthalmic viscoelastic device comprises disulfide bridges, while the cleaving agent is designed to cleave at least some of these disulfide bridges, wherein the viscoelastic polymer can be cleaved in vivo by means of the cleaving agent into polymer chains which have an average molecular weight of at most 4 MDa. In other words, the invention provides that the viscoelastic polymer of the OVD contains shorter-chain polymer orOligomer chains that are linked via disulfide bridges to form a longer-chain polymer with viscoelastic properties. Disulfide bridges, as covalent bonds, act on the one hand much more strongly than non-covalent bonds such as hydrogen bonds, but on the other hand, they are comparatively easy to break chemically, so that chemically aggressive cleaving agents can be dispensed with, which cannot be used in vivo, i.e., in the area of ​​the human or animal eye, due to the associated risk of injury. With the aid of the cleaving agent of the kit according to the invention, at least some of these disulfide bridges can then be cleaved gently in vivo, i.e., directly in the eye, and therefore without risk of injury to the patient, resulting in shorter-chain polymer or oligomer chains with a correspondingly lower molecular weight and different rheological properties.It is understood that this mechanism can also be used in vitro. Typically, the cleavage agent is a reducing agent. These shorter-chain degradation products can then be easily and quickly washed out of the anterior chamber via natural drainage pathways without clogging the trabecular meshwork or Schlemm's canals. Since endogenous hyaluronic acid does not contain disulfide bridges, there is no risk of inadvertent degradation of endogenous hyaluronic acid with the aid of the kit according to the invention, thus avoiding potentially associated problems from the outset.

[0018] 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 and without the risk of degrading the body's own hyaluronic acid. 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.Generally, "a" / "an" should be read as an indefinite article in this disclosure, meaning, unless expressly stated otherwise, "at least one." Conversely, "a" / "an" can also be understood as "only one."

[0019] In an advantageous embodiment of the invention, the viscoelastic polymer and the cleaving agent are matched to one another in such a way that the cleaving agent cleaves at least 70%, in particular at least 80%, of all disulfide bridges 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 viscoelastic polymer can be cleaved in vivo by the cleaving agent into polymer chains having an average molecular weight between 0.5 kDa and 3 MDa, particularly preferably between 0.1 kDa and 1 MDa. Alternatively or additionally, the viscoelastic polymer can be cleaved in vivo by the cleaving agent into particles with an average particle size of 600 nm or less, particularly an average particle size between 200 nm and 500 nm. This also advantageously ensures the gradual washing out of the polymer fragments via the aqueous humor and the trabecular meshwork without causing increased intraocular pressure.

[0020] Further advantages arise from the fact that the cleaving agent comprises a reducing agent, which in particular comprises one or more thiol groups, preferably N-acetylcysteine ​​(L-acetamido-ß-mercaptopropionic acid), glutathione (particularly in its thiol form γ-L-glutamyl-L-cysteinylglycine ("reduced glutathione")), or a mixture thereof. Although other suitable cleaving agents are conceivable in principle, the compounds mentioned and any mixtures thereof offer the advantage that they can be easily used in the eye in the required quantities and cause a sufficiently rapid and at least largely complete cleavage of the disulfide bridges of the viscoelastic polymer in vivo. By mixing these compounds and varying the mixing ratios of the individual compounds, the cleaving agent can also be easily adapted to different OVDs and surgical requirements.

[0021] A second aspect of the invention relates to an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer that can be cleaved in vivo by means of a cleaving agent into polymer chains with a lower molecular weight. According to the invention, the at least one viscoelastic polymer comprises disulfide bridges, wherein the viscoelastic polymer can be cleaved in vivo by means of the cleaving agent into polymer chains having an average molecular weight of at most 4 MDa. In other words, the invention provides that the viscoelastic polymer of the OVD comprises shorter-chain polymer or oligomer chains with an average molecular weight of at most 4 MDa, which are linked via disulfide bridges to form a longer-chain polymer with viscoelastic properties.Disulfide bonds act as covalent bonds, on the one hand, which are significantly stronger than non-covalent bonds such as hydrogen bonds, but on the other hand, they are comparatively easy to break chemically, thus eliminating the need for chemically aggressive breakage agents, which cannot be used in vivo, i.e., in the human or animal eye. The shorter-chain polymeric or oligomeric degradation products can then be easily washed out of the anterior chamber through natural processes without clogging the trabecular meshwork. Since the body's own hyaluronic acid does not contain disulfide bonds, there is no risk of inadvertently breaking down the body's own hyaluronic acid with the aid of the OVD according to the invention, thus avoiding associated problems from the outset.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 eliminated through the body's natural processes without causing a dangerous increase in intraocular pressure and without the risk of degrading the body's own hyaluronic acid. 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 OVD 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 OVD according to the invention can be used in a kit according to the first aspect of the invention.

[0022] In an advantageous embodiment, 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 of the viscoelastic polymer. If necessary, the viscoelastic polymer can be split back into these original formation blocks using the splitting agent.Furthermore, it can be provided that the viscoelastic polymer consists exclusively of one of the mentioned formation blocks, for example only of hyaluronic acid formation blocks, which are cross-linked to the viscoelastic polymer indirectly, i.e. via spacers containing thiol groups or other derivatizations, or directly via thiol groups which are introduced by derivatization of functional groups of the hyaluronic acid.

[0023] Further advantages arise from the fact that the at least one viscoelastic polymer comprises polymer chains that are linked end-to-end via disulfide bridges. 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 disulfide bridges. This allows the size of the polymer chains to be predetermined with particular precision after cleavage of the disulfide bridges, 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 head-to-tail connections or via non-terminal disulfide bridges.Furthermore, the individual polymer chains can be additionally cross-linked via other functional groups, as long as degradability and transportability via natural drainage pathways are sufficiently ensured after the disulfide bonds have been cleaved. This allows the viscoelastic properties, in particular, to be adjusted with particular precision.

[0024] In a further advantageous embodiment of the invention, the at least one viscoelastic polymer comprises polymer chains that are crosslinked by means of at least one crosslinker, in particular from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, dithiodipropionic acid dihydrazide, glutathione, in particular reduced glutathione, and any mixtures thereof, and / or that the at least one viscoelastic polymer has a degree of crosslinking between 0.1% and 100%. This allows the viscoelastic properties and the cleavage properties of the OVD to be optimally adapted to the respective intended use.

[0025] 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.

[0026] Further advantages arise from the fact that the concentration of the at least one viscoelastic polymer, based on 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 first aspect of the invention, the type and amount of the cleaving agent should be adjusted accordingly. In a further advantageous embodiment of the invention, the ophthalmic viscoelastic device comprises at least one therapeutic agent, in particular an analgesic and / or an antioxidant. This enables a release of the therapeutic agent, preferably in a controlled manner and optionally controllable by the degradation rate of the viscoelastic polymer, which can further facilitate eye surgery.The therapeutic agent is preferably not covalently bound to the at least one viscoelastic polymer, but is embedded in the polymer and / or dissolved in the OVD.

[0027] Further features of the invention emerge from the claims and the following description of exemplary embodiments. The features and combinations of features mentioned above in the description, as well as the features and combinations of features mentioned below, 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 also to be regarded as encompassed and disclosed by the invention that are not explicitly explained in the exemplary embodiments, 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 regarded as disclosed, in particular by the embodiments set out above, which go beyond or deviate from the combinations of features set out in the reliances of the claims.

[0028] Preferred embodiment of the invention

[0029] According to one embodiment, a kit according to the invention is provided for use in cataract surgery. The kit comprises a dispersive ophthalmic viscoelastic device comprising a viscoelastic polymer, which in this case consists of hyaluronic acid formation blocks cross-linked via disulfide bridges. The kit also comprises a cleaving agent by means of which at least a portion of the disulfide bridges of the viscoelastic polymer can be cleaved in vivo into shorter-chain polymer or oligomer chains with a correspondingly lower molecular weight. During cataract surgery, the dispersed OVD is applied to the corneal endothelium of a patient undergoing cataract surgery. The cleaving agent can optionally be mixed with the OVD and used together and / or applied before and / or after the OVD.

[0030] In the present embodiment, the thiol-containing reducing agent N-acetylcysteine ​​(NAC) or reduced glutathione (γL-glutamyl-L-cysteinylglycine, GSH), or any mixture thereof, is used as a cleaving agent to cleave the disulfide bonds of the viscoelastic polymer in vivo, resulting in polymer chains or fragments with lower molecular weight. These shorter-chain polymers or oligomers can be rapidly washed out of the anterior chamber via physiological mechanisms and outflow pathways without clogging the trabecular meshwork, Schlemm's canals, etc.

[0031] In general, thiols can be dimerized to disulfide bridges under oxidative conditions according to the general reaction equation (I):

[0032] Various synthetic routes exist for introducing disulfide bonds into hyaluronic acid (HA). Thiol groups can, for example, be introduced via hydrazide bonds at the glucuronic acid moiety of HA to produce the viscoelastic polymer block shown in formula (II):

[0033]

[0034] In general, a D-glucuronic acid-N-acetyl-D-glucosamine disaccharide of hyaluronic acid has a size of approximately 1 nm and comprises various reactive functional groups, thus providing potential reaction centers for the derivatization of hyaluronic acid (HA). These functional groups include a carboxyl group, a primary hydroxyl group, the reductive end group of HA, an N-acetyl group, and secondary hydroxyl groups. Thiol groups can be directly or indirectly attached to or incorporated into the HA backbone via these functional groups in various ways.

[0035] Hyaluronic acid hydrogels modified by thiol chemistry have proven advantageously biocompatible in experiments. Preferably, HA polymer chains are used as cross-linking blocks, which are short or small enough to be washed out of the eye without clogging the trabecular meshwork. These blocks are cross-linked via the free thiol groups to form polymers with an average molecular mass of approximately 1 to 3 MDa. Three-dimensional cross-linking of the polymer chains should be avoided, at least as far as possible, as this would generally result in a hydrogel with elastic rather than viscoelastic properties.

[0036] Alternatively, the HA chains can also be joined end-to-end to produce a polymer with a higher molecular weight. Free SH groups are introduced and cross-linked at the ends of preferably oligomeric or relatively short-chain HA blocks. In general, polymer chains of almost any length can be produced in this way, allowing not only dispersive but also medium- and high-viscosity cohesive OVDs with correspondingly higher molecular weights to be produced.

[0037] Likewise, instead of or in addition to HA, other starting materials such as alginate, chitosan, methylcellulose, hydroxypropylmethylcellulose, chondroitin sulfate, collagen, and gelatin, or corresponding physiologically compatible salts thereof, and other suitable compounds can optionally be derivatized to provide the thiol groups required for cross-linking and subsequently used as a forming block for the viscoelastic polymer of the OVD according to the invention. In principle, it can also be provided that forming blocks are cross-linked using cross-linkers, which in turn already contain a disulfide bridge and link the forming blocks to one another via other functional groups.

[0038] The degradation of the OVD according to the invention can, in principle, occur not only by administering the cleaving agent for the disulfide bridges, but also naturally, i.e., without the addition of a cleaving agent. However, for optimal temporal control of the degradation of the OVD, it is advisable to administer the cleaving agent in the appropriate amount or concentration into the anterior chamber of the eye.

[0039] Since the natural filling time of the anterior chamber is approximately 4.5 hours, OVD degradation by the cleaving agent is preferably also completed within this time when administered intraocularly. Degradation of the disulfide-crosslinked HA polymer using NAC as the cleaving agent is completed after approximately 5 to 6 hours. The OVD may additionally contain one or more therapeutic agents, for example, analgesics such as lidocaine or antioxidants such as sorbitol. These therapeutic agents are preferably not covalently bound to the viscoelastic polymer, but rather dissolved in the OVD and / or incorporated into the viscoelastic polymer. This allows the therapeutic agents to be released in a controlled manner over a predefined period of time during degradation of the viscoelastic polymer.

[0040] 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, DIN tolerances and the like.

Claims

Patent claims 1. 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, characterized in that the at least one viscoelastic polymer of the ophthalmic viscoelastic device comprises disulfide bridges and that the cleaving agent is designed to cleave at least a portion of these disulfide bridges, wherein the viscoelastic polymer can be cleaved in vivo by means of the cleaving agent into polymer chains which have an average molecular weight of at most 4 MDa.

2. Kit according to claim 1, characterized in that the viscoelastic polymer and the cleaving agent are matched to one another in such a way that the cleaving agent cleaves at least 70%, in particular at least 80% of all disulfide bridges of the viscoelastic polymer in vivo 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 the viscoelastic polymer can be cleaved by means of the cleaving agent in vivo into polymer chains which have an average molecular weight between 0.5 kDa and 3 MDa, particularly preferably between 0.1 kDa and 1 MDa, and / or the viscoelastic polymer can be cleaved by means of the cleaving agent in vivo into particles with an average particle size of at most 600 nm, in particular an average particle size between 200 nm and 500 nm.

3. Kit according to claim 1 or 2, characterized in that the cleaving agent comprises a reducing agent which in particular comprises one or more thiol groups, preferably N-acetylcysteine, glutathione or a mixture thereof.

4. An ophthalmic viscoelastic device comprising at least one viscoelastic polymer which is cleavable by means of a cleaving agent into polymer chains of lower molecular weight, characterized in that the at least one viscoelastic polymer comprises disulfide bridges, wherein the viscoelastic polymer is cleavable by means of the cleaving agent in vivo into polymer chains which have an average molecular weight of at most 4 MDa.

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

6. An ophthalmic viscoelastic device according to claim 4 or 5, characterized in that the at least one viscoelastic polymer comprises polymer chains linked end-to-end via disulfide bridges.

7. Ophthalmic viscoelastic device according to one of claims 4 to 6, characterized in that the at least one viscoelastic polymer comprises polymer chains which are cross-linked by means of at least one cross-linker, in particular from the group 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, dithiodipropionic acid dihydrazide, glutathione and any mixtures thereof, and / or that the at least one viscoelastic polymer has a degree of cross-linking between 0.1% and 100%.

8. Ophthalmic viscoelastic device according to one of claims 4 to 7, characterized in that This is designed as a dispersive ophthalmic viscoelastic device.

9. Ophthalmic viscoelastic device according to one of claims 4 to 8, characterized in that a concentration of the at least one viscoelastic polymer based on the total volume of the ophthalmic viscoelastic device is between 0.1 mg / ml and 50 mg / ml.

10. Ophthalmic viscoelastic device according to one of claims 4 to 9, characterized in that it comprises at least one therapeutic agent, in particular an analgesic and / or an antioxidant, wherein the therapeutic agent is preferably non-covalently bound to the at least one viscoelastic polymer.

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