EP4507674A1

EP4507674A1 - Ophthalmological viscoelastic composition

Info

Publication number: EP4507674A1
Application number: EP23719675.3A
Authority: EP
Inventors: Ben Robertson; Michael Haisch; Alexander Morozov
Original assignee: University of Edinburgh; Hyaltech Ltd
Current assignee: University of Edinburgh; Hyaltech Ltd
Priority date: 2022-04-12
Filing date: 2023-04-12
Publication date: 2025-02-19
Also published as: GB202205364D0; GB2617576B; WO2023198737A1; GB2617576A

Abstract

The invention relates to an ophthalmological viscoelastic composition comprising an aqueous solution having a viscoelastic base component and having an additive including at least one water-soluble polymer without covalent bonding to the base component. The additive increases an extensional viscosity of the composition compared to the composition without additive. In addition, the additive is present in a concentration equal to or lower than a concentration of the base component in the aqueous solution.

Description

Ophthalmological viscoelastic composition

Technical field

The invention relates to an ophthalmological viscoelastic composition comprising an aqueous solution having a viscoelastic base component and having an additive including at least one water-soluble polymer without covalent bonding to the base component.

Prior art

Ophthalmological viscoelastic compositions (ophthalmological viscoelastic devices, OVDs) serve as auxiliaries in cataract surgery and have considerably improved the safety and efficacy of this surgical method. OVDs especially maintain the anterior chamber depth and protect the corneal endothelium and other intraocular tissue during the surgical procedure. OVDs are therefore very important for a low complication rate and for the facilitation of the surgical procedure.

However, OVDs must also be postoperatively removable again in a safe and reliable manner, since there can otherwise be a rise in intraocular pressure after the operation, which can damage the optic nerve. Cohesive OVDs can be removed relatively easily. Dispersive OVDs require more effort, but give better protection of the endothelial cells, and are therefore likewise used as standard. Highly cohesive OVDs are used especially when the maintenance of the anterior chamber depth requires additional effort. But these are very difficult to remove.

Summary of the invention

It is an object of the present invention to provide an ophthalmological viscoelastic composition, which can firstly reliably create and maintain the anterior chamber space during a cataract operation, and can secondly be reliably removed postoperatively.

The object is achieved in accordance with the invention by an ophthalmological viscoelastic composition according to Claim 1 . Advantageous refinements of the invention are specified in the dependent claims. The invention relates to an ophthalmological viscoelastic composition comprising an aqueous solution having a viscoelastic base component and having an additive including at least one water-soluble polymer without covalent bonding to the base component. According to the invention, the ophthalmological viscoelastic composition (OVD) can reliably create and maintain the anterior chamber space during a cataract operation and can additionally be reliably removed postoperatively in that the additive increases an extensional viscosity of the composition compared to the composition without additive, and in that the additive is present in a concentration equal to or lower than a concentration of the base component in the aqueous solution. In other words, what is envisaged in accordance with the invention is that the OVD contains an additive comprising at least one water-soluble polymer, where the additive increases the extensional viscosity of the OVD by comparison with an OVD having an otherwise identical composition but without the additive. Extensional viscosity (or elongational viscosity) is understood to mean the resistance to extension of the OVD. In other words, extensional viscosity is a measure of the resistance of a substance to flow in an extensional flow. If, for example, the OVD is introduced between two plates and these plates are then moved away from one another, an OVD having relatively high extensional viscosity forms a longer capillary than an OVD having relatively low extensional viscosity. The additive may in principle contain one kind of polymer or multiple kinds of polymers, provided that these contribute to an increase in extensional viscosity, especially under physiological conditions, i.e. in a patient’s eye. According to the invention, the concentration of the sum total of all water-soluble polymers of the additive corresponds at most to the concentration of the viscoelastic base component or is lower than the concentration of the viscoelastic base component. In the context of the present disclosure, concentration figures should always be regarded as percentages by mass, unless stated otherwise.

The extensional viscosity of the OVD can be quantified by its relaxation time on elongation. Relaxation times on elongation can be measured, for example, with a capillary breakup extensional rheometer (CaBER). It is possible here to determine extensional viscosity by means of visual evaluation. The extended relaxation time that is caused by the additive in accordance with the invention ensures that the OVD has good mobility and nevertheless has the shear viscosity required for reliable maintenance of space. A formulation of the OVD with elevated extensional viscosity thus enables good removability during the aspiration of the OVD from the eye after the operation. Elevated extensional viscosity additionally improves the cohesivity of the OBD and ensures that the suction employed during the phaco operation can completely or at least essentially completely remove the OVD. Extensional viscosity properties are generally less significantly concentration-dependent than shear viscosity properties. The elevated extensional viscosity in accordance with the invention in principle brings about improved reversible deformation of the OVD, whereas the viscous component in principle brings about time-dependent unlimited irreversible deformation. The extensional viscosity of the OVD with additive is preferably higher by at least 2%, especially at least 5%, than without.

In the context of the present disclosure, all viscosity values are reported in the unit of pascal seconds (Pas) based on a temperature of 25°C and an ambient pressure of 1.013 bar, unless stated otherwise. The temperature in the anterior chamber, the site where the ODD is used, is generally above 25°C but below 37°C. During the cataract surgery, the temperature may also rise above 40°C. Controlled by the irrigation system of the phacoemulsification system, there may also be a slight rise in pressure during the operation. It will be apparent that the additive can advantageously increase extensional viscosity in principle even at higher or lower temperatures or at varying ambient pressure.

In an advantageous configuration of the invention, the base component is present in a concentration between 0.5% by weight and 4% by weight, especially between 1.0% by weight and 3.0% by weight, preferably between 1 .4% by weight and 1 .5% by weight, and/or has an intrinsic viscosity between 20 dl/g and 77 dl/g, especially between 32 dl/g and 50 dl/g, preferably between 34 dl/g and 38 dl/g; and/or has an average molar mass between 1 kDa and 5 MDa, especially between 1 MDa and 3 MDa. In this way, it is possible to achieve particularly advantageous shear viscosity properties as required for excellent retention of space.

In a further advantageous configuration of the invention, the base component consists of hyaluronic acid, a hyaluronic acid derivative or a mixture thereof, where the hyaluronic acid and/or the hyaluronic acid derivative has preferably been produced at least partly or entirely by bacterial means. Hyaluronic acid or hyaluronan is a glycosaminoglycan polymer having high molecular weight of the extracellular matrix in vertebrates. It consists of disaccharides consisting alternately of D-glucuronic acid and N-acetyl-D-glucosamine and joined by p-1 ,3 or p-1 ,4 glycosidic bonds. Hyaluronic acid, salts thereof and derivatives thereof have excellent viscoelastic properties and simultaneously a high biocompatibility. For highly cohesive OVDs, primarily HA from animal sources is used, for example from cockscombs. However, this mode of production is being regarded increasingly critically. For that reason, it is advantageous when the OVDs are produced from bacterial HA and not from animal HA, and are especially entirely free of animal products. However, bacterially produced HA typically has a lower average molecular weight than animal HA. In order nevertheless to ensure high retention of space, preference is given to using a higher concentration in the case of bacterial HA. The additive according to the invention advantageously compensates, or more than compensates, for potentially poorer removability of bacterial HA. Accordingly, it is possible to produce an OVD according to the invention which on the one hand is free of animal products, but on the other hand nevertheless has the desired rheological properties.

In a further advantageous configuration of the invention, the additive comprises a water- soluble, preferably biocompatible, polymer which has a higher average molecular weight than the base component and preferably has an average molecular weight between 3 MDa and 10 MDa, especially between 5 MDa and 8 MDa; and/or is present in a concentration between 0.001 % by weight and 0.1 % by weight, especially between 0.01 % and 0.05% by weight; and/or is present in a concentration between 1/10 and 1/1000, especially between 1/30 and 1/100, of the concentration of the base component; and/or is polyethylene oxide, polypropylene oxide or a mixture thereof. In other words, what is envisaged in accordance with the invention is that the additive used is a water-soluble and preferably biocompatible polymer having high molecular weight. As a result, the polymer preferably has very high extensional viscosity, as a result of which the total extensional viscosity of the OVD is correspondingly increased. The polymer is present in a comparatively low concentration compared to the base component, such that it affects only or at least essentially only the extensional viscosity of the OVD and not the shear viscosity thereof. The polymer is preferably a synthetic polymer such as polyethylene oxide (polyethylene glycol, PEG) and/or polypropylene oxide (polypropylene glycol, PPG), since these compounds have good solubility in water and have high extensional viscosity values, such that, even in low concentrations, they contribute to a considerable rise in the overall extensional viscosity of the OVD. Alternatively or additionally, the additive comprises a water-soluble, preferably biocompatible, polymer which has a lower average molecular weight than the base component and preferably has an average molecular weight between 1 kDa and 500 kDa; and/or is present in a concentration between 0.1 % by weight and 2% by weight, especially between 0.5% and 1.0% by weight; and/or is present in a concentration between 60% and 100% of the concentration of the base component; and/or has an intrinsic viscosity between 1 dl/g and 10 dl/g, especially between 3 dl/g and 6 dl/g. In other words, in this variant, an additive composed of one or more polymers having a lower average molecular weight compared to the base component is used, where the average molecular weight of the base component is preferably 2 to 100 times, preferably 10 to 20 times, the average molecular weight of the additive. Such a polymer in itself has a comparatively low extensional viscosity, but instead brings about an increase in the extensional viscosity of the base component by intercalation into the chains of the base component. The additive preferably has a relatively high concentration but a low molecular weight, such that it affects the viscosity of the base component only slightly, but nevertheless increases its extensional viscosity.

In an advantageous configuration of the invention, the additive comprises a polysaccharide, especially hyaluronic acid and/or chondroitin sulfate and/or sodium alginate, and/or a cellulose derivative, especially hydroxyethyl cellulose and/or hydroxypropyl methylcellulose. The compounds mentioned are each of excellent suitability as water- soluble biocompatible additives having lower average molecular weight than the base component since they have good intercalatability between polymer chains of the base component in order thus to increase the extensional viscosity of the OVD.

In a further advantageous configuration of the invention, the OVD has a zero-shear viscosity at 25°C and an air pressure of 1.013 bar of between 800 Pas and 3500 Pas, especially between 1000 Pas and 3000 Pas. In this way, according to the profile of requirements, it is possible to provide supercohesive OVDs according to the invention as a comparatively high-viscosity (~800-~1000 Pas), very high-viscosity (~1000-~3000 Pas) or super-viscous (~3000-~3500 Pas) formulation, where appropriate intermediate viscosity values are also possible.

In a further advantageous configuration of the invention, the ophthalmological viscoelastic composition additionally comprises at least one osmolality additive, especially sodium chloride, and/or at least one pH system that buffers within the pH range of 7.4 ± 2.5, especially a sodium dihydrogenphosphate/disodium hydrogenphosphate buffer system. An osmolality additive in the context of the present disclosure is understood to mean an additive that modifies, and especially increases to the desired value, the osmolality of the OVD, i.e. the concentration of all dissolved and hence osmotically active particles in the aqueous solution (based on 1 kg of OVD). It is possible here as required to establish a hypoosmolal, isoosmolal or hyperosmolal OVD. A pH buffer system in the context of the present disclosure is understood to mean substance mixtures composed of at least one weak acid and its conjugate base (or conjugate bases) and/or at least one weak base and its conjugate acid (or conjugate acids). The pH buffer system is capable of keeping the pH of the OVD at least substantially constant over a certain concentration range in the case of addition of acid or base.

Further advantages arise in that the OVD consists of 15 mg/ml sodium hyaluronate (41 dl/g), 0.1 mg/ml polyethylene oxide or polypropylene oxide or a mixture thereof, 9.0 mg/ml sodium chloride, 0.045 mg/ml sodium dihydrogenphosphate, 0.22 mg/ml disodium hydrogenphosphate and water as the balance. The polyethylene oxide used and/or the polypropylene oxide used preferably has an average molecular weight of at least 5 M Da. In addition, the sodium hyaluronate used preferably comes partly or completely from a bacterial source. More particularly, the OBD is preferably free of animal products or of products from animal sources. The resulting OVD has a zero-shear viscosity of about 3000 Pas and an intrinsic viscosity of > 36 dl/g.

It is alternatively the case that the OVD consists of 14 mg/ml sodium hyaluronate (41 dl/g), 9.5 mg/ml sodium hyaluronate (5 dl/g), 8.5 mg/ml sodium chloride, 0.045 mg/ml sodium dihydrogenphosphate, 0.22 mg/ml disodium hydrogenphosphate and water as the balance. In this advantageous embodiment, both the base component and the additive are hyaluronic acid or hyaluronic salts having different average molecular weight and correspondingly different intrinsic viscosity. Preferably, the shorter-chain sodium hyaluronate (5 dl/g) that functions as additive has a comparatively low molecular weight of not more than 0.5 MDa. In addition, all the sodium hyaluronate used preferably comes partly or completely from a bacterial source. More particularly, the OBD is preferably free of animal products or of products from animal sources. The resulting OVD has a shear viscosity between about 1000 Pas and about 3000 Pas. Preferred execution of the invention

The invention is an OVD which, in one embodiment, contains a composition composed of hyaluronic acid having high molecular weight as base component in combination with a lower concentration of a polymeric additive for improving the extensional viscosity of the OVD.

An ophthalmological viscoelastic composition with elevated extensional viscosity enables good removability during the aspiration of the OVD from the eye after the operation. Elevated extensional viscosity additionally improves the cohesivity of the composition and ensures that maximum amounts of OBD are removed in the course of suction during the phaco operation. In other words, in the context of the present invention, rather than using maximum contents of additives, the rheological properties of the OVD are optimized by the use of a minimum additive concentration that corresponds to not more than the concentration of the base component, but is generally much lower. The additive here binds to the base components only physically or via noncovalent bonds.

The polymeric additions that are useful as additive may be a biopolymer or a synthetic polymer. The working examples that follow describe two methods of increasing extensional viscosity:

The first working example relates to the use of a polymer, especially a biopolymer, as additive having a distinctly lower average molecular weight than the base component. This polymer in itself may have a very low extensional viscosity, but brings about an increase in the extensional viscosity of the base component by intercalation into or by physical binding to the polymer chains of the base component. The additive may be used in a relatively high concentration, but affects the viscosity of the OVD only slightly on account of its low molecular weight.

In the first working example, the ophthalmological viscoelastic composition (OPD) according to the invention consists of the ingredients specified in Table 1 : Table 1 : First working example of an ophthalmological viscoelastic composition according to the invention

Proceeding from hyaluronic acid (HA) having high average molecular weight (between 2 MDa and 4 MDa) as base component which is essential for the general rheological and elastic properties of the OVD and constitutes the main ingredient, HA having comparatively low molecular weight (< 0.5 MDa) is used as additive, present in a concentration of < 1%. The hyaluronate concentration or the concentration of the base component, by contrast, is typically 1.0% to 1.5% and is established in phosphate-buffered sodium chloride solution in order to attain a shear viscosity between about 1000 Pas and about 3000 Pas. Both HA polymers, i.e. the base component and the additive, are produced from HA obtained by bacterial means. The OVD has an intrinsic viscosity of > 36 dl/g and an average molecular weight of > 3-4 MDa.

Rather than sodium hyaluronate (HA) as additive, it is alternatively possible to use a biopolymer, for example a polysaccharide. In addition, it is possible to use chondroitin sulfate, sodium alginate or cellulose derivatives, especially hydroxyethyl cellulose or hydroxypropyl methylcellulose. The biopolymers mentioned may generally be used individually or in any combination as additive for increasing the extensional viscosity of the OVD.

The extensional viscosity of the OVD can be quantified by its relaxation time. Relaxation times after elongation can be measured with a capillary breakup extensional rheometer (CaBER). The relaxation time of the base component is about 60-80 ms. The addition of about 1% HA (5 dl/g) increases this to 150 ms. The extended relaxation time caused by physical intercalation of the polymeric additive into the base component ensures that the OVD is removable postoperatively without difficulty and nevertheless has the high shear viscosity required for excellent retention of space during a cataract operation. The concentration of the additive can be varied to a certain extent since the resulting extensional viscosity of the OVD is less strongly concentration-dependent than its shear viscosity.

The viscosity of the OVD depends on the desired application. Supercohesive OVDs may have, for example, a viscosity between about 1000 Pas and about 3000 Pas. Viscosity and extensional viscosity are the most important factors that should be controlled in the case of these high molecular weight OVDs. The specifications for the concentrations of additives and other additions can be drawn relatively broadly in order to take account of the fact that changes in the molecular weight affect that concentration of the base component required to achieve the desired physical properties of the OVD. The additive used is preferably hyaluronic acid or a salt and/or derivative of hyaluronic acid with a low molecular weight of about 1 kDa - 500 kDa and/or an intrinsic viscosity of 1-10 dl/g, preferably 3-6 dl/g. The low molecular weight polymer is generally present in a concentration of 1-20 mg/ml, more preferably in concentrations of 5-10 mg/ml. The concentration of the additive is less than or at most equal to the concentration of the base component (e.g. hyaluronic acid) and is preferably 60-100% of the concentration of the base component in aqueous solution. If the addition is a polymer having a lower average molecular weight than that of the base component, the average molecular weight of the base component is preferably 2 to 100 times, preferably 10 to 20 times, the average molecular weight of the additive.

The second working example relates to the use of a polymer as additive having a higher average molecular weight than the base component. This polymer has a very high extensional viscosity, which increases the overall extensional viscosity of the OVD merely through addition of a small amount of additive. Since the additive is present in low concentration, it essentially only affects the extensional viscosity and not the shear viscosity of the OVD.

In the second working example, the ophthalmological viscoelastic composition (OPD) according to the invention consists of the ingredients specified in Table 2: Table 2: Second working example of the ophthalmological viscoelastic composition according to the invention

The polymeric additive in the present example is the biocompatible synthetic polymer PEG having a comparatively high average molecular weight (> 3 MDa). Alternatively or additionally, PPG may also be used. In that case too, there is an increase in the relaxation time of the OVD for about 60-80 ms without additive to about 150 ms with additive. The OVD is preferably free of animal products.

The polymer having the higher average molecular weight is generally present in a concentration between 0.001% and 0.1 %, preferably between 0.05% and 0.02%. The concentration of the base component (e.g. hyaluronic acid) may be between 10 and 1000 times, preferably between 30 and 100 times, the concentration of the additive.

In a further working example, the OVD consists of an aqueous solution of 5-20 mg/ml and preferably 10-15 mg/ml sodium hyaluronate (41 dl/mg), 0.01-0.5 mg/ml, preferably 0.05- 0.2 mg/ml, polyethylene oxide having an average molecular weight of 3-10 MDa, preferably 5-8 MDa, and optionally an osmolality additive and/or a pH buffer.

The parameter values specified in the documents to define process and measurement conditions for the characterization of specific properties of the subject matter of the invention should also be considered to be encompassed by the scope of the invention in the context of deviations - for example due to measurement errors, system errors, weighing errors, DIN tolerances and the like.

Claims

1 . Ophthalmological viscoelastic composition comprising an aqueous solution having a viscoelastic base component and having an additive including at least one water- soluble polymer without covalent bonding to the base component, characterized in that the additive increases an extensional viscosity of the composition compared to the composition without additive, and in that the additive is present in a concentration equal to or lower than a concentration of the base component in the aqueous solution.

2. Ophthalmological viscoelastic composition according to Claim 1 , characterized in that the base component is present in a concentration between 0.5% by weight and 4% by weight, especially between 1.0% by weight and 3.0% by weight, preferably between 1.4% and 1.5% by weight; and/or has an intrinsic viscosity between 20 dl/g and 77 dl/g, especially between 32 dl/g and 50 dl/g, preferably between 34 dl/g and 38 dl/g; and/or has an average molar mass between 1 kDa and 5 MDa, especially between 1 MDa and 3 MDa.

3. Ophthalmological viscoelastic composition according to Claim 1 or 2, characterized in that the base component consists of hyaluronic acid, a hyaluronic acid derivative or a mixture thereof, where the hyaluronic acid and/or the hyaluronic acid derivative has preferably been produced at least partly or entirely by bacterial means.

4. Ophthalmological viscoelastic composition according to any of Claims 1 to 3, characterized in that the additive comprises a water-soluble, preferably biocompatible, polymer which has a higher average molecular weight than the base component and preferably has an average molecular weight between 3 MDa and 10 MDa, especially between 5 MDa and 8 MDa; and/or is present in a concentration between 0.001 % by weight and 0.1 % by weight, especially between 0.01% and 0.05% by weight; and/or is present in a concentration between 1/10 and 1/1000, especially between 1/30 and 1/100, of the concentration of the base component; and/or is polyethylene oxide, polypropylene oxide or a mixture thereof.

5. Ophthalmological viscoelastic composition according to any of Claims 1 to 4, characterized in that the additive comprises a water-soluble, preferably biocompatible, polymer which has a lower average molecular weight than the base component and preferably has an average molecular weight between 1 kDa and 500 kDa; and/or is present in a concentration between 0.1% by weight and 2% by weight, especially between 0.5% and 1.0% by weight; and/or is present in a concentration between 60% and 100% of the concentration of the base component; and/or has an intrinsic viscosity between 1 dl/g and 10 dl/g, especially between 3 dl/g and 6 dl/g.

6. Ophthalmological viscoelastic composition according to Claim 5, characterized in that the additive comprises a polysaccharide, especially hyaluronic acid and/or chondroitin sulfate and/or sodium alginate, and/or a cellulose derivative, especially hydroxyethyl cellulose and/or hydroxypropyl methylcellulose.

7. Ophthalmological viscoelastic composition according to any of Claims 1 to 6, characterized in that it has a zero-shear viscosity between 800 Pas and 3500 Pas, especially between 1000 Pas and 3000 Pas.

8. Ophthalmological viscoelastic composition according to any of Claims 1 to 7, characterized in that it additionally comprises at least one osmolality additive, especially sodium chloride, and/or at least one pH buffer system that buffers within the pH range of 7.4 ± 2.5, especially a sodium dihydrogenphosphate/disodium hydrogenphosphate buffer system.

9. Ophthalmological viscoelastic composition according to Claims 1 to 4, 7 and 8, characterized in that it consists of 15 mg/ml sodium hyaluronate (41 dl/g), 0.1 mg/ml polyethylene oxide or polypropylene oxide or a mixture thereof, 9.0 mg/ml sodium chloride, 0.045 mg/ml sodium dihydrogenphosphate, 0.22 mg/ml disodium hydrogenphosphate and water as the balance.

10. Ophthalmological viscoelastic composition according to Claims 1 to 3 and 5 to 8, characterized in that it consists of 14 mg/ml sodium hyaluronate (41 dl/g), 9.5 mg/ml sodium hyaluronate (5 dl/g), 8.5 mg/ml sodium chloride, 0.045 mg/ml sodium dihydrogenphosphate, 0.22 mg/ml disodium hydrogenphosphate and water as the balance.