WO2025062017A1

WO2025062017A1 - Drug eluting devices for intraocular lenses

Info

Publication number: WO2025062017A1
Application number: PCT/EP2024/076543
Authority: WO
Inventors: Darren Pitt; Thomas Kemp; Joanna Mary Gould
Original assignee: Visusnano Ltd
Current assignee: Visusnano Ltd
Priority date: 2023-09-20
Filing date: 2024-09-20
Publication date: 2025-03-27
Anticipated expiration: 2026-03-20
Also published as: GB202314432D0

Abstract

A device for sustained release of a therapeutic agent into the eye of a recipient is provided. The device is suitable for mechanical attachment to a haptic arm on an intraocular lens (IOL). The device is configured to include a first, a second and a third contact surface, wherein at least the first and second contact surfaces are arranged in opposition to each other, and wherein all of the first, second and third contact surfaces are configured to bear upon the haptic arm to facilitate mechanical attachment to the haptic arm. Methods of using the device for the treatment of post operative complications are also provided. Also methods for reducing or eliminating post-implantation rotation of IOLs within the eye of a recipient are also provided.

Description

DRUG ELUTING DEVICES FOR INTRAOCULAR LENSES

FIELD OF THE INVENTION

The invention relates to bioerodable/degradeable drug eluting devices that are attached to intraocular lenses (lOLs) prior to implantation within the eye of a patient.

BACKGROUND

Intraocular lenses (IOL) are lenses implanted in the eye used to treat cataracts or myopia. The most common type of IOL is the pseudophakic IOL. These are implanted during cataract surgery, after the cloudy crystalline lens has been removed. The pseudophakic lOLs replace the original crystalline lens and provide the light focusing function originally undertaken by the crystalline lens. The second type of lOLs, more commonly known as a phakic IOL (PIOL), is a lens which is placed over the existing natural lens and is used in refractive surgery to change the eye's optical power as a treatment for myopia. lOLs usually consist of a small plastic lens with plastic side struts or arms, called haptics, to hold the lens in place within the capsular bag inside the eye. Insertion of an IOL for the treatment of cataracts is the most commonly performed eye surgical procedure. Surgeons annually implant more than 6 million lenses. The procedure can be done under local anaesthesia with the patient awake throughout the operation. The use of a flexible IOL enables the lens to be rolled for insertion into the capsule through a very small incision, thus avoiding the need for sutures, and this procedure usually takes less than 30 minutes in the hands of an experienced ophthalmologist. The recovery period is about 2-3 weeks. After surgery, patients should avoid strenuous exercise or anything else that significantly increases blood pressure and, thus, intraocular pressure.

Posterior capsular opacification (PCO) is a condition where the crystalline lens capsule becomes cloudy and opaque. PCO one of the most common complications of cataract surgery where the natural lens removed and replaced with an artificial IOL as described above. In PCO, the posterior capsule undergoes secondary opacification due to the migration, proliferation, and differentiation of lens epithelial cells. To address post-operative complications such as PCO, strategies have been adopted that involve including a drug eluting component within or attached to an IOL.

EP 3 423 002 B1 describes an IOL comprising a plurality of drug-containing microspheres attached to the IOL. The IOL may comprise an optic and at least one haptic. The microspheres can be attached to one or more haptics and/or the optic of the IOL. The microspheres may be configured to release a drug in a defined manner when the IOL is inserted into the eye of a patient. US 2015/0209274 A1 describes a drug eluting member that is adapted to be attachable onto a perimeter edge of an optic portion of an IOL, the drug eluting member includes an interfacing portion adapted to receive a portion of the perimeter edge.

WO 2020/264425 A1 describes an ophthalmic article configured to associate to a haptic of an IOL that comprises a biocompatible matrix comprising a copolymer derived from a caprolactone monomer and at least one other monomer. The biocompatible matrix polymer is selected to provide elasticity and flexibility. The ophthalmic article may also comprise an active agent or a diagnostic agent.

WO 2023/009664 A1 describes a system for securing a bioerodable drug delivery component to an IOL. The drug delivery component includes a fixation portion affixed to the posterior side of a drug delivery pad assembly. The drug delivery component is in the form of a clip that is attached to the lens via a clamping process requiring a plunger and stand assembly mechanism.

Hence, there is a need to provide improved ways of ensuring secure attachment of a bioerodable/biodegradable device to an IOL that do not require complex fixing arrangements such as clamps or adhesives. Clamping arrangements typically require that the device is applied to a periphery of the IOL or to a haptic arm such that a compressive force is exerted on the material of the IOL. This can increase the complexity of IOL design and assembly and also can result in damage to the IOL if incorrectly installed as well as fragmentation of the drug eluting device during biodegradation. Mechanical performance of the IOL may be altered during biodegradation of complex fixing assemblies contributing to poor in vivo performance.

Bioerodable/biodegradable devices are designed to degrade, in use, in order to ensure release of the encapsulated therapeutic agent, such as a drug, over time. However, it follows that if the rate of degradation is uneven across the device due to its geometry, placement or choice of materials used, the device may degrade into a plurality of device fragments over time after implantation of the IOL. These fragments may migrate or cause irritation and increase scarring within the eye causing postoperative complications such as PCO. IOL associated devices that rely on an applied clamping force will, thus, have an inherent tendency to fragment when there is a loss of structural integrity of the clamping mechanism due to biodegradation and erosion. This is a key weakness of all IOL associated devices that require complex clamping arrangements to hold them in place during delivery and implantation of the IOL into the eye of the patient.

The present devices address the problems associated with the prior art configurations and provide improved approaches and methods for the release of therapeutic agents, such as drugs, via IOL associated drug eluting devices. These and other advantages will be apparent to those skilled in the art from the description of the embodiments of the invention and associated teachings provided herein. SUMMARY

The invention provides improved devices for delivery of timed-release therapeutic agents, such as active pharmaceutical agents (e.g. drugs), that can be attached to lOLs via mechanical engagement with one or more haptics. The devices according to the invention show advantage in that they are relatively straightforward to attach securely to an IOL prior to implantation into the eye of a patient and they also biodegrade evenly presenting a reduced risk of fragmentation when in use.

According to a first aspect of the invention, a device is provided for sustained release of a therapeutic agent, wherein the device is suitable for mechanical attachment to a haptic arm on an intraocular lens (IOL), wherein the device is configured to include a first, a second and a third contact surface, wherein at least the first and second contact surfaces are arranged in opposition to each other, and wherein all of the first, second and third contact surfaces are configured to bear upon the haptic arm to facilitate mechanical attachment to the haptic arm.

In one embodiment, the first and third surfaces are arranged in opposition to the second contact surface.

In a particular embodiment the first, second and third surfaces are arranged in a triangular orientation. Optionally, the triangular orientation consists of an isosceles triangle and/orthe triangular orientation consists of an equilateral triangle.

In embodiments of the invention the first, second and third contact surfaces are interconnected via one or more joining members. Suitably, the one or more joining members define a planar base on one side of the device. Typically, the first, second and third contact surfaces are located on projections, or posts, that extend upwardly from the planar base. Optionally, the one or more joining members fully or partially enclose a space between the first, second and third surfaces so as to define a channel that is configured to receive a haptic arm.

In a specific embodiment, the device comprises a base section and first, second and third surfaces are arranged in linear configuration, wherein the first surface is located upon a first projection that extends upwardly from the base section and wherein the second and third surfaces are located on opposing ends of a second projection that extends upwardly from the base section, with the first and second surfaces orientated in axial opposition to each other so as to define a channel between them, and the third surface faces axially away from the second.

In particular embodiments of the invention, one or more of the first, second and third surfaces are curved. Optionally, one or more of the first, second and third surfaces are substantially concave. Alternatively, one or more of the first, second and third surfaces are substantially convex. In one embodiment, all of the first, second and third surfaces are substantially convex. Suitably, the first, second and third surfaces are arranged to facilitate a sliding engagement onto a haptic arm.

In specific embodiments, the device is comprised of a material that biodegrades or bio-erodes upon implantation into the body of a patient. Suitably, the material is comprised of polymer selected from one or more of the group consisting of: PLGA (Poly(lactic-co-glycolic acid); Poly(lactic acid) (PLA); Poly(glycolic acid) (PGA); Poly(caprolactone) (PCL); Polyethylene glycol) (PEG); Poly(D,L-lactic acid) (PDLLA); Poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV); Polydioxanone (PDO); Poly(s- caprolactone-co-lactide) (PCLA); a Polysaccharide, including chitosan, alginate, and hyaluronic acid; and/or a Polyorthoester (POE).

In further embodiments, the therapeutic agent comprises a molecule having a therapeutic effect selected from one or more of: an anti-proliferative; an anti-hypertensive; a non-steroidal antiinflammatory (NSAID); a steroid; an antibiotic; or a prostaglandin analogue. Typically the therapeutic agent is a drug selected from one or more of: moxifloxacin: cefuroxime: vancomycin; tacrolimus; sirolimus; everolimus; cyclosporine; ascomycin; mycophenolic acid; dexamethasone; prednisolone; loteprednol; fluocinolone; fluoromethoIone; difluprednate; ketorolac; diclofenac; bromfenac; nepafenac; a carbonic anhydrase inhibitor; apraclonidine; travoprost; bimatoprost; latanoprost; and tafluprost, as well as salts, mimetics and analogues thereof, second aspect of the invention provides for an intraocular lens (IOL), wherein the IOL comprises at least one haptic arm and wherein the lens further comprises a device of any described herein, wherein the device is slidably engaged with and mechanically attached to the haptic arm.

In further embodiments, the device further comprises at least one surface modification applied to an outer surface of the device, or to particular sections or zones of the device, that are intended to contact an anterior and/or posterior capsular bag surface within the eye of the recipient patient. Optionally, the at least one surface modification is selected from: textured moulding; chemical, mechanical or laser-etched patterns; ribbing; dimpling; pitting; ridges; or any other variation in surface geometry. Typically, the at least one surface modification is configured to increase a coefficient of friction with a capsular bag surface so as to resist rotation of an associated IOL following implantation into the eye of a recipient patient.

A third aspect of the invention provides an intraocular lens (IOL), wherein the IOL comprises at least one haptic arm and wherein the lens further comprises a device of any described herein, wherein the device is slidably engaged with and mechanically attached to the haptic arm.

A fourth aspect of the invention provides for an intraocular lens (IOL), wherein the IOL comprises at least one closed loop haptic arm and wherein the lens further comprises a device of any described herein, wherein the device is slidably engaged with and mechanically attached to the closed loop haptic arm.

A fifth aspect of the invention provides for a method of treating a post-operative complication following IOL implantation into the eye of a recipient patient in need thereof, comprising slidably engaging and mechanically attaching a device as described herein to an IOL prior to implantation of the IOL into the eye of the said recipient, and thereby treating the post-operative complication. Suitably, the post-operative complication is selected from one or more of: infection; inflammation; immune rejection; fibrosis; Posterior Capsule Opacification (PCO); and hypertension.

A sixth aspect of the invention provides for a method of reducing or eliminating post-implantation IOL rotation in the eye of a recipient patient in need thereof, comprising slidably engaging and mechanically attaching a device as described herein to an IOL prior to implantation of the IOL into the eye of the said recipient, and thereby reducing post-implantation IOL rotation. Suitably, the IOL comprises an aspheric or toric lens.

Within the scope of this application, it is expressly intended that the various aspects, embodiments, examples and alternatives set out in the preceding paragraphs, in the claims and/or in the following description and drawings, and in particular the individual features thereof, may be taken independently or in any combination. That is, all embodiments and/or features of any embodiment can be combined in any way and/or combination, unless such features are incompatible.

DRAWINGS

One or more embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

Figure 1 is a representation of a conventional intraocular lens (IOL) having two haptic arms extending outwardly from a central optic.

Figure 2 is a representation of an embodiment of the invention showing a device engaging with the tip region of a haptic arm.

Figure 3 is a representation of embodiments of the invention showing a transverse section through the device to reveal the opposing engagement surfaces in triangular orientation supported on a joining member to the rear, (a) all three surfaces are substantially flat and in parallel alignment, (b) two of the surfaces are curved, and (c) all three surfaces are substantially flat an in parallel alignment, two the surfaces have chamfered or sloping edges.

Figure 4 (a) is a representation of a device of an embodiment of the invention showing engagement with an IOL having a closed loop (c-loop) haptic. The device has a linear arrangement with two opposing surfaces defining a channel for engagement with the inner portion of the c-loop and a further surface bearing against an outer haptic arm portion of the c-loop. (b) is a representation of the linear device of Figure 4 (a) shown in plan view.

Figure 5 is a representation of an embodiment of a device of Figures 2 and 3 with the relative geometry of the first second and third contact surfaces indicated.

Figure 6 shows a further embodiment of the invention in which a device having a triangular configuration is used with a c-loop style haptic. 6(a) shows the device in two locations on the haptic, initially in position I which is the installation location, and also in position II which is the final location where the device is mechanically engaged with the haptic. 6(b) shows a plan view of an embodiment of a device in position II. Figure 7 is a graph showing the cumulative release of the API Ketorolac from a PLGA polymer device of an embodiment of the invention. The drug release is in target dose range over 28 days to mimic the Ketorolac drops regime typically utilised in post cataract surgery.

Figure 8 in (a) shows a partial representation of a post-implantation IOL in which the haptic engages with a surface of capsular bag by application of an outward biasing force applied to the capsular bag. If the outward biasing force is insufficient, rotation of the IOL may occur within the capsule about the axis denoted as line a «-> a’. 8(b) shows a further embodiment of the invention in which a gripping surface is applied to a device to facilitate engagement with the capsular bag in order to resist rotation of the IOL.

DETAILED DESCRIPTION

All references cited herein are incorporated by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Prior to setting forth the invention in greater detail, a number of definitions are provided that will assist in the understanding of the invention.

As used herein, the term "comprising" means any of the recited elements are necessarily included and other elements may optionally be included as well. "Consisting essentially of’ means any recited elements are necessarily included, elements that would materially affect the basic and novel characteristics of the listed elements are excluded, and other elements may optionally be included. "Consisting of’ means that all elements other than those listed are excluded. Embodiments defined by each of these terms are within the scope of this invention

The devices of the invention are intended for release of a therapeutic agent into the eye of a patient overtime. Hence, in embodiments of the invention, methods of treating a post-operative complication following IOL implantation into the eye of a recipient patient in need thereof are provided.

As defined herein a “therapeutic agent” is considered to include any active pharmaceutical agent (API), or combination of APIs, considered suitable and/or approved for use in treatment of a medical condition associated with the eye or where intraocular release is a desired route of administration more generally to the body of the recipient. In specific embodiments of the present invention the devices allow for slow and controlled release of antibiotics, immune-suppressive, anti-inflammatory, anti-proliferative and/or anti-hypertensive drugs within the eye of a patient. Suitable, antibiotics may be selected from moxifloxacin, cefuroxime, and vancomycin as well as salts, analogues and mimetics thereof. Suitable immunosuppressives may be selected from tacrolimus, sirolimus, everolimus, cyclosporine, ascomycin, or mycophenolic acid as well as salts, analogues and mimetics thereof. Suitable anti-inflammatories may include dexamethasone, prednisolone, loteprednol, fluocinolone, fluoromethoIone, difluprednate, and/or one or more non-steroidal anti-inflammatories such as ketorolac, diclofenac, bromfenac, and nepafenac. A range of these APIs used alone or in combination may address the condition of clouding or opacification that can develop in the posterior capsule of the eye following IOL implantation to treat cataracts, commonly referred to as PCO (Posterior Capsule Opacification). These APIs can target the inflammation and fibrotic processes that contribute to the formation of opacifications. By addressing both the inflammatory response and the opacifications themselves, these drugs may play a crucial role in enhancing visual outcomes and patient satisfaction following eye surgery. Other APIs may be included to prevent PCO, such as carbonic anhydrase inhibitors or apraclonidine as anti-hypotensive agents; and prostaglandin analogues to treat or prevent glaucoma: travoprost; bimatoprost; latanoprost; and tafluprost as well as salts, analogues and mimetics thereof. Antiallergic drugs such as tranilast are also suitable as they are known to exhibit anti-inflammatory effects as well as to inhibit the cell proliferation and fibrosis associated with PCO. It will be appreciated that in embodiments of the invention the devices described herein are suitably adapted to provide controlled release of any combination of the aforementioned APIs to achieve the desired results of reduced inflammation, reduced fibrosis, reduced opacification and/or reduction or elimination of PCO post-implantation of an IOL. In specific embodiments, the devices of the invention may be used in methods of treating post-operative complications associated with IOL implantation selected from one or more of: infection; inflammation; immune rejection; fibrosis; Posterior Capsule Opacification (PCO); and hypertension.

The device according to one embodiment of the invention are comprised of a biodegradable/bioerodable material that comprises one or more APIs. The device is configured to release the one of more APIs over a period of time after implantation into a patient. Biodegradation and bioerosion are used synonymously herein to define the process of breakdown of a polymeric substrate through biological activity including chemical hydrolysis, cellular degradation, enzymic activity or a combination of all of these actions. Biodegradation results in a reduction in the mass of the implanted device as well as consequent release of an encapsulated API or combination of APIs into the surrounding tissue. The release of API may occur over a period of hours, days, weeks or even months after surgical implantation. In a specific embodiment of the invention, the API is released over a period of at least 24 hours, at least 48 hours, at least 72 hours, at least one week, at least two weeks, at least one month, and/or at least two months after implantation.

The devices of the present disclosure can be made in any suitable manner known in the art. By way of non-limiting example, the devices can be made from a polymeric substrate using 3D printing, machine tooling, laser cutting or can be injection moulded. The API may be comprised within the entirety of the polymer substrate used to make the device or localised within specific sections of the polymer matrix, or attached to the surface via a covalent linkage or comprised within a coating. Any suitable methods for applying an API-eluting coatings to the devices of the invention may be employed. By way of non-limiting example, application of an API-eluting coating may comprise:

Spraying or Dipping: The device may be dipped into a solution or suspension containing a polymer and the API, or the coating is sprayed onto the device surface. Excess solution is usually removed, and the device is dried to form a thin, uniform coating. Electrostatic Deposition: A voltage difference is applied between the implant and a solution containing an API-polymer mixture. This causes the polymer to be attracted to the device surface, forming a coating thereon.

Spin Coating: The implant is rotated while the API-polymer solution is applied, leading to the formation of a uniform coating due to centrifugal force.

Layer- by- Layer Deposition: Alternating layers of API-polymer and polymer are deposited onto the implant, such as by using electrostatic interactions or vacuum deposition, creating a controlled API release system.

After the coating is applied to the device it is typically dried and/or cured at controlled temperatures to ensure proper polymerization and solidification of the coating. The specific formulation, coating method can be varied in order to accommodate specific APIs and to modify release kinetics.

Hence the devices of the invention are configured to elute the therapeutic agent from a drug depot within or deposited upon the device as a bolus, or to dissolve or biodegrade to release the therapeutic agent over time.

Suitable polymer materials for making the devices, or inclusion within coatings, according to the present invention may include: PLGA (Poly(lactic-co-glycolic acid); Poly(lactic acid) (PLA); Poly(glycolic acid) (PGA); Poly(caprolactone) (PCL); Polyethylene glycol) (PEG); Poly(D,L-lactic acid) (PDLLA); Poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV); Polydioxanone (PDO); Poly(s- caprolactone-co-lactide) (PCLA); a Polysaccharide, including chitosan, alginate, and hyaluronic acid; and/or a Polyorthoester (POE). In specific embodiments the polymer is selected from: poly(L-lactic acid) (PLLA), poly(lactic-co-glycolic acid) (PLGA), Poly(£-caprolactone) (PCL), and/or Poly(L-lactide- co-e-caprolactone) (PLCL). Such polymers may be in semi-crystalline or amorphous homopolymer or copolymers form. Devices may be defined in technical terms by the ratio of PLLA to PLGA. These biodegradable polymers have regulatory approval for human clinical use and have the advantage that their degradation can be tuned based on the ratio of different monomer units present. Depending on the API being encapsulated and the release rates required, the devices can comprise an amorphous copolymer mixture of poly(lactic-co-glycolic acid) (PLGA) and poly(L-lactic acid)(PLLA). Any combination of these polymers can be used or they can also be combined with each other to control release. For example, in specific embodiments a 50:50 combination of Ashland DLG 5002 acid capped and ester capped polymer may be used. In another embodiment of the invention a polymer comprised of PLGA is selected having a lactic to glycolic acid molar ratio of 75:25. The present inventors have found that Ashland 7509 E polymer is suited for use with NSAIDS such as ketorolac, but this may vary depending upon the preferred release for the specified API. It will be appreciated by the skilled person that release kinetics may be controlled via the molar ratio of glycolic acid to lactic acid from 0:100 to 100:0, respectively, both with acid and ester caps. Specific molar ratios of glycolic acid to lactic acid may include: 5:95, 7.5:92:5, 10:90, 15:85, 20:80, 25:75, 30:70, 45:65, 50:50, and 75:25. Degradation and drug-release rates are typically slower for lactic acid-rich PLGA polymers. The isomer of the lactic acid within the polymer can also be altered to be either the racemate or the D or L form. When using L-lactic acid, PLGA with a glycolic acid percentage of 25%- 70% is amorphous. For the amorphous racemic mixture of DL-lactic acid, this ratio extends to 0%- 70% glycolic acid. Plasticisers or other polymers may also be added to the polymer including caprolactone, trimethylene carbonate, poly oxazolines or PEG. Free carboxyl end-groups of PLGA can be used for chemical modifications to modulate the degradation rate or drug delivery properties further. Among a wide range of PLGA modifications, covalent bonding between carboxyl end-group of PLGA with amine groups as present in API compounds may allow for altered release kinetics.

The IOL preferably may comprise at least one material selected from acrylates (such as polymethylmethacrylate (PMMA), silicone (such as polydimethylsiloxane (PDMS)), hydrophobic acrylate, hydrophilic acrylate and collamer. The one or more haptics may comprise at least one material selected from acrylates (such as poly(methylmethacrylate) (PMMA), fluorinated polymers (such as polyvinylidene fluoride (PVDF), polyimide (elastimide), and poly-olefins (such as polypropylene (prolene). In a specific embodiment, the haptics may thus comprise at least one material selected from PMMA, PVDF, polyimide or polypropylene.

An IOL typically comprises an optic region that is suitably positioned in registration with the visual path of the patient - e.g., in line with the pupil. The optic is stabilised, post implantation, by the presence of one or more projections that typically extend outwardly from the periphery of the optic along a trajectory that can be broadly tangential or radially outward. The stabilising projections are referred to as haptics and serve to prevent unwanted movement, migration or rotation of the IOL post-implantation. A haptic may take the form of an arm that extends outwardly from the periphery of the optic portion of the IOL. Conventionally, the IOL may include a pair of haptic arms located on opposite sides of the IOL, with each arm curving outwardly in opposing directions so as to form the appearance of a spiral conformation.

Whilst some haptic arms are simple outward extensions having uniform width, it is common for the haptic arm to have a narrower diameter at the point where it joins with the periphery of the IOL. This facilitates flexion of the haptic relative to the optic which is particularly important during delivery of the IOL during surgical placement into the eye of the patient. Hence, this is referred to as a haptic hinge region and may have the appearance of a notch at the base of the haptic arm adjacent to the periphery of the optic. It will be appreciated that during the process of delivery the IOL must assume a compact configuration in which the haptics are folded over the IOL in order to pass through the lumenal bore of a delivery device without tearing or otherwise becoming damaged. As the haptic arm extends outwardly from the periphery of the IOL the diameter of the arm may increase to form a section of greater width that extends along the arm. The section of greater width may include a bulbous section serves to increase the mass of the haptic arm in its central portion as well as the stiffness. The bulbous region of the haptic arm tapers towards the rounded tip of the arm thereby enabling the tips to be more capable of flexion during delivery and implantation within the eye of the patient. Alternative haptic configurations may include the addition of a loop section that extends from the haptic tip back toward the periphery of the optic, thereby creating a closed loop (C-loop) structure. Turning to Figure 1 , an exemplary IOL 100 of the type that is conventional in the art is shown. The IOL 100 has a central optic section 180 surrounded by a substantially circular periphery 185 that defines the edge of the optic 185. A pair of haptic arms 160 extend outwardly therefrom along a path that is broadly tangential relative to the curvature of the periphery 185 of the IOL 100. The haptic arms 160 assume a curved shape and when implanted are configured to resist rotation and if compressed will apply an outward biasing force so as to secure the IOL in position (see also Figure 8(a)). The haptic arms 160 adjoin the optic 180 at a hinge 163 which has a reduced diameter relative to the haptic 160 allowing the haptic arms to flex relative to the optic 180 and to be folded over the optic during delivery into the eye of the recipient patient. Following delivery, the haptic arms 160 spring back into position and perform their intended purpose of acting as stabilising anchors. It will be appreciated that there are multiple different arrangements known for haptic configuration that may include arms or closed loops. The presently described devices are not limited to use with any specific type of haptic or IOL system, rather, the devices may be utilised with any configuration of IOL haptic as long as it facilitates the mechanical engagement described herein.

An exemplary device according to an embodiment of the invention is shown in figure 2. The device 210 assumes a broadly trapezoidal configuration with a pair of joining members 240 defining a planar base outwardly from one side of which extend a first projection 220 and a second projection 230. The trapezoid allows for a triangular configuration of a first surface 221 , second surface 232 and a third surface 223. The first surface 221 and second surface 232 are located in opposition to each other but are offset so as not to be in diametric opposition. Likewise, third surface 223 and second surface 232 are located in opposition to each other but are offset so as also not to be in diametric opposition. The first surface 221 and third surface 223 are located on the first projection 220 and face inwardly to define the opposing ends of one side of a channel in the device 210. In alternative embodiments the first and third surfaces 221 , 223 need not be located on a single projection 220 but may be disposed upon separate projections or studs (not shown). The second surface 232 is located on the second projection 230 and also faces inwardly so as to define the other side of the channel. This central channel is configured to accommodate a haptic arm 260 in a sliding engagement. The devices of this embodiment may also be used in conjunction with closed loop design haptics.

The haptic arm 260 is retained within the channel by a pair of overhanging retaining lips 234 and 224. In alternative embodiments a single retaining lip may be sufficient to retain the haptic arm 260 within the channel. Additionally, in alternative embodiments retention may be achieved by including a retaining member that extends across the gap between the first projection 220 and second projection 230 to fully enclose the channel. Alternatively, joining members 240 may be present on both sides of the device with the channel fully enclosed within. Enclosing the channel is not an essential element of the invention and may be desired to increase the mass of material utilised in the device thereby increasing the amount of API available for release. It will be appreciated, however, that the device may assume the simpler open face configuration of Figure 2 and still meet the requirements for secure mechanical engagement with the haptic arm 260. In use, in order to affix the device to the IOL, the device 210 is slid over the haptic tip 261 and along the length of the haptic arm 260. For closed loop type haptics the haptic geometry may be externally constrained to permit out of plane assembly. In reference to the IOL shown in Figure 1 , the device 210 is slid along the haptic arm 160 and over the bulbous region 162 until the device fits snugly within the reduced with region define between the haptic hinge 163 and the optic periphery 185. The triangular arrangement of the first, second and third surfaces 221 , 232, 223 allows for these surfaces to bear upon the haptic arm 160, 260 which effectively acts like a cam surface. The first, second and third surfaces 221 , 232, 223 act as followers and permit the body of the device 210 to rotate around a central axis and pass along the haptic arm 160, 260 without constraining, pinching or compressing the material of the haptic. This is especially effective in passing over the bulbous region 162. A two- surface or four-surface arrangement, where any of the surfaces are diametrically opposed to each other, cannot pass over the bulbous region 162 without either the haptic 160, 260 or the device 210 undergoing some form of plastic deformation which places strain upon the IOL 100 and increases the complexity of assembly as well as risk of damage to both the IOL and the device.

In a particular embodiment of the invention the device is oriented such that the first and third surfaces 221 , 223 are aligned with the inner facing edge of the haptic arm 160, 260 such that they pass over the surface of the bulbous region 163, whilst the second surface 232 is aligned with and passes over the outer edge of the haptic arm 160, 260 (i.e. the edge that faces away from the periphery 185).

The second surface 232 may be substantially flat or curved. When curved the second surface is substantially convex forming an outward curve relative to the projection 230. The first and third surfaces 221 , 223 may also be substantially flat and in parallel alignment with each other and/or with the second surface 232. Alternatively, the first and third surfaces 221 , 223 may also be curved, typically (but not exclusively) being substantially convex forming outward curves relative to the projection 220. The radii of the curves may be the same for each of the surfaces or different. Figure 3 shows devices 310, 310’, 310” with various exemplary arrangements of the surfaces relative to each other.

The relative orientation of the contact surfaces is shown in relation to a specific embodiment as depicted in Figure 5. The device 510 comprises projections 530 and 520 oriented substantially as described previously. First and third surfaces 521 , 523 are shown as substantially curved or convex and are aligned along a line A— A as shown in Figure 5. It will be appreciated that the representation shown in Figure 5 is illustrative and that the configuration of the first and third surfaces 521 , 523 may be different as exemplified elsewhere in the present disclosure. The second surface 532 is located in opposition to the first and third surfaces 521 , 523 but is off set so as to not be located in direct registry with either of the first and third surfaces 521 , 523. Hence, a point B located centrally along the second surface 532 may form a triangle with the termini of the line A— A. In embodiments of the invention the angle a is always less than 90 degrees, which ensures that the second surface 532 is sufficiently offset from and not in diametric opposition either of the first and third surfaces 521 ,523. In embodiments of the invention the distance between the line A— A in Figure 5 and the point B, i.e. the width of the channel, is less than the maximum width of the haptic at its widest point. However, the distance between the first or third surface 521 , 523 and the second surface 532, i.e. along the line A— B, is greater than the maximum width of the haptic at its widest point. In this way the device may be installed on the haptic with only flexural deflection as it moves slidably along the haptic arm and without any need for compression of the material of the haptic.

An alternative embodiment of the invention is shown in Figures 4 (a) and (b). The device 410 shown in Figure 4 (a) also comprises three surfaces that are configured to engage with a C-loop haptic structure. Nevertheless, the underlying operating principle for engagement is similar to that described in previous embodiments. Indeed, as shown in Figure 6, which is described in further detail below, both the linear and triangular configurations of the embodiments of the invention may be used with C-loop style haptics.

The device 410 assumes a linear configuration having a longitudinal axis with the joining member 440 forming a base portion of the device 410 that extends along the longitudinal axis. A first projection 420 extends upwardly from the joining member 440 and is axially aligned with the joining member 440. Opposing faces of the first projection define a first surface 421 and a third surface 423. The third surface 423 bears upon the inner facing edge of the haptic arm 460. The first surface 421 faces in the opposite direction towards a second projection 430 that extends upwardly from the joining member 440 and which provides a second surface 432. The first surface 421 and the second surface 432 are located substantially in diametrical opposition to each other and define a channel therebetween. The channel defined between the first and second surfaces 421 , 432 is configured to receive the returning C-loop portion 464 of the haptic. In this arrangement, the first and second surfaces 421 , 432 are able to contact and bear upon the inner facing and outer facing edges of the C-loop portion 464.

In use, the device 410 may be inserted into the void between the haptic arm 460 and the C-loop portion 464 and then rotated such that the surfaces bear upon and engage with the edges of the haptic. The haptic edges can effectively function as a cam surface with the first, second and third surfaces 421 , 432, 423 of the device 410 acting as followers permitting the device to slidably engage securely within the hinge region 463 of the haptic 460. The device 410 thereby latches into position and is further prevented from being dislodged laterally by first and second retaining lips 424, 425 that extend axially outwardly from the first projection 420.

It will be appreciated that the device shown in Figure 4 (a) and (b) is conveniently comprised of a single piece of material, and may be referred to as a chip device. It is of considerable advantage that the relative simplicity of construction allows for ease of installation on the IOL prior to implantation, and also it helps to ensure that the device biodegrades evenly over time reducing the risk of fragmentation.

The device shown in Figures 4 (a) and (b) comprises retaining lips 424, 425 extending from the first projection 420, however, the skilled person will appreciate that a retaining lip may be included additionally on second projection 430 or instead of the first retaining lip 424. In alternative embodiments of the invention a two-part construction of the device may be considered in which a retaining member extends across from the first projection 420 to the second projection 430 thereby fully enclosing the channel that accommodates the C-loop potion 464. Complete enclosure of the channel is not necessary to ensure secure installation or retention of the device 410, although it may be desirable in order to increase the mass of biodegradable polymer comprised in the device 410 thereby increasing the amount of encapsulated API available for release.

The first, second and third surfaces 421 , 432, 423 of the device 410, may all be substantially curved in profile as shown in Figure 4 (a). In alternative embodiments, one or more of the surfaces may be substantially planar (i.e. flat) or the radii or curvature may vary for each surface. It will be appreciated that the precise configuration of the first, second and third surfaces 421 , 432, 423 may be optimised to ensure best fit with a specific design or sizing of C-loop IOL but without substantially departing from the operating principles described herein.

Figure 6 shows an embodiment of the invention in which the device 610 assumes a triangular configuration substantially as described herein. In Figure 6(a) device 610 may engage with a haptic arm 660 that includes a closed loop portion 664. The process of installing the device 610 onto the haptic arm 660 may include sliding the device 610 onto a location (I) that is towards the distal tip of the haptic arm 660. The device 610 is then displaced along the haptic arm 660 towards a location (II) that is proximate to the main body of the IOL (see also Figure 6 (b)). The movement of the device 610 along the haptic arm 660 may be facilitated by gentle displacement of the haptic arm 660 radially outwardly along line (X) to partially straighten it and reduce curvature around the wider portion of the haptic arm 660. Following installation of the device 610 the inherent resilience of the haptic arm 660 returns to the original configuration thereby mechanically engaging with the device 610 and maintaining it in place.

The devices of the invention are typically configured to be pre-installed on an IOL before surgical placement into the eye of the patient. Optionally, the devices may be preinstalled during the IOL manufacturing process such that the surgeon may simply deliver the IOL directly to the patient/subject without any need to reconfigure or adapt the implant. Alternatively, the device may be procured separately, and the surgeon may seek to install them manually onto the lOL/haptic configuration of their choice prior to implantation.

The IOL implant procedure typically requires a preloaded IOL to be delivered into the eye of the patient/subject through the bore of an inserter. The inserter is typically in the form of an injector needle having a maximum internal bore diameter of between around 2.0 mm and 2.25 mm. Hence, according to embodiments of the present invention the devices described are configured to possess a geometry that allows for at least one orientation of the device to be able pass through the bore of an inserter needle that is at most around 2.25 mm in diameter, at most around 2.2 mm in diameter, at most around 2.1 mm in diameter, and at most around 2 mm in diameter. In one embodiment of the invention, the device has a maximum width of not more than around 2 mm, not more than around

1 .9 mm, not more than around 1 .8 mm, and not more than around 1 .5 mm.

An advantage of the devices described herein is that they do not require application of adhesive, bonding agents, clamping arrangements or complicated retaining assemblies. This is of considerable value in practice because in the rare event that a patient/subject experiences a post-operative complication, e.g. due to an adverse reaction to the API, the device may be removed relatively easily by the surgeon without need to remove the entire IOL. Prior art devices are typically integral with the IOL or are so tightly bonded thereto that removal of the entire implant is necessary which can cause additional trauma to the site of the procedure.

After implantation lOLs are typically rotationally stable in most recipient patient’s eyes over the longer term due to underlying capsular shrinkage that probably occurs within a few weeks to up to a year after cataract surgery. However, lOLs may rotate significantly in individual recipient’s eyes, typically during the first 24 hours after surgery. Figure 8 (a) shows a representation of an IOL 800 located within a capsular bag 890 of a recipient. The inherent resilience of the material of the haptic 860 generates an outward biasing force that resists the constraining force applied by the capsular bag 890. Hence, in the absence of the capsule 890, the haptic 860 would assume a fully relaxed configuration as depicted by the broken line configuration shown 860’. Post-implantation rotation of the IOL may occur within the capsule about the axis denoted as line a «-> a’ (see Schartmuller et al. (2020) Am. J. Ophthalmol., 220:72-81).

Post-operative rotation can represent a significant issue when the IOL is an aspheric or ‘toric’ lens intended to enhance visual acuity to correct corneal astigmatism. The refractive error, depending on the power of the torus, is known to increase with the amount of axis misalignment. Hence, residual astigmatism caused by postoperative rotation of a toric IOL is an important factor affecting visual quality after implantation. To address the challenge of post-operative rotation when implanting toric lOLs, a range of solutions have been proposed to develop lOLs with haptics having altered morphology or surface treatments, however, this only serves to increase the complexity and cost of manufacture of the IOL to solve a problem that exists for a comparatively short period of time immediately post-implantation - as little as 1 hour and typically up to 24 hours at most.

In an embodiment of the present invention, as shown in Figure 8(b), a device 810 (or according to any one of the configurations described herein), may comprise one or more surface modifications that enhance engagement of the device and, thus, the IOL with a capsular bag 890 within the eye of a recipient. Surface modifications may be applied to the entire outer surface of the device or to particular sections or zones of the device that are intended to contact an anterior and/or posterior capsular bag surface within the eye of the recipient patient. Suitable surface modifications that enhance engagement are intended to increase a coefficient of friction and, thus, resist rotation about the axis denoted as line a «-> a’ (Figure 8(a)) within the period immediately post-implantation by gripping the interior surface of the capsular bag. Examples of surface modifications may include, but are not limited to those selected from: textured moulding; chemical, mechanical or laser-etched patterns; ribs; dimpling; pitting; ridges; or any other variation in surface geometry. Hence, in an embodiment of the invention a method of reducing or eliminating post-implantation IOL rotation in the eye of a recipient patient in need thereof is provided. Reduction in rotation may be by less than 180°, 160°, 120°, 90°, 80°, 70°, 60°, 45°, 30°, 20°, or 10°; suitably the rotation is not more than 15°, when compared to the desired orientation of the IOL immediately following completion of an operative procedure to implant the lens.

It is advantageous that the devices of the present invention are comprised of biodegradable/bioerodable materials. This allows for any surface modifications applied thereto to degrade within a short period of time post-implantation and certainly after the acute period that postoperative IOL rotation is most likely to occur. In this way, a wider range of conventional lOLs, particularly toroidal lOLs, may be stabilised rotationally without requiring any additional modifications to the lOLs themselves.

The invention is further exemplified in the following non-limiting example.

EXAMPLE

This example is directed towards demonstrating performance of a PLGA blend and loading for ketorolac release from a device suitable for use within the eye of a subject.

Materials and methods'.

Ashland Viatel 7509E PLGA polymer comprised of extruded pellets incorporating 20%wt of ketorolac as API were formed into a disc having a maximum thickness of 1 .4 mm and a total mass of 0.1126 g. Forming involved melting the polymer under pressure of 1 bar until a temperature on 130°C was reached where it was held for 5 mins. This was then cut into the correct shape for the device using a laith, with the device weighing 0.00125g. The resultant device was placed into the PK-Eye system, a 2-compartment in vitro eye flow model developed to estimate ocular drug clearance by the anterior aqueous outflow pathway (Awwad et al. J. Pharm. Sci (2015) 104 (10):3330-3342). Samples were taken from the PK-Eye and analysed via HPLC to determine the release profile of ketorolac.

Results and Conclusions:

Figure 7 shows that a consistent release of API is observed with for up to 20 days. The release rate was within the desired release range for ketorolac. This demonstrates that the devices of the invention are able to release sufficient quantity of API over the desired time range to be of clinical benefit.

Although particular embodiments of the invention have been disclosed herein in detail, this has been done by way of example and for the purposes of illustration only. The aforementioned embodiments are not intended to be limiting with respect to the scope of the appended claims, which follow. It is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims.

Claims

1 . A device for sustained release of a therapeutic agent, wherein the device is suitable for mechanical attachment to a haptic arm on an intraocular lens (IOL), wherein the device is configured to include a first, a second and a third contact surface, wherein at least the first and second contact surfaces are arranged in opposition to each other, and wherein all of the first, second and third contact surfaces are configured to bear upon the haptic arm to facilitate mechanical attachment to the haptic arm.

2. The device of claim 1 , wherein the first and third surfaces are arranged in opposition to the second contact surface.

3. The device of claims 1 or 2, wherein the first, second and third surfaces are arranged in a triangular orientation.

4. The device of claim 3, wherein the first and second contact surfaces are offset so as not to be in diametrical opposition to each other.

5. The device of claim 4, wherein the triangular orientation consists of an isosceles triangle.

6. The device of claim 4 or 5, wherein the triangular orientation consists of an equilateral triangle.

7. The device of any one of claims 1 to 6, wherein the first, second and third contact surfaces are interconnected via one or more joining members.

8. The device of claim 7, wherein the one or more joining members define a planar base on one side of the device.

9. The device of claim 8, wherein the first, second and third contact surfaces are located on projections that extend upwardly from the planar base.

10. The device of claims 4 to 6, wherein the one or more joining members fully or partially enclose a space between the first, second and third surfaces so as to define a channel that is configured to receive a haptic arm.

11. The device of claims 1 or 2, wherein the device comprises a base section and first, second and third surfaces are arranged in linear configuration, wherein the first surface is located upon a first projection that extends upwardly from the base section and wherein the second and third surfaces are located on opposing ends of a second projection that extends upwardly from the base section, with the first and second surfaces orientated in axial opposition to each other so as to define a channel between them, and the third surface faces axially away from the second.

12. The device of any one of claims 1 to 11 , wherein one or more of the first, second and third surfaces are curved.

13. The device of claim 12, wherein one or more of the first, second and third surfaces are substantially concave.

14. The device of claim 12, wherein one or more of the first, second and third surfaces are substantially convex.

15. The device of claim 14, wherein all of the first, second and third surfaces are substantially convex.

16. The device of any previous claim wherein the first, second and third surfaces are arranged to facilitate a sliding engagement onto a haptic arm.

17. The device of any previous claim wherein the device is comprised of a biodegradable/bio- erodable material.

18. The device of claim 17, wherein the material is comprised of polymer selected from: PLGA (Poly(lactic-co-glycolic acid); Poly(lactic acid) (PLA); Poly(glycolic acid) (PGA); Poly(caprolactone) (PCL); Polyethylene glycol) (PEG); Poly(D,L-lactic acid) (PDLLA); Poly(hydroxybutyrate-co- hydroxyvalerate) (PHBV); Polydioxanone (PDO); Poly(s-caprolactone-co-lactide) (PCLA); a Polysaccharide, including chitosan, alginate, and hyaluronic acid; and/or a Polyorthoester (POE).

19. The device of claim 17, wherein the material is comprised of polymer selected from: poly(L- lactic acid) (PLLA) and poly(lactic-co-glycolic acid) (PLGA) as well as combinations, acid capped and ester capped versions thereof.

20. The device of claim 18, wherein the device comprises an amorphous copolymer mixture of poly(lactic-co-glycolic acid) (PLGA) and poly(L-lactic acid)(PLLA).

21. The device of claim 20, wherein the copolymer mixture comprises a 50:50 combination of acid capped and ester capped copolymer.

22. The device of any one of claims 1 to 21 , wherein the therapeutic agent comprises a molecule having a therapeutic effect selected from one or more of: an anti-proliferative; an anti-hypertensive; a non-steroidal anti-inflammatory (NSAID); a steroid; an antibiotic; or a prostaglandin analogue.

23. The device of claim 22, wherein the therapeutic agent is a drug selected from one or more of: moxifloxacin: cefuroxime: vancomycin; tacrolimus; sirolimus; everolimus; cyclosporine; ascomycin; mycophenolic acid; dexamethasone; prednisolone; loteprednol; fluocinolone; fluoromethoIone; difluprednate; ketorolac; diclofenac; bromfenac; nepafenac; a carbonic anhydrase inhibitor; apraclonidine; travoprost; bimatoprost; latanoprost; and tafluprost, as well as salts, mimetics and analogues thereof.

24. The device of any one of claims 1 to 23, wherein the device further comprises at least one surface modification applied to an outer surface of the device, or to particular sections or zones of the device, that are intended to contact an anterior and/or posterior capsular bag surface within the eye of the recipient patient.

25. The device of claim 24, wherein the at least one surface modification is selected from: textured moulding; chemical, mechanical or laser-etched patterns; ribbing; dimpling; pitting; ridges; or any other variation in surface geometry.

26. The device of any one of claims 24 or 25, wherein the at least one surface modification is configured to increase a coefficient of friction with a capsular bag surface so as to resist rotation of an associated IOL following implantation into the eye of a recipient patient.

27. An intraocular lens (IOL), wherein the IOL comprises at least one haptic arm and wherein the lens further comprises a device of any of claims 1 to 26 slidably engaged with and mechanically attached to the haptic arm.

28. An intraocular lens (IOL), wherein the IOL comprises at least one closed loop haptic arm and wherein the lens further comprises a device of any of claims 1 to 26 slidably engaged with and mechanically attached to the closed loop haptic arm.

29. A method of treating a post-operative complication following IOL implantation into the eye of a recipient patient in need thereof, comprising slidably engaging and mechanically attaching a device as described in any one of claims 1 to 26 to an IOL prior to implantation of the IOL into the eye of the said recipient, and thereby treating the post-operative complication.

30. The method of claim 29, wherein the post-operative complication is selected from one or more of: infection; inflammation; immune rejection; fibrosis; Posterior Capsule Opacification (PCO); and hypertension.

31 . A method of reducing or eliminating post-implantation IOL rotation in the eye of a recipient patient in need thereof, comprising slidably engaging and mechanically attaching a device as described in any one of claims 24 to 26 to an IOL prior to implantation of the IOL into the eye of the said recipient, and thereby reducing post-implantation IOL rotation.

32. The method of claim 31 , wherein the IOL comprises an aspheric or toric lens.