Ocular implant comprising an amorphous solid dispersion comprising a tyrosine kinase inhibitor and a polymer excipient

Abstract

The present invention relates to an ocular implant comprising an amorphous solid dispersion (ASD) comprising a tyrosine kinase inhibitor (TKI), such as axitinib, and a polymer excipient. Further, the invention relates to methods of treatment using the ocular implant of the invention comprising the amorphous solid dispersion (ASD) in treating an ocular disease. According to the present invention, ocular diseases are treated by injecting an amorphous solid dispersion (ASD) or an ocular implant comprising the ASD into the eye, wherein the ocular implant releases the TKI. Moreover, the invention relates to processes for preparing an amorphous solid dispersion (ASD) and an ocular implant of the invention comprising an ASD.

Description

OCULAR IMPLANT COMPRISING AN AMORPHOUS SOLID DISPERSION COMPRISINGA TYROSINE KINASE INHIBITOR AND A POLYMER EXCIPIENT, METHODS OFTREATMENT USING SAID OCULAR IMPLANT AND PROCESSES FOR THE PREPARATION THEREOF FIELD OF THE INVENTION

[0001] The present invention relates to an ocular implant comprising an amorphous soliddispersion (ASD) comprising a tyrosine kinase inhibitor (TKI), such as axitinib, and a polymerexcipient. Further, the invention relates to methods of treatment using the ocular implant of theinvention comprising the amorphous solid dispersion (ASD) in treating an ocular disease. According to the present invention, ocular diseases are treated by injecting an amorphous soliddispersion (ASD) or an ocular implant comprising the ASD into the eye, wherein the ocularimplant releases the TKI. Moreover, the invention relates to processes for preparing anamorphous solid dispersion (ASD) and an ocular implant of the invention comprising an ASD. BACKGROUND OF THE INVENTION

[0002] A number of different processing methods and technologies have been developed toincrease the oral bioavailability of poorly soluble active pharmaceutical ingredients (APIs) including salt formation, complexation, nanocrystal dispersion, liposome formulation, self-emulsification, cyclodextrin complexation, micronization, and amorphous solid dispersions(ASD). Having been originally developed over 50 years ago, ASDs provide greater API solubilitycompared to other technologies as well as simple and cost-effective scale-up with establishedmanufacturing methodologies.

[0003] Amorphous solid dispersion (ASD) is a formulation technology used to stabilizeamorphous active pharmaceutical ingredients and to enhance the dissolution rate andbioavailability of poorly water-soluble APIs. In this method, the API is dispersed in a polymerexcipient, thereby lowering the total energy required for the solubilization. Polymers as excipients also play a key role in the improvement of solubility and bioavailability through their interaction. They can stabilize the ASD system, prevent drug recrystallization through interactionbetween the active pharmaceutical ingredient and the polymer excipient, and improve physicalstability. The glassy state of amorphous polymers below their glass transition temperature (Tg)allows to keep the APIs dispersed by “freezing” them, lowering molecular mobility over storageuntil releasing them in the aqueous environment of the gastro-intestinal tract, intestines, or the eye.

[0004] Despite the formulation technology of ASD development being 50 years old with somecommercial products already approved by the FDA, the formulation can be challenging due tothe multi-variable nature of the API required, the polymer excipient employed and their interactions with one another. Furthermore, the dispersion must remain physically stable duringmanufacturing, storage, and final dissolution. A. Budiman et al. describe ASD formulations forimproving the aqueous solubility of poorly water-soluble anticancer drugs (A. Budiman et al., Polymers 2023, 15, 3380). A few ASDs have been developed for the oral delivery and increase of the water solubility of crystalline anticancer drugs including Everolimus (Afinitor®, Novartis) or Olaparib (Lynparza®, AstraZeneca).

[0005] Tyrosine kinase inhibitors (TKI) were developed as chemotherapeutics that inhibitsignaling of receptor tyrosine kinases (RTKs), which are a family of tyrosine protein kinases. RTKs span the cell membrane with an intracellular (internal) and extracellular (external) portion.Upon ligand binding to the extracellular portion, receptor tyrosine kinases dimerize and initiatean intracellular signaling cascade driven by autophosphorylation using the coenzyme messenger adenosine triphosphate (ATP). Many of the RTK ligands are growth factors such as VEGF. VEGF relates to a family of proteins binding to VEGF-receptor (VEGFR) types, i.e. VEGFR1-3 (all RTKs), thereby inducing angiogenesis. VEGF-A, which binds to VEGFR2, is the target of the anti-VEGF drugs described above. Besides VEGFR1-3 several other RTKs are known to induce angiogenesis such as platelet-derived growth factor receptor (PDGFR) activated by PDGF or stem cell growth factor receptor / type III receptor tyrosine kinase (c-Kit)activated by stem cell factor. Examples of TKIs are axitinib, sorafenib, sunitinib, nintedanib,pazopanib, regorafenib, cabozantinib, and vandetanib.

[0006] Ocular implants are important therapeutic options as they can provide prolongedtreatment of ocular diseases without the need for constant and repeated administration withdrops. Recently, ocular implants have been produced comprising TKI particles dispersed in ahydrogel, that are administered by injection e.g. into the vitreous humor of a patient having wetAMD, wherein the TKI is released in a controlled manner from the implant over an extendedperiod of time, such as several months or longer, so that a therapeutically effective amount ofthe TKI is available over said period of time. These implants are capable of reducing, or at least maintaining (such as in preventing an increase) the central subfield thickness (CSFT) and / orreducing or maintaining (again, preventing an increase) of sub- or intraretinal fluid in patients(see e.g. WO 2021 / 195163 A1, which is incorporated herein by reference in its entirety).

[0007] Results of a phase 1 clinical trial (among other studies) have shown that implantscomprising the TKI axitinib dispersed in a hydrogel made of a polymer network of crosslinked polyethylene glycol (PEG) units have an extended durability in patients with wet AMD, and that the vision (measured by the best corrected visual acuity, BCVA) and CSFT levels of thesubjects treated with one single such implant were comparable to the vision and CSFT levels of subjects treated with the anti-VEGF agent aflibercept (repeated injection every 2 months) up tomonth 12 of the study.

[0008] While known implants comprising a TKI have proven in the clinical studies so far to besafe and effective in patients with wet AMD, there is still a desire to provide further ocularimplants which have release profiles that differ from those of the known ocular implants. Forexample, it is desirable to provide implants comprising a TKI which have an increased rate of release of the TKI, such as an increased amount of TKI released over a certain period of time, or a faster release rate, particularly in the early phase of the release after injection of the implant. Furthermore, it is desirable to provide ocular implants comprising TKI for the treatment of an ocular disease, such as wet AMD, wherein the largest portion of the content of TKI in the implant is released prior to the degradation of the implant, so as to avoid or substantially avoid a remaining drug-depleted implant which first has to be cleared from the eye before a new implant can be injected. At the same time, it is however desirable that sufficient TKI remains in the implant to be released upon biodegradation of the implant so as to maintain the therapeutic effect until the remainders of the implant have been cleared completely from the eye and a new implant can be placed, thus providing a continuous therapy by means of implant repeat dosing. OBJECTS OF THE INVENTION

[0009] Accordingly, there is a need for further ocular implants that enhance the dissolution rateand bioavailability of poorly water-soluble TKIs such as axitinib and therefore their release rate,particularly for use in the treatment of an ocular disease, such as back-of-the-eye diseases suchas any ocular disease of the posterior segment that affects the vasculature and integrity of theretina, macula or choroid leading to visual acuity disturbances, loss of sight or blindness, particularly disease states of the posterior segment resulting from age, trauma, surgical interventions, such as age-related macular degeneration (AMD) cystoid macular edema (CME),diabetic macular edema (DME), posterior uveitis, and diabetic retinopathy.

[0010] It is thus an object of the present invention to provide implants comprising an amorphoussolid dispersion (ASD) comprising a TKI which have an increased rate of release of the TKI, such as an increased amount of TKI released over a certain period of time, or a faster releaserate. It is thus another object of the present invention to provide an ocular implant for sustaineddelivery of a poorly water-soluble TKI.

[0011] It is another object of the present invention to provide an ocular implant comprising atyrosine kinase inhibitor (TKI), for example, wherein the tyrosine kinase inhibitor (TKI) is axitinib,or a pharmaceutically acceptable salt, derivative, or prodrug thereof, allowing a modifiedrelease, or burst control of the TKI.

[0012] It is another object of the present invention to provide methods for treating diseases andconditions, in particular of the eye, comprising administering an ocular implant of the inventionas disclosed herein to a patient in need thereof.

[0013] It is another object of the present invention to provide processes for preparing anamorphous solid dispersion (ASD) comprising a tyrosine kinase inhibitor (TKI), as disclosedherein.

[0014] It is another object of the present invention to provide processes for preparing an ocularimplant of the invention as disclosed herein. SUMMARY OF THE INVENTION

[0015] The present invention, in one embodiment, relates to an ocular implant comprising anamorphous solid dispersion (ASD), the ASD comprising a tyrosine kinase inhibitor (TKI), forexample, wherein the tyrosine kinase inhibitor (TKI) is axitinib, or a polymorph, apharmaceutically acceptable salt, derivative or prodrug thereof, and a polymer excipient.

[0016] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD), oran ocular implant comprising the ASD as defined herein, wherein the tyrosine kinase inhibitor (TKI) is selected from at least one of axitinib, lapatinib, sorafenib, imatinib, gefitinib, erlotinib, nilotinib, pazopanib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib, vandetanib, and dasatinib, or pharmaceutically acceptable salts, derivatives or prodrugs thereof. In an embodiment thereof, the tyrosine kinase inhibitor (TKI) is axitinib, or a pharmaceutically acceptable salt, derivative or prodrug thereof.

[0017] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD), oran ocular implant comprising the ASD as defined herein, wherein the polymer excipient is selected from the group consisting of polyvinyls such as polyvinyl pyrrolidone-vinyl acetate (PVPVA), polyvinylpyrrolidone (PVP), povidone (PVP), such as povidone K25, povidone K17 or povidone K30, or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®); polyethylene glycols (PEG), poloxamers such as poloxamer 188, Pluronic®F127 or Pluronic F68®; polyacrylates and methacrylates such as Carbomer, Eudragit®EPO or Eudragit®RL PO; and cellulose and its derivatives such as methyl cellulose, hydroxypropyl methylcellulose (HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS), or a mixture thereof.

[0018] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD), oran ocular implant comprising the ASD as defined herein, wherein the polymer excipient is apolyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0019] In certain embodiments, the invention relates to an ocular implant comprising the ASDas defined herein, or an amorphous solid dispersion (ASD) as defined herein, wherein thepolymer excipient is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®).

[0020] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD), oran ocular implant comprising the ASD as defined herein, wherein the polymer excipient is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), that mayhave an average molecular weight (Mw) determined by gel permeation chromatography ofapproximately 50,000 to 200,000 g / mol, such as about 60,000 to 180,000 g / mol, or about 90,000to 140,000 g / mol, or a peak Mw of about 100,000 to 130,000 g / mol, such as about 118,000 g / mol.

[0021] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD), oran ocular implant comprising the ASD as defined herein, wherein the polymer excipient is a mixture of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and a polymer selected from the group consisting of polyvinyls such as polyvinyl pyrrolidone-vinyl acetate (PVPVA), polyvinylpyrrolidone (PVP), povidone (PVP), such as povidone K25, povidone K17 or povidone K30; polyethylene glycols (PEG), poloxamers such as poloxamer 188, Pluronic®F127 or Pluronic F68®; polyacrylates and methacrylates such as Carbomer, Eudragit®EPO or Eudragit®RL PO; and cellulose and its derivatives such as methyl cellulose, hydroxypropyl methylcellulose (HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0022] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD), oran ocular implant comprising the ASD as defined herein, wherein the polymer excipient isa mixture of the graft co-polymer polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol(Soluplus®) and hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0023] In an embodiment of the ocular implant or the ASD itself, the amorphous solid dispersion(ASD) includes 1 to 90 wt.% of the TKI, or 10 to 80 wt.%, or 20 to 70 wt.%, such as 25 to 60wt.%, or 30 to 50 wt.%, based on the total weight of the ASD.

[0024] In certain embodiments, the weight ratio of the TKI inhibitor and the polymer excipient inthe ASD ranges from 1:1 to 1:4, such as from 1:2 to 1:3.5.

[0025] In a preferred embodiment, the TKI is axitinib and the weight ratio of axitinib and thepolymer excipient in the ASD ranges from 1:1 to 1:4, such as from 1:2 to 1:3.5, or from 1:2.5 to1:3.

[0026] In certain embodiments, the ASD comprises axitinib in an amount of from about 1% byweight to about 90% by weight, such as in an amount of from about 20% by weight to about70% by weight, particularly preferred in an amount of from about 25% by weight to about 50% by weight, based on the total amount of the ASD.

[0027] In certain embodiments, the ASD comprises about 25% by weight axitinib and about75% by weight Soluplus®based on the total amount of the ASD.

[0028] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD), oran ocular implant comprising the ASD as defined herein, having a solubility enhancement ofgreater than 1, such as greater than 1.5, or greater than 2, particularly greater than 3, comparedto crystalline axitinib measured by using the axitinib solubility method described herein (seeExample 6).

[0029] In an embodiment, the ocular implant essentially consists of the amorphous soliddispersion (ASD) comprising a tyrosine kinase inhibitor (TKI) and a polymer excipient asdescribed herein. In one embodiment the ASD may be delivered as a particle slurry. Forexample, in an embodiment, spray dried ASD particles or milled HME strands can be deliveredin an oil carrier or aqueous solution. Such a slurry may be delivered via intravitreal injectionthrough a 30G-25G needle. The oil carrier may be any of a physiologically acceptablehydrophobic liquid or solvent.

[0030] In another embodiment, the ASD comprising a tyrosine kinase inhibitor (TKI) and apolymer excipient forms a part of the ocular implant.

[0031] In certain embodiments, the ASD is dispersed and / or embedded in a hydrogel implant,such as a biodegradable hydrogel.

[0032] In certain embodiments, the ocular implant comprises a hydrogel portion and the ASD isin separate portions of the implant, such as a stack comprising a hydrogel portion and an ASDportion or a hydrogel portion coated with the ASD.

[0033] In an embodiment, the ocular implant comprises a hydrogel that is at least partiallycoated with the ASD.

[0034] In an embodiment, the implant comprises a sustained release hydrogel comprising theTKI, and a separate portion of the implant comprises the ASD comprising the TKI. In suchimplants, the separate portion of the implant comprising the ASD comprising the TKI is a tipportion or a coating, such as a partial or complete surface coating, of a hydrogel implant, suchas a cylindrical ocular implant or insert, or a plug.

[0035] In an embodiment, a part of the tyrosine kinase inhibitor, optionally in the form ofparticles, such as micronized particles, can be dispersed within the hydrogel, and further TKI,the same or different, preferably the same, can be comprised in the ASD.

[0036] In an embodiment, the hydrogel comprises a polymer network comprising one or moreunits of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyaminoacids, glycosaminoglycans, polysaccharides, or proteins.

[0037] In an embodiment, the hydrogel comprises a polymer network that comprisescrosslinked polymer units, such as one or more crosslinked multi-arm polymer units, which areidentical or different, optionally wherein crosslinked polymer units are one or more crosslinked polyethylene glycol units.

[0038] In an embodiment, the polymer network comprises polyethylene glycol units having anaverage molecular weight (Mn) in the range from about 2,000 to about 100,000 Daltons, suchas about 10,000 to about 60,000 Daltons, or about 20,000 to about 40,000 Daltons such as about 20,000 Daltons.

[0039] In certain embodiments, the ocular implant has an essentially cylindrical shape, oranother cross-sectional shape. In an embodiment, the ocular implant is in the form of a fiber orfilament, or a plurality of filaments.

[0040] The present invention, in another aspect, relates to an amorphous solid dispersion(ASD), or an ocular implant comprising the ASD as defined herein, for use as a medicament, such as for treating an ocular disease, disorder, or medical condition.

[0041] In an embodiment thereof, the implant comprises a hydrogel in a dried state prior toadministration, and the hydrogel becomes hydrated once administered into the eye, optionallywherein the implant in a dried state contains not more than about 1 % by weight water.

[0042] The present invention, in another embodiment, relates to a method comprising treating adisease, disorder, or medical condition in a patient with an amorphous solid dispersion (ASD) oran ocular implant comprising the ASD as defined herein, comprising administering the ocularimplant or ASD as defined herein to a patient in need thereof.

[0043] The present invention, in another aspect, relates to the amorphous solid dispersion(ASD) or the ocular implant comprising the ASD as defined herein, for use as defined above orfor use in the method of treatment as defined above, wherein the amorphous solid dispersion(ASD) or an ocular implant comprising the ASD is used for a treatment of an ocular disease.

[0044] In certain embodiments, the ocular disease can be a disease, disorder or medicalcondition such as back-of-the-eye diseases such as 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, particularly disease states of the posterior segment resulting from age, trauma, surgical interventions, such as age-related macular degeneration (AMD) cystoid macular edema (CME), diabetic macular edema (DME), posterioruveitis, and diabetic retinopathy.

[0045] In certain embodiments of the use or method defined above, the amorphous soliddispersion (ASD) or ocular implant comprising the ASD is used in the treatment of an ocular disease selected from the group consisting of retinal neovascularisation, choroidal neovascularisation, Wet AMD, Dry AMD, retinal vein occlusion, diabetic macular edema, retinal degeneration, hyphema, presbyopia, corneal graft rejection, retinoblastoma, melanoma, myosis, mydriasis, glaucoma, conjunctivitis, intraocular infections, choroidal neovascularization (CNV), intraocular tumors, retinal neuroinflammation, inflammation, autoimmune uveitis, uveitis, proliferative vitreoretinopathy, and corneal degeneration, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, posterior uveitis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis, uveitis syndrome, Vogt-Koyanagi Harada syndrome, retinal arterial occlusive disease, central retinal vein occlusion, disseminatedintravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy, angioid streaks, familial exudative vitreoretinopathy, Eales disease, proliferative vitreal retinopathy, diabetic retinopathy, retinal disease associated with tumors, congenital hypertrophy of the retinal pigment epithelium (RPE), posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors, myopic retinal degeneration, acute retinal pigment epithelitis, glaucoma, endophthalmitis, cytomegalovirus retinitis, retinal cancers, retinitis pigmentosa, Leber's Congenital Amaurosis, Choroideremia, X- linked 106 retinitis pigmentosa, best vitelliform macular dystrophy, x-linked retinoschisis,achromatopsia CNGA3, achromotopsia CNGB3, LHON, Stargardt disease, Usher syndrome,Norrie disease, Bardet-Biedl syndrome, and red-green color blindness.

[0046] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD) asdefined above or to an ocular implant comprising the ASD as defined herein, wherein the ASD or the ocular implant comprises the TKI, such as axitinib, in a dose of at least 15 μg, such as from about 15 μg to about 1200 μg, from about 15 μg to about 1000 μg, from about 150 μg to about 900 μg, or from about 200 μg to about 800 μg, or from about 250 μg to about 700 μg, or from about 300 to about 650 μg.

[0047] In certain embodiments, the ocular implant can be administered to the eye through aneedle. In an embodiment, the needle is a 25- or 27-gauge needle.

[0048] In certain embodiments of the ocular implant for use or the method of treatment, uponhydration in vivo in the eye, or in vitro, the diameter of the implant is increased as compared tothe dry state thereof, or the length of the implant is decreased while its diameter is increased, wherein hydration is measured in vitro in phosphate-buffered saline at a pH of 7.2 at 37 °C after 24 hours.

[0049] The present invention, in another aspect, relates to a process for preparing anamorphous solid dispersion (ASD) or an ocular implant comprising an amorphous soliddispersion (ASD) as defined herein, comprising the following steps:(a) dispersing the tyrosine kinase inhibitor (TKI), such as axitinib, or a pharmaceuticallyacceptable salt, derivative, or prodrug thereof within the polymer excipient matrix,wherein the polymer excipient is as defined herein, optionally using one or moresolvents; and (b) optionally removing the one or more solvent to obtain the amorphous solid dispersion(ASD).

[0050] In an embodiment, the process further comprises a step of dispersing the ASD includingthe TKI in a hydrogel, or at least partially coating a hydrogel with the ASD including the TKI.

[0051] In certain embodiments, the one or more solvent comprises one or more chlorinatedhydrocarbon solvents such as dichloromethane, dichloroethane, and chlorobenzene; alcoholic solvents such as methanol, ethanol, 2-propanol, 1-butanol and t-butyl alcohol; N,N- dimethylformamide; nitriles such as acetonitrile; dimethyl sulfoxide; water and mixtures thereof, preferably the solvent is acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide.

[0052] In certain embodiments, removing of the solvent may comprise distillation, distillationunder vacuum, spray drying, freeze-drying (lyophilization), filtration, decantation and / or centrifugation.

[0053] In an embodiment, the step of dispersing the tyrosine kinase inhibitor (TKI), such asaxitinib, or a pharmaceutically acceptable salt, derivative or prodrug thereof, within the polymer excipient matrix can involve solvent-free extrusion.

[0054] In an embodiment thereof, the process can comprise the following steps:(a) feeding the tyrosine kinase inhibitor (TKI), such as axitinib, or a pharmaceuticallyacceptable salt, derivative, or prodrug thereof, and a polymer excipient as defined herein into a heated extruder to obtain a melt mixture; (b) extruding the melt mixture to obtain an ocular implant comprising an amorphoussolid dispersion (ASD).

[0055] In an embodiment, the process can further comprise coextruding the melt in addition tocrosslinkable hydrogel precursor compounds, or simultaneously coextruding a hydrogel and theASD as defined herein, for example, as a coextruded sheath of ASD over the hydrogel.

[0056] In certain embodiments, the process further comprises mixing the components in theextruder; extruding a strand; optionally stretching the strand into a fiber or filament; and cutting the strand, fiber or filament into unit dose ocular implants.

[0057] In certain embodiments, the tyrosine kinase inhibitor (TKI), such as axitinib, ora pharmaceutically acceptable salt, derivative, or prodrug thereof, and the polymer excipient arefed separately into the extruder, or wherein the tyrosine kinase inhibitor (TKI), such as axitinib,or a pharmaceutically acceptable salt or prodrug thereof, and the polymer excipient are mixedprior to being fed into the extruder.

[0058] In certain embodiments, the tyrosine kinase inhibitor (TKI), such as axitinib, ora pharmaceutically acceptable salt, derivative, or prodrug thereof, and the polymer excipient aremelt mixed and / or milled prior to being fed into the extruder.

[0059] In certain embodiments, the tyrosine kinase inhibitor (TKI) is axitinib, ora pharmaceutically acceptable salt or prodrug thereof, and the process further comprisesmelting the mixture in the extruder or before feeding into the heated extruder at a temperature offrom about 55°C to about 200°C, such as of from about 65°C to about 180°C, and particularlyfrom about 100°C to about 160°C.

[0060] In certain embodiments, the invention relates to an ocular implant as defined herein,wherein the average release rate of tyrosine kinase inhibitor per day from the implant over aperiod defined by any initial number of days up to the day when 80% of the tyrosine kinaseinhibitor contained in the implant is released, is higher than the average release rate of tyrosinekinase inhibitor per day from a comparative implant including the same TKI in the same amountbut no ASD, over the same period of time, wherein the release of tyrosine kinase inhibitor fromboth implants is measured under identical conditions. In certain embodiments, the average release rate, of tyrosine kinase inhibitor from the implant over said period of time is at least10%, or at least 20% higher than the average release rate of tyrosine kinase inhibitor over saidperiod of time from the comparative implant including the same TKI in the same amount but noASD, measured under identical conditions.

[0061] In certain embodiments, the average release rate, such as measured in PBS at a pH of7.2 to 7.4 and 37 °C, of tyrosine kinase inhibitor from the implant in the first half hour, or in thefirst 1, 2 or 3 hours, is higher than the average release rate of tyrosine kinase inhibitor from thecomparative implant including the same TKI in the same amount but no ASD.

[0062] In certain embodiments, the implant provides for an average in vivo release rate in thevitreous of at least 0.5 μg / day, such as at least 0.6 μg / day, or at least 0.7 μg / day, or at least 0.8μg / day for a period of at least 3 months, measured in the vitreous of a non-human primate, suchas a monkey, or in the vitreous of a human.

[0063] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD) oran ocular implant as defined herein, wherein the ASD or the implant is loaded in a needlehaving a gauge of from 20 to 30, such as from 25 to 27.

[0064] The present invention, in another aspect, relates to a needle comprising an amorphoussolid dispersion (ASD) or an ocular implant as defined herein, wherein the needle may have agauge of from 20 to 30, such as from 25 to 27. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 shows the results of a recrystallization inhibition assay demonstrated withAxitinib.

[0066] Figure 2 shows the effect of polymer concentration on API recrystallization of Axitinib.

[0067] Figure 3 shows the DSC analysis of 25% axitinib – Soluplus® ASDs.

[0068] Figure 4 shows time zero DSC analysis of 25% Axitinib blended with Soluplus®

[0069] Figure 5 a) shows the DSC analysis of the axitinib ASDs at different storage conditionsafter one week.

[0070] Figure 5 b) shows the DSC analysis of the axitinib ASDs at different storage conditionsafter one month.

[0071] Figure 6 is a visual representation of ASD aging at different conditions for one month.

[0072] Figure 7 is a graph showing the solubility differences of 25% Axitinib ASDs after onemonth aging at different conditions.

[0073] Figure 8 shows a possible approach to delivering ASD and ELUTYX™ implants togetherto control API release rate.

[0074] Figure 9 shows a heat sealed 25% axitinib ASD needle plug.

[0075] Figure 10 shows in vitro release data of an exemplary ASD comprising axitinib measuredaccording to Method C using a SOTAX apparatus.DEFINITIONS

[0076] The term “implant” as used herein refers to an object that contains an active agent,specifically a tyrosine kinase inhibitor (TKI) such as axitinib, and / or other compounds as disclosed herein, and that is administered into the human or animal body via injection or surgical implantation, such as to the vitreous humor of the eye, or via an existing opening, such as to the canaliculus of the eye, where it remains for a certain period of time while it releases the activeagent into the surrounding environment. In certain embodiments, the implant may essentiallyconsist of an amorphous solid dispersion (ASD) comprising a tyrosine kinase inhibitor (TKI) as an active agent and a polymer excipient. In other embodiments, an ASD comprising a tyrosine kinase inhibitor (TKI) and a polymer excipient may form part of the implant.

[0077] An implant has a predetermined shape before being implanted, which general shape ismaintained to a certain degree upon placing the implant into the desired location, althoughdimensions of the implant (e.g. length and / or diameter) may change after administration due tohydration as further disclosed herein. In other words, what is administered into the body is not asolution or suspension, but an already shaped, coherent object. The implant has thus beencompletely formed as disclosed herein prior to being administered. Over the course of time theimplant may biodegrade (as disclosed herein), may thereby change its shape (e.g. may expandin diameter and decrease in length) until it has been completely dissolved / resorbed. Herein, theterm “implant” is used to refer both to an implant in a hydrated (also referred to herein as “wet”)state when it contains water, e.g. after the implant has been (re-)hydrated once administered tothe body, e.g. the eye, or otherwise immersed into an aqueous environment, and to an implantin its / a dry (dried / dehydrated) state, i.e. after the implant has been produced and dried and justprior to being loaded into a needle, or after having been loaded into a needle as disclosed herein, or wherein the implant has been manufactured in a dry state without the need fordehydration. In other words, the term “dry” or “dried” in connection with an implant of theinvention refers to the implant prior to being administered (into physiological or otherenvironment). In the art, in the dried state a “hydrogel” (such as the hydrogel contained in the implant of the invention) is sometimes also referred to as a “xerogel”. Thus, in certainembodiments, an implant in its dry / dried state in the context of the present invention maycontain no more than about 1% by weight water. The water content of an implant in its dry / driedstate may be measured e.g. by means of a Karl Fischer coulometric method. Wheneverdimensions of an implant (i.e., length, diameter, surface area, or volume) are reported herein for the hydrated state, these dimensions are measured after the implant has been immersed inphosphate-buffered saline (PBS) at 37 °C for 24 hours. Whenever dimensions of an implant arereported herein in the dry state, these dimensions are measured after the implant has been fully dried (and thus, in certain embodiments, contain no more than about 1 % by weight water) andthe implant is in a state to be loaded into a needle for subsequent administration. In certainembodiments, the implant is kept in an inert atmosphere glove box containing below 20 ppm of both oxygen and moisture for at least about 7 days.

[0078] The term “ocular” as used herein refers to the eye in general, or any part or portion of theeye (as an “ocular insert” or “ocular implant” of the invention refers to an implant that can inprinciple be administered to any part or portion of the eye). The present invention in certain embodiments is directed to intracanalicular administration of an ocular insert, and to the treatment of, e.g., dry eye disease (DED) or pain after surgery, as further disclosed herein.

[0079] The term “patient” herein includes both human and animal patients. The implantsaccording to the present invention are therefore suitable for human or veterinary medicinal applications. The patients enrolled and treated in a clinical study may also be referred to as “subjects”. Generally, a “subject” is a (human or animal) individual to which an insert or implant according to the present invention is administered, such as during a clinical study. An animal subject in a study may be e.g. a non-human primate, such as a monkey, such as a Cynomolgus monkey, or may be a rodent, such as a rabbit, such as a Dutch Belted rabbit. A “patient” is a subject in need of treatment due to a particular physiological or pathological condition. In a preferred embodiment of the invention, the patient is a human.

[0080] The term “biodegradable” as used herein refers to a material or object (such as theintracanalicular implant according to the present invention) which becomes degraded in vivo,i.e., when placed in the human or animal body. In the context of the present invention, asdisclosed in detail herein, the implant comprising the hydrogel within which particles of an activeagent are dispersed, slowly biodegrades over time once deposited within the body or eye, e.g., within the canaliculus. In certain embodiments, biodegradation takes place at least in part via ester hydrolysis in the aqueous environment provided by the tear fluid. In certain embodiments,the intracanalicular implants of the present invention slowly soften and liquefy, and areeventually cleared (disposed / washed out) through the nasolacrimal duct.

[0081] The term “hydrogel” used herein refers to a three-dimensional network of hydrophilicnatural or synthetic polymers (as disclosed herein) that can swell in water and hold an amount of water (e.g., greater than 25%, greater than 50%, greater than 75% or from 25% to about 90% or from about 705 to about 99%) while maintaining or substantially maintaining its structure, e.g., due to chemical or physical cross-linking of individual polymer chains. Due to their high water content, hydrogels are soft and flexible, which makes them very similar to natural tissue. In the present invention the term “hydrogel” is used to refer both to a hydrogel in the hydratedstate when it contains water (e.g. after the hydrogel has been formed in an aqueous solution, or after the hydrogel has been (re-)hydrated once inserted or implanted into the eye or otherwiseimmersed into an aqueous environment) and to a hydrogel in its / a dry (dried / dehydrated) state,also called a xerogel, when it has been dried to a low water content of e.g. not more than 1% by weight. In the present invention, wherein an active principle is contained (e.g. dispersed) in a hydrogel, the hydrogel may also be referred to as a “matrix”.

[0082] The term “polymer network” as used herein describes a structure formed of polymerchains (of the same or different molecular structure and of the same or different average molecular weight) that are cross-linked with each other. Types of polymers suitable for the purposes of the present invention are disclosed herein. The polymer network may be formed with the aid of a crosslinking agent as also disclosed herein. The polymer network may comprise polyethylene glycol units having an average molecular weight (Mn) in the range from about 2,000 to about 100,000 Daltons, such as about 10,000 to about 60,000 Daltons, or about 20,000 to about 40,000 Daltons such as about 20,000 Daltons.

[0083] The term “amorphous” refers to a polymer or polymer network which does not exhibitcrystalline structures in X-ray or electron scattering experiments.

[0084] The term “semi-crystalline” refers to a polymer or polymer network which possessessome crystalline character, i.e., exhibits some crystalline properties in X-ray or electron scattering experiments.

[0085] The term “precursor“ or “polymer precursor” herein refers to those molecules orcompounds that are reacted with each other and that, once reacted, are thus connected via crosslinks to form the polymer network and thus the hydrogel matrix. While other materials might be present in the hydrogel, such as active agents, visualization agents or buffers, they are not referred to as “precursors”.

[0086] The molecular weight of a polymer precursor as used for the purposes of the presentinvention and as disclosed herein may be determined by analytical methods known in the art. The molecular weight of polyethylene glycol can for example be determined by any method known in the art, including gel electrophoresis such as SDS-PAGE (sodium dodecyl sulphate– polyacrylamide gel electrophoresis), gel permeation chromatography (GPC), including GPC with dynamic light scattering (DLS), liquid chromatography (LC), as well as mass spectrometry such as matrix-assisted laser desorption / ionization-time of flight (MALDI-TOF) spectrometry or electrospray ionization (ESI) mass spectrometry. The molecular weight of a polymer, including a polyethylene glycol precursor as disclosed herein, is an average molecular weight (based on the polymer’s molecular weight distribution), and may therefore be indicated by means of various average values, including the weight average molecular weight (Mw) and the number average molecular weight (Mn). Any of such average values may be used in the context of the present invention. In certain embodiments, the average molecular weight of the polyethylene glycol units or other precursors as disclosed herein is the number average molecular weight.

[0087] The parts of the precursor molecules that are still present in the final polymer networkare also called “units” herein. The “units” are thus the building blocks or constituents of thepolymer network forming the hydrogel. For example, a polymer network suitable for use in the present invention may contain identical or different polyethylene glycol units as further disclosed herein.

[0088] As used herein, the term “crosslinking agent” refers to any molecule that is suitable forconnecting precursors via crosslinks to form the polymer network and thus the hydrogel matrix.Crosslinking agents may be low-molecular weight compounds or may be polymeric compounds as disclosed herein.

[0089] The term “release” (and accordingly the terms “released”, “releasing” etc.) as usedherein refers to the provision of agents such as an active (pharmaceutical) ingredient (API) froman implant of the present invention to the surrounding environment. The surrounding environment may be an in vitro or in vivo environment as described herein. In certain specific embodiments, the surrounding environment is the vitreous humor and / or ocular tissue, such as the retina or the choroid. Thus, whenever it is herein stated that the implant “releases” or “provides for (sustained) release” of a TKI such as axitinib, this not only refers to the provision of TKI such as axitinib directly from the implant while the hydrogel has not yet (fully) biodegraded,but also refers to the continued provision of TKI such as axitinib to the surrounding environmentfollowing full degradation of the hydrogel when remaining undissolved TKI is still present in this surrounding environment (e.g. as individual or agglomerated particles) for a period of time in which the TKI continues to exert its therapeutic effect.

[0090] The term “sustained release” is defined for the purposes of the present invention to referto pharmaceutical dosage forms which are formulated to make an active agent available over an extended period of time after administration, such as one or more weeks, thereby allowing areduction in dosing frequency compared to an immediate release dosage form, e.g. a solution ofan active agent that is topically applied onto the eye (e.g., glucocorticoid-comprising eye drops). Other terms that may be used herein interchangeably with “sustained release” are “extended release” or “controlled release”. Within the meaning of the invention, the term “sustained release” also comprises a period of constant active agent release per day, which may be followed by a period of tapered active agent release. In other words, during a “sustained release” period, the release rate is not necessarily constant or essentially constant, but may change over time. Within the meaning of the invention, the term “tapered” or “tapering” refers to a decreasing rate of release of active agent such as dexamethasone over time, e.g., until the active agent is completely released.

[0091] In certain embodiments of the invention, implants are characterized by the release profileof the TKI, such as axitinib, as measured in certain in vitro tests. In such in vitro tests, which arefurther disclosed herein, the amount of TKI released during a particular period of time, such as over a period of one or more days, may be determined in terms of the absolute amount (such asin μg) released per day on any given day during the course of the in vitro test (the amountreleased per day also defines the “release rate per day” or “rate of release per day”), or the cumulative absolute amount (again, such as in μg or mg) released over that period of time, suchas the cumulative amount released over a period of 10 days. In in vitro tests, also thepercentage of release may be determined, either the percentage released per day (or over a period of several days), or the cumulative percentage released over a certain period of time, such as over e.g.10 days. The percentage may be defined as being a percentage (ratio / share)of the entire amount (drug load) contained in a certain inserts or implant, or it may be defined asbeing a percentage (ratio / share) of the total amount released from a certain implant in therespective in vitro test (which in certain cases is lower than the actual total amount of activecontained in the implant, e.g. in cases where the release determined in an in vitro testapproaches an equilibrium amount of drug released, which is lower than the actual drug load ofthe implant for a variety of reasons, or in cases where the in vitro test is terminated before all ofthe contained drug load has been released).

[0092] In the context of in vitro release tests, the “amount” herein refers to a weight, such as μgor mg, while the “percentage” (or “share” or “ratio”) refers to a percentage (%).

[0093] The term “average release rate” (such as in μg / day) as used herein, refers to theaverage amount (such as in μg) released per day over a certain number of days. It is calculated by dividing the absolute (cumulative) amount of active agent released over a certain number ofdays by that number of days. By means of example, if one implant of the invention releases atotal (cumulative) amount of 100 μg axitinib over a period of 5 days, the average release rate would be 20 μg / day for this period of 5 days. The actual release rate on any single given day within this period of 5 days may of course differ from the average release rate over the entire period.

[0094] Whenever in the context of in vitro tests and determining the release (rate) of an activeagent from an implant of the invention it is referred herein to an “initial” number of days, or an“initial” period, e.g. an “initial period of 5 days”, this means the period covering the respectivenumber of days from the very start of the respective in vitro test (e.g., the first 5 days of the invitro test).

[0095] In vitro tests may be conducted in various solvents and under various conditions, asdisclosed herein in detail whenever referring to any particular release characteristics. Generally,one implant (or several implants simultaneously if specifically mentioned) is placed into a certainvolume of solvent or solvent mixture and at a certain temperature (which is maintained over thecourse of the in vitro test) as disclosed herein, and the release amount or percentage isdetermined on pre-determined days. The volume of solvent (mixture) into which the implant isplaced for such an in vitro test is determined by a “sink factor” by which a “sink volume” ismultiplied. The “sink volume” is calculated by dividing the amount (such as in μg) of active agentcontained in the implant to be studied by the solubility of that active agent (such as in μg / mL) inthe solvent (mixture) in which the test is to be conducted. For example, if the in vitro test for animplant of the invention that contains axitinib as the TKI is conducted in a solvent mixture of25% ethanol / 75% water (v / v), the amount of axitinib contained in the implant studied is dividedby the solubility of the axitinib in this solvent mixture to determine the sink volume. The solubility of the active agent may differ depending on which form of the active agent is used, as further disclosed herein. For example, different polymorphic forms of an active agent may have different solubilities in the same solvent (mixture). Also, different salts, or co-crystals, or derivatives of an active agent may have different solubilities in the same solvent (mixture). Depending on the purpose of the test and the specific details of the test method applied, either these specific solubility values for the different forms of the active agent are used to calculate the “sink volume”, or for certain simplified or comparative tests also an average solubility for thegiven active agent is used to calculate the “sink volume”, as disclosed herein. In vitro testsreported in the present invention may be conducted under various sink conditions, as disclosed herein, such as under 2x sink conditions, or under 3x sink conditions, or with a higher sink factor, such as under 4x or higher sink conditions. “2x sink conditions” means that the volume ofsolvent (mixture) into which an insert or implant of the invention is immersed (or severalimplants if so indicated) for the specific test is two times the “sink volume” (as defined above),i.e.,. the “sink factor” in this case would be 2; “3x sink conditions” means that the volume ofsolvent (mixture) into which an insert or implant of the invention is immersed (or severalimplants if so indicated) for the specific test is three times the “sink volume” (as defined above),i.e., the “sink factor” in this case would be 3; and so on for other sink factors. Further details onin vitro tests performed with ASDs or implants of the invention in which the TKI is axitinib(specifically, on the sink factor and sink volume) are provided in the present description in thesub-section “In vitro release determination”.

[0096] The term “visualization agent” as used herein refers to a molecule or moiety that may becontained within an insert or implant of the present invention and that provides the possibility of easily visualizing the insert or implant in a non-invasive manner when it is located in the body,e.g., the canaliculus of the eye, e.g. by illuminating the corresponding eye parts with a suitablelight source.

[0097] As used herein, the term “ocular surface” comprises the conjunctiva and the cornea,together with elements such as the lacrimal apparatus, including the lacrimal punctum, as well as the lacrimal canaliculus and associated eyelid structures. Within the meaning of this invention, the ocular surface encompasses also the aqueous humor.

[0098] As used herein, the terms “tear fluid” or “tears” or “tear film” refer to the clear liquidsecreted by the lacrimal glands, which lubricates the eyes. Tears are made up of water, electrolytes, proteins, lipids, and mucins.

[0099] As used herein, the term “bilaterally” or “bilateral” refers (in the context of administrationof the implants of the present invention) to an administration of the implants into both eyes of apatient. “Unilaterally” or “unilateral” thus refers to an administration of the insert or implant intoone eye only. The implants may be inserted into the superior and / or the inferior canaliculus ofboth eyes or of one eye.

[0100] As used herein, the terms “administration” or “administering” or “administered” etc. in thecontext of the implants of the present invention refer to the process of insertion, injection orsurgical implantation of the implants into the body or eye. In certain embodiments, theformulation is inserted through the opening of the punctum into the canaliculus of the eye. The terms “administration” or “administering” or “administered” etc. in the context of topical ophthalmic pharmacological products such as eye drops (which are not the subject of the present invention) refer to topical application of these products onto the eye.

[0101] The term “plug” as used herein refers to a device capable of providing an occlusion ofthe tear duct(s) (“lacrimal occlusion”) thereby preventing draining of tears. A plug thus increases tear retention, which helps to keep the eyes moist. Plugs can be classified into “punctal plugs” and “intracanalicular plugs”. Intracanalicular plugs are also referred to as “canalicular plugs” in literature. Both plug classes are inserted through the upper and / or lower punctum of the eye. Punctal plugs rest at the punctal opening making them easily visible and, hence, removable without much difficulty. However, punctal plugs may show poor retention rates and can be more easily contaminated with microbes due to their exposed localization resulting in infection. In contrast, intracanalicular plugs are essentially not visible and provide a better retention rate compared to punctal plugs as they are placed inside either the vertical or the horizontal canaliculus. However, currently available intracanalicular plugs may not be easy to remove and / or may provide an increased risk of migration due to loose fit. Commercially available plugs are often made of collagen, acrylic polymers, or silicone.

[0102] The terms “canaliculus” (plural “canaliculi”) or alternatively “tear duct” as used hereinrefer to the lacrimal canaliculus, i.e. the small channels in each eyelid that drain lacrimal fluid (tear fluid) from the lacrimal punctum to the nasolacrimal duct. Canaliculi therefore form part of the lacrimal apparatus that drains lacrimal fluid from the ocular surface to the nasal cavity. The canaliculus in the upper eyelid is referred to as “superior canaliculus” or “upper canaliculus”, whereas the canaliculus in the lower eyelid is referred to as “inferior canaliculus” or “lower canaliculus”. Each canaliculus comprises a vertical region, referred to as “vertical canaliculus” following the lacrimal punctum and a horizontal region, referred to as “horizontal canaliculus” following the vertical canaliculus, wherein the horizontal canaliculus merges into the nasolacrimal duct.

[0103] The term “punctum” (plural “puncta”) refers to the lacrimal punctum, an opening on themargins of the eyelids, representing the entrance to the canaliculus. After tears are produced, some fluid evaporates between blinks, and some is drained through the lacrimal punctum. As both the upper and the lower eyelids show the lacrimal punctum, the puncta are therefore referred to as “upper punctum” or “superior punctum” and “lower punctum” or “inferior punctum”.

[0104] The term “intracanalicular insert” refers to an insert that can be administered through theupper and / or lower punctum into the superior and / or inferior canaliculus of the eye, in particular into the superior and / or inferior vertical canaliculus of the eye. Due to the intracanalicular localization of the insert, the insert blocks tear drainage through lacrimal occlusion such as also observed for intracanalicular plugs. The intracanalicular inserts of the present invention may be insert inserted bilaterally or unilaterally into the inferior and / or superior vertical canaliculi of the eyes. According to the present invention, the intracanalicular insert is a sustained release biodegradable insert.

[0105] The terms “API”, “active (pharmaceutical) ingredient”, “active (pharmaceutical) agent”,“active (pharmaceutical) principle”, “(active) therapeutic agent”, “active”, and “drug” are used interchangeably herein and refer to the substance used in a finished pharmaceutical product (FPP) as well as the substance used in the preparation of such a finished pharmaceutical product, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of a disease, or to have direct effect in restoring, correcting or modifying physiological functions in a patient.

[0106] For the purposes of the present invention, active agents in all their possible forms,including any active agent polymorphs or any pharmaceutically acceptable salts, anhydrates, hydrates, other solvates or derivatives of active agents, can be used. Whenever in this description or in the claims an active agent is referred to by name, e.g., “axitinib”, even if not explicitly stated, it also refers to any such pharmaceutically acceptable polymorphs, salts,anhydrates, solvates (including hydrates), derivatives, or prodrugs of the active agent.

[0107] The term “prodrug” as used herein refers to a bio reversible derivative of a drug moleculethat undergoes an enzymatic and / or chemical transformation in vivo to the active (parent) drug,which can then exert its desired pharmacological effect. A prodrug may alter the physicochemical, biopharmaceutical or pharmacokinetic properties of a drug in order to alter, and in certain cases to improve, one or more aspects of the therapeutic applicability, availability and usefulness of the respective drug. For example, a prodrug may be more readily soluble than the parent drug, and by using such prodrug the bioavailability of the parent drug may be increased. A “prodrug” in certain embodiments may be a derivative of a drug, as defined above. For example, a prodrug may be a derivative of a drug wherein at one or more sites of the drug molecule groups are attached which are cleaved again upon immersion in a physiological environment. In other embodiments, a “prodrug” may also be a precursor of the active (parent) drug comprising a portion of the active drug molecule, wherein the precursor reacts in physiological environment with other components being present in said physiological environment, or being intentionally administered for that purpose, to build the structure of theactive (parent) drug. In a preferred embodiment, the prodrug used herein is axitinib N-m(PEG)4-oxymethyl prodrug or axitinib N-succinoyloxymethyl that can be synthesized as disclosed inUS provisional application 63 / 416,292 and International application PCT / US2023 / 035121 fromaxitinib free base.

[0108] The term “polymorph” as used herein refers to any crystalline form of an active agentsuch as axitinib. Frequently, active agents that are solid at room temperature exist in a variety of different crystalline forms, i.e., polymorphs, with one polymorph being the thermodynamically most stable at a given temperature and pressure. Axitinib polymorphs for use in the present invention are further disclosed herein.

[0109] As used herein, the term “therapeutically effective” refers to the amount of drug or activeagent (e.g., axitinib) required to produce a desired therapeutic response or result after administration.

[0110] The term “average” as used herein refers to a central or typical value in a set of data,which is calculated by dividing the sum of the values in the set by their number.

[0111] As used herein, the term “about” in connection with a measured quantity refers to thenormal variations in that measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment.

[0112] As used herein, the singular forms "a," "an", and "the" include plural references unlessthe context clearly indicates otherwise.

[0113] The term "and / or" as used in a phrase such as "A and / or B" herein is intended to includeboth "A and B" and "A or B”.

[0114] Open terms such as "include," "including," "contain," "containing" and the like as usedherein mean "comprising" and are intended to refer to open-ended lists or enumerations ofelements, method steps, or the like and are thus not intended to be limited to the recitedelements, method steps or the like but are intended to also include additional, unrecited elements, method steps or the like.

[0115] The term “up to” when used herein together with a certain value or number is meant toinclude the respective value or number. For example, the term “up to 25 days” means “up to and including 25 days”.

[0116] All references disclosed herein are hereby incorporated by reference in their entirety forall purposes (with the instant specification prevailing in case of conflict).DETAILED DESCRIPTION OF THE INVENTIONTHE OCULAR IMPLANT OF THE INVENTION COMPRISING AN AMORPHOUS SOLIDDISPERSION (ASD) Solubility enhancement of TKI in ASD:

[0117] The amorphous solid dispersion (ASD) stabilizes the TKI in an amorphous state andenhances the dissolution rate and bioavailability of such poorly water-soluble TKIs, such asaxitinib, upon administration. The TKI, such as axitinib, is dispersed in a polymer excipient, thereby lowering the total energy required for its solubilization. Polymer excipients help toimprove the solubilization and bioavailability of the TKI through their interaction. The polymerexcipient can stabilize the ASD, prevent drug recrystallization through interaction between the TKI and the polymer excipient, and improve physical stability. The TKI is molecularly dispersed and ‘frozen’ within the amorphous matrix of the polymer excipient, preventing the TKI from crystallizing and lowering the molecular mobility until the TKI is released into the aqueous environment of the eye.

[0118] In certain embodiments, the amorphous solid dispersion (ASD) comprising a TKI, suchas axitinib, as defined herein, provides a solubility enhancement of greater than 1, such asgreater than 1.5, or greater than 2, particularly greater than 3 compared to the crystalline TKI,such as axitinib, as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37°C after five days of incubation, such as described in Example 6). In an embodiment, an ASDimplant of the invention comprising axitinib has a solubility enhancement of axitinib of 2.4 or greater. The active principle:

[0119] In one aspect, the invention relates to an ocular implant comprising an amorphous soliddispersion (ASD), the ASD comprising a tyrosine kinase inhibitor (TKI), such as axitinib,a pharmaceutically acceptable salt, derivative, or prodrug thereof, and a polymer excipient.Moreover, the ocular implant comprising the amorphous solid dispersion (ASD) can (essentially)consist of the amorphous solid dispersion (ASD) comprising a tyrosine kinase inhibitor (TKI) and a polymer excipient, or the ASD comprising a tyrosine kinase inhibitor (TKI) and a polymer excipient forms only a part of the implant, such as a hydrogel implant coated or stacked with the ASD.

[0120] The active principle contained in an amorphous solid dispersion (ASD), and thus in theocular implant is a TKI. Examples for suitable TKIs are axitinib, lapatinib, sorafenib, imatinib, gefitinib, erlotinib, nilotinib, pazopanib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib, vandetanib, and dasatinib, or pharmaceutically acceptable salts, derivatives or prodrugs of any one thereof. In particular embodiments, the TKI used in this and other aspectsof the present invention is axitinib. Details on axitinib, its chemical structure, polymorphs, solvates, salts etc. and its properties such as solubility are provided herein.

[0121] In a preferred embodiment of the present invention, the ocular implant comprising theamorphous solid dispersion (ASD) contains axitinib as the tyrosine kinase inhibitor. Axitinib freebase is the active ingredient in INLYTA® tablets (Pfizer, NY), indicated for the treatment ofadvanced renal cell carcinoma by oral administration. It is a small molecule (386.47 Daltons)synthetic tyrosine kinase inhibitor. The primary mechanism of action is inhibition of angiogenesis (the formation of new blood vessels) by inhibition of receptor tyrosine kinases, primarily:VEGFR-1, VEGFR-2, VEGFR-3, PDGFR- and c-Kit (Keating. Axitinib: a review in advancedrenal cell carcinoma.2015, Drugs, 75(16):1903-13; Kernt et al., Inhibitory activity of ranibizumab, sorafenib, and pazopanib on light-induced overexpression of platelet-derived growth factor and vascular endothelial growth factor A and the vascular endothelial growth factor receptors 1 and 2 and neuropilin 1 and 2.2012, Retina, 32(8):1652-63), which are involved in pathologic angiogenesis, tumor growth, and cancer progression. Axitinib is therefore a multi-target inhibitor that inhibits both VEGF and PDGF pathways.

[0122] Axitinib inhibits VEGF signaling and it also inhibits PDGF signaling. In addition toinhibiting VEGF / PDGF, it inhibits c-kit, a survival factor for developing blood vessels with aclearance half-life (t1 / 2) of a few hours (Rugo et al., Phase I trial of the oral anti angiogenesisagent AG-013736 in patients with advanced solid tumors.2005, J Clin Oncol., 23(24):5474-83), whereas ranibizumab and aflibercept each have t1 / 2of several days in the human eye. Longer t1 / 2of these large molecule antibodies enable them to maintain efficacious tissue concentrations for weeks, whereas small molecules are cleared more quickly. However, due to the low solubility of axitinib and its inclusion in the implant of the present invention which remains in the vitreous humor (VH) for an extended period of time, such as for months, therapeutically effective amounts of axitinib are delivered over the period the implant persists in the VH. Therefore, intravitreal sustained delivery of axitinib provides a multi-target inhibitor that can in principle inhibit both VEGF and PDGF pathways without the need of combination therapies and without the need for frequent intravitreal injections.

[0123] The molecular formula of axitinib free base is C22H18N4OS, and its IUPAC name isN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide. It has the following chemical structure:

[0124] For the purposes of the present invention in all its aspects, axitinib in all its possibleforms, including any axitinib salts, anhydrates, hydrates, other solvates, polymorphs, derivatives or prodrugs of axitinib, or any mixtures thereof, 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 axitinibsalt, anhydrate, solvate (including hydrates), co-crystal, polymorph, derivative or prodrug ofaxitinib. For the purpose of the present invention, all forms of axitinib used in implants areintended to be pharmaceutically acceptable. Axitinib is commercially available and can beobtained by methods known to the skilled person.

[0125] In certain embodiments of the present invention, specific forms of axitinib, such aspolymorphs or co-crystals may be used for preparing ASDs. In one embodiment, axitinibpolymorph IV can be used for preparing the ASDs and ocular implants of the invention, althoughits structure may not be retained in the ASD. In other embodiments, axitinib free base is usedfor inclusion in the amorphous solid dispersion, optionally micronized axitinib particles.

[0126] The solubility of axitinib free base in biorelevant media (e.g. PBS, pH 7.2 to 7.4, e.g. at37 °C) has been determined to be low. Different forms of axitinib, including different forms of the axitinib free base such as different axitinib salts, derivatives or prodrugs have different solubility.The solubility of axitinib can be measured according to methods known to the skilled person.Moreover, solubility measurements are described herein in Example 6, and in Example 6 ofPCT / US2024 / 023688, which is incorporated herein by reference in its entirety, and make use of a dissolution measurement in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation (such as the time needed to reach equilibrium) using UPLC with UV detection for determining concentrations of the dissolved TKI, for example with a Waters Acquity UPLC system with a photodiode array detector. Solubility of the TKI, in particular of axitinib:

[0127] The solubility of the TKI, and in particular the solubility of axitinib in certain embodimentsof the present invention, is one of the factors that influences the release profile of axitinib from an ASD or implant according to the present invention, optionally further to the solubility enhancement achieved due to incorporating the TKI in the amorphous solid dispersion. Thesolubility of axitinib free base itself is relatively low in physiologic environment, or similaraqueous solvent systems such as PBS, which limits the release rate of the drug from ASDs orimplants containing hydrogel where the release is solubility and diffusion-driven. The use of anASD including the TKI serves to improve or enhance the solubility of the TKI, such as axitinib,and to increase its bioavailability during and after release from the implant.

[0128] In particular embodiments the present invention therefore relates to ASDs and ocularimplants comprising a TKI, wherein the solubility of the TKI, such as axitinib, including any forms of axitinib as disclosed herein, is 0.3 μg / mL or greater than 0.3 μg / mL, such as at least 0.4 μg / mL, or at least 0.5 μg / mL, or at least 0.6 μg / mL, at least 0.7 μg / mL, at least 0.8 μg / mL, atleast 1 μg / mL, at least 2.5 μg / mL, at least 5 μg / mL, at least 10 μg / mL, at least 20 μg / mL, at least 50 μg / mL, at least 100 μg / mL, at least 150 μg / mL, or at least 200 μg / 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 ASDs or 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.

[0129] Without wishing to be limited by this theory, any increased solubility of axitinib (e.g. inform of a particular prodrug, or polymorph) as disclosed herein may result in a faster release ofaxitinib from the ASDs or implants of the invention, as compared to comparative implantswithout ASD . This increased solubility may manifest itself in in vitro release tests as disclosedherein in a higher release rate (released amount of axitinib per day) on one or more days of thein vitro test, and / or a higher average release rate per day (as defined herein) over a certainnumber of days, and / or an increased cumulative amount of axitinib released over a certain period of time (such as one or more days), and / or an increased share / ratio (in %) of the total amount of axitinib contained in the implant released per day or over a certain period of time (any number of days), and / or an increased share / ratio (in %) of the total released amount of axitinibin a certain in vitro test.Thus, providing an ASD or an implant comprising the ASD and containing a TKI with anincreased solubility constitutes a method of increasing the release rate per day and / or the average release rate per day over a certain period of time, and / or the percentage of released TKI on one or more individual days, and / or the cumulative percentage of released TKI (based on the total released TKI) over a certain period of time, and / or the absolute amount of TKIreleased on one or more individual days or over a certain period of time (in vivo or in vitro).Thus, the present invention also relates to such a method of increasing the release rate and / or the average release rate and / or the released amount of total TKI contained in the ASD orimplant and / or the released share of the total TKI contained in the ASD or implant or the totalTKI released from an ASD or implant in a certain period of time, as compared to known ASDs or implants containing TKI. Axitinib derivatives and prodrugs for use in the present invention:

[0130] In all aspects of the present invention, derivatives or prodrugs of the TKI, such asaxitinib, may be used in the ASDs or implants. 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 areparticularly suitable. The axitinib prodrugs are converted in vivo to axitinib. Axitinib polymorphsand prodrugs with increased solubility are described in PCT / US2024 / 023688, which is incorporated herein by reference in its entirety.

[0131] In certain specific embodiments, an axitinib prodrug to be used in the ASDs or implantsaccording 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)1-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.

[0132] Axitinib prodrugs, especially prodrugs with a hydrophilic substituent as disclosed herein,may exhibit a higher solubility than axitinib free base, and may contribute to an even further increased solubility when incorporated into amorphous solid dispersions. 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 ASDs or implants of the invention, as compared to comparative implants wherein the axitinib such as axitinib free base that is present in the ASD or implant has a lower solubility than the axitinib prodrugs.

[0133] Axitinib prodrugs for use in implants of the present invention may have a solubility inPBS at pH 7.4 after 24 hours at 22 °C of at least 50 μg / mL, or at least 90 μg / mL, or at least 150 μg / mL, or at least 200 μg / mL.

[0134] The following are exemplary axitinib prodrugs to be used in the ASDs or implants of thepresent invention:axitinib-N-succinoyloxymethyl prodrug (total Mw: 516.57) solubility in PBS at pH 7.2 to 7.4 after 24 hours incubation at 22 °C: 217.4 μg / mLaxitinib-N-m(PEG)4-oxymethyl prodrug (total Mw: 634.74)solubility in PBS at pH 7.2 to 7.4 after 24 hours incubation at 22 °C: 99.37 μg / mLaxitinib-N-m(PEG)1-oxymethyl prodrug. IUPAC Name: 3-Methoxy-propionic acid 6-(2- methylcarbamoyl-phenylsulfanyl)-3-((E)-2- -pyridin-2-yl-vinyl)-indazol-1-ylmethyl ester(total Mw: 502.28)axitinib-N-m(PEG)2-oxymethyl prodrug. IUPAC Name: 3-(2-Methoxy-ethoxy)-propionic acid 6-(2-methylcarbamoyl-phenylsulfanyl)-3-((E)-2-pyridin-2-yl-vinyl)-indazol-1- ylmethylester (total Mw: 546.63)axitinib-N-m(PEG)3-oxymethyl prodrug. IUPAC Name: 3-[2-(2-Methoxy-ethoxy)-ethoxy]- propionic acid 6-(2-methylcarbamoyl-phenylsulfanyl)-3-((E)-2-pyridin-2-yl-vinyl)-indazol-1- ylmethyl ester (total Mw: 590.68)

[0135] Exemplary syntheses and solubilities of axitinib prodrugs are disclosed in Examples 5.1and 5.2 of PCT / US2024 / 023688. The solubilities of axitinib prodrugs are described herein inExample 6 and in Example 6 of PCT / US2024 / 023688, incorporated herein by reference in itsentirety.

[0136] Suitable axitinib prodrugs for use in the ASDs or implants according to the presentinvention as well as their synthesis and properties are disclosed in co-pending US provisionalapplication US 63 / 416,292 and in WO 2023 / 064578 (corresponding to PCT / US2022 / 046750),incorporated herein by reference in its entirety. Further suitable axitinib prodrugs for use in the implants according to the present invention are disclosed in US 2021 / 0078970, incorporated herein by reference in its entirety. All of the axitinib prodrugs disclosed in any of thesereferences, but not limited to these, are generally suitable for use in the present invention. Forother TKIs than axitinib, similar prodrugs with enhanced water solubility may be used.Polymer excipients for use in the present invention:

[0137] Suitable polymer excipients for use in the ASD implants according to the presentinvention as well as their synthesis and properties are known to the skilled person and arecommercially available.

[0138] In the amorphous solid dispersion (ASD) of the invention as defined herein, a polymerexcipient selected from the group consisting of polyvinyls such as polyvinyl pyrrolidone-vinyl acetate (PVPVA), polyvinylpyrrolidone (PVP), povidone (PVP), such as povidone K25, povidone K17 or povidone K30, or polyvinyl polymercaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®); polyethylene glycols (PEG), poloxamers such as poloxamer 188, Pluronic®F127 or Pluronic F68®; polyacrylates and methacrylates such as Carbomer, Eudragit®EPO or Eudragit®RL PO; and cellulose and its derivatives such as methyl cellulose, hydroxypropyl methylcellulose (HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS), or a mixture thereof, can be used.

[0139] In certain embodiments, a polymer excipient for use in the ASD of the invention is apolyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0140] In a preferred embodiment, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft copolymer (Soluplus®) is used as a polymer excipient in the ASD of the invention.

[0141] In certain embodiments, a polymer excipient for use in the ASD of the invention is apolyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), that mayhave an average molecular weight (Mw) determined by gel permeation chromatography ofapproximately 118,000 g / mol (peak value), the Mw distribution nominally ranging from about 90,000 to 140,000 g / mol.

[0142] In certain embodiments, a polymer excipient for use in the ASD of the invention is amixture of polyvinyl polymercaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and a polymer selected from the group consisting of polyvinyls such as polyvinyl pyrrolidone-vinyl acetate (PVPVA), polyvinylpyrrolidone (PVP), povidone (PVP), such aspovidone K25, povidone K17 or povidone K30; polyethylene glycols (PEG), poloxamers such as poloxamer 188, Pluronic®F127 or Pluronic F68®; polyacrylates and methacrylates such as Carbomer, Eudragit®EPO or Eudragit®RL PO; and cellulose and its derivatives such as methyl cellulose, hydroxypropyl methylcellulose (HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0143] In certain embodiments, a polymer excipient for use in the ASD of the invention isa mixture of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(Soluplus®) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Weight ratio of the TKI inhibitor and the polymer excipient in the ASD of the invention:

[0144] The TKI and the polymer excipient are present in the ASD of the invention in a range ofweight ratios.

[0145] In certain embodiments, the weight ratio of the TKI inhibitor and the polymer excipient inthe ASD of the invention ranges from 1:1 to 1:4, such as from 1:2 to 1:3.5, e.g. from 1:1.1 to 1:4,from 1:1.2 to 1:4, from 1:1.3 to 1:4, from 1:1.4 to 1:4, from 1:1.4 to 1:3.9, from 1:1.5 to 1:3.9, from 1:1.6 to 1:3.8, from 1:1.7 to 1:3.8, from 1:1.8 to 1:3.7, from 1:1.9 to 1:3.6, from 1:2 to 1:3.5, from 1:2.1 to 1:3.5, from 1:2.2 to 1:3.5, from 1:2.3 to 1:3.5, from 1:2.4 to 1:3.5, and from 1:2.5 to 1:3.5.

[0146] In a preferred embodiment of the ASD of the invention, the TKI is axitinib, and the weightratio of axitinib and the polymer excipient ranges from 1:1 to 1:4, such as from 1:2 to 1:3.5, orfrom 1:2.5 to 1:3, e.g. from 1:1.1 to 1:4, from 1:1.2 to 1:4, from 1:1.3 to 1:4, from 1:1.4 to 1:4, from 1:1.4 to 1:3.9, from 1:1.5 to 1:3.9, from 1:1.6 to 1:3.8, from 1:1.7 to 1:3.8, from 1:1.8 to 1:3.7, from 1:1.9 to 1:3.6, from 1:2 to 1:3.5, from 1:2.1 to 1:3.5, from 1:2.2 to 1:3.5, from 1:2.3 to 1:3.5, from 1:2.4 to 1:3.5, and from 1:2.5 to 1:3.5.Amount / dose of the TKI in the ASD or ocular implant of the invention:

[0147] In certain embodiments, the ASD comprises the TKI, such as axitinib, in an amount offrom about 1% by weight to about 90% by weight, such as in an amount of from about 20% byweight to about 70% by weight, particularly in an amount of from about 25% by weight to about50% by weight, based on the total amount of the ASD (dry basis, in %w / w).

[0148] In certain embodiments, the amorphous solid dispersion (ASD) comprises about 25% byweight axitinib and about 75% by weight Soluplus®based on the total amount of the ASD.

[0149] The TKI, such as axitinib, can be present in the ASDs or implants of the invention in arange of doses, depending on the intended use. The amount of TKI contained in an implant is indicated herein in the units “μg” 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 μg or mg, as the case may be) of axitinib free base, including any (anhydrous) axitinib polymorphs such as those that are further disclosed herein. In case axitinib salts, co-crystals, derivatives orprodrugs are used (which have a different molecular weight than axitinib free base), the amountindicated is the corresponding amount of axitinib free base, unless otherwise stated.

[0150] The TKI, such as axitinib, is contained in the ASD or in the implant of the inventiongenerally in a range of doses of at least 15 μg, such as from about 15 μg to about 1200 μg, fromabout 15 μg to about 1000 μg, from about 150 μg to about 900 μg, or from about 200 μg toabout 800 μg, or from about 250 μg to about 700 μg, or from about 300 μg to about 650 μg. In acertain embodiment, the TKI, such as axitinib, is contained in the ocular implant of the inventionin a total dose from about 140 μg to about 1200 μg.

[0151] Any TKI amount within these ranges may be contained in the implant of the invention,and, in case the implant comprises the ASD in addition to or coated onto a hydrogel, the total amount of TKI may be split into a part being dispersed in the ASD itself, and another part beingdispersed in the hydrogel part of the implant. In an embodiment comprising TKI being present ina hydrogel portion and a separate ASD portion, up to 50% by weight of the TKI, such as axitinib,may be included in the ASD portion, or up to 40 % by weight, or up to 30 % by weight, or up to20 % by weight, or up to 10 % by weight of TKI, based on the total amount of TKI in the implant.In another embodiment comprising TKI being present in a hydrogel portion and a separate ASDportion, up to 90% by weight of the TKI, such as axitinib, may be included in the hydrogel portion, or up to 80 % by weight, or up to 70 % by weight, or up to 60 % by weight, or up to 50 % by weight of TKI, based on the total amount of TKI in the implant.

[0152] In case axitinib is used in a form other than the free base, an ASD or implant of theinvention 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 avariance of + / - 10%.

[0153] In one embodiment, a total dose of axitinib contained in one implant of the invention isfrom 100 μg to 200 μg, or about 170 μg. In further embodiments, the axitinib in such ASDs orimplants is in the form of axitinib free base.

[0154] In one embodiment, a total dose of axitinib contained in one implant of the invention isfrom 200 μg to 400 μg, such as from 250 μg to 350 μg, or about 300 μg. In further particularembodiments, the axitinib in such ASDs or implants is in the form of axitinib free base.

[0155] In one particular embodiment, a total dose of axitinib contained in one implant of theinvention is from 300 μg to 600 μg, such as from about 360 μg to about 562.5 μg, or from 400 to500 μg, or is about 450 μg. In further embodiments, the axitinib in such ASDs or implants is in the form of axitinib free base.

[0156] In another particular embodiment, a total dose of axitinib contained in one implant of theinvention is from about 400 μg to 800 μg, from about 480 μg to about 750 μg, or from 500 to700 μg, or is about 600 μg. In further particular embodiments, the axitinib in such ASDs orimplants is in the form of axitinib free base. In some embodiments, a total target dose of axitinib,in an ASD or implant of the present invention is 600 μg, which means an actual amount of –20% and +25% thereof, i.e., from about 480 μg to about 720 μg.

[0157] In one embodiment, a total dose of axitinib contained in one implant of the invention isfrom 200 μg to 1000 μg.

[0158] In one embodiment, a total dose of axitinib contained in one ASD implant of the inventionis from about 250 μg to about 750 μg, such as from about 300 μg to about 600 μg, such as fromabout 350 μg to about 550 μg, such as from about 380 μg to about 520 μg, such as from about 420 μg to about 480 μg, such as from about 400 μg to about 500 μg, such as from about 420 μgto about 480 μg, such as about 450 μg. In some embodiments, a target total dose of axitinib inan implant of the present invention is 450 μg, which means an actual amount of – 20% and+25% thereof, i.e., from about 360 μg to about 562.5 μg.

[0159] In one further embodiment, an implant according to the present invention containsaxitinib in a total dose of from about 400 μg to about 500 μg, such as from about 405 μg to about 495 μg, such as from about 410 μg to about 490 μg, such as from about 420 μg to about 480 μg, such as from about 425 μg to about 475 μg, such as from about 430 μg to about 470 μg, such as from about 440 μg to about 460 μg, such as about 450 μg. In an implant of the present invention having a nominal (i.e., theoretical / label) content of 450 μg or about 450 μg 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.

[0160] If axitinib is not in the form of the free base, but in the form of e.g. a prodrug, one ASD orimplant may contain an amount of such other axitinib form that corresponds to the mentioned doses of axitinib free base.

[0161] The TKI (or axitinib) amount within these ranges in any of the above implants may becontained in the implant of the invention essentially consisting of the ASD, or, in case the implant comprises the ASD in addition to or coated onto or dispersed within a hydrogel, the total amount of TKI may be split into a part of the TKI amount being dispersed in the ASD itself, andanother part of the TKI amount being dispersed in the hydrogel part of the implant. In anembodiment comprising TKI being present in a hydrogel portion and a separate ASD portion, up to 50% by weight of the TKI, such as axitinib, may be included in the ASD portion, or up to 40 %by weight, or up to 30 % by weight, or up to 20 % by weight, or up to 10 % by weight of TKI,based on the total amount of TKI in the implant. In another embodiment comprising TKI being present in a hydrogel portion and a separate ASD portion, up to 90% by weight of the TKI, such as axitinib, may be included in the hydrogel portion, or up to 80 % by weight, or up to 70 % by weight, or up to 60 % by weight, or up to 50 % by weight of TKI, based on the total amount of TKI in the implant.

[0162] The disclosed amounts of TKI, such as axitinib, including the mentioned variances, referto both the final content of the active principle in the implant, as well as to the amount of activeprinciple used as a starting component per ASD implant when manufacturing the implant. Thetotal 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 of 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. Types of TKI in the ASD or in the ASD implant

[0163] The TKI, such as axitinib, is contained in the ASD or in the ocular implant and isdispersed or distributed in the polymer excipient as disclosed herein. In certain embodiments, the particles are homogeneously or essentially homogeneously dispersed in the polymer excipient (matrix). The polymer excipient (matrix) may prevent the particles from agglomerating and may provide a matrix for the particles which holds them in the desired location in the eyewhile gradually releasing the drug.

[0164] In certain embodiments of the invention, the TKI particles such as the axitinib particlesmay 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).

[0165] 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.

[0166] However, in certain embodiments, the TKI particles such as the axitinib particles are notmicroencapsulated and / or do not comprise any additional compounds, but are dispersed in the polymer excipient and thus in the ASD or implant 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.Formulation of an ASD or implant comprising an ASD of the invention

[0167] In certain embodiments, the ASDs or implants comprising an ASD comprising a TKI,such as axitinib, or a pharmaceutically acceptable salt, derivative, or prodrug thereof and apolymer excipient, may optionally further comprise additional components such as salts etc.remaining in the ASD implant from the production process (such as phosphate salts used asbuffers etc.). In some embodiments, the TKI is axitinib. In embodiments, the axitinib is axitinibfree base.

[0168] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD)implant as defined herein, wherein the ASD comprises the TKI, such as axitinib, in an amount offrom about 1% by weight to about 90% by weight, or 10 to 80 % by weight, such as in anamount of from about 20% by weight to about 70% by weight, particularly in an amount of fromabout 25% by weight to about 60% by weight, or 30 to 50 % by weight, based on the totalamount of the ASD (dry basis, in %w / w) and from about 10% to about 99% by weight, such asabout 15 to about 80 % by weight, or from about 20% to about 70% by weight polymerexcipient. An exemplary ASD according to these embodiments of the present invention ispresented in Table 3 in the Examples section.

[0169] In certain embodiments, the invention relates to an amorphous solid dispersion (ASD)implant as defined above, wherein the ASD comprises about 25% by weight axitinib and about 75% by weight Soluplus®based on the total amount of the ASD.

[0170] These compositions are particularly applicable to ASDs or ASD implants that containaxitinib, or a pharmaceutically acceptable salt, derivative or prodrug thereof, in an amountcorresponding to at least 15 μg, such as from about 15 μg to about 1200 μg, from about 15 μg to about 1000 μg, from about 150 μg to about 900 μg, or from about 200 μg to about 800 μg, or from about 250 μg to about 700 μg, or from about 300 to about 650 μg. In one embodiment, the ASD or ASD implant contains from 100 to 200 μg, or from about 120 μg to about 187.5 μg, or about 170 μg axitinib free base.

[0171] In other embodiments, the ASDs or implants may have a composition (dry basis; in %w / w) as follows: from about 30% to about 80% by weight, or from about 50% to about 70% by weight, or from about 55% to about 70% by weight axitinib, and from about 20% to about 60% by weight, or from about 20% to about 50% by weight, or from about 25% to about 35% byweight of polymer (such as polymer excipient and PEG). These compositions are particularlyapplicable to the ASDs or implants of the invention that contain axitinib (i.e., axitinib free base inthe form of any polymorph thereof, such as polymorph IV, or in the form of e.g. a co-crystal or prodrug thereof) in an amount corresponding to from 200 to 1000 μg, 300 to 1000 μg, 300 to800 μg, or from about 480 μg to about 750 μg, or from about 540 μg to about 660 μg, or about600 μg axitinib free base.

[0172] In certain other embodiments, wherein an implant of the invention comprises at least twofilaments, such as from 2 to 10, or from 3 to 7 filaments, the implant, or any of the filaments ofwhich it is composed, may have a composition (dry basis; in % w / w) as follows: from about 30%to about 70% by weight, or from about 30% to about 60% by weight axitinib, and from about 20% to about 60% by weight, or from about 30% to about 60% by weight polymer excipient.

[0173] In certain other embodiments, wherein an implant of the invention has a cross-sectionalgeometry that is not round or oblong, in particular a cross-sectional geometry that is cross-or star-shaped, including but not limited to 5-arm star shaped, the implant may have a composition(dry basis; in % w / w) as follows: from about 30% to about 70% by weight, or from about 40% toabout 70% by weight axitinib, and from about 20% to about 60% by weight, or from about 20% to about 40% by weight polymer carrier.

[0174] In certain embodiments, on a dry weight basis the axitinib to polymer excipient ratio in animplant according to the invention may be from about 1:1 to about 1:3.

[0175] In certain embodiments, the balance of the implant in its dry state (i.e., the remainder ofthe formulation when TKI, such as axitinib, and polymer units, such as polymer excipient, 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 oneembodiment the buffer salt is sodium phosphate (mono- and / or dibasic).

[0176] In certain embodiments, the total weight (also referred to herein as “total mass”) of anASD or implant in its dry state may be from about 200 μg (i.e., 0.2 mg) to about 1.5 mg, or from about 400 μg to about 1.2 mg, or from about 500 μg to about 1 mg. In some embodiments, the total weight of an implant in its dry state is from about 600 μg to about 900 μg, such as from about 700 μg to about 875 μg. In case an implant is a composite (stacked fiber or multi-filament) implant, the total weight of the composite implant may be higher, depending on the number of individual filaments of which it is composed, and their total weights.

[0177] In certain embodiments, an implant in its dry state may contain from about 200 μg toabout 1000 μg TKI, such as axitinib, per mm3(i.e., per 1 mm3volume of the dry implant). In certain specific embodiments, an implant in its dry state may contain from about 200 μg to about 300 μg axitinib per mm3, e.g. in case the implant contains axitinib in an amount of from about 160 μg to about 250 μg. In other embodiments, an implant in its dry state may contain from about 500 μg to about 800 μg axitinib per mm3, e.g. in case the implant contains axitinib in an amount of from about 480 μg to about 750 μg.

[0178] The implants of the present invention may thus have different densities. The densities ofthe 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 (in case of wet casting) when forming a 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. In certain embodiments, the density of hydrogel containing implants produced by means of hot melt extrusion may be higher than the density of comparableimplants (in terms of their content of TKI and polymer, respectively) at least partially producedby means of wet casting.

[0179] In certain embodiments, ASDs or implants according to the invention contain atherapeutically effective amount of TKI such as axitinib for release over a specified period of time, such as an extended period of 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 thepatient’s vision while the implant is in place. The implants of the present invention can combine the benefits of a suitably high dose of the TKI (i.e., a therapeutically effective dose adjusted to aparticular patient’s need) with a relatively small implant size. Furthermore, the ASDs or implantsof the present invention achieve a relatively high rate of release of the TKI, particularly in the early phases of the release, i.e., during an initial period of time after administration (or, in caseof in vitro release tests, during an initial period of time after start of the test), optionally followedby a steady and constant release over a prolonged period of time.

[0180] In certain embodiments, the ocular implant as defined herein provides an averagerelease rate of tyrosine kinase inhibitor, such as aper day from the implant over a period defined by any initial number of days up to the day when 80% of the tyrosine kinase inhibitor containedin the implant is released, is higher than the average release rate of tyrosine kinase inhibitor perday from a comparative implant not comprising the ASD over the same period of time, wherein the release of tyrosine kinase inhibitor from both implants is measured under identicalconditions. In certain embodiments, the average release rate, of tyrosine kinase inhibitor fromthe implant over said period of time is at least 10%, or at least 20% higher than the averagerelease rate of tyrosine kinase inhibitor over said period of time from the comparative implantnot comprising the ASD measured under identical conditions.

[0181] In certain embodiments, the average release rate, measured in PBS at a pH of 7.2 to 7.4and 37 °C, of tyrosine kinase inhibitor from the implant in the first half hour is higher than theaverage release rate of tyrosine kinase inhibitor from the comparative implant.

[0182] In certain embodiments, the implant provides for an average in vivo release rate in thevitreous of at least 0.5 μg / day, such as at least 0.6 μg / day, or at least 0.7 μg / day, or at least 0.8μg / day for a period of at least 3 months, measured in the vitreous of a non-human primate, suchas a monkey, or in the vitreous of a human.

[0183] In certain embodiments, the average release rate, measured in PBS at a pH of 7.2 to 7.4and 37 °C, of tyrosine kinase inhibitor from the implant in the first half hour is higher than theaverage release rate of tyrosine kinase inhibitor from the comparative implant.

[0184] In certain embodiments, the ocular implant releases, measured in accordance withMethod C as described herein, at least about 35% by weight, such as at least about 40% byweight, or such as at least about 42% by weight of the tyrosine kinase inhibitor, such as axitinib,from the ASD or implant in the first half hour, referring to the total weight of the TKI contained inthe implant.

[0185] In some embodiments, the ocular implant releases, measured in accordance withMethod C as described herein, at least about 90% by weight, such as at least about 92% byweight, or such as at least about 94% by weight of the tyrosine kinase inhibitor, such as axitinib,from the ASD or implant in the first two hours, referring to the total weight of the TKI containedin the implant.

[0186] In some embodiments, the ocular implant, measured in accordance with Method C asdescribed herein, almost completely releases the tyrosine kinase inhibitor, such as axitinib, fromthe ASD or implant within about two hours.

[0187] Some exemplary ASDs and implants of various aspects of the present invention aredisclosed in the Examples section.In vitro release determination:

[0188] As shown in the Examples, the inventors have now surprisingly and unexpectedly foundthat an implant comprising an ASD releases the TKI, such as the axitinib, faster thancomparative implants not comprising the TKI in the form of an ASD. Without wishing to belimited by this theory, the ASD may increase the TKI’s solubility, e.g. axitinib’ s solubility, and may result in a faster release of the TKI, e.g. of axitinib from the implant of the invention, particularly from the ASD.

[0189] The in vitro-release of TKIs such as axitinib from the ASDs or from implants of theinvention can be determined by several in vitro methods (see also the Examples section, andsee the Definitions section of this application for further explanations). Methods for determiningin vitro-release of TKIs such as axitinib are disclosed in WO 2023 / 107478 and inPCT / US2024 / 023688, both of which are incorporated herein by reference in their entirety.

[0190] In a particular in-vitro test, release may be measured at 37° C in water with UltraPerformance Liquid Chromatography (UPLC) using an Acquity BEH C8 Column or equivalent; or in pH4 phosphate buffered saline (PBS) on a Mettler Toledo UV5 Spectrometer or equivalent.

[0191] In one particular in vitro test, the study ASD(s) or implant(s) is / are placed into a certainvolume of a solvent mixture of 25% ethanol / 75% water (v / v), and at a certain temperature(37 °C, or another temperature if this is specifically mentioned) as disclosed herein. Thereleased amount or percentage of TKI such as axitinib is determined on several pre-determined days. The volume of solvent is calculated by using the “sink factor” as defined in the“Definitions” section. In vitro tests reported in the present invention may be conducted undervarious sink conditions. In certain embodiments, the in vitro tests may be performed, asdisclosed herein, under 2x sink conditions, or under 3x sink conditions, or with a higher sink factor. “2x sink conditions” means that the volume of solvent (mixture) into which an implant according to the invention is immersed (or several implants if so indicated) for the specific test is two times the “sink volume” (as defined above), i.e., the “sink factor” in this case would be 2. The same applies analogously to any other sink factors. The sink volume is the ratio of the amount of TKI contained in the implant [μg] to the solubility of the TKI in the employed solvent (mixture), i.e., in 25% ethanol / 75% water (v / v) as also defined in the “Definitions” section.

[0192] In certain embodiments, for in vitro release tests reported in the present application thatuse 2x sink conditions (such as “Method A” referred to in the Examples), the sink volume is calculated by dividing the amount (in μg) of axitinib contained in the study ASD or implant by amean solubility value of 18.3 μg / mL. In these embodiments, this mean solubility value is thusused regardless of which axitinib form is employed in the study implant. In Method A, 1L of25:75 Ethanol:Water (v / v) using a graduated cylinder are prepared and allowed to equilibrate.Each ASD or implant is placed in an amber jar. The amount of 25:75 Ethanol:Water equal to 2 times the sink volume (sink volume is the axitinib amount in the implant per assay / axitinibsolubility) was added for a 2× sink factor. The samples are stored in a 37°C incubator on arocker plate to provide moderate agitation. 1mL of the solution is sampled on pre-determineddays until the drug is fully released. Samples are run on either a UV-Vis spectrometer or aUPLC against analytical standards prepared within the last 2 weeks. In vitro release testsmeasured according to Method A are in Example 7.1 of PCT / US2024 / 023688, which isincorporated herein by reference in its entirety.

[0193] In certain embodiments, for in vitro release tests reported in the present application thatuse 3x sink conditions (such as “Method B” referred to in the Examples), the sink volume is calculated by dividing the amount (in μg) of axitinib contained in the study ASD or implant by a solubility value of 13.41 μg / mL (in case axitinib polymorph SAB-I is used) or a solubility value of 20.09 μg / mL (in case axitinib polymorph IV is used).1L of 25:75 Ethanol:Water (v / v) using a graduated cylinder are prepared and allowed to equilibrate. Each ASD or implant is placed in an amber jar. The amount of 25:75 Ethanol:Water equal to three times the sink volume (sink volume is the axitinib amount in the implant per assay / axitinib solubility) is added for a 3× sink factor. The samples are stored in a 37°C incubator on a rocker plate to provide moderate agitation.1mL of the solution is sampled on pre-determined days until the drug is fully released. Samples are run on either a UV-Vis spectrometer or a UPLC against analytical standardsprepared within the last 2 weeks. In vitro release tests measured according to Method B aredescribed in Example 7.2 of PCT / US2024 / 023688, which is incorporated herein by reference inits entirety.

[0194] Concretely, an in vitro test in accordance with the invention for ASDs or implantscontaining axitinib is conducted as follows (“Method A” or “Method B”): 1L of the 25%:75% ethanol / water solvent mixture (also referred to herein as “buffer”) is created and allowed toequilibrate. The study ASD or implant is put in an amber jar. For 2x sink conditions, the volumeof buffer added to the ASD or implant equals 2 times the volume corresponding to the ratio ofthe TKI amount [μg] divided by the axitinib solubility [μg / mL] (which, in certain embodiments, is a mean value 18.3 μg / mL for axitinib free base as explained above). For 3x sink conditions, thevolume of buffer added to the ASD or implant equals 3 times the volume corresponding to theratio of the TKI amount [μg] divided by the axitinib solubility [μg / mL] (which, in certain embodiments, is 13.41 μg / mL for the case the TKI is axitinib polymorph SAB-I or is 20.09 μg / mL for the case the TKI is axitinib polymorph IV). By means of example, in case an ASD orimplant contains 600 μg axitinib polymorph SAB-I, and the in vitro test is to be run under 3x sinkconditions, 134 mL of 25% / 75% ethanol / water mixture is used as the volume in which the studyASD or implant is immersed (i.e., 600 μg divided by13.41 μg / mL, multiplied by a factor of 3).While the in vitro test is running, the jar containing the ASD or implant in the respective volumeof buffer is stored in a 37°C incubator on a rocker plate to provide moderate agitation.1mL of buffer solution is taken and replaced on each of the sampling days. The buffer solution is analyzed either by UV-VIS (in certain embodiments, for the tests performed under 2x sink conditions) or by UPLC (in certain embodiments, for the tests performed under 3x sink conditions) against analytical standards prepared within the last 2 weeks.

[0195] The in vitro-release of TKI, and particularly of axitinib, from the ASDs or implants of theinvention can also be determined by another accelerated in vitro method (“Method C”), asfollows (see also the Examples section and Example 7.3 of PCT / US2024 / 023688). In this in-vitro test, release can be measured at 35° C in aqueous 0.01N HCl with 0.25% cetyl trimethylammonium bromide (CTAB) with Ultra Performance Liquid Chromatography (UPLC) using an USP Apparatus 4 (Flow-through cell) setup as closed system (hereinafter “Method C”).In Method C, the apparatus SOTAX may be used:

[0196] The dissolution medium for this accelerated in vitro release test is 0.01N HCl with 0.25%cetyl trimethyl ammonium bromide (CTAB). The test is performed in a USP apparatus 4 at atemperature of 35 °C. Suitable test parameters are specified in the following Table 1:Table 1:

[0197] Sampling time points may be chosen as desired, such as at one or more time points ofthe following: 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 60, and 83 hours. The samples are analyzed by UPLC against analytical standards. If several (such as n = 6) samples of oneproduct (e.g. same production lot) are measured, an average release can be determined.MANUFACTURE OF AN ASD AND AN IMPLANT OF THE INVENTIONProcesses for the preparation of an ocular implant comprising an ASD

[0198] ASDs can be prepared by several methods such as solvent evaporation spray drying,freeze-drying (lyophilization), filtration, decantation, centrifugation and / or hot melt extrusion(HME), or even or 3D printing. A. Budiman et al. describe several methods for the preparation ofASD formulations (A. Budiman et al., Polymers 2023, 15, 3380, which is incorporated herein by reference in its entirety).

[0199] Thus, in another aspect, a process for preparing an ocular implant comprising anamorphous solid dispersion (ASD) as defined herein is provided, the process comprisingdispersing the tyrosine kinase inhibitor (TKI), such as axitinib, or a pharmaceutically acceptablesalt, derivative or prodrug thereof within the polymer excipient matrix, wherein the polymerexcipient is as defined above.

[0200] In one embodiment, the process involves solvent based methods using one or moresolvents; and subsequently removing the one or more solvent from the solution of the polymerexcipient and the TKI, to obtain the amorphous solid dispersion (ASD). Solvent based methodscan be used in embodiments where the TKI is thermally not stable enough for hot melt extrusion processes.

[0201] In certain embodiments, the one or more solvent used in the process comprises one ormore chlorinated hydrocarbon solvents such as dichloromethane, dichloroethane, and chlorobenzene; alcoholic solvents such as methanol, ethanol, 2-propanol, 1-butanol and t-butyl alcohol; N,N-dimethylformamide; nitriles such as acetonitrile; dimethyl sulfoxide; water andmixtures thereof. In an embodiment, the solvent used in the process for preparing an ASD isone of acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide.

[0202] In certain embodiments, the removing of the solvent can comprise distillation, distillationunder vacuum, spray drying, freeze-drying (lyophilization), filtration, decantation and / orcentrifugation. Solvent evaporation can be carried out by evaporating organic solvents atmoderate temperatures using a rotary evaporator to prevent degradation of the heat-labileacceptance components of the ASD. After the solvent is evaporated, the remaining dry samplemay be subjected to grinding, sieving, and subsequent placement in a vacuum desiccator to eliminate residual solvent.

[0203] A further solvent based method for preparing ASDs is spray drying. It can be used toproduce particles through a hot gaseous drying agent to convert liquid substances into dry particles. Spray drying may employ a nozzle to spray the tyrosine kinase inhibitor (TKI), such asaxitinib, and the polymer excipient as defined herein, necessitating careful consideration of thenozzle type.

[0204] A further solvent based method for preparing ASDs in the process of the invention isfreeze-drying. This technique can be also applied to thermolabile tyrosine kinase inhibitors(TKIs) that exhibit stability in dry conditions but are prone to instability when exposed to water.The resulting ASDs demonstrate good stability when stored in a dry state for extended periods. The process of freeze-drying, also known as lyophilization, involves combining a tyrosine kinaseinhibitor (TKI), such as axitinib, and a polymer excipient as defined herein dissolved in a solventdefined herein. Lyophilization achieves molecular dispersion and facilitates the formation of amorphous systems through the combination of freezing and sublimation.

[0205] In certain embodiments, typically solvent-free, extrusion methods such as hot meltextrusion (HME) is used for preparing the ASD, at elevated temperature such as above the glass transition temperature of the polymer excipient, or at temperatures above the melting point of the polymer excipient. Since axitinib has a rather high melting point and thermal stability, hot melt extrusion can be done above the melting point of the polymer excipient to produce the ASD.

[0206] Thus, in another aspect, the present invention relates to a process for preparing anocular implant comprising an amorphous solid dispersion (ASD) as defined herein, comprising the following steps:(a) feeding the tyrosine kinase inhibitor (TKI), such as axitinib, or a pharmaceuticallyacceptable salt, derivative, or prodrug thereof, and a polymer excipient as defined herein into a heated extruder to obtain a melt mixture;(b) extruding the melt to obtain the ocular implant comprising an amorphous solid dispersion(ASD) as defined herein.

[0207] In the extrusion process, the tyrosine kinase inhibitor (TKI), such as axitinib, and thepolymer excipient can be mixed into a physical mixture. During HME, the polymer excipient isfully molten and the tyrosine kinase inhibitor (TKI), such as axitinib, is dispersed within thepolymer melt. In certain embodiments, the tyrosine kinase inhibitor (TKI) and the polymerexcipient can be fed into the extruder in the form of a preformed melt, i.e. the TKI and thepolymer excipient are mixed and molten before being fed into the extruder. In anotherembodiment, the tyrosine kinase inhibitor (TKI) and the polymer excipient are fed separately intothe extruder, i.e. mixing and melting occurs within the heated extruder. In still anotherembodiment, the tyrosine kinase inhibitor (TKI) and the polymer excipient are mixed prior tobeing fed, as a mixture, into the extruder, and the mixture is then molten in the extruder. Incertain embodiments, the polymer excipient and TKI are melt blended, milled, optionally sieved,and then fed into the extruder. In certain embodiments, the powder or melt feed rate into the extruder is from about 2 g / min to about 10 g / min. The powder feeder can be a plunger feeder or a K-Tron or Brabender feeder.

[0208] In certain embodiments, the tyrosine kinase inhibitor (TKI), such as axitinib, ora pharmaceutically acceptable salt, derivative, or prodrug thereof, are molten and mixed beforeor in the extruder at a temperature of from about 55°C to about 200°C, such as from about 65°Cto about 180°C, and particularly from about 100°C to about 160C.

[0209] In certain embodiments, the process may include coextruding the ASD forming melt inaddition to crosslinkable hydrogel precursor compounds, or simultaneously coextruding a hydrogel and the ASD, such as forming a coextruded sheath of ASD over the hydrogel bycoextrusion, for example by using O-ring nozzle types for coextrusion of two different masses.

[0210] The extrusion process may be carried out at temperatures below the glass transition orTg of the mixture. The tyrosine kinase inhibitor (TKI), such as axitinib, will molecular “dissolve”into the polymer matrix of the polymer excipient described herein even at a temperature ofabout 40 to about 50 °C lower than the tyrosine kinase inhibitor’s (TKI’s) melting temperature.On extrusion, the melt cools quickly to obtain an amorphous solid dispersion. The interaction ofthe polymer excipient with the tyrosine kinase inhibitor (TKI), such as axitinib, can preventcrystallization of the tyrosine kinase inhibitor (TKI), such as axitinib, and the resultingamorphous solid dispersion (ASD) cools beneath the glass transition temperature molecularly“freezing” the tyrosine kinase inhibitor (TKI), such as axitinib, within the matrix of the polymerexcipient.

[0211] The Tg value of ASDs can be estimated through empirical formulations. The Gordon-Taylor equation, developed in the 1950s, estimates binary ASD Tg(Tg,mix) by the individualcomponents Tgs:where w represents component weight fraction, and the fitting parameter K is determined by:where휌 is the true component density and ∆훼 the change in component thermal expansivity atTg.

[0212] The equation is based on the assumptions of ideal mixing and ideal volume additivity.Essentially, the Tgvalue of an ASD is a weighted average of the individual Tgvalues of the APIand the polymer excipient.

[0213] A simple test to determine whether an ASD was effectively produced, regardless of themethod used, is to analyse the sample by differential scanning calorimetry (DSC). The methodof analysing a sample by DSC is well known to the skilled person. If no crystal melt endothermis observed by DSC, then the API is effectively in its amorphous state. Furthermore, if only oneTgvalue is observed rather than two distinct Tgvalues, then the two components wereeffectively mixed.

[0214] Hot melt extrusion (HME) methods for the production of ocular implants are disclosed inWO 2023 / 107478 and in PCT / US2024 / 023688, which are incorporated herein by reference intheir entireties. These methods are also suitable for preparing an ocular implant comprising theamorphous solid dispersion (ASD) of the invention as defined herein. This method generallycomprises melt extruding, reactive extrusion or injection molding a composition comprising a polymer excipient as defined herein and TKI particles, such as axitinib particles, to form the implant.

[0215] In certain embodiments, the process involving HME further comprises extruding a strandfrom the mixed and molten mixture in the extruder; optionally stretching the strand into a fiber orfilament; and cutting the strand, fiber or filament into unit dose ocular implants.

[0216] In certain embodiments, the tyrosine kinase inhibitor (TKI), such as axitinib, ora pharmaceutically acceptable salt or prodrug thereof, and the polymer excipient are fedseparately into the extruder; or the tyrosine kinase inhibitor (TKI), such as axitinib, ora pharmaceutically acceptable salt, derivative, or prodrug thereof, and the polymer excipient aremixed prior to being fed into the extruder.

[0217] In certain embodiments, the tyrosine kinase inhibitor (TKI), such as axitinib, ora pharmaceutically acceptable salt or prodrug thereof, and the polymer excipient are melt mixedand milled prior to being fed into the extruder.

[0218] In certain embodiments, the tyrosine kinase inhibitor (TKI) is axitinib, ora pharmaceutically acceptable salt or prodrug thereof, and further comprises melting the mixturein the extruder at a temperature of from about 55°C to about 200°C, such as from about 65°C toabout 180°C, and particularly from about 100°C to about 160°C.

[0219] Initially, the polymer excipient or polymer precursors and the TKI are fed into anextruder, a (melt) composition comprising the polymer excipient or polymer precursors and TKI is formed in the extruder, and a strand of the (melt) composition is extruded. The polymerexcipient or polymer precursors and the TKI may be fed to the extruder separately, such as viadifferent feeders located at different sites. Alternatively, some or all precursor compounds may be pre-mixed, including melt blended, prior to being fed to the extruder. Such pre-mixing can be done by a method using, e.g., hand-mixing (e.g. in a sealable plastic bag), an orbital mixer, an acoustic mixer or a V-shell blender.

[0220] In certain embodiments, the method comprises melting the polymer excipient or polymerprecursors in the extruder at a temperature above the melting temperature of the polymerexcipient or polymer precursor, but below the melting point of the TKI. The optimal temperatureof the molten polymer excipient or polymer precursor is determined experimentally by itsextrusion properties. Advantageously, the unmelted TKI remains unchanged through this melt extrusion process. However, in certain embodiments, the extrusion may be performed above the melting point of the polymer (precursor) and the TKI, which may result in a color change and / or change in form of the TKI, e.g., from amorphous to crystalline. The temperature can be, e.g., less than about 180°, less than about 150°, less than about 130°, less than about 120°, less than about 100°, less than about 90°, less than about 80°, less than about 70°, less than about 60°, less than about 50°. In some embodiments, the temperature in the extruder is moderately high, such as from about 100° to about 160°C. In other embodiments, the temperature is from about 50° to about 200°, about 60° to about 180° or about 80° to about 140°. An exemplary temperature is from about 40° to about 90°. By virtue of certain embodiments of the present invention, the temperature is kept as low as possible to protectexcipient powders (if present) and TKI, and to optimize stability. In particular embodiments, if the TKI is axitinib, the extrusion is performed at a temperature from about 57 °C to about 200°C,or from about 65 °C to about 150 °C, or from about 70°C to about 90°C.

[0221] In certain embodiments, the screw speed of the extruder is from about 5 rpm to about500 rpm. In certain embodiments, the extruder may be a twin-screw extruder. In otherembodiments, it may be a single-screw extruder.

[0222] In certain embodiments, the extrusion may be performed in a solvent. The solvent maybe present in less than about 10% by weight (w / w), and may be a non-aqueous solvent (such as a natural or synthetic oil). If an oil is used as solvent, the oil may a biocompatible vegetable oil, a synthetic oil or a mineral oil, a liquid fatty acid or triglyceride composition, or it may be a hydrophobic biodegradable liquid polymer, or combinations thereof. In certain embodiments, the oil may comprise triethyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), α- tocopherol (vitamin E), α-tocopherol acetate; plant or vegetable oils such as sesame oil, olive oil, soybean oil, sunflower oil, coconut oil, canola oil, rapeseed oil, nut oils such as hazelnut, walnut, pecan, almond, cottonseed oil, corn oil, safflower oil, linseed oil, etc., ethyl oleate, castor oil and derivatives thereof (Cremophor®), lipids being liquid at 37°C or lower, such as saturated or unsaturated fatty acids, monoglycerides, diglycerides, triglycerides (Myglyols®), phospholipids, glycerophospholipids, sphingolipids, sterols, prenols, polyketides, hydrophobic biodegradable liquid polymers (such as low molecular weight PLGA, PGA or PLA etc.), low melting point waxes such as plant, animal or synthetic waxes, lanolin, jojoba oil, or combinations thereof. In particular embodiments a solvent is used in an amount of less than about 10% w / w, less than about 5% w / w or less than about 1% w / w of the entire composition in the extruder.

[0223] In other embodiments, extrusion is performed in the absence of a solvent (such aswater), and is specifically performed in the absence of water if a salt (such as a multi-amine salt such as trilysine acetate) is used as a crosslinking agent.THERAPY WITH AN ASD OR AN OCULAR IMPLANT OF THE INVENTION

[0224] The present invention, in another aspect, relates to an amorphous solid dispersion(ASD) as defined herein for use as a medicament.

[0225] The present invention, in another aspect, relates to a method comprising treating adisease or medical condition in a patient with an amorphous solid dispersion (ASD) as definedherein comprising administering an amorphous solid dispersion (ASD) as defined herein to apatient in need thereof.

[0226] The present invention, in another aspect, relates to the amorphous solid dispersion(ASD) for use as defined herein or the method of treatment as defined herein, wherein theamorphous solid dispersion (ASD) is used for an ocular treatment.

[0227] The present invention, in another aspect, relates to an ocular implant comprising theamorphous solid dispersion (ASD) as defined herein for use as a medicament.

[0228] The present invention, in another aspect, relates to a method comprising treating adisease or medical condition in a patient with an ocular implant as defined herein comprisingadministering an ocular implant as defined herein to a patient in need thereof.

[0229] The present invention, in another aspect, relates to the ocular implant for use as definedherein or the method of treatment as defined herein, wherein the ocular implant is used for anocular treatment.

[0230] In another specific embodiment, the present invention relates to a method of treating anocular disease, such as wet AMD, in a patient in need thereof, the method comprising injectingan ASD or an ocular implant of the invention as defined herein into the vitreous humour of thepatient, wherein the ASD or the ocular implant has the following composition:

[0231] In the method treatment according to the invention, the dose of TKI such as axitinib pereye administered once during a treatment period, is at least about 15 μg, such as from about 15 μg to about 1200 μg, from about 15 μg to about 1000 μg, from about 150 μg to about 900 μg, or from about 200 μg to about 800 μg, or from about 250 μg to about 700 μg, or from about 300 μg to about 650 μg. (see the sub-section “Amount / dose of the TKI in the ASD or the ocular implantof the invention”). All doses of TKI such as axitinib as disclosed herein in relation to an ASD orimplant may be used in the method of treatment. In particular embodiments the tyrosine kinaseinhibitor is axitinib, in any of the forms disclosed herein, salts, derivatives or prodrugs thereof.The doses indicated herein for therapy are meant to refer to the corresponding amount of axitinib free base (which is the active agent that becomes therapeutically available at the desired site / tissue). The dose administered (per eye) once per treatment period may becontained in one single ASD or implant (including an implant comprising multiple filaments thatare e.g. twisted to form one composite twisted strand), or in two or more ASDs or implantsadministered concurrently, or sequentially. In particular embodiments, the administered dose(per eye) once per treatment period is contained in one single ASD or implant.

[0232] An ASD or implant of the present invention is administered by injection into the eye. TheASD or implant can generally be administered by means of intravitreal, subconjunctival, subtenon, suprachoroidal, or intracameral injection.

[0233] In certain embodiments, the ASD or implant is administered by injection into the anterioror posterior section of the eye, particularly into the posterior section. In particular embodiments, the implant is administered by injection into the vitreous humor of a patient.

[0234] In alternative embodiments, administration of the ASD is suprachoroidal administration.

[0235] In certain embodiments the dry ASDs or implants are loaded in a needle, such as aneedle with a gauge size of from 20 to 30 as disclosed herein, such as a 25-gauge, or a 26- gauge, or a 27-gauge needle, or a smaller gauge needle, and are administered to the eye, such as to the vitreous humor, through this needle. A small needle gauge provides for less potentialof irritation or trauma at the injection site. In one aspect, the present invention relates to aneedle comprising an amorphous solid dispersion (ASD) as described herein or an ocularimplant as described herein.

[0236] In certain embodiments, the ASD or implant is administered through the needle that isconnected to an injection device or injector that is suitable to be connected to a needle pre-loaded with an ASD or implant as disclosed herein and to inject an ASD or implant into the eye.For example, a (modified) Hamilton syringe may be used as an injector. Suitable injection devices for the purposes of the present invention are disclosed in WO 2022 / 204374 and inWO 2021 / 195163. In specific embodiments relating to suprachoroidal injection, a hollowmicroneedle may be used as disclosed in US 8,808,225.

[0237] In certain embodiments, a needle is provided, comprising an ocular implant as describedherein. The needle can have a gauge of from 20 to 30, such as from 25 to 27.

[0238] In some embodiments, a kit is provided, the kit comprising one or more ocular implant(s)as described herein, and one or more needles for injection, wherein each implant is loaded in a needle. The needle can be a hypodermic needle. Furthermore, the needle should be suitable for injection into the eye, such as for injection into the vitreous humor. Such a needle can have agauge size of from 20 to 30, or from 25 to 27. In some kit embodiments, the lumen of eachneedle is occluded by a material that is solid at room temperature and soft or liquid at bodytemperature, such as the ASD comprising a TKI as described herein. A hydrogel implant maybe placed behind the ASD occlusion on the tip of the needle for co-injection. Also, the one ormore ocular implant(s) in the needle may be a stacked sequence od ASD implants, such as forfast release of the TKI, and a hydrogel implant for sustained release of the TKI or another active agent.

[0239] In one embodiment the kit can further comprise one or more injection device(s), whereineach needle is pre-connected or is not pre-connected to an injection device.

[0240] In certain embodiments, a treatment period for the treatment of an ocular disease asdisclosed herein with an ASD or implant of the present invention is least 3 months, at least 4.5 months, at least 6 months, at least 9 months, at least 10 months, at least 12 months, at least 14 months or even longer. In particular embodiments, a treatment period may be about 6 to about 12 months, or about 6 to about 9 months, or may be about 9 months “Treatment period” according to one embodiment of the invention means that a certain therapeutic effect of an ASD or implant of the present invention once administered is maintained, essentially maintained or partially maintained over that period of time. In other words, only one injection (of the ASD or implant of the present invention or of several ASDs or implants concurrently in certain cases) isrequired in certain embodiments for maintaining a therapeutic effect. The therapeutic effect may be reducing or essentially maintaining or preventing a clinically significant increase of the central subfield thickness as measured by optical coherence tomography (CSFT, as further disclosed herein), or increasing or essentially maintaining or preventing a clinically significant reduction of the best corrected visual acuity (BCVA, as further disclosed herein) in a patient’s eye during the treatment period.

[0241] One ASD or implant per eye may be administered per treatment period (although incertain cases the intended dose of TKI may be contained in more than one, such as in two orthree ASDs or implants administered concurrently as disclosed herein). In embodimentswherein two or more ASDs or implants are administered concurrently, the ASDs or implants canbe 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 forinstance administration of two ASDs or implants 7 days apart, i.e., within about 1 or about 2weeks of the first injection. This may still be considered as a “concurrent” administration in the context of the present invention as disclosed herein.

[0242] Ocular diseases that can be treated with the ASDs or implants and methods of thepresent invention may include any ophthalmic condition such as front of the eye conditions or back of the eye conditions.

[0243] Front of the eye conditions may be associated with cellular or subcellular components ofthe front of the eye anatomy such as the acellular tear film layer and its corresponding lipid aqueous mucin components. Front of the eye conditions may also be associated with the upperand lower eyelids including conditions of the meibomian gland and its corresponding cellularand tissue components such as the muscle, lipid producing holocrine, exocrine and endocrine glands and vascular and connective tissue components; and the conjunctiva and its corresponding cells including goblet cells, fibroblast cells, vascular and component blood cells. Front of the eye conditions may further be associated with the corneal layers of the eye including the layers of epithelial cells, stromal cells and fibroblasts, corneal endothelial cells, corneal nerve its associated cells and ground substances. Front of the eye conditions may also include inflammation, diffuse lamellar keratitis, corneal diseases, edemas, or opacifications with an exudative or inflammatory component, eye conditions related to systemic autoimmune diseases, ocular surface disorders from dry eye (e.g., keratoconjunctivitis such as vernal keratoconjunctivitis, atopic keratoconjunctivitis and sicca keratoconjunctivitis), lid margin diseases, meibomian gland conditions, dysfunctional tear syndromes, anterior and posterior blepharitis, staphylococcal blepharitis, microbial infection, conjunctivitis (e.g., persistent allergic, giant papillary, seasonal intermittent allergic, perennial allergic, toxic and infectious conjunctivitis), conjunctival edema, anterior uveitis, inflammatory conditions, edema, genetic conditions of the cornea (e.g., corneal dystrophies such as keratoconus, posteriorpolymorphous dystrophy), Fuchs' dystrophies, aphakic and pseudophakic bullous keratopathy, scleral diseases, ocular cicatricial pemphigoid and pterygium.

[0244] Back of the eye conditions may be related to cellular or subcellular components of theback of the eye anatomy including the retina and all of the cells of the layers of the retina suchas outer and inner photoreceptor layers, nuclear cell layers, amacrine and ganglion cells,macula, fovea, and vitreous. Additional components of the back of the eye include the ciliary body, iris, uvea and the retinal pigment cells. Back of the eye conditions may include conditions of the optic nerve (including corresponding cellular and sub cellular components such as theaxons and associated innervations), glaucoma (e.g., primary open angle glaucoma, acute andchronic closed angle glaucoma and secondary glaucoma), myopic retinopathies, macular edema (including clinical macular edema or angiographic cystoid macular edema arising from conditions such as diabetes, exudative macular degeneration and macular edema associated with laser treatment of the retina), diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, retinal ischemia and choroidal neovascularization, genetic disease of the retina, pars planitis, Posner Schlossman syndrome, Bechet's disease, Vogt-Koyanagi- Harada syndrome, hypersensitivity reactions, toxoplasmosis chorioretinitis, inflammatory pseudotumor of the orbit, chemosis, conjunctival venous congestion, periorbital cellulitis, acute dacryocystitis, non-specific vasculitis, sarcoidosis, and cytomegalovirus infection.

[0245] In certain embodiments, the invention relates to the amorphous solid dispersion (ASD) orthe ocular implant for use as defined herein or the method of treatment as defined herein,wherein the amorphous solid dispersion (ASD) or the ocular implant is used in the treatment ofan ocular disease such as back-of-the-eye diseases such as 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, particularly disease states of the posterior segment resulting from age, trauma, surgical interventions, such as age-related macular degeneration (AMD) cystoid macular edema (CME), diabetic macular edema (DME), posterioruveitis, and diabetic retinopathy.

[0246] In certain embodiments, the invention relates to the amorphous solid dispersion (ASD) orthe ocular implant for use as defined herein or the method of treatment as defined herein,wherein the amorphous solid dispersion (ASD) or the ocular implant is used in the treatment ofan ocular disease selected from the group consisting of retinal neovascularisation, choroidal neovascularisation, Wet AMD, Dry AMD, retinal vein occlusion, diabetic macular edema, retinal degeneration, hyphema, presbyopia, corneal graft rejection, retinoblastoma, melanoma, myosis, mydriasis, glaucoma, conjunctivitis, intraocular infections, choroidal neovascularization (CNV), intraocular tumors, retinal neuroinflammation, inflammation, autoimmune uveitis, uveitis, proliferative vitreoretinopathy, and corneal degeneration, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, posterior uveitis,posterior scleritis, serpiginous choroiditis, subretinal fibrosis, uveitis syndrome, Vogt-Koyanagi Harada syndrome, retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy, angioid streaks, familial exudative vitreoretinopathy, Eales disease, proliferative vitreal retinopathy, diabetic retinopathy, retinal disease associated with tumors, congenital hypertrophy of the retinal pigment epithelium (RPE), posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors, myopic retinal degeneration, acute retinal pigment epithelitis, glaucoma, endophthalmitis, cytomegalovirus retinitis, retinal cancers, retinitis pigmentosa, Leber's Congenital Amaurosis, Choroideremia, X- linked 106 retinitis pigmentosa, best vitelliform macular dystrophy, x-linked retinoschisis, achromatopsia CNGA3, achromotopsia CNGB3, LHON, Stargardt disease, Usher syndrome, Norrie disease, Bardet-Biedl syndrome, and red-green color blindness.

[0247] Specific active agents that can additionally be utilized in the ASDs, implants andmethods of the present invention include but are not limited to immunosuppressants, complement protein C5 agents (e.g., eculizumab or avacincaptad pegol), steroids, anti- inflammatories such as steroidal and non-steroidal anti-inflammatories (e.g., COX1 or COX 2 inhibitors), antivirals, antibiotics, anti-glaucoma agents, anti-VEGF agents, analgesics and combinations thereof.

[0248] Immunosuppressants include but are not limited to cyclosporine, mTOR inhibitors (e.g.,rapamycin, tacrolimus, temsirolimus, sirolimus, everolimus, KU-0063794, WYE-354, AZD8055, metformin, or Torin-2), cyclophosphamide, atoposide, thiotepa, methotrexate, azathioprine, mercaptopurine, interferons, infliximab, etanercept, mycophenolate mofetil, 15-deoxyspergualin, thalidomide, glatiramer, leflunomide, vincristine, cytarabine, pharmaceutically acceptable salts thereof and combinations thereof.

[0249] Non-steroidal anti-inflammatory compounds include inhibitors of the cyclooxygenase(COX) enzyme such as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isozymes. General classes of non-steroidal anti-inflammatory compounds include salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, and anthranilic acid derivatives. Examples of non-steroidal anti-inflammatory compounds include acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dex-ibuprofen, naproxen, nepafenac, fenoprofen, ketoprofen, dex- ketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, tenoxicam, tenoxicam, loroxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, pharmaceutically acceptable salts thereof and combinations thereof.

[0250] Anti-inflammatory agents that may be utilized in the ASDs, implants and methods of thepresent invention may include agents that target inflammatory cytokines such as TNFα, IL-1, IL- 4, IL-5 or IL-17, or CD20. Such agents may include etanercept, infliximab, adalimumab, daclizumab, rituximab, tocilizumab, certolizumab pegol, golimumab, pharmaceutically acceptable salts thereof and combinations thereof.

[0251] Analgesics that may be utilized in the ASDs, implants and methods of the presentinvention include acetaminophen, acetaminosalol, aminochlorthenoxazin, acetylsalicylic 2- amino-4-picoline acid, acetylsalicylsalicylic acid, anileridine, benoxaprofen, benzylmorphine, 5- bromosalicylic acetate acid, bucetin, buprenorphine, butorphanol, capsaicin, cinchophen, ciramadol, clometacin, clonixin, codeine, desomorphine, dezocine, dihydrocodeine, dihydromorphine, dimepheptanol, dipyrocetyl, eptazocine, ethoxazene, ethylmorphine, eugenol, floctafenine, fosfosal, glafenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p- lactophenetide, levorphanol, meptazinol, metazocine, metopon, morphine, nalbuphine, nicomorphine, norlevorphanol, normorphine, oxycodone, oxymorphone, pentazocine, phenazocine, phenocoll, phenoperidine, phenylbutazone, phenylsalicylate, phenylramidol, salicin, salicylamide, tiorphan, tramadol, diacerein, actarit, pharmaceutically acceptable salts thereof and combinations thereof.

[0252] Antibiotics that may be utilized in the ASDs, implants and methods of the presentinvention include aminoglycosides, penicillins, cephalosporins, fluoroquinolones, macrolides, and combinations thereof. Aminoglycosides may include tobramycin, kanamycin A, amikacin, dibekacin, gentamicin, sisomicin, netilmicin, neomycin B, neomycin C, neomycin E, streptomycin, paramomycin, pharmaceutically acceptable salts thereof and combinations thereof. Penicillins may include amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, pivampicillin, pivmecillinam, ticarcillin, pharmaceutically acceptable salts thereof and combinations thereof. Cephalosporins may include cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefuzonam, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefclidine, cefepime, cefluprenam, cefoselis, cefozopran, cefpirome, cefquinome,ceftobiprole, ceftaroline, cefaclomezine, cefaloram, cefaparole, cefcanel, cefedrolor,cefempidone, cefetrizole, cefivitril, cefmatilen, cefmepidium, cefovecin, cefoxazole, cefrotil, cefsumide, cefuracetime, ceftioxide, pharmaceutically acceptable salts thereof and combinations thereof. Fluoroquinolones may include ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, ofloxacin, norfloxacin, pharmaceutically acceptable salts thereof and combinationsthereof. Macrolides may include azithromycin, erythromycin, clarithromycin, dirithromycin, oxithromycin, telithromycin, pharmaceutically acceptable salts thereof and combinations thereof.

[0253] Antivirals that may be utilized in the ASDs, implants and methods of the presentinvention include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, integrase inhibitors, nucleoside analogs, protease inhibitors, and reverse transcriptase inhibitors. Examples of antiviral agents include, but are not limited to, abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, boceprevir, cidofovir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramiding saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, pharmaceutically acceptable salts thereof and combinations thereof.

[0254] Steroidal anti-inflammatory agents that may be utilized in the ASDs, implants andmethods of the present invention include dexamethasone, budensonide, triamcinolone, hydrocortisone, loteprednol, prednisolone, mometasone, fluticasone, rimexolone, fluorometholone, beclomethasone, flunisolide, pharmaceutically acceptable salts thereof and combinations thereof.

[0255] Anti-glaucoma agents that may be utilized in the ASDs, implants and methods of thepresent invention include beta-blockers such as atenolol propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, levobunolol timolol, pharmaceutically acceptable salts thereof and combinations thereof; adrenergic agonists or sympathomimetic agents such as epinephrine, dipivefrin, clonidine, aparclonidine, brimonidine, pharmaceutically acceptable salts thereof andcombinations thereof; parasympathomimetics or cholinergic agonists such as pilocarpine,carbachol, phospholine iodine, physostigmine, pharmaceutically acceptable salts thereof and combinations thereof; carbonic anhydrase inhibitor agents, including topical or systemic agentssuch as acetozolamide, brinzolamide, dorzolamide; methazolamide, ethoxzolamide,dichlorphenamide, pharmaceutically acceptable salts thereof and combinations thereof; mydriatic-cycloplegic agents such as atropine, cyclopentolate, succinylcholine, homatropine, phenylephrine, scopolamine, tropicamide, pharmaceutically acceptable salts thereof and combinations thereof; prostaglandins such as prostaglandin F2 alpha, antiprostaglandins, prostaglandin precursors, or prostaglandin analog agents such as bimatoprost, latanoprost, travoprost, unoprostone, tafluprost, pharmaceutically acceptable salts thereof and combinations thereof.

[0256] Anti-VEGF agents that may be utilized in the ASDs, implants and methods of the presentinvention include bevacizumab, pegaptanib, ranibizumab, brolucizumab, pharmaceutically acceptable salts thereof and combinations thereof. Further embodiment

[0257] A further method of increasing the solubility of a TKI, such as axitinib, and thusimproving its bioavailability when being released from an ocular implant, including an ocular implant comprising the TKI in a polymer matrix, such as a hydrogel, such as a PEG-basedhydrogel, is complexation with cyclodextrin. Axitinib solubility can be enhanced from 0.2 μg / mLto at least 12,000 μg / mL by complexation with cyclodextrin, such as (2-hydroxypropyl)-β-cyclodextrin, hydroxy propyl methylcellulose, for example, with or without complex stabilizerssuch as caffeine.

[0258] By forming TKI-cyclodextrin complexes, such as axitinib-cyclodextrin complexes, anddispersing them within an implant, such as a hydrogel implant, the rate of active agent (API)release can be improved. By dispersing a micronized API, such as a TKI, such as axitinib,atomically within individual molecules of cyclodextrin the solubility can be enhanced in animplant. Micronized TKI and TKI-cyclodextrin complexes may both be added during implantformulation, such as hydrogel implant formulation. This can provide greater control over theentire release profile of the (ocular) implant.

[0259] TKI-cyclodextrin complexes, such as axitinib-cyclodextrin complexes can be preparedutilizing a co-precipitation method for complexation. The resulting product is highly crystalline.Alternatively, a freeze-drying method for producing complexes can be utilized for preparing TKI-cyclodextrin complexes, such as axitinib-cyclodextrin complexes, in which an aqueoussuspension of the API is mixed with (2-hydroxypropyl)-β-cyclodextrin for several days atelevated temperatures (37°C). The solution is then either filtered, e.g. with a 0.45 μm filter, orleft as is and lyophilized to create a powder product. That powder product can then either be redispersed during wet casting of a hydrogel implant or powder mixed for hot melt extrusion (HME). In some embodiments, complexes were based on a 1:1 molar ratio of Axitinib to cyclodextrin.

[0260] Evaluating just the drug solubility based on complexation, without including in an implantmatrix, the improvement in axitinib solubility is significant compared to micronized control. Thesolubility can be measured by UV-VIS following the same method as described in Example 6herein. A significant increase in axitinib solubility of either unfiltered or filtered complexation with(2-hydroxypropyl)-β-cyclodextrin is observed compared to micronized control. The increase insolubility was determined to be 2.5x for unfiltered complexes and 3.6x for filtered complexes. The difference between filtered (clear solution) and unfiltered (milky solution) may be attributable to the influence of uncomplexed axitinib.

[0261] Using such axitinib complexes, both wet cast and HME PEG based hydrogel implants asdescribed herein before were produced. For wet cast controls, the concentration of axitinibeither in micronized form or complexed was kept constant but the overall solids loading changedbased on the inclusion of cyclodextrin. Table A below shows the exemplary compositions.Table A:

[0262] For HME production, a small scale Femto extruder was utilized for proof of concept witha 2.0 mm diameter die. It was found that at high cyclodextrin complex solids loading of 60% (sample B) the material was too thick to be extruded but was workable at a lower concentrationof 40% (sample D). The results are shown in Table B below.Table B:EXAMPLES

[0263] The following Examples and Comparative Examples are included to demonstrate certainaspects and embodiments of the invention as described in the claims. It should be appreciatedby those of skill in the art, however, that the following description is illustrative only and should not be taken in any way as a restriction of the invention. Example 1: Recrystallization Screening

[0264] For producing ASD’s one of the first evaluation steps is to determine which polymerexcipients display a high degree of molecular interaction with the desired API. Many different polymer excipients have been utilized in the development of ASD’s in the prior art. Therefore,utilizing a screening technique has been done in order to choose the best polymer candidatesprior to production of the ASD. One such approach is to employ a recrystallization inhibition assay, for example the assay as described in Q. Zhang et al., "Effect of HPMCAS on recrystallization inhibition of nimodipine solid dispersions prepared by hot-melt extrusion and dissolution enhancement of nimodipine tablets," Colloids and Surfaces B: Biointerfaces, vol. 172, pp.118-126, 2018, which is incorporated herein by reference. In this technique, the API is dissolved into a water miscible solvent including the polymer excipient at a concentrationgreater than its water solubility. A small volume, e.g.10 to 25 μL of the dissolved API is thenadded to a given volume of water, e.g. to 200 μL of water in a 96 well plate, where the solvent dissolves and forces the API to crystallize The effect of various dissolved polymer excipients to inhibit recrystallization can then be used to determine the greatest interactions between polymer in API.

[0265] The recrystallization inhibition assay has been demonstrated with Axitinib (depicted asMSN), the results of which are shown Figure 1. The drug was utilized in particular because itsabsorbance (directly proportional to their concentration in solution) could be measured by UV-VIS. From the analyses, it can be observed that the polymers Soluplus and HMPCAS (gradeHMP) resulted in the greatest absorbance values and therefore demonstrated the greatest recrystallization inhibition.

[0266] The inhibition assay can also be used to determine the composition of the ASDsproducts. By varying the ratio of the API to the polymer excipient the recrystallization inhibitory effect can be used to determine the amount of polymer necessary during hot melt extrusion (HME) of the ASD. The ratio screening of the polymer HMPCAS and Soluplus®with Axitinib is shown in Figure 2. Visually, the recrystallization can also be observed under a microscope.

[0267] As can be seen from Figure 2, a ratio of 25% Axitinib to 75% polymer results in thegreatest absorbance. This result underlies the importance of screening different polymers andratios for the API. Interestingly, lower API load does not always mean better crystal inhibition orperformance when it comes to ASD production. Each API with a given polymer may have adifferent optimal concentration based on the molecular interactions, molecular weight, and molecular packing.Example 2: HME of Axitinib / Soluplus®

[0268] ASDs can be created during the high temperature and high shear environment of hotmelt extrusion (HME) production. During HME, the polymer excipient is fully melted and the APIdispersed within the melt. It is commonly accepted that the API will molecularly ‘dissolve’ intothe polymer matrix even at a temperature 40-50°C lower than the API’s melting temperature. As the material is extruded the melt quickly cools. The interaction of the polymer with the API prevents drug crystallization and the product cools beneath the composites glass transition temperature molecularly ‘freezing’ the API within the matrix.

[0269] The Tg value of ASD formulations can be estimated through empirical formulations. TheGordon-Taylor equation, developed in the 1950s, estimates binary ASD Tg(Tg,mix) by individualcomponent Tg’s:Where w represents component weight fraction, and the fitting parameter K is determined by:Where휌 is the true component density and ∆훼 the change in component thermal expansivity atTg. The equation is based off the assumptions of ideal mixing and ideal volume additivity. Essentially, the Tgvalue of an ASD is a weighted average of the individual Tgvalues of the API and the polymer. A simple test to determine whether an ASD was effectively produced is to analyze the sample by differential scanning calorimetry (DSC). If no crystal melt endotherm is observed than the API is effectively in its amorphous state. Furthermore, if only one Tgvalue is observed rather than two distinct Tgvalues, then the two components were effectively mixed.

[0270] Based on the recrystallization inhibition studies, Axitinib based ASDs were producedusing the polymer Soluplus. Soluplus was chosen because it is readily water soluble as compared to the next leading polymer candidate of HMPCAS which is not water soluble. Therefore, ASDs produced with Soluplus would be able to dissolve in vitro, which is desirableespecially for ocular implants. An ASD product was produced containing 25% Axitinib(Example #1A (invention, ASD formulation)). The product was produced from a five-grambatch run on a Mini CTW extruder at a temperature of 140°C and using a die size of 1.0 mm.The product was shown to be an ASD by DSC analysis. The material produced is quite ductileleaving the extruder and can be drawn down to very short diameters despite the original diesize. Some melt crystallization is observed with these Axitinib ASD samples suggesting thatthey are not totally amorphous (Example #1A) as shown in Figure 3. The HME ASDformulations are summarized in Table 2.Table 2: ASD formulations produced by HMEExample 3: Stability of the ASD

[0271] The stability of ASD formulations can be impaired by absorbed water during storage.Water, because of its very low Tgvalue, is a strong plasticizer and lowers the Tgof the ASD when absorbed, increasing molecular mobility. Assessing polymer hygroscopicity is therefore asuitable selection parameter which can be made early on in ASD development to better storageperformance. In terms of storage of an ASD itself, along with temperature, humidity plays acrucial role in ASD stability. To this end, accelerated aging studies are often employed whereinthe ASD sample is tested at a stressed condition of 40℃ and 75% RH.

[0272] The ASD formulations outlined in this example were tested under three differentconditions to quantity their stability over time. These conditions were at 4℃ under nitrogen, atroom, temperature and ambient humidity, and a stressed condition of 37℃ and 75% RH. Thesamples were tested at time zero, one week, and one month using DSC, SEM, FTIR, anddissolution performance. ASD blends of axitinib and Soluplus were tested by DSC analysis attime zero to demonstrate the worst-case scenario of full API crystallization during storage, as shown in Figure 4.

[0273] The DSC analysis of the ASD samples after aging for one week and one month at thegiven storage conditions is shown in Figure 5..

[0274] Figure 6 shows the visual analysis of the implants following one month aging at givenconditions. It can visually oberserved that implants are the accelerated conditions (37℃ and75%) change in appearance underlying drug recrystallization

[0275] Finally, Figure 7 shows the solubility of 25% Axitinib ASDs after one month aging at thegiven conditions. For the 25% Axitinib ASDs there was a significant difference in API solubility between the room temperature and accelerated conditions but not compared to the control underlying that these implants do not yet have a significant degree of recrystallization.Example 4: ASD Application Examples

[0276] ASDs including a TKI may be used for posterior injection in the eye together withsustained release hydrogel ocular implants such as implants based on available ELUTYX™ technology of Ocular Therapeutics, USA, for example hydrogel based AXPAXLI (axitinibintravitreal implant), also referenced as laboratory code OTX-TKI. One possible mode ofadministration is using thin ASD implants drawn-down during extrusion to a diameter reflectingOTX-TKI (Figure 8) and then stacking the ASD implant and a traditional OTX implant one on topof another in a syringe, such as a 25G syringe. Both implants can then be applied together fromone syringe to augment release rate of the TKI, i.e., by combining a faster releasing ASD with adelayed release hydrogel, for example, for rapid onset of TKI release avoiding an initial lag phase. This approach is visually outlined in Figure 8.

[0277] Another mode to utilize the melt properties of ASDs is an ASD implant that is placed atthe bevel of a syringe needle, such as a 25G needle loaded with a hydrogel implant such asOTX-TKI, and then using a heat source that is quickly passed over the ASD causing it to heat seal and act as a water-soluble plug on the needle tip. An ASD heat sealed needle is shown in Figure 9. This approach was demonstrated with a 25% Axitinib ASD wherein the ASD holds the OTX implant such as AXPAXLI within the syringe and dissolves when applied to an aqueous environment to control the release profile of Axitinib. Example 5: Ocular implant

[0278] An implant of the invention and comparative implants are provided in Table 3 below. Thefast releasing hydrogel based comparative implants were produced according to the processes as described in Example 1 of PCT / US2024 / 023688, which is incorporated herein by reference. Table 3: Overview of Overview of an implant #1of the invention and of comparative implantsExample 5.1: Preparation of the ASD implant Example #1

[0279] The ASD implant Example #1 was produced by hot melt extrusion (HME / single strand)as follows: Implant 1 according to the present invention was formed by a melt extrusion processas exemplarily disclosed herein, from the following raw materials: the polymer excipient Soluplus® from BASF, Germany, and the TKI (in this case axitinib). These materials are firstcombined and mixed for 10 minutes in the melt form to provide a homogenous molten material.The combined molten material is then loaded in 5 g batches into a MiniCTW melt extruder witha 1.0 mm diameter die (Thermofisher, Inc.), which has been set to a temperature of about140°C) and a screw rotation speed (20-100 rpm).

[0280] Material can then be extruded through the die of the extruder onto a conveyer belt at aspeed of 1000RPM (1.4in / sec). The rate of drawing determines the diameter of the extrudate. Drawing keeps material straight and allows it to cool and harden before being cut away from the extruder and collected for downstream processing. After extrusion, the material is cooled in ambient air at which point it is ready to be cut and inspected

[0281] Table 4 outlines these steps and considers exemplary equipment for each step as wellas exemplary settings for each step. Table 4: Laboratory bench top process stepsExample 5.2: In vitro release determination of the implants according to Method B

[0282] Table 5 below outlines the in vitro release of the implants of Table 3, the comparativeexamples manufactured by wet casting and Implant 1 by HME The release was measuredaccording to Method B as disclosed herein above in 25:75 ethanol:water (v / v) with an overallvolume equal to three times the sink volume (sink volume is the axitinib amount in the implantper assay / axitinib solubility). The samples were stored in a 37°C incubator on a rocker plate to provide moderate agitation.1mL of the solution was sampled on pre-determined days until the drug is fully released. Samples were run on either a UV-Vis spectrometer or a UPLC against analytical standards prepared within the last 2 weeks. In this Method B, two different solubility values were used for SAB-I and Polymorph-IV, namely 13.41 and 20.09 μg / mL, respectively, to calculate the sink volume. The release profiles are shown in Figure 10. Table 5: Implant in vitro release data

[0283] The results in Table 5 and Figure 10 show that despite having a much lower surface areaand drug load, the inventive ASD implant (Example #1) had a faster release rate than thecomparative examples in the first 0.5h. According to the Higuchi kinetics modeling of release rate,the faster release rate can be explained by an increase in API solubility.Example 6: Solubility measurementsExample 6.1: Solubility of Axitinib free base

[0284] In this study, the solubility of different polymorphs of axitinib was measured (Table 6).Table 6: Particle size of SAB-I and Polymorph IV

[0285] Materials and MethodsReagents: 1 x PBS, pH 7.2 Water 100 mL amber sample bottle Equipment:Eppendorf Microcentrifuge 5424 Capacity 1.5 - 2.2 mL microcentrifuge tubesMax. Speed 15,000 rpmMax. RCF 21,130 rcf

[0286] Add approximately 10-20 mg of the axitinib into ~75 mL of 1 x PBS pH 7.2-7.4. Place onrocker table at 37 °C at 200 rpm. Remove 1-2 mL at each time interval and transfer to 2 mL centrifuge tube. Centrifuge at 15,000 RPM for 30 minutes. Aliquot 1 mL of supernatant to aUPLC vial. Samples are placed in a 37 °C incubator for the duration of the study. Care is takento sample through a clear area as much as possible. The pipet tip is wiped clean for this transfer step.

[0287] An Example injection sequence is shown below:Table 7: Example injection for UPLCNote: A bracket standard should be analyzed after every 10 sample injections. Table 7a: UPLC conditions

[0288] The solubility results are as follows: Axitinib polymorph IV has a solubility in PBS at37 °C and pH 7.2 to 7.4 after five days of incubation of greater than 0.3 μg / mL, and evengreater than 0.4 μg / mL. Axitinib polymorph SAB-I (all particles’ sizes tested) has a solubility inPBS at 37 °C and pH 7.2 to 7.4 of less than 0.3 μg / mL. From the solubility results presented in Table 7b, it can be taken that after five days of incubation an equilibrium state is achieved. An average equilibrium solubility could be determined (equilibrium of days 5, 6 and 8 in Table 7b) for each polymorph. The equilibrium solubility of axitinib SAB-I in PBS at 37 °C and pH 7.2 to 7.4 was an average of 0.191, 0.226 and 0.252 μg / mL, depending on the particle size (non- micronized, micronized and super-micronized). The equilibrium solubility of axitinib polymorph IV (micronized) was 0.435 μg / mL.Table 7b: Equilibrium solubility of axitinib SAB-I and Polymorph IV in PBSExample 6.2: Solubility of axitinib (ASD implant #1)

[0289] A given mass or ASD implant (Example #1) being cut in small chunks was placed in avessel. A given volume of deionised water or PBS was added to reach the sink condition for agiven mass of ASD implant (Example #1) in the vessel. The samples were then measured inanalogy to day 5 of Example 6.1 at the indicated time intervals on the supernatant on a UV-VISspectrometer.

[0290] It was found that the ASD implant (Example #1) provides a solubility enhancement ofgreater than 1, such as greater than 1.5, or greater than 2, particularly greater than 3 comparedto the crystalline TKI, such as axitinib, 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 an embodiment, an ASD implant(Example #1) of the invention comprising axitinib has a solubility enhancement of axitinib of 2.4or greater.

Claims

CLAIMS1. An ocular implant comprising an amorphous solid dispersion (ASD), the ASD comprisinga tyrosine kinase inhibitor (TKI) and a polymer excipient.

2. The ocular implant of claim 1, wherein the tyrosine kinase inhibitor (TKI) is selected fromat least one of axitinib, lapatinib, sorafenib, imatinib, gefitinib, erlotinib, nilotinib, pazopanib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib, vandetanib, and dasatinib, or pharmaceutically acceptable salts, derivatives or prodrugs thereof.

3. The ocular implant of claim 1 or 2, wherein the tyrosine kinase inhibitor (TKI) is axitinib,or a pharmaceutically acceptable salt, derivative or prodrug thereof.

4. The ocular implant of any one of the preceding claims, wherein the polymer excipient isselected from the group consisting of polyvinyls such as polyvinyl pyrrolidone-vinylacetate (PVPVA), polyvinylpyrrolidone (PVP), povidone (PVP), such as povidone K25, povidone K17 or povidone K30, or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®); polyethylene glycols (PEG), poloxamers such aspoloxamer 188, Pluronic® F127 or Pluronic F68®; polyacrylates and methacrylates suchas Carbomer, Eudragit® EPO or Eudragit® RL PO; and cellulose and its derivatives suchas methyl cellulose, hydroxypropyl methylcellulose (HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS), or a mixture thereof.

5. The ocular implant of any one of the preceding claims, wherein the polymer excipient isa polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), or hydroxypropyl methylcellulose acetate succinate (HPMCAS), such as Soluplus®.

6. The ocular implant of any one of the preceding claims, wherein the polymer excipient isa mixture of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and a polymer selected from the group consisting of polyvinyls such aspolyvinyl pyrrolidone-vinyl acetate (PVPVA), polyvinylpyrrolidone (PVP), povidone (PVP), such as povidone K25, povidone K17 or povidone K30; polyethylene glycols (PEG), poloxamers such as poloxamer 188, Pluronic® F127 or Pluronic F68®;polyacrylates and methacrylates such as Carbomer, Eudragit® EPO or Eudragit® RL PO;and cellulose and its derivatives such as methyl cellulose, hydroxypropyl methylcellulose(HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

7. The ocular implant of claim 6, wherein the polymer excipient is a mixture of polyvinylpolymercaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and hydroxypropyl methylcellulose acetate succinate (HPMCAS).

8. The ocular implant of any one of the preceding claims, wherein the amorphous soliddispersion (ASD) includes 1 to 90 wt.% of the TKI, or 10 to 80 wt.%, or 20 to 70 wt.%, such as 25 to 60 wt.%, or 30 to 50 wt.%, based on the total weight of the ASD.

9. The ocular implant of any one of the preceding claims, wherein the TKI is axitinib and theweight ratio of axitinib and the polymer excipient ranges from 1:1 to 1:4, such as from 1:2 to 1:3.5, or from 1:2.5 to 1:3.

10. The ocular implant of any one of the preceding claims, wherein the ASD has a solubilityenhancement of greater than 1, or greater than 1.5, such as greater than 2, particularlygreater than 3 compared to crystalline axitinib measured by using the axitinib solubility method described in Example 6.

11. The ocular implant of any one of the preceding claims, wherein the implant essentiallyconsists of the amorphous solid dispersion (ASD) comprising a tyrosine kinase inhibitor (TKI) and a polymer excipient, or wherein the ASD comprising a tyrosine kinase inhibitor (TKI) and a polymer excipient forms part of the implant.

12. The ocular implant of any one of the preceding claims, wherein the implant essentiallyconsists of the amorphous solid dispersion (ASD) comprising a tyrosine kinase inhibitor (TKI) and a polymer excipient and is delivered as a particle slurry, such as spray driedASD particles or milled HME strands in an oil carrier.

13. The ocular implant of claim 11, wherein the ASD is dispersed and / or embedded in ahydrogel, such as a biodegradable hydrogel.

14. The ocular implant of claim 11 or 13, wherein the implant comprises a hydrogel and theASD in separate portions of the implant, such as a stack comprising a hydrogel portion and an ASD portion, or a hydrogel portion coated with an ASD.

15. The ocular implant of claim 14, wherein the implant comprises a hydrogel that is at leastpartially coated with the ASD.

16. The ocular implant of claim 14, wherein the implant comprises a sustained releasehydrogel comprising the TKI, and a separate portion of the implant comprises the ASD comprising the TKI.

17. The ocular implant of claim 14 to 16, wherein the separate portion of the implantcomprising the ASD comprising the TKI is a tip portion or a coating of a hydrogel implant,such as a cylindrical ocular implant, or a plug.

18. The ocular implant of any one of the preceding claims, wherein a part of the tyrosinekinase inhibitor, optionally in the form of particles, such as micronized particles, is dispersed within the hydrogel, and further TKI, the same or different, preferably the same, is comprised in the ASD.

19. The ocular implant of any one of the preceding claims, wherein the ocular implantcomprises a sustained release hydrogel and the ASD, both comprising the TKI, such as axitinib, in a combined total dose of at least 15 μg, such as from about 15 μg to about1200 μg, from about 150 μg to about 1000 μg, from about 150 μg to about 900 μg, or from about 200 μg to about 800 μg, or from about 250 μg to about 700 μg, or from about 300 to about 650 μg.

20. The ocular implant of any one of the preceding claims, wherein the hydrogel comprises apolymer network comprising one or more units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyaminoacids, glycosaminoglycans, polysaccharides, or proteins.

21. The ocular implant of claim 20, wherein the hydrogel comprises a polymer network that comprises crosslinked polymer units, such as one or more crosslinked multi-arm polymer units, which are identical or different.

22. The ocular implant of claim 21, wherein crosslinked polymer units are one or more crosslinked polyethylene glycol units.

23. The ocular implant of any one of claims 20 to 22, wherein the polymer network comprises polyethylene glycol units having an average molecular weight (Mw) in the range from about 2,000 to about 100,000 Daltons, such as about 10,000 to about 60,000 Daltons, or about 20,000 to about 40,000 Daltons such as about 20,000 Daltons.

24. The ocular implant of any of the preceding claims, wherein the implant has an essentiallycylindrical shape, or another cross-sectional shape.

25. The ocular implant of any of the preceding claims, wherein the implant is in the form of afiber or filament, or a plurality of filaments.

26. An ocular implant of any one of the previous claims, for use as a medicament, such asfor treating an ocular disease, disorder, or medical condition.

27. The ocular implant of claim 26,wherein the implant comprises a hydrogel in a dried state prior to administration, and the hydrogel becomes hydrated once administered into the eye, optionally wherein the implant in a dried state contains not more than about 1 % by weight water.

28. A method of treatment, wherein the method comprises treating a disease, disorder, ormedical condition in a patient with an ocular implant of any one of the previous claims, comprising administering the ocular implant to a patient in need thereof.

29. The ocular implant for use or the method of treatment of any one of claims 26 to 28,wherein ocular disease, disorder, or medical condition comprises back-of-the-eye diseases such as 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, particularly disease states of the posterior segment resulting from age, trauma, surgical interventions, such as age-related macular degeneration (AMD) cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis, and diabetic retinopathy.

30. The ocular implant for use or the method of treatment of any one of claims 26 to 29,wherein the implant is used in the treatment of an ocular disease, disorder, or medical condition selected from the group consisting of retinal neovascularisation, choroidal neovascularisation, Wet AMD, Dry AMD, retinal vein occlusion, diabetic macular edema, retinal degeneration, hyphema, presbyopia, corneal graft rejection, retinoblastoma, melanoma, myosis, mydriasis, glaucoma, conjunctivitis, intraocular infections, choroidal neovascularization (CNV), intraocular tumors, retinal neuroinflammation, inflammation, autoimmune uveitis, uveitis, proliferative vitreoretinopathy, and corneal degeneration, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, posterior uveitis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis, uveitis syndrome, Vogt-Koyanagi Harada syndrome, retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafovealtelangiectasis, hemi-retinal vein occlusion, papillophlebitis, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy, angioid streaks, familial exudative vitreoretinopathy, Eales disease, proliferative vitreal retinopathy, diabetic retinopathy,retinal disease associated with tumors, congenital hypertrophy of the retinal pigment epithelium (RPE), posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors, myopic retinal degeneration, acute retinal pigment epithelitis, glaucoma, endophthalmitis, cytomegalovirus retinitis, retinal cancers, retinitis pigmentosa, Leber's Congenital Amaurosis, Choroideremia, X-linked 106 retinitis pigmentosa, best vitelliform macular dystrophy, x-linked retinoschisis, achromatopsia CNGA3, achromotopsia CNGB3, LHON, Stargardt disease, Usher syndrome, Norrie disease, Bardet-Biedl syndrome, and red-green color blindness.

31. The ocular implant for use or the method of treatment of any one of claims 26 to 30,wherein the implant is administered to the eye through a needle.

32. The ocular implant for use or the method of treatment of claim 31, wherein the needle isa 25- or 27-gauge needle.

33. The ocular implant for use or the method of treatment of any one of claims 26 to 33,wherein upon hydration in vivo in the eye, or in vitro, the diameter of the implant is increased, or the length of the implant is decreased while its diameter is increased, wherein hydration is measured in vitro in phosphate-buffered saline at a pH of 7.2 at 37 °C after 24 hours.

34. A process for preparing an ocular implant comprising an amorphous solid dispersion(ASD) as defined in any one of the preceding claims, comprising the following steps:(a) dispersing the tyrosine kinase inhibitor (TKI), such as axitinib, ora pharmaceutically acceptable salt, derivative or prodrug thereof within thepolymer excipient matrix, wherein the polymer excipient is as defined in claim 4 to 7, optionally using one or more solvents; and (b) optionally removing the one or more solvent to obtain the amorphous soliddispersion (ASD).

35. The process of claim 34, further comprising a step of dispersing the ASD including theTKI in a hydrogel, or at least partially coating a hydrogel with the ASD including the TKI.

36. The process of claim 34 or 35 wherein the one or more solvent comprises one or moreof chlorinated hydrocarbon solvents such as dichloromethane, dichloroethane, and chlorobenzene; alcoholic solvents such as methanol, ethanol, 2-propanol, 1-butanol and t-butyl alcohol; N,N-dimethylformamide; nitriles such as acetonitrile; dimethyl sulfoxide; water and mixtures thereof, preferably the solvent is acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide.

37. The process of any one of claims 34 to 36, wherein removing of the solvent comprisesdistillation, distillation under vacuum, spray drying, freeze-drying (lyophilization), filtration, decantation and / or centrifugation.

38. The process of claim 34 or 35, wherein the step of dispersing the tyrosine kinaseinhibitor (TKI), such as axitinib, or a pharmaceutically acceptable salt, derivative orprodrug thereof, within the polymer excipient matrix involves solvent-free extrusion.

39. The process of claim 38, comprising the following steps:(a) feeding the tyrosine kinase inhibitor (TKI), such as axitinib, or a pharmaceuticallyacceptable salt, derivative, or prodrug thereof, and a polymer excipient as defined in claim 4 to 7 into a heated extruder to obtain a melt mixture; (b) extruding the melt mixture to obtain an ocular implant comprising an amorphoussolid dispersion (ASD).

40. The process of claim 39, further comprising coextruding the melt in addition to crosslinkable hydrogel precursor compounds, or simultaneously coextruding a hydrogeland the ASD, such as forming a coextruded sheath of ASD over the hydrogel by coextrusion.

41. The process of claim 39 or 40, wherein the tyrosine kinase inhibitor (TKI) and thepolymer excipient are fed into the extruder in the form of a preformed melt; or the tyrosine kinase inhibitor (TKI) and the polymer excipient are fed separately into the extruder; or wherein the tyrosine kinase inhibitor (TKI) and the polymer excipient are mixed prior to being fed into and molten in the extruder.

42. The process any one of claims 39 to 41, wherein the process further comprises mixingthe components in the extruder; extruding a strand; optionally stretching the strand into a fiber or filament; and cutting the strand, fiber or filament into unit dose ocular implants.

43. The process of any one of claims 39 to 42, wherein the tyrosine kinase inhibitor (TKI) isaxitinib, or a pharmaceutically acceptable salt, derivative, or prodrug thereof, andwherein the process further comprises melting the mixture in the extruder at atemperature of from about 55°C to about 200°C, such as from about 65°C to about180°C , and particularly from about 100°C to about 160°C.

44. The ocular implant of any one of claims 1 to 33, wherein the average release rate oftyrosine kinase inhibitor per day from the ocular implant over a period defined by any initial number of days up to the day when 80% of the tyrosine kinase inhibitor contained in the ocular implant is released is higher than the average release rate of tyrosine kinase inhibitor per day, over the same period of time, from a comparative ocular implantincluding the same TKI in the same amount but no ASD, and wherein the release of tyrosine kinase inhibitor from both ocular implants is measured under identical conditions.

45. The ocular implant of claim 44, wherein the average release rate of tyrosine kinaseinhibitor from the ocular implant over said period of time is at least 10%, or at least 20% higher than the average release rate of tyrosine kinase inhibitor over said period of timefrom the comparative ocular implant.

46. The ocular implant of any one of the preceding claims, wherein the average release rateof tyrosine kinase inhibitor from the implant in the first half hour is higher than theaverage release rate of tyrosine kinase inhibitor from the comparative implant.

47. The ocular implant of any one of the preceding claims, wherein the ocular implantprovides for an average in vivo release rate in the vitreous of at least 0.5 μg / day, such as at least 0.6 μg / day, or at least 0.7 μg / day, or at least 0.8 μg / day for a period of at least 3months, measured in the vitreous of a non-human primate, such as a monkey, or in the vitreous of a human.

48. The ocular implant of any one of the preceding claims, wherein the ocular implantreleases, measured in accordance with Method C as described herein, at least about35% by weight, such as at least about 40% by weight, or such as at least about 42% by weight of the tyrosine kinase inhibitor, such as axitinib, from the implant in the first half hour, referring to the total weight of the TKI contained in the implant.

49. The ocular implant of any one of the preceding claims, wherein the ocular implantreleases, measured in accordance with Method C as described herein, at least about90% by weight, such as at least about 92% by weight, or such as at least about 94% by weight of the tyrosine kinase inhibitor, such as axitinib, from the implant in the first two hours, referring to the total weight of the TKI contained in the implant.

50. The ocular implant of any one of the preceding claims, wherein the ocular implant,measured in accordance with Method C as described herein, almost completely releasesthe tyrosine kinase inhibitor, such as axitinib, from the ASD or implant within about two hours.

51. The ocular implant of any one of claims 1 to 33 or 44 to 50, wherein the ocular implant isloaded in a needle having a gauge of from 20 to 30, such as from 25 to 27.

52. A needle comprising an ocular implant of any one of claims 1 to 33 or 44 to 51,preferably wherein the needle has a gauge of from 20 to 30, such as from 25 to 27.

53. A kit comprising one or more ocular implant(s) of any one of claims 1 to 33 or 44 to 51,and one or more needles for injection, wherein each implant is loaded in a needle.

54. The kit of claim 53, wherein the needle is a hypodermic needle.

55. The kit of claim 53 or 54, wherein the needle is suitable for injection into the eye.

56. The kit of claim 55, wherein the needle is suitable for injection into the vitreous humor.

57. The kit of any of claims 53 to 56, wherein the needle(s) have a gauge size of from 20 to30, or from 25 to 27.

58. The kit of any of claims 53 to 57, wherein the lumen of each needle is occluded by amaterial that is solid at room temperature and soft or liquid at body temperature, such as the ASD comprising a TKI as described in any one of the previous claims.

59. The kit of any of claims 53 to 58, further comprising one or more injection device(s),wherein each needle is pre-connected or is not pre-connected to an injection device.

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