Implant injector device

Abstract

Disclosed in certain embodiments is an implant injector device that includes: a body forming an interior volume; a slider structure disposed within the interior volume; a spring connecting a proximal portion of the body to a proximal portion of the slider structure; a wire connected to a distal portion of the slider structure; a button structure configured to receive user input to actuate the slider structure towards a distal portion of the body; and a lock pin structure configured to interface with the body and the slider structure to prevent actuation of the button structure.

Description

IMPLANT INJECTOR DEVICETECHNICAL FIELD

[0001] Embodiments of the present disclosure relate to an injector device, an ocular implant, as well as systems, kits and methods of treatments thereof.BACKGROUND

[0002] Injectors are widely used in medical practice to deploy therapeutic materials into the body, including the eye. In ophthalmology, intravitreal and intracameral injections have become a mainstay for delivering small molecules, biologies, and sustained-release implants for conditions such as age-related macular degeneration (AMD), diabetic macular edema (DME), retinal vein occlusion, posterior uveitis, diabetic retinopathy, glaucoma, and other back- and front-of-the-eye diseases. Despite their general availability, conventional injector devices present persistent challenges when precision placement, control over ejection mechanics, and mitigation of tissue injury are required — particularly for delivering elongated, drug-loaded depots through fine-gauge needles into the eye.

[0003] There continues to exists a need in the art for improved injector devices, ocular implants and drug-device combinations for the treatment of ocular conditions.OBJECTS AND SUMMARY OF THE INVENTION

[0004] It is an object of certain embodiments of the present invention to provide an implant injector device forthe precise, safe, and reliable deployment of therapeutic ocular implants, including hydrogel implants containing tyrosine kinase inhibitors such as axitinib, into intraocular locations such as the intravitreal space.

[0005] It is an object of certain embodiment of the invention to provide a kit comprising an injector device as disclosed herein and an ocular implant (e.g., as disclosed herein).

[0006] It is an object of certain embodiments of the present invention to provide a system comprising an injector device as disclosed herein that contains an ocular insert (e.g., as disclosed herein).

[0007] It is an object of certain embodiments of the present invention to provide an ocular implant that has decreased friction or that meets a threshold friction (e.g., acceptable friction) such that it is easily loaded into and expelled from an injector device.

[0008] It is an object of certain embodiment of the invention to provide kit comprising an ocular implant as disclosed herein and an injector device (e.g., as disclosed herein).

[0009] It is an object of certain embodiments of the present invention to provide a system comprising an ocular implant comprising an injector device (e.g., as disclosed herein) that contains an ocular implant as disclosed herein).BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The present disclosure is illustrated by way of example, and not by way of limitation, in the figures of the accompanying drawings in which like references indicate similar elements. It should be noted that different references to “an” or “one” embodiment in this disclosure are not necessarily to the same embodiment, and such references mean at least one.

[0011] FIGS. 1A-G illustrate components of implant injector devices, according to certain embodiments.

[0012] FIG. 2 illustrates a method of treatment of administering an implant using an injector device, according to certain embodiments.

[0013] FIG. 3 is a schematic representation ofimplant injector device packaging, according to certain embodiments.

[0014] FIG. 4 depicts weight increase for each sample at each stage of relative humidity of Example 2.

[0015] FIG. 5 depicts the rate of D VS by showing the weight increase per minute (% / min) at increased humidity (% RH) of Example 2.

[0016] FIG. 6 depicts the % weight change at 40%RH based on %PEG (Dry) of a formulation of Example 2.DETAILED DESCRIPTION OF EMBODIMENTS

[0017] Embodiments described herein are related to implant injector devices.

[0018] Injectors are used to deploy material, such as implants, into patients. Some material is therapeutic material. Some material is to be deployed at specific locations in a patient. Some material is to be deployed below a threshold speed into a patient.

[0019] Conventionally, material may be deployed into incorrect locations in a patient. For example, an implant may be designed to be deployed into the pars plana of a patient and if the implant is not deployed correctly, the implant could impact the back of the retina and cause issues for the patient.

[0020] Conventionally, deploying of an implant into a patient is error prone. For example, an actuating device may be unintentionally pushed into or pulled out of an injector.Unintentionally moving an actuating device may cause errors in deployment of the implant.

[0021] Conventionally, an injector may eject an implant at a high velocity into a patient. This may cause damage to the retina of the patient.

[0022] The devices, systems, and methods disclosed herein provide an implant injector device.

[0023] In some embodiments, the implant injector device includes a slider structure disposed within the interior volume. The implant injector device may further include a spring connecting a proximal portion of the body to a proximal portion of the slider structure. The implant injector device may further include a wire connected to a distal portion of the slider structure. The implant injector device may further include a button structure configured to receive user input to actuate the slider structure towards a distal portion of the body. The implant injector device may further include a lock pin structure configured to interface with the body and the slider structure to prevent actuation of the button structure.

[0024] In some embodiments, the implant injector device further includes a hub structure connected to the distal portion of the body. The implant injector device may further include a needle coupled to the hub structure. The needle is configured to receive an implant. The implant is to be deployed from the needle via the wire responsive to removal of the lock pin structure and the actuation of the button structure.

[0025] In some embodiments, the implant injector device further includes a sleeve structure disposed around at least a portion of the needle. An outer surface of at least one of the needle or the sleeve structure may have a coating (e.g., needle coating). The implant injector device may further include a cap structure. The cap structure may be configured to cover (e.g., be disposed over) the hub structure and at least a portion of the needle. The cap structure may be attached to the body. The cap structure may be configured to cover and / or protect (e.g., disposed to cover or disposed to protect) the hub structure and needle (e.g., hub-needle structure).

[0026] In some embodiments, the implant is disposed in the needle. The lock pin structure may be removed from the body, the needle may be inserted into a patient, and the button structure may be actuated to cause the slider structure to actuate the wire into the needle to cause the implant to be provided into the patient.

[0027] In some embodiments, the implant injector device further includes a biocompatible material tip disposed ata distal end of the needle. The implant may be secured in the needlebetween the wire and the biocompatible material tip. The biocompatible material tip may be configured to at least partially dissolve within a patient to allow the implant to be deployed into the patient.

[0028] In some embodiments, the body includes a first body half having a pattern of staggered clips and staggered recesses and a second body half having the pattern of the staggered clips and the staggered recesses. The first body half and the second body half may be configured to interconnect with each other via the staggered clips and the staggered recesses.

[0029] The systems, devices, and methods disclosed herein have advantages over conventional solutions. The implant injector device of the present disclosure may deploy an implant in a more correct location in a patient than a conventional system. The implant injector device of the present disclosure may deploy an implant in a more correct location (and / or more often in a more correct location) in a patient than a conventional system. The implant injector device of the present disclosure may prevent unintentional actuation of an actuation device than a conventional system. The implant injector device of the present disclosure may deploy an implant at a lower speed (and / or at a more consistent speed) into a patient than a conventional system. The implant injector device of the present disclosure may prevent more damage (e.g., to the retina) than a conventional system.

[0030] Although certain embodiments of the present disclosure refer to implants to be deployed in the pars plana, embodiments of the present disclosure may be used with one or more objects that are to be inserted into a patient. In some embodiments, an object may include one or more of an object to be deployed into a liquid within a patient, into fatty tissue within a patient, into an eye of a patient, and / or the like.

[0031] FIGS. 1A-G illustrate components ofimplant injector devices 100 (e.g., applicators, button-actuated implant injector devices, etc.), according to certain embodiments. FIG. 1A illustrates an exploded view of an implant injector device 100. FIG. IB illustrates an assembled view of an implant injector device 100. FIG. 1C illustrates an assembled view of an implant injector device 100 in an enclosure 190. FIGS. 1D-E illustrate cross-sectional views of an implant injector device 100. FIG. IF illustrates a cross-sectional view of a needle of an implant injector device 100 that includes a biocompatible tip 162. FIG. 1 G illustrates an implant injector device 100 that includes a slider structure 134 that has a ramp 135.

[0032] In some embodiments, implant injector device 100 is packaged in enclosure 190 (e.g., see FIG. 1C). The enclosure 190 maybe a peelable foil pouch. In some embodiments, implant injector device 100 is a single assembly and / or is packaged in a single enclosure 190.In some embodiments, implant injector device 100 includes more than one assembly and / or is packaged in more than one enclosure 190.

[0033] Implant injector device 100 includes a body 120, a button structure 130, a slider structure 134, a wire 132 (e.g., a push-wire; wire 132 maybe a push wire secured to the slider structure 134 via adhesive such as ultraviolet (UV) cure adhesive or glue; wire 132 may be a push wire bonded to slider structure 134; push wire may be secured to the slider structure 134 via adhesive by insert molding; push wire may be secured to the slider structure 134 by insert molding, etc.), and a lock pin structure 140. In some embodiments, a spring 136 couples(e.g, attaches) the slider structure 134 to the body 120. In some embodiments, the body 120 includes a body half 120A and body half 120B. The body 120 forms an interior volume and the slider structure 134, spring 136, and a portion of the button structure 130 are disposed in the interior volume of the body. The wire 132 has a proximal end secured to the distal end of the slider structure 134 within the body 120. The lock pin structure 140 is configured to interface with the body 120 and the slider structure 134 (e.g., via corresponding slots of the body 120 and / or the slider structure 134) to prevent actuation of the button structure 130 (e.g., prevent pushing button structure 130 further into the body 120 and to prevent actuation of slider structure 134 and the wire 132.). The wire 132 may be Nitinol, stainless steel, and / or plastic.

[0034] Implant injector device 100 may further include a hub structure 150, a needle 160, a cap structure 152, and a sleeve structure 170 (e.g., depth limiting sleeve). The needle 160 may include a hub (e.g., disposed within hub structure 150) and a shaft (e.g., tube, protruding from hub structure 150). The needle may be bonded to the hub structure 150. The sleeve structure 170 may be disposed around a portion of the shaft of the needle 160. In some embodiments, the sleeve structure 170 includes a single sleeve (e.g., single heat shrink). In some embodiments, the sleeve structure 170 includes an inner sleeve and / or an outer sleeve (e.g., double heat shrink). The inner sleeve and / or the outer sleeve may be cut to particular lengths. In some embodiments, a hub -sleeve-needle assembly (e.g., hub structure 150, needle 160, and / or sleeve structure 170) is insert molded (e.g., this may eliminate adhesive and the sleeve structure for the hub-sleeve-needle assembly). In some embodiments, the needle 160 has a biocompatible tip 162 secured to the shaft. The hub structure 150 forms an interior volume and the hub of the needle 160 is disposed in the interior volume of the hub structure 150. The proximal end of the shaft is connected to the hub of the needle 160. The shaft is configured to receive an implant 180. The implant 180 is secured in the shaft (e.g., prevented from falling out of the shaft) by the wire 132 proximate the proximal end of the shaft and thebiocompatible tip 162 on a distal end of the shaft. In some embodiments, the needle 160 undergoes manual and / or abrasive grinding. In some embodiments, the needle 160 undergoes electrochemical grinding (ECG) (e.g., electrochemical burr free grinding). In some embodiments, the needle 160 undergoes electrochemical grinding (ECG) on ultra thin wall tube. The needle 160 may be electropolished. The needle may have silicone coating.

[0035] In some embodiments, the implant injector device 100 is an Axitinib Intravitreal Implant injector. Implant injector device 100 may include an actuating device (e.g., button structure) and a needle (e.g., 25G Injector) and / or the Intravitreal Implant. The implant injector device 100 may be packaged as a single component. One or more components of implant injector device 100 may be made of acrylonitrile butadiene styrene (ABS), polypropylene, and / or medical grade material (e.g., medical grade plastic).

[0036] The shaft (e.g., tube) of the needle 160 may be used for intravitreal injection by injecting the shaft of the needle 160 into the pars plana approximately 3.5 - 4 mm posterior to the limbus, with a slight downward (inferior) trajectory to the full penetration depth of the exposed portion of the shaft of the needle 160 (e.g., the portion of the shaft not covered by the hub structure 150 and / or the sleeve structure 170).

[0037] In some embodiments, the implant injector device 100 may use an off-the shelf needle 160. In some embodiments, the needle 160 is custom-made for the implant injector device 100.

[0038] The hub structure 150 may have one or more features that couple (e.g., hook features that clip) securely onto the body 120. In some embodiments, the hub structure 150 is bonded to the body 120. Markings (e.g., alignment arrows) may be used to align the hub structure 150 with the body 120.

[0039] The combination of design features associated with the wire 132 (e.g., rounded distal ends of the wire), body 120 (e.g., tapered or funneled interior surface of the body 120), and hub structure 150 (e.g., tapered or funneled interior surface of the hub structure 150) facilitate progression of the wire into the lumen of the shaft of the needle 160 to deploy the implant 180.

[0040] A lateral force exerted on the button structure 130 causes the button structure 130 to push the slider structure 134 in a lateral direction to advance the wire 132 into the lumen of the shaft of the needle 160 to deploy the implant 180.

[0041] The lock pin structure 140 is used to hold the button structure 130 locked in the loaded position. The lock pin structure 140 has a protrusion that his configured to extend into the body 120 (e.g., via one or more openings formed by the body 120) and through slots onthe slider structure 134 to prevent movement of the slider structure 134 (and / or the button structure 130 and / or spring 136) until the lock pin structure 140 is removed.

[0042] One or more protrusions of the button structure 130 interacts with the body 120 to prevent the button structure 130 from being removed from the body 120.

[0043] In some embodiments, the wire 132 is insert molded to, glued onto, and / or bonded to the slider structure 134 (e.g., with adhesive), two body halves 120A-B are clipped together, an assembly of the wire 132 and button structure 130 glued and / or bonded together (e.g., via adhesive) is slotted into the body 120 which funnels the wire 132 into the correct position. A needle 160 is located in the hub structure 150 (e.g., located within a hub structure 150 that is a single component, sandwiched between two halves of hub structure 150).

[0044] Migration of the implant 180 is prevented by at least two factors: 1) the wire 132 is inserted into the hub of needle 160 to prevent proximal migration; and 2) a polyethylene glycol (PEG), such as a linear PEG (e.g., biocompatible tip 162) is deposited at the tip of the shaft (e.g., needle tip, tip of tube) to prevent distal migration.

[0045] The enclosure 190 maybe a foil package. The implant injector device 100B may be packaged in a foil pouch for sterile and moisture barrier. The enclosure 190 may be hermetically sealed barrier to moisture and oxygen. The enclosure 190 may be a light barrier (e.g., to provide photostability). The enclosure 190 may be one or more of a moisture barrier, oxygen barrier, light barrier, etc.

[0046] The hub structure 150 and / or sleeve structure 170 may constrain injection depth to about 3 to 7 millimeters (mm), about 4.3 to 6.3 mm, about 4.5 to 6 mm, about 4 mm, about 5.3 mm, etc. to mitigate potential of the implant 180 contacting the retina during implantation, prior to hydration of the implant 180 (e.g., once hydrated the implant 180 becomes soft).

[0047] In some embodiments, the biocompatible tip 162 (e.g., PEG tip) occludes the shaft of the needle 160 to prevent coring of thin ocular tissue. Displaced tissue matter (e.g., foreign tissue matter) left in the virous humor could elicit an inflammatory response (e.g., immune response), infection (e.g., possibly introduce infectious contaminants), and / or could impact tolerability associated with drug product. Although embodiments of the present disclosure describe a biocompatible tip 162 on a distal end of a shaft of needle 160 of an implant injector device 100, in some embodiments, the biocompatible tip 162 can be used on a distal end of a shaft of a needle of other devices for similar or different applications. The biocompatible tip 162 (e.g., linear PEG) may prevent ingress of vitreous fluid and pre-hydration of the implant 180. The biocompatible tip 162 (e.g., PEG) may dissolve or liquefy (e.g., go into solution) when introduced to vitreous fluid to allow passage of the implant 180).

[0048] In some embodiments, the biocompatible tip 162 (e.g., PEG tip) is a PEG (e.g., linear or branched 1,000 molecular weight PEG to about 8000 molecular weight PEG) that is deposited at the tip of the shaft of the needle 160. The biocompatible tip 162 may prevent ingress of vitreous fluid that could pre hydrate the implant, which could cause the implant 180 to swell andjam during actuation. The biocompatible tip 162 may be 3350 Mw PEG for quick dissolution, however other molecular weights may work as well. The biocompatible tip 162 may prevent coring of the ocular tissue which can remain in the vitreous and cause issues with tolerability and safety. The biocompatible tip 162 may prevent the implant 180 from falling out of the needle. In some embodiments, the biocompatible tip 162 (e.g., PEG tip) is a Ik PEG (1,000 molecular weight PEG). In some embodiments, the biocompatible tip 162 (e.g., PEG tip) is a 3550 PEG (3,550 molecular weight PEG). In some embodiments, the biocompatible tip 162 (e.g., PEG tip) is an 8k PEG (8,000 molecular weight PEG). In some embodiments, the biocompatible tip 162 (e.g., PEG tip) is about Ik to about 8k PEG (about 1,000 to about 8,000 molecular weight PEG) and / or includes mixtures of molecular weight.

[0049] Table 1 includes mechanical data of the implant injector device 100, according to some embodiments.

[0050] Table 1 :

[0051] In some embodiments, the values and / or ranges in Table 1 may be “about” or “approximately” one or more of the values and / or one or more of the ranges as shown and as such the nominal value presented may be precise within ± 20%, ± 18%, ± 16%, ± 14%, ± 12%, ± 10%, ± 8%, ± 6%, ± 4%, ± 3%, ± 2%, ± 1%, and / or ± 0.5%.

[0052] In some embodiments, the coating 164 of needle 160 is silicone. In some embodiments, the coating 164 of needle 160 is a mixture of Liveo MDX4-4159 and Liveo 360 medical fluid 12,500 centistoke (cSt) (unit of viscosity). In some embodiments, the coating 164 of needle 160 includes one or more of:active silicone ingredients in mixed aliphatic and isopropanol solvents; aminofunctional dimethylsiloxane copolymer; clear and colorless poly dimethylsiloxane liquid; hydrophobic lubricant; high purity medical grade silicone oil; clear and colorless oily liquid; viscosities of about 20, 100,350, 500, 1000, and / or 12500 cSt; and / or high water repellency.

[0053] In some embodiments, the implant injector device 100 has an improved actuation mechanism (e.g., button structure 130, slider structure 134, etc.) by reducing chances of the implant 180 ejecting from the needle at a threshold velocity and / or an ejection distance from the tip of needle 160 (e.g., travel distance of less than about 4 mm which prevents implant contact with the retina). This reduces damage to the retina compared to conventional systems.

[0054] The implant injector device 100 may not have a multi-fold plastic linkage that unfolds as a button is depressed (as such a linkage unfolds, the wire advances within the needle to expel the pre-loaded implant).

[0055] To prevent (e.g., reduce the chances) of the implant 180 being expelled from the implant injector device 100 at a threshold velocity, the implant injector device 100 may include a slider structure 134 (e.g., higher rigidity sliding mechanism) that has a higher rigidity than a multi-fold plastic linkage. The implant injector device 100 may have an actuation mechanism that includes a button structure 130 and a wire 132 (e.g., push wire) and a slider structure 134 (e.g., a substantially rigid slider / cam follower type mechanism). Responsive to the button structure 130 being depressed, the slider structure 134 advances forward as the downward protrusion of the button structure 130 slides down the ramp of the slider structure 134. As the slider structure 134 advances, the wire 132 within the needle 160 expels the pre-loaded implant 180.

[0056] Referring to FIG. 1 A, wire 132 may be connected to slider structure 134 via adhesive 138. In some embodiments, sleeve structure 170 is connected to hub structure 150 via adhesive 138. In some embodiments, sleeve structure 170 is heat shrunk onto the needle 160 and held in place (e.g., on needle 160, within hub structure 150) via friction. Needle 160and / or sleeve structure 170 may have a coating 164. One or more interior surfaces of body 120 (e.g., proximate the slider structure 134, that interfaces with one or more surfaces of the slider structure 134 during actuation of button structure 130) may have a lubricant 122.

[0057] Spring 136 may be connected to the body 120 and the slider structure 134 to prevent the slider structure 134 from moving (e.g., in one or more directions) unless the lock pin structure 140 is removed and the button structure 130 is actuated. Body halves 120A-B may be connected to each other responsive to the spring 136, slider structure 134, and a portion of button structure 130 being disposed in the body 120. Responsive to the body halves 120A-B being connected to each other, the hub structure 150 maybe coupled (e.g., friction fit) to the body 120. Cap structure 152 may be coupled to the hub structure 150 and / or the body 120. Lock pin structure 140 may be partially inserted into body 120 and slider structure 134 to prevent actuation of one or more of button structure 130, slider structure 134, and / or wire 132.

[0058] Referring to FIG. IB, implant injector device 100 may include a body 120, a hub structure 150 coupled to body 120, and a sleeve structure 170 andneedle 160 extending from the hub structure 150.

[0059] Referring to FIG. 1C, implant injector device 100 may be disposed in an enclosure 190. In some embodiments, an implant injector device lOOloaded with an implant 180 (e.g., implant 180 is disposed in the needle 160 of the implant injector device 100) is located in the enclosure 190.

[0060] Referring to FIG. ID, a portion of a lock pin structure 140 may extend through an opening formed by body 120 (e.g., body half 120A may be shown in FIG. ID) and a slot formed by slider structure 134 to prevent the slider structure 134 and button structure 130 from being actuated.

[0061] Referringto FIG. IE, responsive to the lock pin structure 140 being removed from the opening formed by body 120 (e.g., body half 120A may be shown in FIG. IE) and the slot formed by slider structure 134. Spring 136 may preventthe slider structure 134 from moving towards hub structure 150 without a threshold force being applied to button structure 130. Responsive to a threshold force being applied to button structure 130, the button structure 130 may push the slider structure 134 towards hub structure 150 and may cause the spring 136 to expand. The wire 132 connected to slider structure 134 may push the implant out of the needle 160 (e.g., and into a patient).

[0062] Referringto FIG. IF, to preventthe implant 180 from falling out of the needle 160 during shipping and handling, the implant injector device 100 may obstruct the lumen of theneedle 160. The implant injector device 100 may include a biocompatible tip 162 (e.g., a PEG droplet) on the needle 160 (e.g., not within the needle 160) to prevent the implant 180 from leaving the needle 160. In some embodiments, the implant injector device 100 does not include a biocompatible tip 162 (e.g., a PEG droplet) within the needle 160 (e.g., within the lumen of the needle 160). The biocompatible tip 162 may be easier to apply to the location of the implant injector device 100 and has lower force to dislodge during deployment of the implant 180 compared to conventional systems. This may further reduce the chance that the implant 180 will expel above a threshold velocity. FIG. IF shows an approximate location of the biocompatible tip 162 (e.g., a PEG droplet) on the needle 160 according to certain embodiments.

[0063] Referringto FIG. 1G, implant injector device 100 may have a slider structure 134 that has a ramp 135. A protrusion of the button structure 130 interfaces with the ramp 135 to cause the slider structure 134 to push the wire 132 towards the hub structure 150 to eject the implant 180 via the needle 160.

[0064] The implant injector device 100 may accommodate implants 180 that have a length of up to about 10 mm (e.g., up to about 9.75 mm), the ramp angle 133 of ramp 135 and the push button travel may be adjusted to accommodate various lengths of implant 180.

[0065] In some embodiments, the angle 133 of ramp 135 is about 25° to about 68°.

[0066] Table 2 shows a range of angles 133 (e.g., angles 133 of ramp 135, ramp angles 133) to accommodate an array of stroke length and button depress distances.

[0067] Table 2:

[0068] * note, in some embodiments, 25° may be the lowest practical angle

[0069] In some embodiments, the angles 133 on Table 2 may be a minimum of about 25°.

[0070] In some embodiments, the following equation may be used:

[0071] a =arctan(B / L)

[0072] where a is the ramp angle 133, B is the button travel, and L is the stroke length

[0073] The desired stroke length may accommodate the implant length (1), the PEG tip (P), a standoff distance from the PEG tip (S), and a travel beyond the needle tip (E) (to make sure the implant is fully ejected). This may be shown by the following equation:

[0074] L=l+S+P+E

[0075] B / L may have a limit (e.g., practical limit). The button may be harder to press below a threshold B / L. The maximum button force (e.g., to eject the implant 180) maybe about 2 to 25 Newtons (N) of force, about2.5 to about25 N of force, about2.5 to about 11.3Nof force, etc.

[0076] In some embodiments, there is an optimum combination of a and B to achieve the required L within an acceptable actuation force range (with lubricant). The maximum actuation force may be the upper limit and the minimum stroke length may be the lower limit. The lubricant may have attributes including a reduction of button force, being stable to gamma irradiation, being stable under long term storage (e.g., runoff), etc.

[0077] FIG. 2 illustrates a method 200 of treatment of administering an implant (e.g., implant 180) using an implant injector device (e.g., implant injector device 100), according to certain embodiments. Although shown in a particular sequence or order, unless otherwise specified, the order of the operations can be modified. Thus, the illustrated embodiments should be understood only as examples, and the illustrated operations can be performed in a different order, and some operations can be performed in parallel. Additionally, one or more operations can be omitted in various embodiments. Thus, not all operations are required in every embodiment.

[0078] At block 202, an implant injector device (e.g., implant injector device 100 of one or more of FIGS. 1A-G) is removed from an enclosure.

[0079] At block 204, a cap structure (e.g., cap structure 152 of FIG. 1 A) is removed from a hub structure (e.g., hub structure 150 of one or more of FIGS. 1 A-E) of the implant injector device. The hub structure is coupled (e.g., connected, friction fitted, etc.) to a body (e.g., body 120 of one or more of FIGS. 1 A-E) of the implant injector device.

[0080] At block 206, a lock pin structure (e.g., lock pin structure 140 of one or more of FIGS. 1A-C)is removed from the body and slider structure (e.g., slider structure 134 of one or more of FIGS. 1A, 1D-E, or 1G) disposed in the body. The lock pin structure may be inserted into the body via openings formed by the body. The lock pin structure may be at least partially inserted into slots formed by the slider structure.

[0081] At block 208, a portion of the shaft of the needle is inserted in a patient. The portion of the shaft may be the length of the shaft that is not covered by the hub structure and / orsleeve structure (e.g., sleeve structure 170 of FIGS. 1 A-E). The portion of the shaft may be in the patient for a threshold amount of time (e.g., about 1 to about 5 seconds). In some embodiments, the biocompatible tip (e.g., PEG, polymer) at least partially dissolves on the shaft (e.g., on the bevel of the shaft) to allow the implant to pass through the shaft. In some embodiments, the biocompatible tip (e.g., PEG, polymer) does not dissolve (e.g., does not completely dissolve) before deployment of the implant 180 (e.g., the PEG not dissolving before deployment of the implant 180 does not prevent proper functioning of the implant injector device 100).

[0082] At block 210, the button structure is actuated to cause the slider structure to push a wire (e.g., wire 132 of FIGS. 1 A-E) coupled to the slider structure to deploy the implantfrom the shaft into the patient. A threshold force may be used to actuate the button structure.

[0083] FIG. 3 is a schematic representation of implant injector device packaging, according to certain embodiments. One or more of the features (e.g., structure, functionality, etc.) of implant injector devices described herein may be used with the implant injector devices of FIG. 3.

[0084] In some embodiments, implants are pre-loaded into thin-walled needles (e.g., needle 160 of one or more of FIGS. 1A-G) separately packaged from the injection device. In some embodiments, the implant is pre-loaded into the implant injector device.

[0085] In some embodiments, an implant injector device, such as a syringe or another injection device, may be separately packaged and sterilized e.g. via gamma irradiation.

[0086] In certain embodiments, a kit (which may also be referred to as a “system”) includes one or more sustained release biodegradable ocular implant(s) or manufactured in accordance and one or more needle(s) for injection, wherein the one or more needle(s) is / are each pre-loaded with one sustained release biodegradable ocular implant in a dried state. In some embodiments the needle(s) is / are 25- or 27-gauge needle(s) or may be smaller gauge, such as 30-gauge needle(s). The diameter of the needle maybe chosen based on the final diameter of the implant in the dried (and optionally stretched) state and can be, e.g.,18-gauge to 34-gauge. The active contained in the implant is generally a TKI, such as axitinib.

[0087] In some embodiments the kit comprises one or more, such as two or three 25 - or 27-gauge needle(s) each loaded with an implant containing axitinib in an amount in the range from about 180 pg to about 450 pg, about 180 pg to about 220 pg, or in an amount of about 200 pg.

[0088] In some embodiments the kit comprises one 25-gauge needle loaded with an implant containing axitinib in an amount in the range from about 540 pg to about 660 pg, inan amount of about 600 pg, or in an amount of about 450 pg. In another embodiment, the kit comprises one 27-gauge needle loaded with an implant containing axitinib in an amount in the range from about 540 pg to about 660 pg, in an amount of about 450 pg, or in an amount of about 600 pg.

[0089] If two or more implants are contained in the kit, these implants may be identical or different, and may contain identical or different doses of TKI.

[0090] In certain embodiments, the lumen of the needle containing the implant may be occluded by a material that is solid at room temperature but soft or liquid at body temperature, such as a Ik PEG material.

[0091] The kit may further contain an injection device for injecting the implant(s) into the eye of a patient, such as into the vitreous humor of the patient. In certain embodiments the injection device is provided and / or packaged separately from the one or more needle(s) loaded with implant. In such embodiments the injection device may be connected to the one or more needle(s) loaded with implant prior to injection.

[0092] In some embodiments the number of injection devices provided separately in the kit equals the number of needles loaded with the implant provided in the kit. In these embodiments the injection devices are only used once for injection of one implant.

[0093] In some embodiments the kit contains one or more injection device(s) for injecting the implant into the eye of a patient, such as into the vitreous humor of the patient, wherein each injection device is or is not pre-connected to a needle loaded with implant. A pharmaceutical product may include a sustained release biodegradable ocular implant loaded in a needle and an injection device, wherein the needle is pre-connected to the injection device. In case the needle is not yet pre-connected to the injection device, the physician administering the implant is to remove both the needle containing the implant and the injection device from the packaging and connect the needle to the injection device to be able to inject the implant into the patient’s eye.

[0094] In some embodiments, the injection device contains a push wire to deploy the implant from the needle into the vitreous humor. The push wire may be aNitinol push wire or may be a stainless steel / Teflon push wire (e.g., coated push wire). The push wire allows deploying the implant from the needle more easily.

[0095] In some embodiments, the injection device and / or the injection needle may contain a stop feature that controls the injection depth.

[0096] In some embodiments, the injection device is or comprises a modified Hamilton glass syringe that may be placed into a plastic syringe housing, such as inside an injectionmolded housing. A push wire, such as a Nitinol wire, is inserted into the syringe and advances with the button structure of the syringe during deployment of the implant. To facilitate entry of the nitinol push wire into the needle, a hub insert may be added into the needle hub.

[0097] In some embodiments, implant injector device 100 may be used for injecting an implant into the vitreous humor of a patient, according to certain embodiments.

[0098] In some embodiments, implant injector device 100 may include a Hamilton syringe body and / or a Nitinol push wire to deploy the implant. In some embodiments, implant injector device 100 includes a body (e.g., Hamilton syringe body) inside of an injection molded casing. In some embodiments, the implant injector device 100 includes a body (e.g., Hamilton syringe body) and plastic housing parts that are pre-assembled in a kit and the injector is ready for use (without or without mounted needle containing the implant). In some embodiments, the implant injector device 100 may be assembled by the physician prior to mounting the needle containing the implant.

[0099] In some embodiments, the implant injector device 100 is an injection molded injector. In some embodiments, the number of assembly steps of the implant injector device 100 by the physician just prior to administering the implant to a patient is less than a conventional device.

[0100] The kit may further comprise one or more doses, in particular one dose, of an anti-VEGF agent ready for injection. The anti-VEGF agent may be selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab, and brolucizumab. In certain embodiments the anti-VEGF agent is bevacizumab. In other embodiments the anti-VEGF agent is aflibercept. The anti-VEGF agent may be provided in a separate injection device connected to a needle or may be provided as a solution or suspension in a sealed vial, from which the solution or suspension may be aspirated through a needle into a syringe or other injection device prior to administration.

[0101] The kit may further comprise an operation manual for the physician whois injecting the ocular implant(s). The kit may further comprise a package insert with product-related information.

[0102] In addition to the kit, an injection device per se that is suitable for injecting a sustained release biodegradable ocular implant into the eye. The injection device may connect the injection device to a needle, wherein the needle is pre-loaded with the implant. The injection device may further contain a push wire to deploy the implant from the needle into the eye when the injection device has been connected to the needle, which push wiremay be made of Nitinol, stainless steel, polytetrafluoroethylene (PTFE) (e.g., Teflon), fluoroopolymer, or another suitable material. The injection device may further be obtainable by affixing the wire to the button structure and encasing it between two snap fit injector body parts and securing the button structure with a clip. An injection device and a needle pre-loaded with implant in accordance with certain embodiments of the present disclosure is depicted in FIG. 3.

[0103] In certain embodiments, the implant may be administered via an injection device according to the present disclosure connected to a needle pre-loaded with implant as disclosed herein or may be administered via another injection device suitable to be connected to a needle pre-loaded with an implant as disclosed herein, such as a (modified) Hamilton syringe. In other embodiments, a hollow microneedle may be used for suprachoroidal administration as disclosed in US 8,808,225 which is incorporated by reference herein.

[0104] In embodiments wherein two or more implants are administered, the implants are generally administered concurrently as disclosed herein above. The implants administered concurrently can be the same or different. In cases where an administration during the same session is not possible e.g. due to administration complications or patient-related reasons a successive administration during two or more different sessions may alternatively be applied, such as for instance administration of two implants 7 days apart. This may still be considered as a “concurrent” administration in the context of the present disclosure.

[0105] In certain embodiments the dry implants are loaded in a needle, such as a 25 -gauge or a 27-gauge needle, or a smaller gauge needle, for injection and are administered to the eye, e.g. to the vitreous humor, through this needle. In one embodiment, the injector used for injecting the implant into the eye is an injection device according to another aspect of the present disclosure as disclosed above. Implants containing 200 pg and 600 pg, respectively, that are suitable for the therapeutic applications.

[0106] In some embodiments, a pharmaceutical product comprising the sustained release biodegradable ocular implant loaded in a needle and an injection device, wherein the needle is pre-connected to the injection device.

[0107] In some embodiments, loaded needles (e.g., implant injector device 100) may be placed into a glove box for 6 to 9 days to remove any moisture (the remaining water content in the implant is intended to not exceed 1% water). All operations from then on may be performed in the glove box. The loaded needle may be dipped into a melted low-molecular weight 1 k PEG to tip the needle. Upon cooling a hardened small drop of PEG remains, which provides lubricity, keeps the implant in place within the needle, allows successful deploymentand prevents premature rehydration of the implant within the needle during administration. Moreover, PEG tipping is minimizing tissue injury i.e. tissue coring, a process by which pieces of tissue are removed by a needle as it passes through the tissue. The PEG-tipped needles may then be again inspected, needles which did not meet the quality requirements may be discarded. Passed needles may be again capped to ensure the needles are not suffering any additional damage. Needles may then be individually pouched and sealed to prevent them from moisture and keep them sterile. The injection device, for instance a modified Hamilton glass syringe, had a push wire (e.g. a Nitinol push wire) that allows deploying the implant from the needle more easily. The injection needle may contain a stop feature that controls the injection depth. The injection device can be separately packaged and sealed under nitrogen in foil pouches in the same way as described for the needle (FIG. 3) or could be pre-assembled with the implant-loaded needle or within a preloaded injector. The packaged needles and injection devices may be removed from the glove box and stored refrigerated (2-8 °C) prior to sterilization using gamma irradiation. After sterilization the packages may be stored refrigerated (2-8 °C) or frozen protected from light prior to use and may be equilibrated 30 min to room temperature prior to injection.

[0108] In many anatomical locations, very fine needle sizes are used for injection. Implants for sustained drug delivery can be injected using syringe-like devices where the implant is housed within the needle lumen and ejected using a wire (e.g., wire 132) after tissue penetration. These implants may have specific size requirements so they can hold an adequate dose of drug, and possibly other excipients. Fine needles, with very narrow internal diameter, may require elongation of the implant to achieve adequate overall dimensions or mass to contain the drug dose, thus may use long wires to eject the implant.

[0109] The force to eject implants under physiological conditions may provide a power law function of transmitted force to wire slenderness ratio. The slenderness ratio is the length of wire from the end of the needle to the end of the slider structure (e.g., slider structure 134) prior to initiation of the injection stroke. The force to move the implant within the needle lumen (Ff) is to be exceeded by the force transmitted through the push-wire (Fm), i.e. Fm / Ffis to be greater than 1 or the device may fail. Solving the best fit power law function for Fm / Ff= 1 provides the maximum allowable slenderness ratio capable of transmitting the force for implant ejection. Multiplying the maximum slenderness ratio by the wire radius gives the maximum length of wire within the lumen of the button structure. The ability to transmit force was found to be proportionate to the wire modulus, which is material specific.

[0110] The wire OD may be snugly matched to the ID of the needle. A snug fit prevents lateral deflection and buckling within the needle lumen. A snug fit also prevents lateral overlap of the push-wire and the implant within the needle lumen during deployment.

[0111] The implant diameter may be snugly matched to the wire ID. A snug fit minimizes potential for deflection and buckling of the implant during deployment. In addition, a snug fit prevents lateral overlap of the push-wire within the needle lumen during deployment. The implant may not be longer than the maximum length of the push wire spanning the button structure lumen prior to initiation of the injection stroke. The implant length may also be reduced to accommodate an offset from the needle tip and a small amount of wire protrusion from the needle at the end of the injection stroke, to ensure complete deployment and separation from the needle.

[0112] This injector concept may deploy hydrogel depots with lengths of an abnormally longbutton structure stroke. User depresses a button structure. The button structure actuates the slider structure that is connected to a staked push wire which progresses into a needle cannula as the button structure is depressed. The long hydrogel fibers are staged inside the needle cannula. The push wire is supported throughout the entire deployment stroke as it is advancing the fibers through the needle cannula.

[0113] In certain embodiments, the device herein (e.g., implant injector device 100) contains a sustained release biodegradable ocular implant (e.g., implant 180) comprising a hydrogel and at least about 150 pg of a tyrosine kinase inhibitor (TKI), wherein TKI particles are dispersed within the hydrogel, and wherein the implant in its dry state has a length of less than about 17 mm. In certain embodiments, the TKI is axitinib. The term “implant” and “insert or used interchangeably herein.

[0114] In certain embodiments, the sustained release biodegradable ocular is cylindrical and in its dry state has a diameter of about 0.1 mm to about 0.5 mm. In other embodiments, the implant is non-cylindrical.

[0115] In certain embodiments, the sustained release biodegradable ocular implant comprises axitinib in an amount of about 150 pg to about 1800 pg, in an amount of about 150 pg to about 1200 pg, in an amount of about 480 pg to about 750 pg, in an amount of about 400 pgto about 500 pg, in an amount of about 450 pg, or in an amount of about 160 pg to about 250 pg.

[0116] In certain embodiments, the sustained release biodegradable ocular implant in its dry state has a total weight of about 0.2 mg to about 1.5 mg, or a total weight of about 0.75 mg to 1.25 mg.

[0117] In certain embodiments, the sustained release biodegradable ocular implant is for administration into the posterior section of the eye.

[0118] In certain embodiments, the implant is an intravitreal implant.

[0119] In certain embodiments, the sustained release biodegradable ocular implant is cylindrical and in its dry state has a length of about 5 mm to about 10 mm, about 6 mm to about 10 mm, about 6.7 to about 6.9 mm, about 6.8 mm, etc.

[0120] In certain embodiments, the sustained release biodegradable ocular is cylindrical and in its dry state has a diameter of about 0.2 mm to about 0.4 mm.

[0121] In certain embodiments, the sustained release biodegradable ocular implant is cylindrical and in its hydrated state (after 24 hours in phosphate-buffered saline at a pH of 7.2 at 37 °C) has a length of equal to or less than about 10 mm and a diameter of one or more of equal to or less than about 1 mm, equal to or less than about 0.8 mm, etc..

[0122] In certain embodiments, the sustained release biodegradable ocular implant is cylindrical and has a ratio of the diameter in the hydrated state to the diameter in the dry state of less than about 5, or less than about 2.25.

[0123] In certain embodiments, the sustained release biodegradable ocular implant is cylindrical and has a ratio of the length in the dry state to the length in the hydrated state of greater than about 0.7, or greater than about 0.8.

[0124] In certain embodiments, the sustained release biodegradable ocular implant provides forthe release of axitinib atan average rate of about0.25 pg to about2.5 pgper day, of about 0.25 pg to about 1.5 pgper day, about 1.0 to about 1.4 pgper day, about 1.2 pgper day, or of about0.3 pgto about0.5 pgper day, in phosphate-buffered saline at a pH of 7.2 and 37 °C for a period of 30 days, about 6 months, about 8 months, etc. (e.g., in vivo).

[0125] In certain embodiments, the sustained release biodegradable ocular implant provides forthe release of the TKIfor a period of at least 3 months after administration, or a period of at least 6 months after administration, or a period of at least 9 months after administration, or a period of at least 12 months after administration, or a period of about 6 months to about 9 months after administration.

[0126] In certain embodiments, the sustained release biodegradable ocular implant biodegrades within about 2 to about 15 months, within about 4 to about 13 months, or within about 9 to about 12 months, after administration to the vitreous humor.

[0127] In certain embodiments, the hydrogel comprises a polymer network comprising one or more units of polyalkylene glycol, polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolicacid, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyaminoacids, glycosaminoglycans, polysaccharides, or proteins.

[0128] In certain embodiments, the hydrogel comprises polyethylene glycol (PEG) units.

[0129] In certain embodiments, the hydrogel comprises multi-arm PEG units that are the same or different, and that have a number average molecular weight of from about 10,000 to about 60,000 Daltons, or about 20,000 Daltons.

[0130] In certain embodiments, the hydrogel comprises crosslinked PEG units and the crosslinks between the PEG units include a group represented by the following formula

[0132] wherein m is an integer from 0 to 10, preferably m is 6.

[0133] In certain embodiments, the PEG units comprise 4-arm and / or 8-arm PEG units, or 4a20k and 8a20k PEG units.

[0134] In certain embodiments, the implant in its wet state contains no more than about 40% by weight TKI of the wet composition.

[0135] In certain embodiments, the implant in its dry state contains from about 25% to about 75% by weight TKI and from about 20% to about 60% by weight PEG units (dry composition).

[0136] In certain embodiments, the implant in its dry state contains from about 60% to about 75% by weight TKI and from about 21% to about 31% by weight PEG units or contains from about 45% to about 55% by weight TKI and from about 37% to about 47% by weight PEG units (dry composition).

[0137] In certain embodiments, the implant in its dry state contains from about 200 pg to about 1000 pg TKI per mm3, and preferably contains from about 500 pg to about 800 pg axitinib per mm3.

[0138] In certain embodiments, the implant is an intravitreal implant and comprises from about 480 pg to about 750 pg axitinib or from about 540 pg to about 660 pg axitinib, or about 600 pg axitinib, is cylindrical and has in its dry state a length of less than or equal to 10 mm and a diameter of about 0.3 mm to about 0.4 mm, and in its hydrated state (after 24 hours in phosphate-buffered saline at a pH of 7.2 at 37 °C) has a length of from about 6 mm to about 10.5 mm and a diameter of from about 0.6 mm to about 0.8 mm, and wherein the hydrogel comprises crosslinked 4a20kand 8a20kPEGunits, wherein the crosslinks between the PEG units include a group represented by the following formula

[0140] wherein m is 6.

[0141] In certain embodiments, the implant is an intravitreal implant and comprises from about 160 pgto about 500 pg axitinib, about 160 pgto about 250 pg axitinib, or from about 180 pg to about 220 pg axitinib, or about 200 pg axitinib, about 400 pg to about 500 pg axitinib, about 450 pg axitinib, is cylindrical and has in its dry state a length of less than about 17 mm and a diameter of about 0.2 mm to about 0.3 mm, and in its hydrated state (after 24 hours in phosphate-buffered saline at a pH of 7.2 at 37 °C) has a length of from about 6.5 mm to about 8 mm and a diameter of from about 0.7 mm to about 0.8 mm, and wherein the hydrogel comprises crosslinked 4a20kand 8a20kPEGunits, wherein the crosslinks between the PEG units include a group represented by the following formula

[0142]

[0143] wherein m is 6.

[0144] In certain embodiments, the TKI particles have a d90 particle size of less than about 30 pm as determined by laser diffraction.

[0145] In certain embodiments, the implant is free or substantially free of antimicrobial preservatives.

[0146] In certain embodiments, the implant (e.g., implant 180) comprises a therapeutic agent. The therapeutic agent can be a prostaglandin antagonist, such as travoprost, bimatoprost or latanoprost.

[0147] In certain embodiments, the administering of the ocular implant (e.g., implant 180) via a device of the present disclosure is to treat an ocular disease.

[0148] In certain embodiments, the ocular implant (e.g., implant 180) includes an active agent.

[0149] In certain embodiments, the administering of the ocular implant (e.g., implant 180) is intravitreal or intracameral.

[0150] In certain embodiments, the ocular implant (e.g., implant 180) includes an active agent that is a tyrosine kinase inhibitor.

[0151] In certain embodiments, the ocular implant (e.g., implant 180) includes an active agent that is a tyrosine kinase inhibitor that is axitinib.

[0152] In certain embodiments, the administering of the ocular implant (e.g., implant 180) via a device of the present disclosure is to treat an ocular disease that is a back of eye disease.

[0153] In certain embodiments, the administering of the ocular implant (e.g., implant 180) via a device of the present disclosure is to treat an ocular disease that is a back of eye disease that is retinal disease.

[0154] In certain embodiments, the administering of the ocular implant (e.g., implant 180) via a device of the present disclosure is to treat an ocular disease that is age-related macular degeneration (AMD) cystoid macular edema (CME), diabetic macular edema (DME), retinal vein occlusion, posterior uveitis, diabetic retinopathy, or glaucoma.

[0155] In certain embodiments, the administering of the ocular implant (e.g., implant 180) is to an anterior chamber or a vitreous chamber.

[0156] In certain embodiments, the ocular implant (e.g., implant 180) includes an active agent that is a prostaglandin.

[0157] In certain embodiments, the ocular implant (e.g., implant 180) includes an active agent that is travoprost.

[0158] In certain embodiments, the ocular implant (e.g., implant 180) is used to treat an ocular disease that is a front of the eye disease.

[0159] In certain embodiments, the ocular implant (e.g., implant 180) is used to treat an ocular disease that is high pressure in the eye caused by open-angle glaucoma or ocular hypertension.

[0160] Therapeutic agents also include, for example, agents for treating conditions that may result from inflammatory or abnormal vascular conditions, retinal vein occlusion, geographic atrophy, retinitis pigmentosa, retinoblastoma, etc. For cancer, agents maybe, e.g., anti-cancer drugs, anti-VEGFs, or drugs known for use in cancer treatment.

[0161] Therapeutic agents may be those that are, e.g., anti-VEGF, blocks VEGFR1 , blocks VEGFR2, blocks VEGFR3, anti-PDGF, anti-angiogenesis, Sunitinib, E7080, Takeda-6d, Tivozanib, Regorafenib, Sorafenib, Pazopanib, Axitinib, Nintedanib, Cediranib, Vatalanib, Motesanib, macrolides, sirolimus, everolimus, tyrosine kinase inhibitors (TKIs), Imatinib (GLEEVAC) gefinitib (IRESSA), toceranib (PALLADIA), Erlotinib (TARCEVA), Lapatinib (TYKERB) Nilotinib, Bosutinib Neratinib, lapatinib, Vatalanib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, toceranib, vandetanib.

[0162] The therapeutic agent may comprise a macromolecule, for example an antibody or antibody fragment. The therapeutic macromolecule may comprise a VEGF inhibitor, for example ranibizumab, the active ingredient in the commercially available Lucentis™. TheVEGF (Vascular Endothelial Growth Factor) inhibitor can cause regression of the abnormal blood vessels and improvement of vision when released into the vitreous humor of the eye. Examples of VEGF inhibitors include Lucentis™ (ranibizumab), Eylea™ (VEGF Trap), Avastin™ (bevacizumab), Macugen™ (pegaptanib). Platelet derived growth factor (PDGF) inhibitors may also be delivered, e.g. Fovista™, an anti-PGDF aptamer.

[0163] The therapeutic agent may comprise small molecules such as of a steroid or corticosteroid and analogues thereof. For example, the therapeutic corticosteroid may comprise one or more of trimacinolone, trimacinolone acetonide, dexamethasone, dexamethasone acetate, fluocinolone, fluocinolone acetate, loteprednol etabonate, or analogues thereof. Alternatively, or in combination, the small molecules of therapeutic agent may comprise a tyrosine kinase inhibitor.

[0164] The therapeutic agent may comprise an anti-VEGF therapeutic agent. Anti-VEGF therapies and agents can be used in the treatment of certain cancers and in age-related macular degeneration. Examples of anti-VEGF therapeutic agents suitable for use in accordance with the embodiments described herein include one or more of monoclonal antibodies such as bevacizumab (Avastin™) or antibody derivatives such as ranibizumab (Lucentis™), or small molecules that inhibit the tyrosine kinases stimulated by VEGF such as lapatinib (Tykerb™), sunitinib (Sutent™) sorafenib (Nexavar™), axitinib, orpazopanib.

[0165] The therapeutic agent may comprise a therapeutic agent suitable for treatment of dry AMD such as one or more of Sirolimus™ (Rapamycin), Copaxone™ (Glatiramer Acetate), Othera™ Complement C5aR blocker, Ciliary Neurotrophic Factor, Fenretinide or Rheopheresis.

[0166] The therapeutic agent may comprise a therapeutic agent suitable for treatment of wet AMD such as one or more of REDD14NP (Quark), Sirolimus™ (Rapamycin), ATG003; EYELEA (VEGF Trap) or complement inhibitor (POT-4).

[0167] The therapeutic agent may comprise a kinase inhibitor such as one or more of BIBW 2992 (small molecule targeting EGFR / Erb2), imatinib (small molecule), gefitinib (small molecule), ranibizumab (monoclonal antibody), pegaptanib (small molecule), sorafenib (small molecule), dasatinib (small molecule), sunitinib (small molecule), erlotinib (small molecule), nilotinib (small molecule), lapatinib (small molecule), panitumumab (monoclonal antibody), vandetanib (small molecule) or E7080 (targeting VEGFR2 / VEGFR2, small molecule commercially available fromEsai, Co.). The therapeutic agent may comprise antibody drugs, e.g. bevacizumab, trastuzumab, cetuximab, and panitumumab.

[0168] Therapeutic agents may include various classes of drugs. Drugs include, for instance, steroids, non-steroidal anti-inflammatory drugs (NSAIDS), anti-cancer drugs, antibiotics, an anti-inflammatory (e.g., Diclofenac), a pain reliever (e.g., Bupivacaine), a Calcium channel blocker (e.g., Nifedipine), an Antibiotic (e.g., Ciprofloxacin), a Cell cycle inhibitor (e.g., Simvastatin), a protein (e.g., Insulin). Therapeutic agents include classes of drugs including steroids, NSAIDS, antioxidants, antibiotics, pain relievers, inhibitors of vascular endothelial growth factor (VEGF), chemotherapeutics, anti-viral drugs, for instance. Examples of NSAIDS are Ibuprofen, Meclofenamate sodium, mefanamic acid, salsalate, sulindac, tolmetin sodium, ketoprofen, diflunisal, piroxicam, naproxen, etodolac, flurbiprofen, fenoprofen calcium, Indomethacin, celecoxib, ketorolac, and nepafenac. The drugs themselves may be small molecules, proteins, RNA fragments, proteins, glycosaminoglycans, carbohydrates, nucleic acid, inorganic and organic biologically active compounds where specific biologically active agents include but are not limited to: enzymes, antibiotics, antineoplastic agents, local anesthetics, hormones, angiogenic agents, anti-angiogenic agents, growth factors, antibodies, neurotransmitters, psychoactive drugs, anticancer drugs, chemotherapeutic drugs, drugs affecting reproductive organs, genes, and oligonucleotides, or other configurations.

[0169] Therapeutic agents may include a protein or other water-soluble biologies. These include peptides of various molecular weights. Peptides include therapeutic proteins and peptides, antibodies, antibody fragments, short chain variable fragments (scFv), growth factors, angiogenic factors, and insulin. Other water-soluble biologies are carbohydrates, polysaccharides, nucleic acids, antisense nucleic acids, RNA, DNA, small interfering RNA (siRNA), and aptamers.

[0170] The therapeutic agents may be used as part of a method of treating the indicated condition or making a composition for treating the indicated condition. For example, AZOPT (a brinzolamide ophthalmic suspension) may be used for treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. BETADINE in a Povidone-iodine ophthalmic solution may be used for prepping of the periocular region and irrigation of the ocular surface. BETOPTIC (betaxolol HC1) may be used to lower intraocular pressure, or for chronic open-angle glaucoma and / or ocular hypertension. CILOXAN (Ciprofloxacin HC1 ophthalmic solution) may be used to treat infections caused by susceptible strains of microorganisms. NATACYN (Natamycin ophthalmic suspension) may be used for treatment of fungal blepharitis, conjunctivitis, and keratitis. NEVANAC (Nepafenac ophthalmic suspension) may be used for treatment of pain and inflammationassociated with cataract surgery. TRAVATAN (Travoprost ophthalmic solution) may be used for reduction of elevated intraocular pressure-open-angle glaucoma or ocular hypertension. FML FORTE (FluoromethoIone ophthalmic suspension) may be used for treatment of corticosteroid-responsive inflammation of the palperbral and bulbar conjunctiva, cornea and anterior segment of the globe. LUMIGAN (Bimatoprost ophthalmic solution) may be used for reduction of elevated intraocular pressure-open-angle glaucoma or ocular hypertension. PRED FORTE (Prednisolone acetate) may be used for treatment of steroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe. PROPINE (Dipivefrin hydrochloride) may be used for control of intraocular pressure in chronic open-angle glaucoma. RESTASIS (Cyclosporine ophthalmic emulsion) may be used to increases tear production in patients, e.g., those with ocular inflammation associated with keratoconjunctivitis sicca. ALREX (Loteprednol etabonate ophthalmic suspension) may be used for temporary relief of seasonal allergic conjunctivitis. LOTEMAX (Loteprednol etabonate ophthalmic suspension) may be used for treatment of steroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe. MACUGEN (Pegaptanib sodium injection) may be used for Treatment of neovascular (wet) age-related macular degeneration. OPTIVAR (Azelastine hydrochloride) may be used for treatment of itching of the eye associated with allergic conjunctivitis. XALATAN (Latanoprost ophthalmic solution) may be used to reduce elevated intraocular pressure in patients, e.g., with open-angle glaucoma or ocular hypertension. BETIMOL (Timolol ophthalmic solution) may be used for treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Latanoprost is the pro-drug of the free acid form, which is a prostanoid selective FP receptor agonist. Latanoprost reduces intraocular pressure in glaucoma patients with few side effects. Latanoprost has a relatively low solubility in aqueous solutions but is readily soluble in organic solvents typically employed for fabrication of microspheres using solvent evaporation.

[0171] Further embodiments of therapeutic agents for delivery include those that specifically bind a target peptide in vivo to prevent the interaction of the target peptide with its natural receptor or other ligands. AVASTIN, for instance, is an antibody that binds VEGF. An IL-1 trap that makes use of the extracellular domains of IL-1 receptors is also known; the trap blocks IL-1 from binding and activating receptors on the surface of cells. Embodiments of agents for delivery include nucleic acids, e.g., aptamers. Pegaptanib (MACUGEN), for example, is a pegylated anti-VEGF aptamer. An advantage of the particle-and-hydrogel delivery process is that the aptamers are protected from the in vivo environment until they arereleased. Further embodiments of agents for delivery include macromolecular drugs, a term that refers to drugs that are significantly larger than classical small molecule drugs, i.e., drugs such as oligonucleotides (aptamers, antisense, RNAi), ribozymes, gene therapy nucleic acids, recombinant peptides, and antibodies.

[0172] One embodiment comprises extended release of a medication for allergic conjunctivitis. For instance, ketotifen, an antihistamine and mast cell stabilizer, may be provided in particles and released to the eye as described herein in effective amounts to treat allergic conjunctivitis. Seasonal Allergic Conjunctivitis (SAC) and Perennial Allergic Conjunctivitis (PAC) are allergic conjunctival disorders. Symptoms include itching and pink to reddish eyes. These two eye conditions are mediated by mast cells. Non-specific measures to ameliorate symptoms conventionally include: cold compresses, eyewashes with tear substitutes, and avoidance of allergens. Treatment conventionally consists of antihistamine mast cell stabilizers, dual mechanism anti-allergen agents, or topical antihistamines.Corticosteroids might be effective but, because of side effects, are reserved for more severe forms of allergic conjunctivitis such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC).

[0173] Moxifloxacin is the active ingredient in VIGAMOX, which is a fluoroquinolone approved for use to treat or prevent ophthalmic bacterial infections. VKC and AKC are chronic allergic diseases where eosinophils, conjunctival fibroblasts, epithelial cells, mast cells, and / or TH2 lymphocytes aggravate the biochemistry and histology of the conjunctiva. VKC and AKC can be treated by medications used to combat allergic conjunctivitis.Permeation agents are agents and may also be included in a gel, hydrogel, organogel, xerogel, and biomaterials as described herein. These are agents that assist in permeation of a drug into an intended tissue. Permeation agents may be chosen as needed for the tissue, e.g., permeation agents for skin, permeation agents for an eardrum, permeation agents for an eye, etc.

[0174] The agent may be treatment of aback of the eye disease, e.g., wherein the back of the eye disease is age-related macular degeneration (AMD) cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis, and diabetic retinopathy, or glaucoma.

[0175] The agents may be, e.g., an agent comprises anti-VEGF, blocks VEGFR1, blocks VEGFR2, blocks VEGFR3, anti-PDGF, anti -PDGF-R blocks PDGFRP, an anti-angiogenic agent, Sunitinib, E7080, Takeda-6d, Tivozanib,Regorafenib, Sorafenib, Pazopanib, Axitinib, Nintedanib, Cediranib, Vatalanib, Motesanib, macrolides, sirolimus, everolimus, tyrosine kinase inhibitors (TKIs), Imatinibn gefinitib, toceranib, Erlotinib, Lapatinib, Nilotinib,Bosutinib Neratinib, lapatinib, Vatalanib, comprises low-soluble prostaglandin analogues for glaucoma, nepafenac, macrolides, rapamycin, sirolimus, tacrolimus, or serves to block mTOR receptors for AMD (also known as choroidal neovascularization (CNV). mTOR refers to mammalian target of rapamycin. Agents may be, e.g., moxifloxacin, dexamethasone, travoprost, steroids, fluoroquinolones, prostaglandin analogs, prostamides.

[0176] Ocular diseases include ocular pathologies, with hyphema, ocular hypertension, and glaucoma being conditions for treatment with an anterior chamber depot. Many agents are suitable for ocular delivery, e.g., NSAIDs, steroids, anti-glaucoma drugs, antivirals, antibiotics, mydriatics, and antifungals administered via intracameral injections.

[0177] Some of the disease states are back-of-the-eye diseases. The term back-of-the eye disease is recognized by artisans in these fields of endeavor and generally refers to any ocular disease of the posterior segment that affects the vasculature and integrity of the retina, macula or choroid leading to visual acuity disturbances, loss of sight or blindness. Disease states of the posterior segment may result from age, trauma, surgical interventions, and hereditary factors. Some back-of-the-eye disease are; age-related macular degeneration (AMD) cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis, and diabetic retinopathy. Some back-of-the-eye diseases result from unwanted angiogenesis or vascular proliferation, such as macular degeneration or diabetic retinopathy. Drug treatment options for these and other ocular conditions maybe provided by delivery of agents from an implant.

[0178] Other Embodiments

[0179] In certain embodiments, the present invention is directed to a device as disclosed herein, an implant as disclosed herein, a system comprising an ocular injection device as disclosed herein loaded with an implant comprising an active agent or a system comprising an ocular injection device and an implants as disclosed herein.

[0180] The implant

[0181] The active principle:

[0182] One aspect of the present invention is a sustained release biodegradable ocular implant comprising a hydrogel and at least about 150 pg of a tyrosine kinase inhibitor (TKI), wherein TKI particles are dispersed within the hydrogel. In one embodiment, the present invention provides a sustained release biodegradable ocular implant comprising a hydrogel and at least about 150 pg of a tyrosine kinase inhibitor (TKI), wherein TKI particles are dispersed within the hydrogel, and wherein the implant in its dry state has a length of less than about 17 mm.

[0183] The active principle contained in an implant of this aspect of the invention is a TKI. Examples for suitable TKIs are axitinib, sorafenib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib, and vandetanib. In particular embodiments, the TKI used in this and other aspects of the present invention is axitinib. Details on axitinib, its chemical structure, polymorphs, solvates, salts etc. and its properties such as solubility are provided above in the definitions section.

[0184] All features (individually or any combinations of features) disclosed herein with respect to an implant according to the present invention may be used to characterize the sustained release biodegradable ocular implant comprising a hydrogel and at least about 150 pg of a tyrosine kinase inhibitor (TKI), wherein TKI particles are dispersed within the hydrogel.

[0185] In certain embodiments, the implant in its dry state has a length of less than about 17 mm, from about 5 mm to about 10 mm, from about 6 mm to about 8 mm, about 7 mm to about 6.8 mm.

[0186] In particular embodiments, the implant of the invention is an intravitreal implant, i.e., is administered to the vitreous humor (also referred to herein as “administered intravitreally”).

[0187] The TKI, such as axitinib, is contained in the implant of the invention in a range of doses as disclosed herein of at least 150 pg, such as from about 150 pg to about 1800 pg, from about 150 pg to about 1200 pg, or from about 200 pg to about 800 pg. Any TKI, such as axitinib, amount within these ranges may be used, such as about 150 pg, about 200 pg, about 300 pg, about 400 pg, about 500 pg, about 600 pg, about 700 pg, about 800 pg, about 900 pg, about 1000 pg, about 1100 pg or about 1200 pg. In alternative embodiments, the dose of TKI contained in an implant of the invention, such as axitinib, may also be up to about 1800 pg, such as about 1300 pg, about 1400 pg, about 1500 pg, about 1600 pg, about 1700 pg, or about 1800 pg. In further alternative embodiments, the dose of TKI contained in an implant of the invention, such as axitinib, may be even higher than about 1800 pg or higher than about 2000 pg, such as up to about 3000 pg, up to about 6000 pg, or up to about 10000 pg. All mentioned values also include a variance of +25% and -20%, or a variance of + / - 10%.

[0188] In certain particular embodiments, the doses of axitinib contained in an implant of the invention are:

[0189] a range from about 160 pg to about 250 pg, or from about 180 pg to about 220 pg, or about 200 pg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 200 pg)

[0190] a range from about 320 pgto about 500 pg, or from about 360 pgto about 440 pg, or about 400 pg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 400 pg)

[0191] a range from about 375 pgto about 600 pg, or from about 450 pgto about 550 pg, or about 500 pg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 500 pg)

[0192] a range from about 480 pgto about 750 pg, or from about 540 pgto about 660 pg, or about 600 pg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 600 pg)

[0193] a range from about 640 pgto about 1000 pg, or from about 720 pgto about 880 pg, or about 800 pg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 800 pg)

[0194] a range from about 800 pgto about 1250 pg, or from about 900 pgto about 1100 pg, or about 1000 pg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 1000 pg)

[0195] a range from about 960 pgto about 1500 gg, or from about 1080 gg to about 1320 pg, or about 1200 gg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 1200 pg)

[0196] a range from about 1440 pgto about 2250 gg, or from about 1620 gg to about 1980 pg, or about 1800 gg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 1800 pg).

[0197] In one embodiment, the dose of axitinib contained in one implant of the invention is from about 480 pg to about 750 pg, or from about 540 pg to about 660 pg, or in particular embodiments is about 450 pg to about 600 pg.

[0198] The disclosed amounts of TKI, such as axitinib, including the mentioned variances, refer to both the final content of the active principle in the implant, as well as to the amount of active principle used as a starting component per implant when manufacturing the implant.

[0199] In certain embodiments of the invention the total dose of the TKI, such as axitinib, to be administered to a patient, may be contained in two, three or more implants administered concurrently. For example, a dose of about 400 pg of TKI, such as axitinib, may be administered in one implant containing about 400 pg axitinib, or in two implants e.g. eachcontaining about 200 pg axitinib and so on. Of course, one may not only combine two or more identical implants (or implants containing the identical dose), but also two or more different implants (or implants containing different doses) in order to arrive at a desired total dose. In a particular embodiment, a total axitinib dose of from about 480 pg to about 750 pg, or from about 540 pg to about 660 pg, or of about 600 pg, is contained in one implant and only one such implant is administered to a patient in need of such treatment in accordance with the invention. In another embodiment, a total dose of higher than about 600 pg, such as from about 800 pg to about 1250 pg, or from about 900 pg to about 1100 pg, or of about 1000 pg, or a total dose from about 960 pg to about 1500 pg, or from about 1080 pg to about 1320 pg, or of about 1200 pg, or a total dose from about 1440 pg to about 2250 pg, or from about 1620 pg to about 1980 pg, or of about 1800 pg is contained in one implant and only one such implant is administered to a patient in need of such treatment in accordance with the invention. In other embodiments, the total dose administered to a patient in accordance with the present invention may be contained in two or more implants (containing the same or different amounts of API) administered concurrently.

[0200] The TKI, such as axitinib, is contained in the implant an embodiment of the invention and can be dispersed or distributed in the hydrogel that is comprised of a polymer network. In certain embodiments, the particles are homogeneously or essentially homogeneously dispersed in the hydrogel. The hydrogel may prevent the particles from agglomerating and may provide a matrix for the particles which holds them in the desired location in the eye while slowly releasing drug.

[0201] In certain embodiments of the invention, the TKI particles such as the axitinib particles may be microencapsulated. The term “microcapsule” (also referred to as “microparticle”) is sometimes defined as a roughly spherical particle with a size varying between e.g. about 50 nm to about 2 mm. Microcapsules have at least one discrete domain (or core) of active agent encapsulated in a surrounding material, sometimes also referred to as a shell. One suitable agent (without limiting the present disclosure to this) for microencapsulating the TKI, such as the axitinib, for the purposes of the present invention, is poly (lactic-co-gly colic acid).

[0202] In other embodiments, the TKI particles such as the axitinib particles are not microencapsulated and are thus dispersed in the hydrogel and thus in the implant of the invention as they are, i.e., without being admixed to or adjoined with or microencapsulated by another material such as (but not limited to) poly (lactic-co-gly colic acid).

[0203] In one embodiment, the TKI particles, such as the axitinib particles, may be micronized particles. In another embodiment, the TKI particles, such as the axitinib particles, may not be micronized. Micronization refers to the process of reducing the average diameter of particles of a solid material. Particles with reduced diameters may have inter alia higher dissolution and erosion rates when exposed to tissue fluids, which increases the bioavailability of active pharmaceutical ingredients and may have in certain embodiments a positive impact on release kinetics. Furthermore, micronized particles may have a reduced tendency to agglomerate during manufacturing operations. In the composite materials field, particle size is known to affect the mechanical properties when combined with a matrix, with smaller particles providing superior reinforcement for a given mass fraction. Thus, a hydrogel matrix filled with micronized TKI particles may have improved mechanical properties (e.g., reduced brittleness, increased strain to failure, etc.) compared to a similar mass fraction of larger TKI particles. Such properties are important in manufacturing, during implantation, and during degradation of the implant. Micronization may also promote a more homogeneous distribution of the active ingredient in the chosen dosage form or matrix. The particle size distribution can be measured by methods known in the art, including sieving, laser diffraction or dynamic light scattering. In certain embodiments of the invention the TKI, such as the axitinib, particles used in preparing the implants of the present invention may have a d90 of less than about 100 pm and / or a d50 of less than about 50 pm, or a d90 of less than about 75 pm and / or a d50 or less than about 20 pm as determined by laser diffraction. In specific embodiments, the d90 of the TKI, such as the axitinib, may be less than about 30 pm, less than about 20 pm as determined by laser diffraction. In very particular embodiments, the d90 of the TKI, such as axitinib, is less than about 10 pm as determined by laser diffraction. In these or other embodiments, the d50 of the TKI, such as axitinib, particles used in preparing the implants of the present invention may be less than about 5 pm as determined by laser diffraction. In these or other embodiments, the dlO of the TKI, such as the axitinib, particles used in the present invention may be less than about 3 pm as determined by laser diffraction. In certain embodiments, the dlOO of the TKI, such as the axitinib, particles used in the preparation of the implants of the present invention may be less than about 20 pm as determined by laser diffraction. The “d90” (also referred to as “D90” herein) value means that 90 volume-% of all particles within the measured bulk material (which has a certain particle size distribution) have a particle size below the indicated value. For example, a d90 particle size of less than about 10 pm means that 90 volume-% of the particles in the measured bulk material have a particle size below about 10 pm. Corresponding definitionsapply to other “d” values, such as the “dlO”, “d50” or the “dlOO” values (also referred to herein as the “DIO”, “D50” and “DlOO” values, respectively). In certain other embodiments also TKI, such as axitinib, particles with diameters above this specification may be used.

[0204] Micronized TKI such as axitinib particles may be purchased per specification from the supplier, or may be prepared e.g. according to the following exemplary procedure for axitinib (disclosed in WO 2016 / 183296 Al, Example 13): 1800 mL of sterile Water For Injection (WFI) is measured into a 2 L beaker and placed on a stir plate stirring at 600 RPM with a stir bar, creating a large WFI vortex in the center of the beaker. One 60 mL BD syringe containing axitinib in ethanol is placed on a syringe pump which is clamped above the WFI beaker. A hypodermic needle (21G, BD) is connected to the syringe and aimed directly into the center of the vortex for dispensation of the axitinib solution. The syringe pump is then run at 7.5 mL / min in order to add the axitinib solution dropwise to the WFI to precipitate micronized axitinib. After micronization, the axitinib is filtered, e.g. through a 0.2 pm vacuum filter and rinsed with WFI. After filtration, the axitinib powder is collected from the filter e.g. by using a spatula and vacuum dried for an extended period of time, such as for about 12 or about 24 hours, in order to remove excess solvent. Another exemplary method of micronizing axitinib is disclosed in Example 9 of WO 2017 / 091749. The described method of micronization is not limiting, and other methods of micronizing the active agent such as axitinib may equally be used. The disclosed micronization method (or other methods) may also be used for other actives than axitinib.

[0205] Another aspect of the present invention is a sustained release biodegradable ocular implant comprising a hydrogel and at least about 150 pg of a tyrosine kinase inhibitor (TKI), wherein TKI particles are dispersed within the hydrogel, and wherein the implant in its dry state has a total weight of about 0.2 mg to about 1.5 mg. In certain embodiments, the TKI is axitinib or another TKI as disclosed herein.

[0206] In certain embodiments, the total weight (also referred to herein as “total mass”) of an implant according to the present invention in its dry state may be from about 400 pg to about 1.2 mg. In certain specific embodiments, the total weight of an implant according to the invention in its dry state may be from about 0.3 mg to about 0.6 mg, such as from about 0.4 mg to about 0.5 mg, or may be from about 0.8 mg to about 1.1 mg, such as from about 0.9 mg to about 1.0 mg or about 0.65 mg to about 0.75 mg or about 0.7 mg to about 0.75 mg.

[0207] All features (individually or any combinations of features) disclosed herein with respect to an implant according to the present invention may be used to characterize the sustained release biodegradable ocular implant comprising a hydrogel and at least about 150pg of a tyrosine kinase inhibitor (TKI), wherein TKI particles are dispersed within the hydrogel, and wherein the implant in its dry state has a total weight of about 0.2 mg to about 1.5 mg.

[0208] Examples for suitable TKIs are axitinib, sorafenib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib, and vandetanib. In particular embodiments, the TKI used in this and other aspects of the present invention is axitinib.

[0209] The molecular formula of axitinib free base is C22Hi8N4OS, and its IUPAC name is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide. It has the following chemical structure:

[0210] For the purposes of the present invention in all its aspects, axitinib in all its possible forms, including any axitinib polymorphs, salts, anhydrates, hydrates, other solvates, derivatives or prodrugs of axitinib, can be used. Whenever in this description or in the claims it is referred to “axitinib”, if not otherwise explicitly stated this refers to any axitinib polymorph, salt, anhydrate, solvate (including hydrates), co-crystal, derivative or prodrug of axitinib. For the purpose of the present invention, all forms of axitinib used in implants are intended to be pharmaceutically acceptable.

[0211] In certain embodiments of the present invention, specific forms of axitinib are used.

[0212] The solubility of axitinib free base in biorelevant media (e.g. PBS, pH 7.2 to 7.4, e.g. at 37 °C) has been determined to be low. Different forms of axitinib, including different forms of the axitinib free base such as different axitinib polymorphs have different solubility.

[0213] The present invention in one aspect relates to a sustained release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor (TKI), such as axitinib, wherein tyrosine kinase inhibitor particles are dispersed within the hydrogel, characterized in that the solubility of the tyrosine kinase inhibitor is greater than 0.3 pg / mL as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation. In specific embodiments, the TKI is axitinib. According to this aspect of the invention, any forms of axitinib, such as axitinib polymorphs, co-crystals, derivatives and prodrugs, including but not limited to those further disclosed herein may be used that have a solubility of greater than 0.3 pg / mL as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation.

[0214] Another aspect of the present invention relates to a sustained release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor, such as axitinib, wherein tyrosine kinase inhibitor particles are dispersed within the hydrogel, characterized in that the hydrated surface area of the implant is at least 25 mm2as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after 24 hours of incubation. According to this aspect of the invention, generally all forms of axitinib maybe used, regardless of their solubility, including but not limited to the axitinib polymorphs, co-crystals, derivatives and prodrugs as further disclosed herein, as long as the hydrated surface area of the implant is at least 25 mm2as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after 24 hours of incubation.

[0215] The above two aspects of the present invention may also be combined, i.e., the present invention also relates to a sustained release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor, such as axitinib, wherein tyrosine kinase inhibitor particles are dispersed within the hydrogel, characterized in that the solubility of the tyrosine kinase inhibitor is greater than 0.3 pg / mL as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation, and further characterized in that the hydrated surface area of the implant is at least 25 mm2as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after 24 hours of incubation.

[0216] Axitinib Polymorphs for use in the present invention:

[0217] With respect to axitinib, suitable solid forms and polymorphs of axitinib including anhydrous forms and solvates are disclosed in the scientific literature, e.g. A.M.Campeta et al., Journal of Pharmaceutical Sciences, Vol. 99, No. 9, September 2010, 3874-3886; B.P. Chekal et al., Organic Process Research & Development 2009, 13, 1327-1337; and in the patent literature, including, butnot limited to US 8,791,140 B2, US 2006 / 0094763 Al, andWO 2016 / 178150 Al. The most thermodynamically stable polymorph of axitinib is referred to as form XLIin e.g. US 8,791, 140B2. XLIis an anhydrous crystalline form of axitinib. In certain embodiments of the invention, the axitinib used for preparing the implants according to the present invention is the anhydrous crystalline form XLI. In addition to the anhydrous forms, there exist numerous solvates of axitinib with various solvents, as also described in the cited art, which can all be used for preparing implants according to the present invention. Any of the axitinib polymorphic forms known and disclosed in the art, specifically (but not limited to) the references cited herein, may generally be used in the present invention (unless the specific aspect of the invention requires a particular solubility, as explained above, in which case only those axitinib polymorphs that meet this requirement may be used).

[0218] In certain aspects and embodiments of the invention, the non-solvated crystalline form SAB-I of axitinib disclosed in WO 2016 / 178150 may be used for preparing the implants according to the present invention. It is characterized by an XRD pattern comprising at least three, or at least four, or at least five characteristic 20° peaks selected from 8.3, 15.6, 16.5, 18.6, 21.0, 23.1, 24.1 and 26.0 20° (all values ± 0.3), and / or13C NMR in DMSO solvent comprising chemical shifts at 26.1, 114.7, 154.8 and 167.8, each shift ± 0.2 ppm, and / or13C solid state NMR comprising chemical shifts at 171.1, 153.2, 142.6, 139.5, 131.2, 128.1 and 126.3, each shift ± 0.2 ppm, and / or characterized by a DSC isotherm comprising two endothermic peaks ranging between 213 °C to 217 °C (Peak 1) and 219 °C to 224 °C (Peak 2).

[0219] The solubility of axitinib polymorph SAB-I measured at 37°C in PBS with a pH of 7.2 to 7.4 after 5 days of incubation has been determined to be below 0.3 pg / mL. In those aspects and embodiments of the present invention, in which the solubility of the tyrosine kinase inhibitor is greater than 0.3 pg / mL as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation, polymorph form IV is a particularly suitable polymorph of axitinib. Polymorph IV is disclosed for example in US 2006 / 0094763 Al . In specific embodiments, axitinib polymorph IV is used for preparing the implants according to this aspect of the present invention. Additionally, axitinib polymorph IV is also suitable for preparing the implants according any other aspect of the invention, including aspects wherein the solubility of the TKI is not required to be in a certain range, such as the aspect of the invention wherein the hydrated surface area of the implant is at least 25 mm2as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after24 hours of incubation. Axitinib polymorph IV is thus a particular form of axitinib used in all aspects of the present invention.

[0220] The solubility of axitinib polymorph IV is abouttwice the solubility of e.g. axitinib polymorph SAB-I, and at 37°C in PBS with a pH of 7.2 to 7.4 (or ata pH of 7.2) after 5 days of incubation has been determined to be above 0.3 pg / mL, and is at least 0.4 pg / mL under these conditions. In one embodiment, axitinib polymorph IV is used for preparing the implants according to this aspect of the invention requiring a solubility of greater than 0.3 pg / mL as measured in phosphate-buffered saline (PBS) ata pH of 7.2 to 7.4 and 37 °C after five days of incubation but may also be used for preparing implants according to any other aspect of the present invention.

[0221] In certain specific embodiments, the axitinib, specifically the axitinib polymorph IV, contained in or used for preparing the implants according to the present invention alternatively is characterized by a powder X-ray diffraction pattern comprising at least two, such as at least three, or at least four, or at least five of the following peaks at diffraction angles (26) of 8.90, 9.40, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, 26.10 (all values ± 0.2). Particularly, the axitinib, specifically the axitinib polymorph IV, used for preparing the implants according to this aspect of the present invention may be characterized by a powder X-ray diffraction pattern comprising the following peaks at diffraction angles (26) of: 8.90, 12.0, 14.60, 15.75, and 19.30 (all ±0.2), and / or characterized by a DSC peak at about 221 °C at a scan rate of 5°C / min (over a range of 25 to 300 °C).

[0222] In certain embodiments, the axitinib used for preparing the implants according to the present invention is polymorph IV as characterized in US 2006 / 0094763 Al, which discloses axitinib polymorph IV (e.g. in paragraphs

[0021] ,

[0118] and

[0119] , and in claims 3 to 5 of US 2006 / 0094763 Al, also with reference to Figs. 4A and 4B of US 2006 / 0094763 Al). Thus, the axitinib having a solubility of greater than 0.3 pg / mL as measured in phosphate-buffered saline(PBS) ata pH of 7.2 to 7.4 and 37 °C after five days of incubation, specifically the axitinib polymorph IV, used for preparing the implants according to certain embodiments of the present invention may be characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles (26) of 8.9, 14.6, 15.7, and 19.2 (all ± 0.1), or by a powder X-ray diffraction pattern comprising peaks at diffraction angles (26) of 8.9 and 15.7 (all ± 0.1).

[0223] In one embodiment, an implant according to the present invention comprises axitinib, and at least 90%, or at least 95% by weight of the entire axitinib contained in the implant is polymorph IV.

[0224] Polymorph IV has been demonstrated to be chemically and physically stable in an implant according to the invention throughout 6 months.

[0225] Photostability studies with implants containing axitinib polymorph IV have demonstrated that the XRD patterns post-sterilization and after light exposure (visible light of wavelength of 380-700 nm, and UV-A light of wavelength 315 to 400 nm) did not change with respect to the respective XRD patterns at the start of these studies, before light exposure. These results were the same as those obtained with implants containing axitinib polymorph SAB-I.

[0226] Further photostability studies comparing axitinib polymorph IV powder, implants according to the present invention containing axitinib polymorph IV, such implants loaded in needles for injection, and such implant-loaded needles sealed in secondary foil packaging have been conducted using visible light and UV light as described above and have been compared to no light exposure (control). The major impurity that can result from axitinib polymorph IV being exposed to light is a dimerization of axitinib polymorph IV API (while with the axitinib polymorph SAB-I API the two major impurities - although to a lesser extent than with the polymorph IV API - are the dimer and the cis-isomer). The axitinib polymorph IV API powder showed light-induced degradation resulting in impurities (dimer) of above 30% (for both visible and UV light). When axitinib polymorph IV was dispersed in a PEG hydrogel within an implant according to the present invention, less dimerization was observed upon light exposure (both visible and UV light) than for the axitinib polymorph IV API powder itself, namely only about 25% (visible light) and about 14 % (UV light).

[0227] In certain embodiments, the present invention further provides axitinib polymorph IV in a form that is more photostable than axitinib polymorph IV in powder form, such as at least 10%, such as at least 15%, such as at least 20% more stable in visible light than axitinib polymorph IV in powder form after the same exposure time and at the same exposure conditions, and / or such as at least 10%, such as at least 20%, such as at least 30%, such as at least 40% more stable in UV light than axitinib polymorph IV in powder form after the same exposure time and at the same exposure conditions. The term “at least 10%” higher photostability means that at least 10% less total impurities (i.e., mainly dimer) are detected for the axitinib polymorph IV in an implant according to the present invention (such as dispersed in PEG hydrogel), as compared to the amount of impurities (again, mainly dimer)detected for the axitinib polymorph IV API as a powder. The same meaning applies to the other percentages indicated herein. In certain embodiments, exposure to visible light as referred to herein means exposure to light at wavelength 380 to 700 nm, such as for at least 1 day, or for at least 2 days, such as for at least 0.5 million lux hours / m2, such as for at least 1 million lux hours / m2, such as for at least 1.2 million lux hours / m2. In certain embodiments, exposure to UV light means exposure to UV A light at wavelength 315 to 400 nm, such as for at least 4 hours, such as for at least 8 hours, such as for at least 10 hours, such as for at least 100 watt hours / m2, or at least 150 hours / m2, or at least 200 hours / m2.

[0228] It has been demonstrated that axitinib polymorph IV withstands significant photodegradation (mainly dimerization) under conditions required to manufacture implants containing axitinib polymorph IV according to the present invention. In particular, once axitinib polymorph IV is included in the hydrogel, such as the PEG hydrogel, dimerization is significantly reduced. Furthermore, once an implant is loaded into a needle for injection, this further significantly shields the implant and thus the API to protect the API during storage and shipping.

[0229] In certain specific embodiments, an implant of the invention contains axitinib polymorph IV in an amount of from 300 to 600 pg, such as from about 360 pg to about 562.5 pg, or from about 405 pg to about 495 pg, or about 450 pg. In certain other specific embodiments, an implant of the invention contains axitinib polymorph IV in an amount of from about480 pgto about 750 pg, or from about 540 pg to about 660 pg, or about 600 pg.

[0230] In other embodiments, further axitinib polymorphic forms that also have a solubility of above 0.3 pg / mL measured at 37°C in PBS with a pH of 7.2 to 7.4 after 5 days of incubation may be used in this aspect of the invention.

[0231] In terms of the manufacturing of an implant according to the invention (any aspect thereof), the manufacturing process and conditions, as well as the composition / amount of the ingredients of the implant, are generally independent of which axitinib polymorphic form is used. Therefore, generally, all amounts and compositions, as well as all manufacturing steps and conditions disclosed herein with respect to a TKI, or axitinib specifically, equally apply to any of the axitinib polymorphs disclosed herein, specifically axitinib polymorph IV and axitinib polymorphs SAB-I or XLI.

[0232] Axitinib co-crystals for use in the present invention:

[0233] In certain embodiments of the present invention, an implant contains axitinib in the form of an axitinib co-cry stal. Specifically, in the aspect of the present invention in which the TKI (such as axitinib) has a solubility of greater than 0.3 pg / mL as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation, one or more axitinib co-crystals may be used (including those further disclosed herein) in the implants according to the present invention, as long as they fulfill this solubility criterion. Alternatively, if axitinib co-crystals do not meet this solubility criterion, they may still be used in all other aspects of the present invention in which this solubility criterion does not have to be fulfilled.

[0234] Axitinib co-crystals with carboxylic acids as co-formers are particularly suitable to be used in the present invention, as the carboxylic acid generally increases the hydrophilicity and thereby the solubility of the axitinib is increased. Any carboxylic acids are generally suitable for forming co-crystals with axitinib in the context of the present invention.Particular carboxylic acids that may be used for forming axitinib co-crystals are Ci to Ci2carboxylic acids, such as C2to Cio carboxylic acids, and specifically C2, C3, C4, C5, C6, C7, C8, C9or Cio carboxylic acids. The carboxylic acids may be saturated or unsaturated. They may contain one or more aryl groups, including heteroaryl groups. The carboxylic acids may either be free of, or may contain one or more additional functional groups, in particular functional groups that either further increase the hydrophilicity, or at least do not significantly decrease the hydrophilicity. Suitable such groups are for example hydroxyl groups. If the carboxylic acid that forms a co-crystal with axitinib can have one or more enantiomeric forms or one or more other configurations (such as cis / trans), it can be present in the co-crystal in any enantiomeric form and / or in any configuration. Co-crystals of axitinib are disclosed for example in B-Y Ren et al., Cryst Eng Comm. 2021, 23, 5504-5515.

[0235] Specific examples of carboxylic acids suitable for forming a co-crystal with axitinib is one or more of citric acid, fumaric acid, (+)-L- or (-)-D tartaric acid, glutaric acid, (trans-or cis) cinnamic acid, suberic acid, succinic acid, adipic acid, pimelic acid, salicylic acid. This list is not intended to be limiting, and further carboxylic acids or other compounds as mentioned above maybe used in the present invention to form axitinib co-crystals. In the cocrystal lattice also more than one molecule of co-former, such as a carboxylic acid, may be present per one molecule of axitinib. In such a case, the more than one molecule of co-former may be the same co-former, such as the same carboxylic acid, or may be different co-formers, such as different carboxylic acids.

[0236] Axitinib co-crystals can be prepared for example by crystallizing the co-crystals from a solution or slurry, for example by combining a certain amount of axitinib and the chosen co-former in a 1 : 1 molar ratio, adding a solvent (such as acetonitrile), and stirring the resulting slurry for a certain number of days (such as 3 days) and optionally at elevatedtemperature (such as at least 30 °C, or at least 40 °C). After that, the solids can be isolated e.g. by filtration or centrifugation and analyzed. Alternatively, the co-crystals can also be prepared by seeding (once a desired co-crystal is already available for a seeding procedure) co-crystals in a low amount of solvent, and allowing the seeded mixture to stir for a number of days (such as at least 1 day) and optionally at elevated temperature (again, such as at least 30 °C, or at least 40 °C). After that, the solids can be isolated as described above.

[0237] In certain embodiments, an axitinib co-crystal may have a solubility that is at least 2 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 75 times, or at least 100 times the solubility of axitinib free base.

[0238] In particular embodiments, an axitinib co-crystal has a solubility in PBS at pH 7.4 after 24 hours at 37 °C of at least 10 pg / mL, such as at least 12 pg / mL, at least 15 pg / mL, or at least 18 pg / mL. An axitinib co-crystal with citric acid has a mean solubility in PBS at pH 7.4 after24 hours at37 °C of about 19 pg / mL; an axitinib co-crystal with fumaric acid has a mean solubility in PBS atpH 7.4 after 24 hours at37 °C of about 12 pg / mL; and an axitinib co-crystal with (+)-L-tartaric acid has amean solubility in PBS at pH 7.4 after 24 hours at 37 °C of between about 19 and 20 pg / mL.

[0239] Axitinib derivatives and prodrugs for use in the present invention:

[0240] In all aspects of the present invention, derivatives or prodrugs of the TKI, such as axitinib, may be used in the implants. However, in the aspect of the present invention in which the solubility of the TKI is greater than 0.3 pg / mL as measured in phosphate-buff ered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation, prodrugs are particularly suitable if they increase the solubility of the parent TKI compound. In embodiments of the invention where the TKI is axitinib, axitinib prodrugs with increased solubility as compared to the axitinib free base are particularly suitable. The axitinib pro drug; are converted in vivo to axitinib.

[0241] Prodrugs of axitinib with increased solubility may be derivatives of axitinib, in which one or more atoms or moieties of the axitinib are replaced by one or more substituent groups which render the resulting derivative (i.e., the prodrug) more soluble, such as by the introduction of hydrophilic groups in these substituent groups. Upon immersion of physiological environment, which can be simulated by in vitro tests, these substituent group(s) may be enzymatically or chemically removed, thus releasing the parent drug molecule. In the present invention, examples for particularly suitable axitinib prodrugs are those wherein the axitinib molecule is functionalized at one or more of the nitrogen atoms of the axitinib free base. For example, in an axitinib prodrug for use according to the presentinvention one or more of the nitrogen atoms in the axitinib free base may be independently substituted with one or more of the following groups: acyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, arylthiocarbonyl, alkylcarbamoyl, arylcarbamoyl, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted a-aminoalkanoyl, an acyl group derived from a natural or an unnatural amino acid with or without substitution, an acyl group of a peptide residue, phosphonyl, phosphinyl, aminophosphinyl, alkylaminophosphinyl, sulfonyl, cycloalkane-carbonyl, heterocycloalkanecarbonyl, alkoxy carbonyl, aryloxy carbonyl, heteroalkoxy carbonyl, heteroaryloxy carbonyl, and an O-substituted hydroxymethyl group with or without substituents.

[0242] In certain embodiments, an axitinib prodrug for use in the present invention is a compound of general formula (I) depicted below, or a salt or solvate thereof:

[0243] (I)

[0244] wherein:

[0245] X1is selected from N or N+Y1;

[0246] X2is selected from NH or NY2;

[0247] X3is selected from NH or NY3;

[0248] Y1is selected from -CH2OCO(OCH2CH2)n'OM'; or -CH2OCO(CH2CH2O)nlaZ'; or -CH2OCO(CH2)nlbCOOH;

[0249] Y2is selected from -CH2OCO(OCH2CH2)n2OM2; or -CH2OCO(CH2CH2O)n2aZ2; or -CH2OCO(CH2)n2bCOOH;

[0250] Y3is selected from -CH2OCO(OCH2CH2)n3OM3; or -CH2OCO(CH2CH2O)n3aZ3; or -CH2OCO(CH2)n3bCOOH;

[0251] n1, nla, nlb, n2n2a, n2b, n3, n3aand n3bare independently 0 or an integer from 1 to 8;

[0252] M1, M2, M3, Z1, Z2and Z3are independently selected from H, optionally substituted Ci-6 alkyl and optionally substituted aryl;

[0253] wherein at least one of X1, X2and X3is not N or NH;

[0254] wherein at least one of Y1, Y2or Y3is / are the respective -CH2OCO(CH2CH2O)nZ.

[0255] In certain other embodiments, in the above general formula (I) Y1, Y2and Y3are independently selected from the respective -(CH2)p1OCO(O(CH2)p2)n1OM; or-(CH^p^CO CH^O^ CH^Z; or -(CH^piOCO CH^qiCOOH; wherein p1, plaand p2are independently selected from an integer from 1 to 4, and q1is independently selected from an integer from 0 to 4, with the other meanings as defined above for formula (I).

[0256] In certain embodiments, the following prodrugs are suitable in the present invention, wherein in the above formula (I):

[0257] X1is N+Y1; X2is NH; X3is NH; and Y1is -CH2OCO(CH2CH2O)nlZ' or -CH2OCO(CH2)nlbCOOH, or:

[0258] X1is N; X2is NY2; X3is NH; and Y2is -CH2OCO(CH2CH2O)n2aZ2or -CH2OCO(CH2)n2bCOOH, or:

[0259] X1is N; X2is NH; X3is NY3; and Y3is -CH2OCO(CH2CH2O)n3aZ3or -CH2OCO(CH2)n3bCOOH.

[0260] In certain embodiments, in the above formula (I):

[0261] n10, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0262] n2is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0263] n3is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0264] nlais 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0265] n2ais 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0266] n3ais 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0267] nlbis 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0268] n2bis 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0269] n3bis 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0270] In certain embodiments, in the above formula (I):

[0271] M1is methyl, ethyl, propyl or phenyl;

[0272] M2is methyl, ethyl, propyl or phenyl;

[0273] M3is methyl, ethyl, propyl or phenyl;

[0274] Z1is methyl, ethyl, propyl or phenyl;

[0275] Z2is methyl, ethyl, propyl or phenyl;

[0276] Z3is methyl, ethyl, propyl or phenyl.

[0277] In certain further embodiments, n1, n2or n3is 2, 3 or 4, and / or nla, n2aor n3ais 2, 3 or 4 and / or nlb, n2bor n3bis 2, 3 or 4.

[0278] In certain specific embodiments, an axitinib prodrug to be used in the implants according to the present invention is selected from : axitinib-N-succinoyloxymethyl prodrug, axitinib-N-mPEG-oxymethyl prodrug, including but not limited to axitinib-N-m(PEG)i-oxymethyl, axitinib-N-m(PEG)2-oxymethyl, axitinib-N-m(PEG)3-oxymethyl, axitinib-N-m(PEG)4-oxymethyl, or a salt or solvate thereof, as shown below.

[0279] Axitinib prodrugs, especially prodrugs with a hydrophilic substituent as disclosed herein, may exhibit a higher solubility than axitinib free base. Such prodrugs may have a solubility that is at least 2 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 75 times, at least 100 times, at least 150 times, at least 200 times, at least 250 times, or at least 500 times, or at least 1000 times the solubility of axitinib free base. Without wishing to be limited by this theory, the increased solubility of the axitinib prodrugs as disclosed herein may result in a faster release of axitinib from the implants according to the invention, as compared to comparative implants wherein the axitinib that is present in the implant (such as axitinib free base) has a lower solubility than the axitinib prodrugs.

[0280] Axitinib prodrugs for use in implants of the present invention may have a solubility in PBS at pH 7.4 after 24 hours at 22 °C of at least 50 pg / mL, or at least 90 pg / mL, or at least 150 pg / mL, or at least 200 pg / mL.

[0281] The following are exemplary axitinib prodrugs to be used in implants of the present invention:

[0282] axitinib-N-succinoyloxymethyl prodrug (total Mw: 516.57)

[0283] solubility in PBS at pH 7.2 to 7.4 after 24 hours incubation at 22 °C: 217.4 pg / mL

[0286] axitinib-N-m(PEG)4-oxymethyl prodrug (total Mw: 634.74)

[0287] solubility in PBS at pH 7.2 to 7.4 after 24 hours incubation at 22 °C: 99.37 pg / mL

[0288] Axitinib-N-m(PEG)i-oxymethyl prodrug. lUPACName: 3 -Methoxy -propionic acid 6-(2-methylcarbamoyl-phenylsulfanyl)-3-((E)-2- -pyridin-2-yl-vinyl)-indazol-l-ylmethyl ester

[0289] (total Mw: 502.28)

[0290]

[0291] Axitinib-N-m(PEG)2-oxymethyl prodrug. IUPAC Name: 3 -(2 -Meth oxy -ethoxy )-propionic acid 6-(2-methylcarbamoyl-phenylsulfanyl)-3-((E)-2-pyridin-2-yl-vinyl)-indazol-l-ylmethylester

[0292] (total Mw: 546.63)

[0293] Axitinib-N-m(PEG)3-oxymethyl prodrug. IUPAC Name: 3 -[2-(2 -Methoxy-ethoxy )-ethoxy]-

[0294] propionic acid 6-(2-methylcarbamoyl-phenylsulfanyl)-3 -((E)-2-pyridin-2-yl-vinyl)-indazol-l-ylmethyl ester (total Mw: 590.68)

[0295] Suitable axitinib prodrugs for use in the implants according to the present invention as well as their synthesis and properties are disclosed in co-pending international application PCT / US2023 / 035121 and in co-pending international application PCT / US2022 / 046750(published as WO 2023 / 064578 Al), which are incorporated by reference. Further suitable axitinib prodrugs for use in the implants according to the present invention are disclosed in US 2021 / 0078970. All of the axitinib prodrugs disclosed in any of these references, but not limited to these, are generally suitable for use in the present invention.

[0296] Solubility

[0297] The solubility of the TKI, and in particular the solubility of axitinib in certain embodiments of the present invention, is one of the factors that influences the release profile of axitinib from an implant according to the present invention. The solubility of axitinib free base, in particular the polymorph SAB-I, is relatively low in physiologic environment, or similar aqueous solvent systems such as PBS, which limits the release rate of the drug from implants containing hydrogel where the release is solubility and diffusion-driven.

[0298] In particular embodiments the present invention therefore relates to sustained release biodegradable ocular implants comprising a TKI, wherein the solubility of the TKI, such as axitinib, including any forms of axitinib as disclosed herein, is 0.3 pg / mL or greater than 0.3 pg / mL, such as at least 0.4 pg / mL, or at least 0.5 pg / mL, or at least 0.6 pg / mL, at least 0.7 pg / mL, at least 0.8 pg / mL, at least 1 pg / mL, at least 2.5 pg / mL, at least 5 pg / mL, at least 10 pg / mL, at least 20 pg / mL, at least 50 pg / mL, at least 100 pg / mL, at least 150 pg / mL, or at least 200 pg / mL in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation. A pH value of 7.2 to 7.4 as mentioned herein includes the individual values of 7.2, 7.3 and 7.4. In particular embodiments of the present invention, wherein the TKI is axitinib, the solubility of the axitinib used in the sustained release biodegradable ocular implants of the invention is higher than the solubility of axitinib polymorph SAB-I, such as at least 1.5 times the solubility of axitinib polymorph SAB-I, such as at least about 2 times the solubility of axitinib polymorph SAB-I, such as at least 2.3 times the solubility of axitinib polymorph SAB-I.

[0299] In particular embodiments, the solubility of the TKI such as axitinib in any and all embodiments of the invention which refer to it is 0.3 pg / mL or greater (such as at least 0.4 pg / mL, or at least 0.5 pg / mL, or at least 0.6 pg / mL, at least 0.7 pg / mL, at least 0.8 pg / mL, at least 1 pg / mL, at least 2.5 pg / mL, at least 5 pg / mL, at least 10 pg / mL, at least 20 pg / mL, at least 50 pg / mL, at least 100 pg / mL, at least 150 pg / mL, or at least 200 pg / mL) in PBS at a pH of 7.2 and 37 °C after five days of incubation. Axitinib forms (including axitinib polymorphs, co-crystals and prodrugs as disclosed herein) meeting any of these solubility ranges thus have a higher solubility than axitinib (free base) polymorph SAB-I, which has a solubility under these same conditions of around 0.2 pg / mL and below 0.3 pg / mL.Specifically, axitinib polymorph SAB-I has an equilibrium solubility in PBS after five days at a pH of 7.4 and 37 °C of from about 0.191 to about 0.252 pg / mL (measured by UPLC), or of an average of about 0.223 pg / mL under these conditions, depending on its particle size, i.e., whether or not it is in micronized form (or the degree of micronization). For example, non-micronized, micronized, and super-micronized axitinib polymorph SAB-I has an equilibrium solubility of about 0.191, about 0.226, and about 0.252 pg / mL (measured by UPLC), respectively, in PBS after five days at a pH of 7.4 and 37 °C. Polymorph IV is a particularly suitable axitinib polymorph for use in the present invention in all its aspects. Its solubility is about two times the solubility of e.g. polymorph SAB-I, as disclosed herein. Specifically, axitinib polymorphIV has an equilibrium solubility in PBS after 5 days at a pH of 7.4 and 37 °C of about 0.435 pg / mL (measured by UPLC), e.g. when in micronized form. Thus, in certain embodiments, the implants of the present invention comprise axitinib polymorph IV. In certain embodiments, at least 90%, such as at least 95% by weight of the axitinib contained in an implant of the invention is axitinib polymorph IV.

[0300] Amount / dose

[0301] The TKI is present in the implants of the invention in a range of doses. The amount of TKI contained in an implant is indicated herein in the units “ pg” or “mg” . In case the TKI used according to the present invention is axitinib, the amounts / doses of axitinib indicated herein refer to the amounts (in pg or mg, as the case may be) of axitinib free base, including any (anhydrous) axitinib polymorphs such as those that are further disclosed herein, particularly polymorph IV. In case axitinib salts, co-crystals, derivatives or prodrugs are used (which have a different molecular weight than axitinib free base), the amount indicated is the corresponding amount of axitinib free base, unless otherwise stated.

[0302] The TKI, such as axitinib, is contained in the implant of the invention generally in a range of doses of at least 150 pg, such as from about 150 pg to about 1000 pg, from about 150 pg to about 900 pg, orfrom about200 pgto about800 pg, or from about 250 pgto about 700 pg, orfrom about 300 to about 650 pg or from about 400 to about 500 pg or about 450 pg . Any TKI, such as axitinib, amount within these ranges may be contained in an implant of the invention. In case axitinib is used in a form other than the free base, an implant of the invention may contain a dose that corresponds to the mentioned doses of axitinib free base. For the purpose of the present disclosure, when talking about TKI, such as axitinib, doses contained in an implant, all mentioned values are meant to include a variance of +25% and -20%, or a variance of + / - 10%.

[0303] In certain particular embodiments, doses of axitinib (which doses are meant to refer to axitinib free base, or the respective amount of another form of axitinib, such as an axitinib co-crystal or prodrug corresponding to these recited amounts of axitinib free base) contained in an implant of the invention are:

[0304] a range from about 120 pgto about 187.5 pg, or from about 135 pgto about 165 pg, or about 150 pg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 150 pg)

[0305] a range from about 240 pgtoabout375 pg, orfrom about270 pgto about330 pg, or about 300 pg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 300 pg)

[0306] a range from about 360 pg to about 562.5 pg, or from about 400 pg to about 500 pg, or from about 405 pg to about 495 pg, or about 450 pg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 450 pg)

[0307] a range from about 480 pgto about 750 pg, orfrom about 540 pgto about 660 pg, or about 600 pg (i.e., including a variance of +25% and -20%, or a variance of + / - 10% of 600 pg)

[0308] In one particular embodiment, a dose of axitinib contained in one implant of the invention is from 100 to 200 pg, or about 150 pg. In further particular embodiments, the axitinib in such implants is in the form of axitinib free base.

[0309] In one particular embodiment, a dose of axitinib contained in one implant of the invention is from 200 to 400 pg, such as from 250 to 350 pg, or about 300 pg. In further particular embodiments, the axitinib in such implants is in the form of axitinib free base.

[0310] In one particular embodiment, a dose of axitinib contained in one implant of the invention is from 300 to 600 pg, such as from about 360 pgto about 562.5 pg, orfrom 400 to 500 pg, oris about 450 pg. In further particular embodiments, the axitinib in such implants is in the form of axitinib free base.

[0311] In another particular embodiment, a dose of axitinib contained in one implant of the invention is from about 400 to 800 pg, from about 480 pg to about 750 pg, or from 500 to 700 pg, or is about 600 pg. In further particular embodiments, the axitinib in such implants is in the form of axitinib free base.

[0312] In another particular embodiment, a dose of axitinib contained in one implant of the invention is from about 400 to 1000 pg, from about 480 pgto about 800 pg, from about 480 pg to about 750 pg, orfrom 500 to 700 pg, or from 400 to 500 pg or is about 600 pg or about450 pg. In further particular embodiments, the axitinib in such implants is in the form of axitinib free base.

[0313] In particular embodiments, a dose of axitinib contained in one implant of the invention is from about 250 to about 750 pg, such as from about 300 to about 600 pg, such as from about 350 to about 550 pg, such as from about 380 to about 520 pg, such as from about 420 to about 480 pg, such as from about 400 to about 500 pg, such as from about 420 to about 480 pg, such as about 450 pg. In particular embodiments, a target (also referred to as “label”) dose of axitinib, such as axitinib polymorph IV, in an implant of the present invention is 450 pg, which means an actual amount of - 20% and +25% thereof, i.e., from about 360 pg to about 562.5 pg.

[0314] In most particular embodiments, an implant according to the present invention contains axitinib in the form of polymorph IV in a dose of from about 400 pg to about 500 pg, such as from about 405 pg to about 495 pg, such as from about 410 pg to about 490 pg, or from about 420 pg to about 490 pg, such as from about 420 pg to about 480 pg, such as from about430 pgto about480 pg, such as from about 425 pgto about475 pg, such as from about 430 pgto about470 pg, such as from about 440 pgto about 460 pg, such as about 450 pg. In an implant of the present invention having a nominal (i.e., theoretical / label) content of 450 pg or about 450 pg axitinib (specifically, axitinib polymorph IV), the actual (assay) amount of axitinib contained in the implant may vary within the limits of the ranges disclosed in the preceding sentence.

[0315] If axitinib is notin the form of the free base, but in the form of e.g. a co-crystal or prodrug, one implant may contain an amount of such other axitinib form that corresponds to the mentioned doses of axitinib free base.

[0316] The disclosed amounts of TKI, such as axitinib, including the mentioned variances, refer to both the final content of the active principle in the implant, as well as to the amount of active principle used as a starting component per implant when manufacturing the implant. The total dose of the TKI, such as axitinib, to be administered to a patient, may in certain embodiments be contained in two or more implants administered concurrently as further disclosed herein. The dose may also be contained in an implant according to the invention that is a multi-filament implant, i.e., is made of several filaments combined and optionally stretched and twisted to form one composite strand as further disclosed herein.

[0317] TKI particles

[0318] The TKI, such as axitinib, is contained in the implant of the invention and is dispersed or distributed in the hydrogel that is comprised of a polymer network as furtherdisclosed herein. In certain embodiments, the particles are homogeneously or essentially homogeneously dispersed in the hydrogel. The hydrogel may prevent the particles from agglomerating and may provide a matrix for the particles which holds them in the desired location in the eye while gradually releasing drug.

[0319] In certain embodiments of the invention, the TKI particles such as the axitinib particles may be microencapsulated. The term “microcapsule” (also referred to as “microparticle”) is sometimes defined as a roughly spherical particle with a size varying between e.g. about 50 nm to about 2 mm. Microcapsules have at least one discrete domain (or core) of active agent encapsulated in a surrounding material, sometimes also referred to as a shell. One suitable agent (without limiting the present disclosure to this) for microencapsulating the TKI, such as the axitinib, if that is desired for the purposes of the present invention, is poly (lactic-co-glycolic acid).

[0320] In other embodiments, the TKI particles comprise additional compounds beside the TKI. These may be for example be processing aids, stabilizers, fillers, etc. Sometimes active agents are routinely stabilized by the supplier by adding minute amounts of e.g. an antioxidant or other stabilizer, which may also be the case for the TKI such as axitinib particles as used herein.

[0321] However, in certain embodiments, the TKI particles such as the axitinib particles are not microencapsulated and / or do not comprise any additional compounds, but are dispersed in the hydrogel and thus in the implant of the invention as they are, i.e., as received from a supplier, i.e., without being further admixed to or adjoined with or microencapsulated by another material.

[0322] In one embodiment, the TKI particles, such as the axitinib particles, may be micronized or even nanonized particles. Micronization refers to the process of reducing the average diameter of particles of a solid material. In another embodiment, the TKI particles, such as the axitinib particles, may not be micronized. In the composite materials field, particle size is known to affect the mechanical properties when combined with a matrix, with smaller particles providing superior reinforcement for a given mass fraction. Thus, a hydrogel matrix filled with micronized TKI particles may have improved mechanical properties (e.g. brittleness, strain to failure, etc.) compared to a similar mass fraction of larger TKI particles. Such properties are important in manufacturing, during implantation, and during degradation of the implant. Micronization may also promote a more homogeneous distribution of the active ingredient in the chosen dosage form or matrix. The particle size distribution can begenerally measured by methods known in the art, including sieving, laser diffraction or dynamic light scattering.

[0323] In certain embodiments, the TKI, such as the axitinib, particles have a d90 particle size of less than 10 pm, or less than 8 pm, or less than 7 pm, or 7.5 pm or less, or 6.5 pm or less, or 5 pm or less, or less than 1 pm, or less than 0.5 pm, or less than 0.4 pm as determined by laser diffraction.

[0324] In certain embodiments, the TKI, such as the axitinib, particles have a d50 particle size of less than 5 pm, less than 3 pm, less than 2.6 pm, less than 2 pm, less than 1.5 pm, less than 1 pm, less than 0.5 pm, less than 0.25 pm, or less than 0.2 pm, as determined by laser diffraction. In specific embodiments, the d50 particle size of the TKI particles, such as the axitinib particles, contained in an implant of the invention is 0.15 pm or less, as determined by laser diffraction. In the latter case, the particles may be referred to herein as “nanonized particles”.

[0325] In certain embodiments, the TKI, such as the axitinib, particles have a dlO particle size of less than 1 pm, or less than 0.5 pm, or 0.25 pm or less, or 0.2 pm or less, or less than 0.1 pm as determined by laser diffraction.

[0326] In specific embodiments, the TKI present in the implants of the invention is axitinib free base (any polymorphic form as disclosed herein), wherein the axitinib particles have a dlO particle size of less than 8 pm, a d50 particle size of less than 20 pm, and / or a d90 particle size of less than 50 pm. These particles may sometimes be referred to herein as “non-micronized particles”.

[0327] In other specific embodiments, the TKI present in the implants of the invention is axitinib free base (any polymorphic form as disclosed herein, including axitinib polymorph IV), wherein the axitinib particles have a dlO particle size of less than 0.25 pm, a d50 particle size of less than 3 pm or less than 2.6 pm, and a d90 particle size of less than 8 pm or less than 6.5 pm. These particles may also be referred to herein as “micronized particles”. In particular embodiments, the particle size of axitinib, particularly axitinib polymorph IV, contained in implants of the present invention, is as follows: a dlO particle size of less than 0.25 pm, a d50 particle size of less than 2.6 pm, and a d90 particle size of less than 8 pm as determined by laser diffraction.

[0328] In other specific embodiments, the TKI present in the implants of the invention is axitinib free base (any polymorphic form as disclosed herein), wherein the axitinib particles have a dlO particle size of less than 0.2 pm, a d50 particle size of less than 1.5 pm, and a d90particle size of less than 5 pm as determined by laser diffraction. These particles may also be referred to herein as “super micronized particles”.

[0329] In other specific embodiments, the TKI present in the implants of the invention is axitinib free base (any polymorphic form as disclosed herein, particularly including polymorph IV), wherein the axitinib particleshave a dlO particle size of less than 0.1 pm, a d50 particle size of less than 0.2 pm, and a d90 particle size of less than 0.4 pm as determined by laser diffraction. These particles may also be referred to herein as “nanonized particles”.

[0330] Generally, micronized TKI such as axitinib particles may be purchased per specification from the supplier, or may be prepared e.g. according to an exemplary procedure for axitinib as disclosed in WO 2016 / 183296 Al , Example 13: 1800 mL of sterile Water For Injection (WFI) is measured into a 2 L beaker and placed on a stir plate stirring at 600 RPM with a stir bar, creating a large WFI vortex in the center of the beaker. One 60 mL BD syringe containing axitinib in ethanol is placed on a syringe pump which is clamped above the WFI beaker. A hypodermic needle (21G, BD) is connected to the syringe and aimed directly into the center of the vortex for dispensation of the axitinib solution. The syringe pump is then run at 7.5 mL / min in order to add the axitinib solution dropwise to the WFI to precipitate micronized axitinib. After micronization, the axitinib is filtered, e.g. through a 0.2 pm vacuum filter and rinsed with WFI. After filtration, the axitinib powder is collected from the filter e.g. by using a spatula and vacuum dried for an extended period of time, such as for about 12 or about 24 hours, in order to remove excess solvent. Another exemplary method of micronizing axitinib is disclosed in Example 9 of WO 2017 / 091749. The described method of micronization is not limiting, and other methods of micronizing the active agent such as axitinib may equally be used. The disclosed micronization method (or other methods) may also be used for other TKI than axitinib.

[0331] The polymer network:

[0332] In certain embodiments, the hydrogel may be formed from precursors having functional groups that form crosslinks to create a polymer network. These crosslinks between polymer strands or arms may be chemical (i.e., maybe covalent bonds) and / or physical (such as ionic bonds, hydrophobic association, hydrogen bridges etc.) in nature.

[0333] The polymer network may be prepared from precursors, either from one type of precursor or from two or more types of precursors that are allowed to react. Precursors are chosen in consideration of the properties that are desired for the resultant hydrogel. There are various suitable precursors for use in making the hydrogels. Generally, any pharmaceuticallyacceptable and crosslinkable polymers forming a hydrogel may be used for the purposes of the present invention. The hydrogel and thus the components incorporated into it, including the polymers used for making the polymer network, should be physiologically safe such that they do not elicit e.g. an immune response or other adverse effects. Hydrogels may be formed from natural, synthetic, or biosynthetic polymers.

[0334] Natural polymers may include glycosaminoglycans, polysaccharides (e.g. dextran), polyaminoacids and proteins or mixtures or combinations thereof.

[0335] Synthetic polymers may generally be any polymers that are synthetically produced from a variety of feedstocks by different types of polymerization, including free radical polymerization, anionic or cationic polymerization, chain-growth or addition polymerization, condensation polymerization, ring-opening polymerization etc. The polymerization may be initiated by certain initiators, by light and / or heat, and may be mediated by catalysts.

[0336] Generally, for the purposes of the present invention one or more synthetic polymers of the group comprising one or more units of polyalkylene glycol, such as polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers, or polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-gly colic acid, random or block copolymers or combinations / mixtures of any of these can be used, while this list is not intended to be limiting.

[0337] To form covalently crosslinked polymer networks, the precursors may be covalently crosslinked with each other. In certain embodiments, precursors with at least two reactive centers (for example, in free radical polymerization) can serve as crosslinkers since each reactive group can participate in the formation of a different growing polymer chain.

[0338] The precursors may have biologically inert and hydrophilic portions, e.g., a core. In the case of a branched polymer, a core refers to a contiguous portion of a molecule joined to arms that extend from the core, where the arms carry a functional group, which is often at the terminus of the arm orbranch. Multi-armed PEG precursors are examples of such precursors and are further disclosed herein below.

[0339] Thus, a hydrogel for use in the present invention can be made e.g. from one multiarmed precursor with a first (set of) functional group(s) and another multi-armed precursor having a second (set of) functional group(s). By way of example, a multi-armed precursor may have hydrophilic arms, e.g., polyethylene glycol units, terminated with primary amines (nucleophile), or may have activated ester end groups (electrophile). The polymer networkaccording to the present invention may contain identical or different polymer units crosslinked with each other.

[0340] Certain functional groups can be made more reactive by using an activating group. Such activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N-hydroxysuccinimidyl ester, succinimidyl ester, epoxide, aldehyde, maleimides, imidoesters, acrylates and the like. The N-hydroxysuccinimide esters (NHS) are useful groups for crosslinking of nucleophilic polymers, e.g., primary amine-terminated or thiol-terminated polyethylene glycols. An NHS-amine crosslinking reaction may be carried out in aqueous solution and in the presence of buffers, e.g., phosphate buffer (pH 5.0-7.5), triethanolamine buffer (pH 7.5-9.0), borate buffer (pH 9.0-12), or sodium bicarbonate buffer (pH 9.0-10.0).

[0341] In certain embodiments, each precursor may comprise only nucleophilic or only electrophilic functional groups, so long as both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if a crosslinker has only nucleophilic functional groups such as amines, the precursor polymer may have electrophilic functional groups such asN-hydroxysuccinimides. On the other hand, if a crosslinker has electrophilic functional groups such as sulfosuccinimides, then the functional polymer may have nucleophilic functional groups such as amines or thiols. Thus, functional polymers such as proteins, poly (allyl amine), or amine-terminated di-or multifunctional polyethylene glycol) can be also used to prepare the polymer network of the present invention.

[0342] In one embodiment a first reactive precursor has about 2 to about 16 nucleophilic functional groups each (termed functionality), and a second reactive precursor allowed to react with the first reactive precursor to form the polymer network has about 2 to about 16 electrophilic functional groups each. Reactive precursors having a number of reactive (nucleophilic or electrophilic) groups as a multiple of 4, thus for example 4, 8 and 16 reactive groups, are particularly suitable for the present invention. Any number of functional groups, such as includingany of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups, is possible for precursors to be used in accordance with the present invention, while ensuring that the functionality is sufficient to form an adequately crosslinked network.

[0343] PEG hydrogels:

[0344] In a certain embodiments of the present invention, the polymer network forming the hydrogel contains polyethylene glycol (PEG) units. PEGs are known in the art to form hydrogels when crosslinked, and these PEG hydrogels are suitable for pharmaceuticalapplications e.g. as matrix fordrugs intended to be administered to all parts of the human or animal body.

[0345] The polymer network of the hydrogel implants of the present invention may comprise one or more multi-arm PEG units having from 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7 or 8 arms. The PEG units may have a different or the same number of arms. In certain embodiments, the PEG units used in the hydrogel of the present invention have 4 and / or 8 arms. In certain particular embodiments, a combination of 4- and 8-arm PEG units is utilized.

[0346] The number of arms of the PEG used contributes to controlling the flexibility or softness of the resulting hydrogel. For example, hydrogels formed by crosslinking 4-arm PEGs are generally softer and more flexible than those formed from 8-arm PEGs of the same molecular weight. In particular, if stretching the hydrogel prior to or after drying as disclosed herein below in the section relating to the manufacture of the implant is desired, a more flexible hydrogel maybe used, such as a 4-arm PEG, optionally in combination with another multi-arm PEG, such as an 8-arm PEG as disclosed above.

[0347] In certain embodiments of the present invention, polyethylene glycol units used as precursors have an average molecular weight in the range from about 2,000 to about 100,000 Daltons, or in a range from about 10,000 to about 60,000 Daltons, or in a range from about 15,000 to about 50,000 Daltons. In certain particular embodiments the polyethylene glycol units have an average molecular weight in a range from about 10,000 to about 40,000 Daltons, or of about 20,000 Daltons. PEG precursors of the same average molecular weight may be used, or PEG precursors of different average molecular weight may be combined with each other. The average molecular weight of the PEG precursors used in the present invention is given as the number average molecular weight (Mn), which, in certain embodiments, may be determined by MALDI.

[0348] In a 4-arm PEG, each of the arms may have an average arm length (or molecular weight) of the total molecular weight of the PEG divided by 4. A 4a20kPEG precursor, which is one precursor that can be utilized in the present invention thus has 4 arms with an average molecular weight of about 5,000 Daltons each. An 8a20k PEG precursor, which may be used in addition to the 4a20kPEG precursor in the present invention, thus has 8 arms each having an average molecular weight of 2,500 Daltons. Longer arms may provide increased flexibility as compared to shorter arms. PEGs with longer arms may swell more as compared to PEGs with shorter arms. A PEG with a lower number of arms also may swell more and may be more flexible than a PEG with a higher number of arms. In certain particular embodiments, combinations ofPEG precursors with different numbers of arms, such as a combination of a4-arm PEG precursor and an 8-arm precursor, may be utilized in the present invention. In addition, longer PEG arms have higher melting temperatures when dry, which may provide more dimensional stability during storage. For example, an 8-arm PEG with a molecular weight of 15,000 Dalton crosslinked with trilysine may not be able to maintain a stretched configuration at room temperature, whereas a 4-arm 20,000 Dalton PEG crosslinked with an 8-arm 20,000 Dalton PEG may be dimensionally stable in a stretched configuration at room temperature.

[0349] When referring to a PEG precursor having a certain average molecular weight, such as a 15kPEG- or a 20kPEG-precursor, the indicated average molecular weight (i.e., a Mn of 15,000 or 20,000, respectively) refers to the PEG part of the precursor, before end groups are added (“20k” here means 20,000 Daltons, and “15k” means 15,000 Daltons - the same abbreviation is used herein for other average molecular weights of PEG precursors). In certain embodiments, the Mn of the PEG part of the precursor is determined by MALDI. The degree of substitution with end groups as disclosed herein may be determined by means of 'H-NMR. after end group functionalization.

[0350] In certain embodiments, electrophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are N-hydroxysuccinimidyl (NHS) esters, including but not limited to: “SAZ” referring to a succinimidylazelate end group, “SAP” referringto a succinimidyladipate end group, “SG” referring to a succinimidylglutarate end group, and “SS” referringto a succinimidylsuccinate end group.

[0351] In certain embodiments, nucleophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are amine (denoted as “NH2”) end groups. Thiol (-SH) end groups or other nucleophilic end groups are also possible.

[0352] In certain preferred embodiments, 4-arm PEGs with an average molecular weight of about 20,000 Daltons and an electrophilic end group as disclosed above and 8-arm PEGs also with an average molecular weight of about 20,000 Daltons and with a nucleophilic end group as disclosed above are crosslinked for forming the polymer network and thus the hydrogel according to the present invention.

[0353] Reaction of nucleophilic group -containing PEG units and electrophilic group-containing PEG units, such as amine end-group containing PEG units and activated estergroup containing PEG units, results in a plurality of PEG units being crosslinked by a0 to 10, and specifically is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one particular embodiment, m is 6, e.g. in the case a SAZ-end group -containing PEG is used. For an SAP-end group, m would be 3, fora SG-end group, m would be 2 and for an SS-end group m would be 1. All crosslinks within the polymer network may be the same or may be different.

[0354] In certain preferred embodiments, the SAZ end group is utilized in the present invention. This end group may provide for increased duration in the eye, and the implant of certain embodiments of the present invention comprising a hydrogel comprising PEG-SAZ units is biodegraded in the eye, such as in the vitreous humor of a human eye, only after an extended period of time, e.g., 9 to 12 months as further disclosed below, and may in certain circumstance persist even longer. The SAZ group is more hydrophobic than e.g. the SAP-, SG- or SS-end groups because of a higher number of carbon atoms in the chain (m being 6, and the total of carbon atoms between the amide group and the ester group being 7).

[0355] In certain preferred embodiments, a 4-arm 20,000 Dalton PEG precursor is combined with an 8-arm 20,000 Dalton PEG precursor, such as a 4-arm 20,000 Dalton PEG precursor having a SAZ group (as defined above) combined with an 8-arm 20,000 Dalton PEG precursor having an amine group (as defined above). These precursors are also abbreviated herein as 4a20kPEG-SAZ and 8a20kPEG-NH2, respectively. The chemical structure of 4a20kPEG-SAZ is:

[0357] wherein R represents a pentaerythritol core structure. The chemical structure of 8a20kPEG-NH2(with a hexaglycerol core) is:

[0358] R - hexaglycerol core structure

[0359] In the above formulae, n is determined by the molecular weight of the respective PEG-arm.

[0360] In certain embodiments, the molar ratio of the nucleophilic and the electrophilic end groups reacting with each other is about 1:1, i.e., one amine group is provided per one SAZ group. In the case of 4a20kPEG-SAZ and 8a20kPEG-NH2this results in a weight ratio of about 2:1, as the 8-arm PEG contains double the amount of end groups as the 4-arm PEG.However, an excess of either the electrophilic (e.g. the NHS end groups, such as the SAZ) end groups or of the nucleophilic (e.g. the amine) end groups may be used. In particular, an excess of the nucleophilic, such as the amine-end group containing precursor may be used, i.e., the weight ratio of 4a20kPEG-SAZ and 8a20kPEG-NH2may also be less than 2:1.

[0361] Each and any combination of electrophilic- and nucleophilic-group containing PEG precursors disclosed herein may be used for preparing the implant according to the present invention. For example, any 4-arm or 8-arm PEG-NHS precursor (e.g. having a SAZ, SAP, SG or SS end group) may be combined with any 4-arm or 8-arm PEG-NH2precursor (or any other PEG precursor having a nucleophilic group). Furthermore, the PEG units of the electrophilic- and the nucleophilic group-containing precursors may have the same or may have a different average molecular weight.

[0362] Another nucleophilic group-containing crosslinking agent may be used instead of a PEG-based crosslinking agent. For example, a low-molecular weight amine linker can be used, such as trilysine (or a trilysine salt or derivative, such as trilysine acetate) or other low-molecular weight multi-arm amines.

[0363] In certain embodiments, the nucleophilic group-containing crosslinking agent may be bound to or conjugated with a visualization agent. A visualization agent is an agent that contains a fluorophoric or other visualization-enabling group. Fluorophores such as fluorescein, rhodamine, coumarin, and cyanine may for example be used as visualization agents. The visualization agent may be conjugated with the crosslinking agent e.g. through some of the nucleophilic groups of the crosslinking agent. Since a sufficient amount of the nucleophilic groups are necessary for crosslinking, “conjugated” or “conjugation” in general includes partial conjugation, meaning that only a part of the nucleophilic groups is used for conjugation with the visualization agent, such as about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups of the crosslinking agent may be conjugated with a visualization agent. In other embodiments, a visualization agent may also be conjugated with the polymer precursor, e.g. through certain reactive (such as electrophilic) groups of the polymer precursors.

[0364] Additional ingredients:

[0365] The implant of the present invention may contain, in addition to the polymer units forming the polymer network as disclosed above and the active principle, other additional ingredients. Such additional ingredients are for example salts originating from buffers used during the preparation of the hydrogel, such as phosphates, borates, bicarbonates, or otherbuffer agents such as triethanolamine. In certain embodiments of the present invention sodium phosphate buffers (specifically, mono- and dibasic sodium phosphate) are used.

[0366] Optionally, preservatives may be used for the implants of the present invention. However, in certain embodiments, the implants of the present invention including the implants containing axitinib as active agent, are free of preservatives, such as anti-microbial preservatives (including, but not limited to benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized oxychloro complex (SOC)), or are substantially free of such preservatives.

[0367] If an in-situ gelation is preferred in an embodiment of the invention, possible additional ingredient may be other agents used during manufacture of the hydrogel, such as (without being limited to) viscosity-influencing agents (such as hyaluronic acid etc.), surfactants etc.

[0368] In certain embodiments, the inserts of the present invention may contain a visualization agent. Visualization agents that may be usedin the context of the invention are all agents that can be conjugated with the components of the hydrogel or can be entrapped within the hydrogel, and that are visible, or may be made visible when exposed e.g. to light of a certain wavelength, or that are contrast agents. Suitable visualization agents for use in the present invention are (but are not limited to) e.g. fluoresceins, rhodamines, coumarins, cyanines, europium chelate complexes, boron dipyromethenes, benzofurazans, dansyls, bimanes, acridines, triazapentalenes, pyrenes and derivatives thereof. A visualization agent may be conjugated with either the nucleophilic- or the electrophilic group-containing precursor of which the polymer network is formed, as disclosed above, or the visualization agent may be a separate (non-conjugated) agent that is added during the manufacture of the implant and that is present in the hydrogel.

[0369] Formulation:

[0370] In certain embodiments, implants according to the present invention comprise a TKI, a polymer network made from one or more polymer precursors as disclosed herein above in the form of a hydrogel, and optional additional components such as salts etc. remaining in the implant from the production process (such as phosphate salts used as buffers etc.). In certain preferred embodiments, the TKI is axitinib.

[0371] In certain embodiments, the implants according to the present invention in their dry state may contain from about 15% to about 80%, such as from about 25% to about 75% by weight TKI and from about 15% to about 80%, such as from about 20% to about 60% by weight polymer units, or in particular embodiments from about 35% to about 65% by weightTKI and from about 25% to about 50% by weight polymer units (dry composition). In specific embodiments, the implants according to the present invention may contain from about 45% to about 55% by weight TKI and from about 37% to about 47% by weight polymer units (dry composition), with the TKI and the polymer units being selected from those disclosed herein above. In other specific embodiments, the implants according to the present invention in their dry state may contain from about 55% to about 75% by weight TKI and from about 20% to about 40% by weight polymer units (dry composition), with the TKI and the polymer units being selected from those disclosed herein above. In other specific embodiments, the implants according to the present invention in their dry state may contain from about30%to about 45%by weight TKI and from about 47% to about 70% by weight polymer units (dry composition), with the TKI and the polymer units being selected from those disclosed herein above.

[0372] In one particular embodiment, the implants according to the present invention in their dry state may contain from about 25% to about 75% by weight axitinib and from about 20% to about 60% by weight PEG units, or from about 35% to about 65% by weight axitinib and from about 25% to about 50% by weight PEG units, or from about 45% to about 55% by weight axitinib and from about 37% to about 47% by weight PEG units, or from about 48% to about 52% by weight axitinib and from about 40% to about 44% by weight PEG units (dry composition). In other particular embodiments, the implants according to the present invention in their dry state may contain from about 55% to about 75% by weight axitinib and from about 20% to about 40% by weight PEG units, or from about 60% to about 75% by weight axitinib and from about 21% to about 31% by weight PEG units (dry composition).

[0373] In one further particular embodiment, on a dry weight basis the axitinib to PEG ratio in an implant according to the invention may be approximately 50% by weight or more axitinib to approximately 40% by weight or less PEG, the balance being phosphate salt. Alternatively, on a dry weight basis the axitinib to PEG ratio in an implant according to the invention may be from about 1 :1 to about 3:1.

[0374] In certain embodiments, the balance of the implant in its dried state (i.e., the remainder of the formulation when TKI, such as axitinib, and polymer hydrogel, such as PEG hydrogel, have already been taken account of) may be salts remaining from buffer solutions as disclosed above. In certain embodiments, such salts are phosphate, borate or (bi) carbonate salts. In one embodiment the buffer salt is sodium phosphate (mono- and / or dibasic).

[0375] The amounts of the TKI and the polymer(s) may be varied, and other amounts of the TKI and the polymer hydrogel may be used to prepare implants according to the invention.

[0376] In certain embodiments, the maximum amount of drug within the formulation is about two times the amount of the polymer (e.g., PEG) units, but may be higher in certain cases, but it is desired that the mixture comprising, e.g., the precursors, buffers and drug (in the state before the hydrogel has gelled completely) can be uniformly cast into a mold or tubing.

[0377] In one embodiment of the invention, the hydrogel after being formed and prior to being dried, i.e., in a wet state, may comprise about 3% to about 20% polyethylene glycol representing the polyethylene glycol weight divided by the fluid weight x 100. In one embodiment, the hydrogel in a wet state comprises about 5% to about 15%, such as about 7.5% to about 15%, or about 5% to about 10% polyethylene glycol representing the polyethylene glycol weight divided by the fluid weight x 100.

[0378] In one embodiment of the invention, the wet hydrogel composition (i.e., after the hydrogel composition has been formed, i.e., all components forming the hydrogel have been admixed) comprises from about 5% to about 50% by weight active principle, such as axitinib, and from about 5% to about 50% or from about 5% to about 30% by weight PEG units.

[0379] In certain embodiments, a solids content of about 10% to about 50%, or of about 25% to about 50% (w / v) (wherein “solids” means the combined weight of polymer precursor(s), salts and the drug in solution / suspension) may be utilized in the wet composition when forming the hydrogel for the implants according to the present invention. Thus, in certain embodiments, the total solids content of the wet hydrogel composition to be cast into a mold or tubing in order to shape the hydrogel may be no more than about 60%, or no more than about 50%, or no more than about 40%, such as equal to or lower than about 35% (w / v). The content of TKI, such as axitinib, may be no more than about 40%, or no more than about 30%, such as equal to or lower than about 25% (w / v) of the wet composition. The solids content may influence the viscosity and thus may also influence the castability of the wet hydrogel composition.

[0380] In certain embodiments, the water content of the hydrogel implant in its dry (dehydrated / dried) state, e.g. prior to being loaded into a needle, or when loaded in a needle, may be very low, such as not more than 1% by weight of water. The water content may in certain embodiments also be lower than that, possibly not more than 0.25% by weight or even not more than 0.1% by weight. In the present invention the term “implant” is used to refer both to an implant in a hydrated state when it contains water (e.g. after the implant has been (re-)hydrated once administered to the eye or otherwise immersed into an aqueous environment) as well as to an implant in its dry (dried / dehydrated) state, e.g., when it hasbeen dried to a low water content of e.g. not more than about 1% by weight or when the preparation results in such alow water content implant without the necessity of a drying step. In certain embodiments, an implant in its dry state is an implant that after production is kept under inert nitrogen atmosphere (containing less than 20 ppm of both oxygen and moisture) in a glove box for at least about 7 days prior to being loaded into a needle. The water content of an implant may be e.g. measured using a Karl Fischer coulometric method.

[0381] In certain embodiments, the total weight (also referred to herein as “total mass”) of an implant accordingto the present invention in its dry state may be from about 200 pg (i.e., 0.2 mg) to about 1.5 mg, or from about 400 pg to about 1.2 mg. In certain specific embodiments, the total weight of an implant accordingto the invention in its dry state may be from about 0.3 mgto about 0.6 mg, such as from about 0.4 mg to about 0.5 mg, e.g. in case the implant contains axitinib in an amount of from about 160 pg to about 250 pg. In certain other specific embodiments, the total mass of an implant according to the invention in its dry state may be from about0.75 mgto about 1.25mg, orfrom about0.8 mgto about 1.1 mg, or from about 0.9 mgto about 1.0 mg, e.g. in case the implant contains axitinib in an amount of from about 480 pg to about 750 pg.

[0382] In certain embodiments, an implant accordingto the present invention in its dry state may contain from about 200 pg to about 1000 pg TKI, such as axitinib, per mm3(i.e., per 1 mm3volume of the dry implant). In certain specific embodiments, an implant according to the present invention in its dry state may contain from about 200 pg to about 300 pg axitinib per mm3, e.g. in case the implant contains axitinib in an amount of from about 160 pg to about 250 pg. In certain other specific embodiments, an implant according to the present invention in its dry state may contain from about 500 pg to about 800 pg axitinib per mm3, e.g. in case the implant contains axitinib in an amount of from about 480 pg to about 750 pg.

[0383] The implants of the present invention may thus have different densities. The densities of the final implants (i.e., in their dry state) may be controlled and determined by various factors, including but not limited to the concentration of the ingredients in the wet composition when forming the hydrogel, and certain conditions during manufacturing of the implant. For example, the density of the final implant in certain embodiments can be increased by means of sonication or degassing, e.g. using vacuum, at certain points during the manufacturing process.

[0384] In certain embodiments, implants accordingto the invention contain a therapeutically effective amount of TKI such as axitinib for release over an extended periodof time but are nevertheless relatively small in length and / or diameter. This is advantageous both in terms of ease of administration (injection) as well as in terms of reducing possible damage to ocular tissue and reducing a possible impact of the patient’s vision while the implant is in place. The implants of the present invention combine the benefits of a suitably high dose of the TKI (i.e., a therapeutically effective dose adjusted to a particular patient’s need) with a relatively small implant size.Other Formulation and Device Embodiments

[0385] In certain embodiments, the formulations have decreased friction or acceptable friction such that they are easily loaded into and expelled from an injector device, e.g., with a 25-gauge needle. This may reduce damage to the retina.

[0386] In certain axitinib embodiments, the axitinib is present in the dry insert comprises from about 60% to about 70% axitinib, from about 25% to about 35% PEG hydrogel (e.g., PEG(SAZ / NH2)) and from about 2% to about 8% phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 6 mm to about 8 mm or about 7 mm or about 6.8 mm.

[0387] In certain axitinib embodiments, the axitinib is present in the dry insert comprises from about 60% to about 65% axitinib, from about 28% to about 33% PEG hydrogel (e.g., PEG(SAZ / NH2)) and from about 3% to about 7% phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 6 mm to about 8 mm or about 7 mm or about 6.8 mm.

[0388] In certain axitinib embodiments, the axitinib is present in the dry insert comprises from about 63% to about 65% axitinib, from about 30% to about 32% PEG hydrogel (e.g., PEG(SAZ / NH2)) and from about 4% to about 6% or about 5% to about 6% phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 6 mm to about 8 mm or about 7 mm or about 6.8 mm

[0389] In certain axitinib embodiments, the axitinib is present in the dry insert comprises from about 62% to about 64% axitinib, from about 29% to about 31% PEG hydrogel (e.g., PEG(SAZ / NH2)) and from about 4% to about 5% phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 6 mm to about 8 mm or about 7 mm or about 6.8 mm.

[0390] In certain axitinib embodiments, the axitinib is present in the dry insert comprises about 63.9% axitinib, about 30.7% PEG hydrogel (e.g., PEG(SAZ / NH2)) and about 5.3% phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 7 mm or about 6.8 mm

[0391] In certain axitinib embodiments, the axitinib is present in the dry insert comprises about 63.7% axitinib, about 30.6% PEG hydrogel (e.g., PEG(SAZ / NH2)) and about 5.7% phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 7 mm or about 6.8 mm.

[0392] In certain axitinib embodiments, the axitinib is present in the dry insert comprises from about 400 pg to about 500 pg axitinib, from about 180 pg to about 240 pg PEG hydrogel (e.g., PEG(SAZ / NH2)) and from about .02 pg to about .06 pg phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 6 mm to about 8 mm or about 7 mm or about 6.8 mm.

[0393] In certain axitinib embodiments, the axitinib is present in the dry insert comprises from about 425 pg to about 475 pg axitinib, from about 190 pg to about 230 pg PEG hydrogel (e.g., PEG(SAZ / NH2)) and from about .03 pg to about .05 pg phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 6 mm to about 8 mm or about 7 mm or about 6.8 mm.

[0394] In certain axitinib embodiments, the axitinib is present in the dry insert comprises from about 440 pg to about 460 pg axitinib, from about 210 pg to about 220 pg PEG hydrogel (e.g., PEG(SAZ / NH2)) and from about .035 pg to about .045 pg phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 6 mm to about 8 mm or about 7 mm or about 6.8 mm.

[0395] In certain axitinib embodiments, the axitinib is present in the dry insert comprises from about 445 pg to about 455 pg axitinib, from about 200 pg to about 220 pg PEG hydrogel (e.g., PEG(SAZ / NH2)) and from about .038 pg to about .042 pg phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 6 mm to about 8 mm or about 7 mm or about 6.8 mm.

[0396] In certain axitinib embodiments, the axitinib is present in the dry insert comprises from about 450 pg axitinib, about 218 pg PEG hydrogel (e.g., PEG(SAZ / NH2)) and about .042 pg phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 6 mm to about 8 mm or about 7 mm or about 6.8 mm.

[0397] In certain axitinib embodiments, the axitinib is present in the dry insert comprises from about 450 pg axitinib, about 210 pg PEG hydrogel (e.g., PEG(SAZ / NH2)) and about .04 pg phosphate buffer (e.g., sodium phosphate), wherein the dry insert has a length of about 6 mm to about 8 mm or about 7 mm or about 6.8 mm

[0398] In certain axitinib embodiments, the ratio of axitinib to PEG hydrogel (e.g., PEG(SAZ / NH2)) is about 1.8 to about2.2, about 1.9 to about 2.1, about 2.0 to about2.1, about 2.0 to about 2.2, about 2 or about 2.1 or about 2.2.

[0399] In certain axitinib embodiments, the ratio of axitinib to buffer salt (e.g., sodium phosphate) is about 8 to about 12, about 9 to about 11, about 10 to about 12, about 10 to about 11, about 11 to about 12, about 10, about 11 or about 12.

[0400] In certain axitinib embodiments, the ratio of PEG hydrogel (e.g., PEG(SAZ / NH2)) to buffer salt (e.g., sodium phosphate) is about 2 to about 8, about 3 to about 7, about 4 to about 6, about 5 to about 6, about 5 or about 6.

[0401] In certain embodiments, the PEG hydrogel comprises 4a20k PEG SAZ and 8a20k PEG NHZ in a ratio of about3:l to about 1:3, about2:l to about 1:2, about3:l, about2.5:l or about 2:1.

[0402] In certain embodiments, the sodium phosphate comprises dibasic sodium phosphate and monobasic sodium phosphate in a ratio of about 3:1 to about 1 :3, about 2:1 to about 1 :2, about 3:1, about 2.5:1 or about 2:1

[0403] In certain embodiments, the implant disclosed herein exhibits a Dynamic Vapor Sorption (DVS) weight gain at 40% relative humidity (RH) of less than about 2%, less than about 1.9%, less than about 1.8%, less than about 1.7%, less than about 1.6%, about 0.5% to about 2%, about 1% to about 1.8% or about 1.2% to about 1.6%.

[0404] In certain embodiments, the implant disclosed herein exhibits a Dynamic Vapor Sorption (DVS) weight gain at 50% relative humidity (RH) of less than about 3%, less than about 2.9%, less than about 2.8%, less than about 2.7%, about l%to about 3%, about 1.5% to about 2.9% or about 1.8% to about 2.8%.

[0405] In certain embodiments, the implant disclosed herein exhibits a Dynamic Vapor Sorption (DVS) weight gain at 60% relative humidity (RH) of less than about 4.5%, less than about4.3%, less than about 4%, about2%to about4.5%, about2.5%to about4.4% or about 3.5% to about 4.2%.

[0406] In certain embodiments, the implant disclosed herein exhibits a Dynamic Vapor Sorption (DVS) weight gain at 70% relative humidity (RH) of less than about 6.3%, less than about 6%, less than about 5.8%, less than about 5.7%, about 3% to about 6.2%, about 4% to about 6% or about 4.5% to about 5.8%.

[0407] In certain embodiments, the implant disclosed herein exhibits a Dynamic Vapor Sorption (DVS) weight gain at 80% relative humidity (RH) of less than about 9.5%, less thanabout 9.5%, less than about 9%, less thanabout 8.8%, less than about 8.6%, about 5% to about 9%, about 6.5% to about 8.8% or about 8% to about 8.8%

[0408] In certain embodiments, the implant disclosed herein exhibits a Dynamic Vapor Sorption (DVS) weight gain at 90% relative humidity (RH) of less than about 22%, less than about 21.5%, less than about 21%, less than about 20.5%, about 18% to about 22%, about 19 to about 21% or about 19.5% to about 20.5%.

[0409] In certain embodiments, the implant disclosed herein exhibits a Dynamic Vapor Sorption (DVS) weight gain at 95% relative humidity (RH) of less than about 40%, less than about 38%, less than about 37%, less than about 35%, about 25% to about 40%, about 30% to about 38% or about 32% to about 37%.

[0410] In certain embodiments, the implant disclosed herein exhibits one, or more or all of the Dynamic Vapor Sorption weight gain 40%, 50%, 60%, 70%, 80%, 90% and 95%.

[0411] In certain embodiments, the Dynamic Vapor Sorption is measured on a Hiden Isochema IGASorp instrument. In certain embodiments, prior to initial testing, the samples is dried at 40°C for at least one hour. In certain embodiments, relative humidity is increased in 10% increments up to 95% RH, with the system waiting for the sample's weight change rate to stabilize before each humidity change.

[0412] In the above embodiments, the total weight of the implant may be, e.g., about 650 pg to about750 pg, about 675 pgto about725 pg, 700 pg to about 725 pg, about 710 pg or about 720 pg.

[0413] In certain embodiments, the mean piercing force of a device of the present invention may be, e.g., 0.45 N or less, 0.35 N or less, or 0.25 N or less and in certain embodiments, the mean cutting force of a device of the present invention maybe, e.g., 0.75 N or less, 0.65 N or less or0.5 N or less. These values are based on, e.g., according to nomenclature DIN 13097 (ISO 7864) and SO 9626 for the force to penetrate a standardized 0.4 mm polyurethane foil as measured by a penetrometer, when the needle is piercing, cutting and sliding through the foil and plotted as a load displacement diagram. See Meyer et al. “Penetration Force, Geometry, and Cutting Profile of the Novel and Old Ozurdex Needle: The MONO Study: Journal of Ocular Pharmacology and Therapeutics Volume 30, Number 5, 2014, hereby incorporated by reference.

[0414] In certain embodiments, the mean impact velocity of a device of the present invention may be, e.g., 200 cm / sec or less, 180cm / sec or less, 160 cm / secor less, 140 cm / sec or less, 120 cm / sec or less, 100 cm / sec or less, 80 cm / secor less, 60 cm / sec or less, 40 cm / sec or less, 20 cm / sec or less, 15 cm / sec or less, 10 cm / sec or less or 5 cm / sec or less. In otherembodiments, the mean pellet force at impact velocity may be, e.g., 0.6 mN or less, 0.5 mN or less, 0.4 mN or less, 0.3 mN or less, 0.2 mN or less, 0.1 mN or less, 0.5 mN or less, 0.2 mN or 0.1 mN or less. These values are based on, e.g., a technique wherein a test chamber is constructed and filled with water in order to simulate the typical resistance of a vitrectomized eye. A hole is made on the side of the test chamber to allow for insertion of the injector, a grid of 0.2-inch squaresis placed behind the test chamber to measure the distance travelled by the pellet, and a high-speed photography camera (240 frames per second) is placed in front of the setup to capture the events. After actuation, the values are calculated include impact velocity (Vf), which refers to the velocity of the pellet at approximately 16 mm from the tip of the needle to represent the hypothetical location of the retina. Velocity is calculated by measuring the change of pellet position on the square grid relative to the elapsed time recorded by the camera. The force at Vf is calculated by multiplying the average mass of the pellets by acceleration at the impact point. See Krambeer et al. “A New Suggested Strategy for Safe Injection of Ozurdex” Clinical Science Feb. 1019, Vol. 50 No. 2, hereby incorporated by reference.

[0415] The preceding description sets forth numerous specific details such as examples of specific systems, components, methods, and so forth in order to provide a good understanding of several embodiments of the present disclosure. It will be apparent to one skilled in the art, however, that at least some embodiments of the present disclosure may be practiced without these specific details. In other instances, well-known components or methods are not described in detail or are presented in simple block diagram format in order to avoid unnecessarily obscuringthe present disclosure. Thus, the specific details set forth are merely exemplary. Particular implementations may vary from these exemplary details and still be contemplated to be within the scope of the present disclosure.

[0416] Reference throughout this specification to “one embodiment,” “an embodiment,” “certain embodiments,” or “some embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase “in one embodiment,” “in an embodiment,” “in certain embodiments,” or “in some embodiments” in various places throughout this specification are not necessarily all referring to the same embodiment. In addition, the term “or” is intended to mean an inclusive “or” rather than an exclusive “or.” When the term “about” or “approximately” is used herein, this is intended to mean that the nominal value presented is precise within ± 20%, ± 18%, ± 16%, ± 14%, ± 12%, ± 10%, ± 8%, ± 6%, ± 4%, ± 3%, ± 2%, ± 1%, and / or ± 0.5%.

[0417] Although the operations of the methods herein are shown and described in a particular order, the order of operations of each method may be altered so that certain operations may be performed in an inverse order so that certain operations may be performed, at least in part, concurrently with other operations. In another embodiment, instructions or sub-operations of distinct operations may be in an intermittent and / or alternating manner.

[0418] It is understood that the above description is intended to be illustrative, and not restrictive. Many other embodiments will be apparent to those of skill in the art upon reading and understanding the above description. The scope of the disclosure should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.EXAMPLESExample 1A

[0419] A 0.45 mg Form IV axitinib ocular implant having the formula in Table 1 was prepared in accordance with the general procedures disclosed herein.TABLE 1Example 1B-E

[0420] Examples B-E were prepared in accordance with Example 1 except with a different amount of axitinib on a wet basis as shown in Table IB. Additional components are shown in Table 1C.TABLE IBTable 1CExample 2

[0421] The implants of Examples 1 A-E underwent humidity water sorption testing using Dynamic Vapor Sorption (DVS) analysis on a Hiden IsochemalGASorp instrument. Prior to testing, samples were dried at 40°C for one hour. Relative humidity was increased in 10% increments up to 95% RH, with the system waiting for the sample's weight change rate to stabilize before each humidity change. Each sample was cut to about 4 mm in length. The results are disclosed in Fig. 4 which depicts weight increase for each sample at each stage of relative humidity. The results show that increasing the percent PEG increases water uptake and that SAB-1 is more hydroscopic than Form IV.

[0422] Fig. 5 depicts the rate of DVS by showing the weight increase per minute (% / min) at increased humidity (% RH).

[0423] Fig. 6 depicts the % weight change at 40%RH based on %PEG (Dry).

[0424] The data from the Fig. 1 is presented in Table 2A.1Table 2A

Claims

CLAIMSWhat is claimed is:

1. An implant injector device comprising:a body forming an interior volume;a slider structure disposed within the interior volume;a spring connecting a proximal portion of the body to a proximal portion of the slider structure;a wire connected to a distal portion of the slider structure;a button structure configured to receive user input to actuate the slider structure towards a distal portion of the body; anda lock pin structure configured to interface with the body and the slider structure to prevent actuation of the button structure.

2. The implant injector device of claim 1 further comprising:a hub structure connected to the distal portion of the body; anda needle coupled to the hub structure, wherein the needle is configured to receive an implant, wherein the implant is to be deployed from the needle via the wire responsive to removal of the lock pin structure and the actuation of the button structure.

3. The implant injector device of claim 2 further comprising:a sleeve structure disposed around at least a portion of the needle, wherein an outer surface of at least one of the needle or the sleeve structure has a coating; anda cap structure configured to cover the hub structure and at least a corresponding portion of the needle.

4. The implant injector device of claim 1, wherein lubricant is disposed in the interior volume.

5. The implant injector device of claim 1, wherein the wire is connected to the slider structure via at least one of adhesive or insert molding.

6. The implant injector device of claim 2, wherein the implant is disposed in the needle, wherein the lock pin structure is to be removed from the body, the needle is to be insertedinto a patient, and the button structure is to be actuated to cause the slider structure to actuate the wire into the needle to cause the implant to be provided into the patient.

7. The implant injector device of claim 2 further comprising a biocompatible material tip disposed ata distal end of the needle, wherein the implant is secured in the needle between the wire and the biocompatible material tip, wherein the biocompatible material tip is configured to at least partially dissolve within a patient to allow the implant to be deployed into the patient.

8. The implant injector device of claim 1, wherein the body comprises a first body half having a pattern of staggered clips and staggered recesses, wherein the body further comprises a second body half having the pattern of the staggered clips and the staggered recesses, wherein the first body half and the second body half are configured to interconnect with each other via the staggered clips and the staggered recesses.

9. A kit comprising:an enclosure to house an implant injector device, the implant injector device comprising:a body forming an interior volume;a slider structure disposed within the interior volume;a spring connecting a proximal portion of the body to a proximal portion of the slider structure;a wire connected to a distal portion of the slider structure;a button structure configured to receive user input to actuate the slider structure towards a distal portion of the body; anda lock pin structure configured to interface with the body and the slider structure to prevent actuation of the button structure.

10. A method of treatment of administering an implant, the method comprising:removing a cap structure from the body of an implant injector device; removing a lock pin structure from a body and a slider structure disposed in an interior volume of the body;inserting a distal end of a needle coupled to the hub into a patient; andactuating a button structure into the body to actuate the slider structure to push the implant through the needle and into the patient via a wire secured to a distal end of the slider structure.

11. A method of treating an ocular disease comprising administering an ocular implant comprising an active agent utilizing the implant injector device of any of claims 1-8.

12. The method of claim 11, wherein the administering of the ocular implant is intravitreal or intracameral.

13. The method of claim 11 or 12, wherein the active agent is a tyrosine kinase inhibitor.

14. The method of claim 13, wherein the tyrosine kinase inhibitor is axitinib.

15. The method of any of claims 11-14, wherein the ocular disease is a back of eye disease.

16. The method of claim 15, wherein the back of eye disease is retinal disease.

17. The method of claim 15, wherein the ocular disease is age-related macular degeneration (AMD) cystoid macular edema (CME), diabetic macular edema (DME), retinal vein occlusion, posterior uveitis, diabetic retinopathy, or glaucoma.

18. The method of claim 11, wherein the administering of the ocular implant is to an anterior chamber or a vitreous chamber.

19. The method of claim 11 or 12, wherein the active agent is a prostaglandin.

20. The method of claim 19, wherein the prostaglandin is travoprost.

21. The method of any of claims 18-20, wherein the ocular disease is a front of eye disease.

22. The method of any of claims 18-20, wherein the ocular disease is high pressure in eye caused by open-angle glaucoma or ocular hypertension.

23. A system comprising:an implant injector device comprising:a body forming an interior volume;a slider structure disposed within the interior volume;a spring connecting a proximal portion of the body to a proximal portion of the slider structure;a wire connected to a distal portion of the slider structure;a button structure configured to receive user input to actuate the slider structure towards a distal portion of the body; anda lock pin structure configured to interface with the body and the slider structure to prevent actuation of the button structure; andan implant disposed within a needle within the implant injector device, wherein the implant comprises an active agent.

24. The system of claim 23, wherein the active agent is a tyrosine kinase inhibitor.

25. The system of claim 24, wherein the tyrosine kinase inhibitor is axitinib.

26. The implant injector device of any of claims 1-8 further comprising an implant disposed within a needle of the implant injector device, wherein the implant comprises an active agent.

27. The implant injector device of claim 26, wherein the active agent is a tyrosine kinase inhibitor.

28. The implant injector device of claim 27, wherein the tyrosine kinase inhibitor is axitinib .

29. The kit of claim 9 further comprising an implant disposed within a needle of the implant injector device, wherein the implant comprises an active agent.

30. The kit of claim 29, wherein the active agent is a tyrosine kinase inhibitor.

31. The kit of claim 30, wherein the tyrosine kinase inhibitor is axitinib.

32. An ocular insert comprising from about 60% to about 70% axitinib, from about 25% to about 35% PEG hydrogel and from about 2% to about 8% phosphate buffer, wherein the dry insert has a length of about 6 mm to about 8 mm.

33. The ocular insert of claim 32, comprising from about 60% to about 65% axitinib, from about 28% to about 33% PEG hydrogel and from about 3% to about 7% phosphate buffer.

34. The ocular insert of claim 32, comprising from about 63% to about 65% axitinib, from about 30% to about 32% PEG hydrogel and from about 4% to about 6% phosphate buffer.

35. The ocular insert of claim 32, comprising from about 62% to about 64% axitinib, from about 29% to about 31% PEG hydrogel and from about 4% to about 5% phosphate buffer.

36. The ocular insert of claim 32, comprising from about 400 pg to about 500 pg axitinib, from about 180 pg to about 240 pg PEG hydrogel and from about .02 pg to about .06 pg phosphate buffer.

37. The ocular insert of claim 32, comprising from about 425 pg to about 475 pg axitinib, from about 190 pg to about 230 pg PEG hydrogel and from about .03 pg to about .05 pg phosphate buffer.

38. The ocular insert of claim 32, comprising from about 440 pg to about 460 pg axitinib, from about 210 pg to about 220 pg PEG hydrogel and from about .035 pg to about .045 pg phosphate buffer.

39. The ocular insert of claim 32, comprising one or more of:a Dynamic Vapor Sorption (DVS) weight gain at 40% relative humidity (RH) of less than about 2%, less than about 1.9%, less than about 1.8%, less than about 1.7%, less than about 1.6%, about 0.5% to about 2%, about 1% to about 1.8% or about 1.2% to about 1.6%;a Dynamic Vapor Sorption (DVS) weight gain at 50% relative humidity (RH) of less than about 3%, less than about 2.9%, less than about 2.8%, less than about 2.7%, about 1% to about 3%, about 1.5% to about 2.9% or about 1.8% to about 2.8%;a Dynamic Vapor Sorption (DVS) weight gain at 60% relative humidity (RH) of less than about 4.5%, less than about 4.3%, less than about 4%, about 2% to about 4.5%, about 2.5% to about 4.4% or about 3.5% to about 4.2%;a Dynamic Vapor Sorption (DVS) weight gain at 70% relative humidity (RH) of less than about 6.3%, less than about 6%, less than about 5.8%, less thanabout 5.7%, about 3% to about 6.2%, about 4% to about 6% or about 4.5% to about 5.8%;a Dynamic Vapor Sorption (DVS) weight gain at 80% relative humidity (RH) of less than about 9.5%, less than about 9.5%, less than about 9%, less than about 8.8%, less than about 8.6%, about 5% to about 9%, about 6.5% to about 8.8% or about 8% to about 8.8%;a Dynamic Vapor Sorption (DVS) weight gain at 90% relative humidity (RH) of less than about22%, less than about 21.5%, less than about 21%, less than about20.5%, about 18% to about 22%, about 19 to about 21% or about 19.5% to about 20.5%; anda Dynamic Vapor Sorption (DVS) weight gain at 95% relative humidity (RH) of less than about 40%, less than about 38%, less than about 37%, less than about 35%, about 25% to about 40%, about 30% to about 38% or about 32% to about 37%.

40. A system comprising an implant injector device and an implant of any of claims 32-39 disposed within a needle within the implant injector device.

Images