Treatment methods for diabetic macular edema

Abstract

This disclosure relates to a method for treating diabetic macular edema in human subjects requiring treatment, and the method is as follows: (i) An induction phase in which an eye drop formulation containing 1.5% (w / v) dexamethasone is administered topically to the affected eye for 3, 4, 5, and 6 weeks at a dose of 5 to 7 drops per day, followed by, (ii) During the maintenance phase, the eye drop formulation containing 1.5% (w / v) dexamethasone is administered topically to the affected eye at a daily dose less frequently than during the induction phase (e.g., 1 to 3 drops). Includes.

Description

Detailed description of the invention

[0001] This disclosure describes an improved method for treating human subjects requiring treatment for diabetic macular edema with topical eye drops, which provides therapeutic efficacy equivalent to or better than current state-of-the-art techniques using intraocular implants.

[0002] 〔background〕 Diabetic macular edema (DME) is a leading cause of vision loss and legal blindness in people with diabetes. Currently, it is estimated that approximately 37 million people worldwide are affected, and this number is projected to increase to 53 million by 2040 as diabetes increases (Yau et al. Diabetes Care 2012 Mar; 35(3): 556-564; International Diabetes Federation - diabetesatlas.org Estimated diabetes prevalence worldwide in 2021: 537m, reaching 783m in 2045). DME is an irreversible and progressive complication of diabetic retinopathy, associated with damage to nerves and blood vessels in the macula, the area of ​​the retina responsible for clear vision, due to persistently high blood sugar levels. DME occurs when retinal blood vessels swell, then leak, causing fluid to accumulate in the retina (edema). There remains a great need for safer, more effective, longer-lasting, and less burdensome treatments for DME patients.

[0003] Most eye conditions can be treated and / or managed to mitigate their adverse effects, including complete blindness. However, current treatments for eye conditions are limited by the difficulty of delivering effective doses of medication to target tissues within the eye. In current treatments, topical administration of eye drops is preferred as a means of administering medication to the eye due to its convenience and safety compared to other routes of administration of ophthalmic medications, such as intravitreal injection and implants (Le Souriais, C., et al., 1998. Progress in Retinal and Eye Research 17, 33-58). Medications are transported from the ocular surface to the intraocular and surrounding tissues primarily by passive diffusion, where they migrate into the eye via a gradient of dissolved drug molecules according to Fick's law. Passive drug diffusion into the eye is inhibited by three main barriers (Gan, L., et al, 2013. Drug Discov. Today 18, 290-297; Loftsson, T., et al., 2008. Pharmazie 63, 171-179; Urtti, A, 2006. Adv. Drug Del. Rev. 58, 1131-1135).

[0004] However, achieving therapeutic concentrations of the drug in the posterior region of the eye through topical administration using eye drops is extremely difficult. Currently, the available options are limited to more invasive methods such as intravitreal injection, vitreous implants, periorbital injection, or systemic administration. Each of these invasive methods has numerous drawbacks.

[0005] For example, dexamethasone as an intravitreal implant is registered for use in DME, macular edema in retinal vein occlusion, and posterior uveitis (OZURDEX® 700 microgram intravitreal implant with applicator, full US prescribing information available at https: / / www.ozurdex.com / ). In two separate DME clinical trials involving OZURDEX®, the mean change from baseline in the number of best corrected visual acuity (BCVA) letters for all patients (pool) at 3 months was 6. The mean change in the number of BCVA letters for all patients (pool) from baseline to 39 months was 2.2. The proportion of all study subjects (pool) showing an improvement of 15 letters or more in BCVA from baseline was 13% at 3 months and 20% at 39 months. However, the use of OZURDEX® is associated with serious ocular adverse events. As stated in the U.S. prescribing information, intravitreal implants are associated with endophthalmitis, ocular inflammation, elevated intraocular pressure, and retinal detachment. Separately, as stated in the U.S. prescribing information, the use of corticosteroids may cause posterior subcapsular cataracts, elevated intraocular pressure, and glaucoma, and may promote the development of secondary ocular infections by bacteria, fungi, or viruses. According to the U.S. prescribing information for OZURDEX®, 68% of study patients treated with OZURDEX® developed cataracts (including cataracts, nuclear cataracts, subcapsular cataracts, and lens opacity), and 61% of study patients who developed cataracts underwent surgery. Furthermore, 28% of study subjects treated with OZURDEX® showed an IOP increase of 10 mmHg or more from baseline at any given visit. In 15% of the study participants, IOP reached 30 mmHg or higher at any given visit, and in 6% of the study participants, IOP reached 35 mmHg or higher at any given visit.

[0006] Current eye drop formulations are a preferred route of administration for the treatment of anterior segment conditions; however, drug penetration, particularly of insoluble molecules, is often limited by loss by tear fluid in the anterior cornea and drainage into the nasolacrimal duct (Johannsdottir S, Jansook P, Stefansson E., Topical drug delivery to the posterior segment of the eye: Dexamethasone concentrations in various eye tissues after topical administration for up to 15 days to rabbits. J Drug Deliv Sci Tech. 2018; 45: 449-54). Dexamethasone, administered as an over-the-counter eye drop, is used to treat a wide range of indications, including inflammatory diseases of the conjunctiva, cornea, and other anterior segment tissues, such as anterior uveitis, iritis, cyclitis, allergic and vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis, and nonspecific superficial keratitis (MAXIDEX® 0.1%, w / v, eye drops, U.S. Prescription Information (Alcon Laboratories Inc, Forth Worth, Texas, USA. MAXIDEX®-Dexamethasone Ophthalmic Suspension. Full Prescription Information. See: https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2017 / 013422s045lbl.pdf. Accessed November 12, 2020).

[0007] To increase the concentration of locally administered drugs in the posterior region of the eye, an ophthalmic suspension using γ-CD was developed (Jansook P, Stefansson E, Thorsteinsdottir M, Sigurdsson BB, Kristjansdottir SS, Bas JF, et al. Cyclodextrin solubilization of carbonic anhydrase inhibitor drugs: formulation of dorzolamide eye drop microparticle suspension. Eur J Pharm Biopharm. 2010; 76: 208-14).

[0008] Recently, the applicants have described the preparation and testing of cyclodextrin eye drops containing 1.5% (w / v) dexamethasone as the active ingredient. Such cyclodextrin eye drops containing dexamethasone are described in particular in WO2007 / 12974, WO2018 / 100434, and WO2021 / 001366.

[0009] Tanito et al. (2011) (Opthalmol Vis Sci 2011; 52: 7944-8) reported a small, non-comparative pilot study (19 patients) using a 1.5% (w / v) dexamethasone / cyclodextrin eye drop formulation in patients with DME. Participants received treatment for 4 weeks with either three times daily (N=11) or six times daily (N=8) treatment regimens. This study showed that 63% of treated patients experienced at least a 10% reduction in central macular thickness (CMT), and overall, CMT at 4 weeks was approximately 20% lower than baseline. However, according to Tanito et al., there was no significant difference in CMT change between patients receiving the three-times-daily and six-times-daily treatment regimens. In 74% of participants, visual acuity, measured using the logarithm of the minimum resolution angle (logMAR), improved by 0.1 or more (corresponding to 5 letters of BVCA) at 4 weeks. The mean improvement from baseline at 4 weeks was 0.15 logMAR (equivalent to 7.5 letters of BCVA). However, after discontinuation of treatment at 4 weeks, there was no significant difference in CMT and visual acuity (logMAR) at 8 weeks compared to baseline. Because a regression to baseline was observed, the authors concluded that the 4-week treatment "did not provide a sustained therapeutic effect." Importantly, Tanito et al. pointed out that intraocular pressure (IOP) increased by an average of 2 mm at 4 weeks in the treatment group. Furthermore, the use of corticosteroids on the eye is associated with increased IOP, and longer-term studies may predict an increased risk of cataract development and infection.

[0010] Ohira et al. (2015) (Acta Ophthalmol. 2015: 93: 610-15) also reported a small, prospective, randomized, controlled trial using a 1.5% dexamethasone / cyclodextrin eye drop formulation in DME patients (N=12). The administration regimens were 3 drops per day for 4 weeks, 2 drops per day for 4 weeks, and 1 drop per day for 4 weeks. In subjects treated with the 1.5% dexamethasone / cyclodextrin eye drop formulation, the mean improvement in logMAR compared to baseline was 0.09+ / -0.15 at 4 weeks (equivalent to 4.5 letters of BCVA), 0.11+ / -0.13 at 8 weeks (equivalent to 5.5 letters of BVCA), and 0.09+ / -0.17 at 12 weeks (equivalent to 4.5 letters of BCVA). In four patients, logMAR improved by 0.3 or more (corresponding to 15 or more letters of BVCA). However, the mean improvement in logMAR at 16 weeks had decreased to 0.01+ / -0.26 (corresponding to 0.5 letters of BVCA), which was not statistically significant compared to baseline. In subjects treated with 1.5% dexamethasone / cyclodextrin eye drops, a mean decrease in CMT was observed compared to baseline: 99+ / -169 at 4 weeks, 141+ / -211 at 8 weeks, and 76+ / -139 at 12 weeks. However, similar to visual acuity measurements, the mean CMT measurements were not statistically significant at 4 weeks post-treatment (16 weeks). Ohira et al. pointed out that in subjects treated with 1.5% dexamethasone / cyclodextrin eye drops, intraocular pressure at follow-up was significantly higher compared to baseline, with three subjects having intraocular pressure exceeding 30 mm, requiring the administration of antihypertensive drugs. Similar to Tanito et al., Ohira et al. also point out that there is a known side effect profile for the use of corticosteroids on the eye, and that IOP was significantly elevated in subjects treated with 1.5% dexamethasone cyclodextrin eye drops. Furthermore, Ohira et al. note that "cataract formation was not observed, but it would be expected with longer treatment periods."

[0011] Stefansson et al. reported the results of a Phase II trial (N=99) on the topical treatment of DME with a 1.5% (w / v) dexamethasone / cyclodextrin eye drop regimen administered three drops daily for 12 weeks (Acta Ophthalmologica 2023, 101:22-33). At 12 weeks, the mean CMT in the control group was -53.6 μm, and the mean change from baseline in the BCVA letter score at 12 weeks was +2.6 letters. 5% of the subjects showed an improvement of 15 letters or more at 12 weeks. In subjects treated with the 1.5% dexamethasone / cyclodextrin, an increase in mean IOP was observed from 1.17 mmHg at 2 weeks to 4.53 mmHg at 12 weeks. 14% of patients experienced an increase of 10 mmHg or more in IOP at 12 weeks, and 7 patients received IOP-lowering medication. Stefansson et al. noted that mean CMT measurements "began to return to baseline during the 4-week follow-up period."

[0012] There remains a need to provide patients with long-term, suitable treatment options other than intravitreal injections—namely, topical treatment regimens that minimize side effects, ensure good compliance, and deliver long-term visual improvement equivalent to or better than currently approved treatments.

[0013] 〔overview〕 The inventors have remarkably found that a 1.5% (w / v) dexamethasone cyclodextrin eye drop formulation, administered topically at a dose of 5-7 drops (e.g., 6 drops) per day for 4-6 weeks (e.g., 6 weeks), followed by a maintenance phase of 1-3 drops (e.g., 2 or 3 drops) per day, resulted in sustained improvement in visual acuity and a reduction in central macular thickness (CMT). This effect is comparable to, or surpasses, that of the currently approved dexamethasone intravitreal implant OZURDEX® and conventional topical administration regimens. Remarkably, this new administration regimen offers a more convenient and less invasive topical administration while achieving at least comparable efficacy to intravitreal implants. The inventors found that a high-dose induction dose, for example, six drops daily of 1.5% (w / v) dexamethasone cyclodextrin eye drops for six weeks, induced a rapid therapeutic response, resulting in a significant visual acuity improvement equivalent to or greater than that observed with OZURDEX® during the same period, and which could be maintained long-term with a lower-dose maintenance dose. This increased induction dose may be particularly important for rapidly inducing a therapeutic response in DME patients who may not respond well to lower doses. Therefore, achieving significant and sustained improvements in visual acuity and CMT using topically administered eye drops to treat posterior ocular disorders represents a remarkable and important advance in the treatment of DME in terms of both therapeutic efficacy and patient compliance. Importantly, the sustained improvement in visual acuity and reduction in CMT are achieved without a significant increase in dexamethasone-related adverse ocular side effects, such as elevated intraocular pressure (IOP), cataracts, and / or ocular infections, compared to conventional techniques.

[0014] As further detailed herein, extensive human clinical trials have established that topical administration of an increased induction dose of 1.5% (w / v) dexamethasone cyclodextrin eye drops during the 6-week induction period, followed by an extended maintenance dose, significantly and sustainably improves visual acuity in DME patients. Human clinical trials, further detailed in Example 2, showed that the use of the induction and maintenance doses described herein resulted in an average visual acuity improvement of 7.2 BCVA letters at 6 weeks, 7.1 BCVA letters at 8 weeks, and 7.6 BCVA letters at 12 weeks compared to baseline (see Figure 1), with over 27% of patients showing an improvement of 15 letters or more at 12 weeks (see Example 2, Table 1). In comparison, in the pooled study patients who received the intravitreal implant OZURDEX®, the average visual acuity improvement at 12 weeks was 6 letters, and only 13% of the pooled study patients showed an improvement of 15 letters or more at 12 weeks (see OZURDEX® US Prescription Information, Table 4).

[0015] Similarly, Ohira et al. and Stefansson et al. showed significantly lower average improvements in BCVA character count compared to the induction / maintenance doses described herein. For example, Ohira et al. reported an average improvement of 5.5 characters from baseline at 8 weeks and an average improvement of 4.5 characters at 12 weeks, while Stefansson et al. reported an average improvement of only 2.6 characters from baseline at 12 weeks.

[0016] As described herein, the use of an extended maintenance dose following an increased induction dose also demonstrated a sustained reduction in mean central subfield thickness (CST) across the entire study patient population. This indicates that the maintenance dose adequately sustained the CST reduction induced by the increased induction dose (see Example 2, Figure 2).

[0017] In particular, the therapeutic improvements achieved using the increased induction and maintenance dose regimens described herein were not associated with a significant increase in ocular adverse events with dexamethasone use compared to prior art dexamethasone administration regimens (see Example 2, Tables 2 and 3). For example, despite the substantial increase in dose during the induction phase, only 16.5% of subjects experienced an IOP increase of 10 mmHg or more at any visit within 12 weeks of treatment initiation (see Example 2, Table 2). This is similar to the percentage of subjects (14%) who experienced an IOP increase of 10 mmHg or more using the administration regimen described by Ohira et al. In comparison, 28% of patients treated with OZURDEX® showed an IOP increase of 10 mmHg or more at any point in time during the reported 39-month clinical trial study (see OZURDEX® US prescribing information). As shown in Figure 3, when using the dosing regimens described herein, the mean change in IOP from baseline in treated study patients during the first 12 weeks of the trial was 0.64 mmHg at week 2 and 2.79 mmHg at week 12.

[0018] Similarly, initial data on cataract incidence in study subjects receiving the increased induction and maintenance dose regimens described herein show no significant difference or acceleration in cataract incidence compared to the control group (1.0% vs. 2.1%, respectively). This initial data, showing no acceleration compared to the control group, supports the use of the induction and maintenance dose regimens described herein, achieving therapeutic efficacy in controlling DME and improving visual acuity with a safety profile that is at least equivalent to or better than OZURDEX®. During the 39-month trial period of OZURDEX®, 68% of study subjects treated with OZURDEX® developed cataracts, compared to 21% of subjects in the control group (see OZURDEX® U.S. prescribing information).

[0019] Accordingly, a first object of the present disclosure is a method for treating diabetic macular edema (DME) in a human subject in need thereof, the method comprising: (i) an induction phase of topically administering an ophthalmic formulation comprising 1.5% (w / v) dexamethasone to the affected eye of the subject at a dosage of 5 to 7 drops per day, followed by, (ii) a maintenance phase of topically administering the ophthalmic formulation comprising 1.5% (w / v) dexamethasone to the affected eye of the subject at a lower administration frequency per day than that in the induction phase, including.

[0020] The present disclosure also relates to an ophthalmic formulation comprising 1.5% (w / v) dexamethasone for use in a method of treating diabetic macular edema in a subject in need of such treatment, the method comprising: (i) an induction phase of topically administering an ophthalmic formulation comprising 1.5% (w / v) dexamethasone to the affected eye of the subject at a dosage of 5 to 7 drops per day, followed by, (ii) a maintenance phase of topically administering the ophthalmic formulation comprising 1.5% (w / v) dexamethasone to the affected eye of the subject at a lower administration frequency per day than that in the induction phase, including.

[0021] The present disclosure also relates to the use of dexamethasone in the manufacture of an ophthalmic formulation comprising 1.5% (w / v) dexamethasone for treating diabetic macular edema in a subject in need of such treatment, the method comprising: (i) an induction phase of topically administering an ophthalmic formulation comprising 1.5% (w / v) dexamethasone to the affected eye of the subject at a dosage of 5 to 7 drops per day, followed by, (ii) a maintenance phase of topically administering the ophthalmic formulation comprising 1.5% (w / v) dexamethasone to the affected eye of the subject at a lower administration frequency per day than that in the induction phase, including.

[0022] In some embodiments, the induction phase is administered for a period ranging from at least 5 days to about 4 to 6 weeks. In some embodiments, the induction phase is administered over 4 to 6 weeks. In some embodiments, the induction phase is administered over 6 weeks. In some embodiments, the induction phase is administered as 5 drops per day. In some embodiments, the induction phase is administered as 6 drops per day. In some embodiments, the induction phase is administered as 7 drops per day. In some embodiments, the induction phase is administered as 6 drops per day over 6 weeks. In some embodiments, the maintenance phase is administered as 1 drop per day. In some embodiments, the maintenance phase is administered as 2 drops per day. In some embodiments, the maintenance phase is administered as 3 drops per day. In some embodiments, the ophthalmic formulation is administered during the maintenance phase for at least 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks, 36 weeks, 40 weeks, 46 weeks, or more than 46 weeks, 18 months, 24 months, or longer (including indefinitely).

[0023] In some embodiments, the administration regimens described herein result in an improvement of 15 letters or more from baseline at 12 months in the BCVA / ETDRS letter count assessment in at least 25%, at least 30%, at least 35%, or more than 35% of the treated patient population.

[0024] In certain embodiments, the ophthalmic formulation is: - 1.5% dexamethasone; - 12 to 16% gamma-cyclodextrin; - 2.2 to 2.7% polymer, usually poloxamer; - 0 to 0.1% chelating agent, for example 0.1% chelating agent, such as but not limited to disodium edetate; - Additives to prevent oxidation of dexamethasone in an amount of 0% to 0.6% (e.g., between 0.05% and 0.5%, or between 0.05% and 0.3%), and additives to prevent oxidation of corticosteroids, such as water-soluble natural antioxidants, sodium thiosulfate, L-methionine, or phenolic antioxidants or reducing agents such as 3,4-dihydroxybenzoic acid (but not limited to these); - 0-1% electrolytes, for example 0.57% electrolytes, for example sodium chloride (but not limited to this); and, - water, This includes, or essentially consists of, Here, % is weight % based on the volume of the composition. In some embodiments, the poloxamer is poloxamer 407. In some embodiments, the eye drop formulation contains a non-derivativeized natural γ-cyclodextrin.

[0025] In a preferred embodiment, the eye drop formulation is: - 1.5% dexamethasone; - 14% γ-cyclodextrin; - 2.5% poloxamer; - 0-0.1% chelating agent, e.g., 0.1% disodium edetate; - 0-1% electrolyte, for example, 0.57% sodium chloride; - An additive to prevent oxidation of the dexamethasone, such as 0.3% STS; and - water, This includes, or essentially consists of, Here, % is weight % based on the volume of the composition. In some embodiments, the poloxamer is poloxamer 407. In some embodiments, the eye drop formulation contains a non-derivativeized natural γ-cyclodextrin.

[0026] Advantageously, the eye drop formulations described herein are solid complexes of dexamethasone and γ-cyclodextrin (e.g., diameter D 50Because it is formulated to include a microsuspension containing particles (with a diameter in the range of approximately 1 μm to 20 μm), it is particularly useful for the treatment of DME. These microparticles effectively treat DME by allowing dexamethasone to be continuously released into the eye and reaching a sufficient concentration of dexamethasone in the posterior part of the eye. In some embodiments, the microsuspension has a diameter of D 50 It contains microparticles between approximately 1 μm and 10 μm. In some embodiments, the viscosity (cP) of the microsuspension is between approximately 2 and 16 cP. In some embodiments, the pH of the eye drop formulation is between approximately 4.5 and 7. In some embodiments, the pH of the eye drop formulation is between approximately 5 and 6. In certain embodiments, the eye drop formulation does not contain preservatives.

[0027] [Detailed explanation] [Definition] In this specification, the term “treatment” includes reversal, alleviation, inhibition of progression, prevention, or reduction of the probability of onset of a disease, disorder, or condition to which the term applies, or one or more symptoms or signs of such disease, disorder, or condition. Prevention means preventing the worsening of a disease, disorder, condition, or their symptoms or signs, or their severity. Accordingly, the compositions disclosed herein may also be administered prophylactically to prevent or reduce the onset or recurrence of a disease, disorder, or condition.

[0028] In this specification, the term "weight % of compound X based on the volume of the composition" (also abbreviated as "%(w / v)") corresponds to the amount (in grams) of compound X introduced into 100 mL of the composition.

[0029] In this specification, the term "microparticle" means a particle with a diameter of D 50 This refers to particles with a diameter of approximately 1 μm to approximately 100 μm. In the exemplary example, D 50 The possible diameters range from 1 μm to approximately 100 μm.

[0030] The term "microsuspension" refers to a composition containing microparticles suspended in a liquid phase (typically an ophthalmic formulation).

[0031] In this specification, the term "ophthalmic preparation" refers to a pharmaceutical composition containing a therapeutic active ingredient (drug) in a medium suitable for topical administration of the drug to the eye of a person requiring treatment.

[0032] The term "ophthalmologically acceptable medium" refers to a medium suitable for ophthalmic administration of the composition. The ophthalmologically acceptable medium is preferably a liquid (e.g., water).

[0033] [Eye drop formulations] Dexamethasone as an active therapeutic ingredient The eye drop formulation for use as described in this disclosure is dexamethasone (C 16 This includes glucocorticoids having methyl substitutions (betamethasone-type corticosteroids), or pharmaceutically acceptable salts, esters, or derivatives thereof.

[0034] Dexamethasone is commercially available and is given the following formula:

[0035] [ka]

[0036] The concentration of dexamethasone in the eye drop formulation for use according to this disclosure may be approximately 10 mg / mL to approximately 25 mg / mL.

[0037] In certain embodiments, the amount of dexamethasone in the eye drop formulation is approximately 1.0 to 2.5% by weight (w / v) of the drug based on the volume of the formulation, for example, 1.5% by weight (w / v).

[0038] In certain embodiments, the eye drop formulation contains cyclodextrin.

[0039] Cyclodextrins are cyclic oligosaccharides containing six (α-cyclodextrin), seven (β-cyclodextrin), and eight (γ-cyclodextrin) glucopyranose monomers linked via α-1,4-glycosidic bonds. α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin are natural products produced by the microbial degradation of starch. The outer surface of the donut-shaped cyclodextrin molecule is hydrophilic and has numerous hydroxyl groups, while its central cavity is somewhat lipophilic (Kurkov, SV, Loftsson, T., 2013. Int J Pharm 453, 167-180; Loftsson, T., Brewster, ME, 1996. Journal of Pharmaceutical Sciences 85, 1017-1025). In addition to three types of natural cyclodextrins, numerous water-soluble cyclodextrin derivatives, including cyclodextrin polymers, have been synthesized and tested as drug carriers (Stella, VJ, He, Q., 2008. Cyclodextrins. Tox. Pathol. 36, 30-42).

[0040] Cyclodextrins can enhance the solubility and bioavailability of hydrophobic compounds. In aqueous solutions, cyclodextrins form inclusion complexes with many drugs by incorporating drug molecules, or more frequently, lipophilic substructures of molecules, into their central cavity. This property has been utilized in formulation and drug delivery. The formation of drug / cyclodextrin inclusion complexes, their effects on the physicochemical properties of drugs, their effects on biomembrane permeability, and the use of cyclodextrins in pharmaceuticals have been reviewed in the following publications (Loftsson, T., Brewster, ME, 2010. Journal of Pharmacy and Pharmacology 62, 1607-1621; Loftsson, T., Brewster, ME, 2011. J. Pharm. Pharmacol. 63, 1119-1135; Loftsson, T., Jarvinen, T., 1999. Advanced Drug Delivery Reviews 36, 59-79).

[0041] Cyclodextrins and drug / cyclodextrin complexes can self-assemble in aqueous solutions, forming nano- and micro-sized aggregates and micelle-like structures. These can also solubilize poorly soluble drugs through non-inclusion complex formation and micelle-like solubilization (Messner, M., et al, 2010. Int J Pharm 387, 199-208). Generally, the tendency of cyclodextrins to self-assemble and aggregate increases with the formation of drug / cyclodextrin complexes, and this aggregation increases with increasing concentration of the drug / cyclodextrin complex. Generally, hydrophilic cyclodextrin derivatives such as 2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin, as well as their complexes, are freely soluble in water. On the other hand, natural α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, as well as their complexes, have limited solubility in pure water, at 129.5±0.7 mg / mL, 18.4±0.2 mg / mL, and 249.2±0.2 mg / mL, respectively, at 25°C (Sabadini E., et al., 2006. Carbohydr Res 341, 270-274).

[0042] In certain embodiments, the eye drop formulation for use according to this disclosure comprises at least γ-cyclodextrin. In some embodiments, γ-cyclodextrin is the only cyclodextrin in the eye drop formulation.

[0043] In certain embodiments, the eye drop formulation comprises γ-cyclodextrin, or a combination of γ-cyclodextrin and a hydrophilic cyclodextrin derivative (such as 2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin).

[0044] In certain embodiments, the eye drop formulation for use according to the present disclosure comprises a solid complex of a drug and a cyclodextrin. The complex comprising dexamethasone and cyclodextrin may refer to a “dexamethasone / cyclodextrin complex.” If the cyclodextrin is γ-cyclodextrin, the complex comprising dexamethasone and γ-cyclodextrin may refer to a “dexamethasone / γ-cyclodextrin complex.”

[0045] In a particular embodiment using 1.5% (w / v) dexamethasone as the drug, the amount of γ-cyclodextrin in the eye drop formulation for use according to this disclosure is 5 to 25% by weight, particularly 12 to 16% by weight, preferably about 14% by weight, of the γ-cyclodextrin, based on the volume of the formulation.

[0046] The complex of the eye drop formulation forms aggregates, which are hereafter referred to as complex aggregates. These complex aggregates may correspond to aggregates of multiple complexes (particularly multiple inclusion complexes containing dexamethasone and γ-cyclodextrin).

[0047] According to one preferred embodiment, the eye drop formulation for use according to the present disclosure is a microsuspension comprising a solid complex of dexamethasone and γ-cyclodextrin. This does not preclude the aggregation from also comprising γ-cyclodextrin that is not complexed with dexamethasone.

[0048] According to one more preferred embodiment, the eye drop formulation for use according to the present disclosure is a microsuspension comprising a solid complex of dexamethasone, γ-cyclodextrin, and poloxamer. This does not preclude the aggregation from also comprising cyclodextrin that is not complexed with dexamethasone and / or cyclodextrin that does not contain poloxamer.

[0049] In certain embodiments, the eye drop formulation for use according to this disclosure has a diameter of D 50This is a microsuspension containing microparticles formed by aggregates whose diameter is less than approximately 90 μm, particularly between approximately 1 μm and approximately 90 μm. In one embodiment, the particle diameter D of the microsuspension is 50 This range may be approximately 1 μm to approximately 25 μm, particularly approximately 1 μm to approximately 20 μm, and more specifically, approximately 1 μm to approximately 10 μm, and most specifically, approximately 2 μm to approximately 10 μm.

[0050] The microparticles may contain cyclodextrin aggregates and / or dexamethasone / cyclodextrin / polymer complexes. In certain embodiments, the particles of the microsuspension contain γ-cyclodextrin aggregates and / or dexamethasone / γ-cyclodextrin / poloxamer complexes.

[0051] The diameter and / or size of the particles or composite can be measured according to any method known to those skilled in the art. For example, diameter D 50This is measured by laser diffraction particle size analysis. Generally, the number of techniques for measuring / evaluating the diameter and / or size of cyclodextrin / drug particles or complexes is limited. Those skilled in the art know that physical properties (e.g., particle size, diameter, mean diameter, mean particle size, etc.) are usually evaluated / measured using such limited typical known techniques. For example, such known techniques are described in Int.J.Pharm.493(2015),86-95, which are incorporated herein by reference in their entirety. Furthermore, such limited known measurement / evaluation techniques are also supported by other technical literature, such as the European Pharmacopoeia (2.9.31 Particle size analysis by laser diffraction, Jan 2010) and Saurabh Bhatia, Nanoparticles types, classification, characterization, fabrication methods and drug delivery applications, Chapter 2, Natural Polymer Drug Delivery Systems, pp. 33-94, Springer, 2016, which are also incorporated herein by reference in their entirety.

[0052] In particular, 60 to 95% by weight, and more specifically 70 to 90% by weight, of the drug in the composition may be in the form of a solid complex of the drug and γ-cyclodextrin.

[0053] More specifically, 5 to 40% by weight, particularly 10 to 30% by weight, of the drug in the composition may be in soluble form. The soluble form includes water-soluble nanoparticles consisting of uncompounded drug dissolved in the liquid phase, complexes of drug and cyclodextrin dissolved in the liquid phase, and drug / γ-cyclodextrin complex aggregates.

[0054] Preferably, 0% to 0.5% by weight of the drug in the composition may be in an uncompounded solid form. Therefore, the compositions of this disclosure do not need to contain substantially any solid uncompounded particles of the drug.

[0055] In one embodiment, the microsuspension may contain approximately 70% to 99% of the drug dexamethasone as microparticles and approximately 1% to 30% of the drug dexamethasone as nanoparticles. More specifically, the microsuspension may contain approximately 80% to 95% of the drug dexamethasone as microparticles with a diameter of approximately 1 μm to 90 μm and approximately 20% to 5% of the drug dexamethasone as nanoparticles. The microsuspension may contain approximately 80% of the drug dexamethasone as microparticles with a diameter of approximately 1 μm to 20 μm and approximately 20% of the drug dexamethasone as nanoparticles.

[0056] In another embodiment, the microsuspension may contain about 40% to about 99% of the drug dexamethasone as microparticles, and about 1% to about 60% of the drug dexamethasone as nanoparticles or a water-soluble dexamethasone / cyclodextrin complex. In particular, the microsuspension may contain about 80% to about 95% of the drug dexamethasone as microparticles with a diameter of about 1 μm to about 10 μm, and about 5% to about 20% of the drug dexamethasone as nanoparticles or a water-soluble dexamethasone / γ-cyclodextrin complex.

[0057] Examples of eye drop formulations containing dexamethasone / cyclodextrin complex and methods for their manufacture are disclosed in WO2018 / 100434 and US20230042785, which are incorporated herein by reference. Further examples of compositions containing dexamethasone / cyclodextrin complex are also disclosed in CN115837027A.

[0058] additives According to certain embodiments, eye drop formulations for use according to the present disclosure comprise water and optionally, additives selected from the group consisting of preservatives, chelating agents, electrolytes, and combinations thereof. In particular, ophthalmologically acceptable media may contain preservatives.

[0059] Preservatives may be used to inhibit bacterial growth in the composition. Examples of preservatives include benzalkonium chloride, chlorobutanol, thimerosal, phenylmercury acetate, phenylmercury nitrate, methylparaben, phenylethyl alcohol, and combinations thereof. The amount of preservative in the eye drop formulation for use according to this disclosure may be 0 to 1% by weight, particularly 0.001 to 0.5% by weight, more specifically 0.005 to 0.1% by weight, and even more specifically 0.01 to 0.04% by weight, based on the volume of the composition. In a preferred embodiment, the eye drop formulation is preservative-free.

[0060] In particular, eye drop formulations may contain a chelating agent. An example of a suitable chelating agent is disodium edetate. The amount of chelating agent in the compositions of this disclosure is 0 to 1% by weight, particularly 0.01 to 0.5% by weight, more specifically 0 to 0.2% by weight, and even more specifically 0.08 to 0.2% by weight, for example, about 0.1% by weight, based on the volume of the composition.

[0061] In particular, eye drop formulations may contain electrolytes. Electrolytes may be used specifically to make the composition isotonic. Examples of suitable electrolytes include sodium chloride, potassium chloride, and combinations thereof. Preferably, the electrolyte is sodium chloride. The amount of electrolyte in the compositions of this disclosure is 0 to 2% by weight, particularly 0.1 to 1.5% by weight, more specifically 0 to 1% by weight, and even more specifically 0.2 to 1% by weight, for example, about 0.57% by weight, based on the volume of the composition.

[0062] The eye drop formulation may further contain a polymer. In particular, the polymer may be a water-soluble polymer. Furthermore, the polymer may be a thickening polymer. The term “thickening polymer” means a polymer that increases the viscosity of a liquid. The polymer increases the viscosity of the eye drop formulation for use according to this disclosure. The increase in viscosity improves the physical stability of the composition. Therefore, when the composition contains a polymer, precipitation of the solid complex is less likely to occur. In certain embodiments, the polymer (e.g., poloxamer) is part of the dexamethasone / γ-cyclodextrin complex of the microsuspension.

[0063] In certain embodiments, the polymer is selected such that the viscosity of the microsuspension is between 1 cP and 30 cP, as measured according to European Pharmacopoeia 2.2.10.

[0064] In certain embodiments, polymers are used to disperse and stabilize particles in a microsuspension, increase viscosity, and impart mucosal adhesion.

[0065] Therefore, polymers may be considered polymer stabilizers. In particular, polymers may be surfactant polymers. The term "surfactant polymer" refers to polymers that exhibit surfactant properties. Surfactant polymers include, for example, hydrophobic chains grafted onto a hydrophilic main chain polymer, hydrophilic chains grafted onto a hydrophobic main chain, or alternating hydrophilic and hydrophobic segments. The first two types are called graft copolymers, and the third type is called a block copolymer.

[0066] In one embodiment, eye drop formulations for use according to the present disclosure include polymers selected from the group consisting of polyoxyethylene fatty acid esters; polyoxyethylene alkylphenyl ethers; polyoxyethylene alkyl ethers; cellulose derivatives (such as alkylcellulose, hydroxyalkylcellulose, and hydroxyalkylalkylcellulose); carboxyvinyl polymers such as carbomers (e.g., Carbopol 971 and Carbopol 974); polyvinyl polymers; polyvinyl alcohols; polyvinylpyrrolidone; copolymers of polyoxypropylene and polyoxyethylene; tyroxapole; and combinations thereof. Examples of suitable polymers include polyethylene glycol monostearate, polyethylene glycol distearate, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyoxyethylene lauryl ether, polyoxyethylene octyldodecyl ether, polyoxyethylene stearyl ether, polyoxyethylene myristyl ether, polyoxyethylene oleyl ether, sorbitan esters, polyoxyethylene hexadecyl ether (e.g., cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., Tween 20 and Tween 80 (ICI Specialty Chemicals)); polyethylene glycol (e.g., Carbowax 3550 and 934 (Union Examples of polyoxamines include, but are not limited to, carbides, polyoxyethylene stearate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, cellulose, polyvinyl alcohol (PVA), poloxamers (e.g., Pluronic F68 and FI08, which are block copolymers of ethylene oxide and propylene oxide); polyoxamines (e.g., Tetronic 908, also known as poloxamine 908, is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ)); Tetronic 1508 (T-1508) (BASF Wyandotte Corporation), Tritons X-200 (Rohm and Haas), which is an alkylaryl polyether sulfonate; PEG-derivativeized phospholipids, PEG-derivativeized cholesterol, PEG-derivativeized cholesterol derivatives, PEG-derivativeized vitamin A, PEG-derivativeized vitamin E, random copolymers of vinylpyrrolidone and vinyl acetate, and combinations thereof).

[0067] Particularly preferred examples of polymers include tyloxapole and copolymers of polyoxypropylene and polyoxyethylene. More specifically, the copolymer of polyoxypropylene and polyoxyethylene may be a triblock copolymer comprising a hydrophilic block-hydrophobic block-hydrophilic block configuration.

[0068] In one embodiment, the eye drop formulation for use according to the present disclosure comprises a polymer that is a poloxamer. The poloxamer may include any type of poloxamer known in the art. Examples of poloxamers include poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, and poloxamer Examples include poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, poloxamer 407, poloxamer 105 benzoate, and poloxamer 182 dibenzoate.Poloxamer is also known by the trade name "Pluronic," for example, Pluronic 10R5, Pluronic 17R2, Pluronic 17R4, Pluronic 25R2, Pluronic 25R4, Pluronic 31R1, Pluronic F108, Pluronic F108, Pluronic F108, Pluronic F108NF, Pluronic F127, Pluronic F127NF, Pluronic F127, Pluronic F127, Pluronic F38, Pluronic F38, Pluronic F68, Pluronic F77, Pluronic F87, Pluronic F88, Pluronic F98, Pluronic L10, Pluronic L101, Pluronic L121, Pluronic L31, Pluronic L3S, Pluronic L43, Pluronic L44, Pluronic L61, Pluronic These include L62, Pluronic L62LF, Pluronic L620, Pluronic L64, Pluronic L81, Pluronic L92, Pluronic L44, Pluronic N3, Pluronic P103, Pluronic P104, Pluronic P85, Pluronic P123, Pluronic P65, Pluronic P84, Pluronic P85, and combinations thereof.

[0069] A polymer particularly useful as a stabilizer is poloxamer. Poloxamer may include any type of poloxamer known in the art. Poloxamers include poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, and poloxamer... Examples include poloxamer 23S, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 33S, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, poloxamer 407, poloxamer 105 benzoate, and poloxamer 182 dibenzoate.Poloxamer is also known by the trade name "Pluronic," and examples include Pluronic 10R5, Pluronic 17R2, Pluronic 17R4, Pluronic 25R2, Pluronic 25R4, Pluronic 31R1, Pluronic F108 Cast Solid Surfactant, Pluronic F108NF, Pluronic F108 Pastil, Pluronic F108NF Prillpoloxamer 338, Pluronic F127, Pluronic F127NF, Pluronic F127NF500BHT Prill, Pluronic F127NF Prillpoloxamer 407, Pluronic F38, Pluronic F38 Pastil, Pluronic F68, Pluronic F68 Pastil, Pluronic F68LF Pastil, Pluronic F68NF, and Pluronic F68NF Prillpoloxamer 188, Pluronic F77, Pluronic F77 Micropastil, Pluronic F87, Pluronic F87NF, Pluronic F87NF Prillpoloxamer 237, Pluronic F88, Pluronic F88 Pastil, Pluronic F98, Pluronic L10, Pluronic L101, Pluronic L121, Pluronic L31, Pluronic L35, Pluronic L43, Pluronic L44NF Poloxamer 124, Pluronic L61, Pluronic L62, Pluronic L62LF, Pluronic L620, Pluronic L64, Pluronic L81, Pluronic L92, Pluronic L44NF INH Surfactant Poloxamer 124View, Pluronic N3, Pluronic P103, Pluronic P104, Pluronic P105, Pluronic These include P123 surfactants, Pluronic P65, Pluronic P84, Pluronic P85, and combinations thereof. In particular, the polymer is poloxamer 407.

[0070] A further polymeric stabilizer compatible with the compositions and methods described herein is tyroxapol. In preferred embodiments, the stabilizer and co-solubilizer is tyroxapol, which is a polymer of 4-(1,1,3,3-tetramethylbutyl)phenol with formaldehyde and oxirane.

[0071] The amount of polymer, for example poloxamer, more preferably poloxamer 407, in the eye drop formulation for use according to this disclosure may be 0.1 to 5% by weight, particularly 0.5 to 4% by weight, more particularly 1 to 3% by weight, and even more particularly 2 to 3% by weight, based on the volume of the composition, and may be, for example, about 2.5% by weight.

[0072] Additives to prevent oxidation of drugs The eye drop formulation may contain additives to prevent oxidation of dexamethasone. For example, additives such as those disclosed in WO2021 / 001366 and US20220354869, which are incorporated herein by reference in their entirety. In a preferred embodiment, the additives to prevent oxidation of dexamethasone are selected from antioxidants, oxygen scavengers, and mixtures thereof.

[0073] Antioxidants typically include phenolic antioxidants and reducing agents. Phenolic antioxidants are sterically hindered phenols that react with free radicals to inhibit oxidation reactions. Examples of phenolic antioxidants include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), or 3,4-dihydroxybenzoic acid, dodecyl 3,4,5-trihydroxybenzoate (lauryl gallate). Reducing agents are compounds with a lower redox potential than antioxidants. Reducing agents scavenge oxygen in a medium, slowing or preventing oxidation. Examples of reducing agents include sodium thiosulfate (STS), or other industrial food preservatives with antioxidant properties. Further examples of antioxidants include water-soluble natural antioxidants such as ascorbic acid, malic acid, citric acid, tartaric acid, lactic acid, other organic acids, and their derivatives. Other antioxidants may be further selected from known food antioxidants.

[0074] In certain embodiments, the additive used to prevent the oxidation of dexamethasone is sodium thiosulfate.

[0075] In another specific embodiment, additives for preventing oxidation of dexamethasone are selected from sodium thiosulfate, methionine, 3,4-dihydroxybenzoic acid, sodium citrate, malic acid, sodium ascorbate, tartaric acid, α-monothioglycerol, butylated hydroxyanisole, lauryl gallate, lactic acid, tert-butylhydroquinone, and salts or derivatives thereof, or mixtures thereof. More preferably, the additive is selected from sodium thiosulfate, methionine (typically L-methionine), 3,4-dihydroxybenzoic acid, sodium citrate (e.g., tribasic sodium citrate dehydrate), malic acid (typically DL-malic acid), sodium ascorbate (e.g., (+)-L-sodium ascorbate), tartaric acid (typically DL-tartaric acid), α-monothioglycerol, and butylated hydroxyanisole, and more preferably, the additive is selected from sodium thiosulfate, methionine, and 3,4-dihydroxybenzoic acid. Naturally, a mixture of the antioxidants may be added as an additive to prevent oxidation of the drug.

[0076] The amount of additives to prevent oxidation of dexamethasone in the eye drop formulation may be 0 to 2% by weight, particularly 0 to 1% by weight, more specifically 0 to 0.8% by weight, and even more specifically 0.05 to 0.3% by weight, based on the volume of the composition.

[0077] Additives to prevent oxidation of dexamethasone (typically sodium thiosulfate, methionine, or 3,4-dihydroxybenzoic acid) may be added at a concentration of at least 0.05% (w / v), preferably between 0.05% (w / v) and 1% (w / v), more preferably between 0.05% (w / v) and 0.5%, and even more preferably between 0.05% (w / v) and 0.4% (w / v). Additives to prevent oxidation of the drug (typically sodium thiosulfate) may be added at a concentration of 0.05% (w / v) and 0.3% (w / v). Any form of sodium thiosulfate can be used in this formulation. Examples of forms of sodium thiosulfate include amorphous, anhydrous, monohydrate, dihydrate, and pentahydrate, each of which may have polymorphisms. The weight used should be adjusted accordingly.

[0078] In this specification, a concentration of 0.3% (w / v) sodium thiosulfate corresponds to anhydrous sodium thiosulfate. For example, this corresponds to 0.471 g / 100 mL of sodium thiosulfate pentahydrate. For other stable sodium thiosulfate hydrates, such as sodium thiosulfate monohydrate and sodium thiosulfate dihydrate, and other antioxidants, a molar amount equivalent to 0.3% sodium thiosulfate may typically be used in eye drop formulations.

[0079] In a particularly preferred embodiment, the eye drop formulation for use according to this disclosure is: - 1.5% dexamethasone; - 5-25% γ-cyclodextrin, e.g., 12-16% γ-cyclodextrin; - 2-2.7% polymer, e.g., 2% or 2.7% poloxamer; - 0-0.1% chelating agent, e.g., 0.1% chelating agent, typically disodium edetate; - 0.05% to 0.45% of an additive to prevent oxidation of dexamethasone, for example, 0.05% to 0.4% or 0.05% to 0.3% of an additive to prevent oxidation of corticosteroids, typically a phenolic antioxidant or reducing agent (such as a water-soluble natural antioxidant), more preferably sodium thiosulfate, L-methionine, or 3,4-dihydroxybenzoic acid; - 0-1% electrolytes, e.g., 0.57% electrolyte, typically sodium chloride; and, - water, Includes, Here, % represents weight % based on the volume of the composition.

[0080] Eye drops containing dexamethasone and gamma-cyclodextrin can be stored in plastic vials (typically LDPE vials) or glass vials.

[0081] In certain embodiments, an eye drop formulation containing dexamethasone, γ-cyclodextrin, and an additive to prevent oxidation can be stored in a plastic vial, such as an LDPE vial.

[0082] The pH of the eye drop formulation is preferably in the range of 4.5 to 7.0, for example, 4.7 to 6.0.

[0083] [Preferred eye drop formulations for use in this treatment method] In a particular embodiment, the eye drop formulation for use in this treatment is: - 1.5% dexamethasone; - 5-25% γ-cyclodextrin, e.g., 12-16% γ-cyclodextrin; - 0-0.1% chelating agent, e.g., 0.1% disodium edetate; - 0-1% electrolytes, e.g., 0.57% electrolyte, typically sodium chloride; and, - water, This includes, or essentially consists of, Here, % represents weight % based on the volume of the composition.

[0084] In a particularly preferred embodiment, the eye drop formulation for use as described herein is: - 1.5% dexamethasone; - 5-25% γ-cyclodextrin, e.g., 12-16% γ-cyclodextrin; - 2-2.7% polymer, e.g., 2% or 2.7% poloxamer (e.g., poloxamer 407); - 0-0.2% chelating agent, e.g., 0.1% chelating agent, typically disodium edetate; - An additive to prevent oxidation of dexamethasone, in an amount of 0% to 0.6%, for example, an additive to prevent oxidation of corticosteroids, in an amount of 0.05% to 0.45% or 0.05% to 0.3%, typically a phenolic antioxidant or reducing agent (such as a water-soluble natural antioxidant), more preferably sodium thiosulfate, L-methionine, or 3,4-dihydroxybenzoic acid; - 0-1% electrolytes, e.g., 0.57% electrolyte, typically sodium chloride; and, - water, This includes, or essentially consists of, Here, % represents weight % based on the volume of the composition.

[0085] In a particularly preferred embodiment, the eye drop formulation for use in the therapeutic methods described herein is: - 1.5% dexamethasone; - 14% γ-cyclodextrin; - 2.5% poloxamer (e.g., poloxamer 407); - 0-0.2% chelating agent, e.g., 0.1% disodium edetate; - 0-1% electrolyte, for example, 0.57% sodium chloride; - An additive to prevent oxidation of dexamethasone, 0% to 0.6%, for example, an additive to prevent oxidation of corticosteroids, 0.05% to 0.3%, typically a phenolic antioxidant or reducing agent (such as a water-soluble natural antioxidant), more preferably sodium thiosulfate, L-methionine, or 3,4-dihydroxybenzoic acid; and, - water, This includes, or essentially consists of, Here, % represents weight % based on the volume of the composition.

[0086] Typically, eye drop formulations for use in the therapeutic methods described herein contain the following ingredients: - 1.5% dexamethasone; - 14% γ-cyclodextrin; - 2.5% poloxamer (e.g., poloxamer 407); - 0.1% disodium edetate; - 0.57% sodium chloride; and, - 0.05% to 0.3% sodium thiosulfate; - water, Having the above characteristics, all of the above-mentioned formulations or aqueous compositions are advantageously free of preservatives.

[0087] In a preferred embodiment, the eye drop formulation is prepared as a microsuspension containing a complex aggregate of dexamethasone and γ-cyclodextrin. In a particular embodiment, 60 to 95% by weight, more specifically 70 to 90% by weight, of the dexamethasone in the composition may be in the form of a solid complex of dexamethasone and γ-cyclodextrin.

[0088] A method for preparing such a formulation includes the following steps: a) A step of mixing dexamethasone with other excipients in an ophthalmologically acceptable medium and optionally heating to sterilize it; b) A step of suspending γ-cyclodextrin in an ophthalmologically acceptable medium to form a suspension, and optionally heating the suspension to sterilize it; c) A step of mixing the compositions from steps a) and b) at a temperature T1 below 120°C for a time t; for example, between 50°C and 110°C, preferably between 50°C and 95°C, for example between 80°C and 95°C; and, d) A step of cooling the obtained solution to a temperature T2 to obtain an aqueous composition containing a solid complex of dexamethasone and cyclodextrin (preferably γ-cyclodextrin).

[0089] In the above manufacturing method, dexamethasone may be optionally suspended together with other excipients in an ophthalmologically acceptable medium that does not contain cyclodextrin. Separately, γ-cyclodextrin may be suspended in an ophthalmologically acceptable medium that does not contain any active pharmaceutical ingredient. The two suspensions may be heated or sterilized, for example, by heating in an autoclave at 121°C for 20 minutes. After that, these two suspensions or high-temperature solutions may be mixed at a temperature of 80-95°C.

[0090] The resulting solution may be cooled at a rate sufficient to produce a microsuspension containing a solid pharmaceutical active ingredient / γ-cyclodextrin complex.

[0091] Detailed methods for preparing microsuspensions are also described in WO2018100434, and the entire content of that document is incorporated herein.

[0092] The micro-suspensions described above are stable and may be used as eye drops.

[0093] In a specific embodiment, an eye drop formulation containing 1.5% (w / v) dexamethasone is a preservative-free ophthalmic microsuspension. These may be provided, for example, in an LDPE plastic material as a single dose of 0.3 mL. The resulting suspension may be stored at room temperature below 25°C for at least 2, 3, 6, 12, 18, or 24 months, or even 3 years.

[0094] [Use of eye drops containing dexamethasone] Eye drop formulations for use in the treatment of diabetic macular edema (DME) are prepared according to methods using specific dosing regimens disclosed herein.

[0095] More specifically, the eye drops containing dexamethasone described herein are for use in the affected eye of a human subject requiring treatment. (i) An induction phase in which an eye drop formulation containing 1.5% (w / v) dexamethasone is administered topically to the affected eye in a dose of 4 to 6 drops per day, followed by, (ii) Maintenance phase, in which the administration is performed at a lower frequency per day than in the induction phase, It is administered locally according to a dosage regimen that includes [the drug].

[0096] The initial goal is to achieve rapid clinical effects in patients with diabetic macular edema, particularly in reducing symptoms associated with the condition and improving visual acuity.

[0097] The induction period is a period ranging from 5 days to 1, 2, 3, 4, 5, or 6 weeks (preferably 6 weeks), during which the drug is administered at a dose of 5, 6, or 7 drops per day.

[0098] The goal of the maintenance phase is to maintain the effects achieved at the end of the induction phase while minimizing the daily dose of dexamethasone administered to the patient, with a daily administration frequency at least less than that of the induction phase.

[0099] The maintenance phase may be continued for as long as necessary for the patient, preferably for at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 40, or 46 weeks, or indefinitely, with a dosage of 1, 2, or 3 drops per day (e.g., 3 drops per day).

[0100] In a particular embodiment, the induction phase includes the step of topically administering an eye drop formulation containing 1.5% (w / v) dexamethasone to the affected eye at a dose of 5 to 7 drops per day for a period ranging from 5 days to 6 weeks.

[0101] In another embodiment, the induction phase includes the step of topically administering an eye drop formulation containing 1.5% (w / v) dexamethasone to the affected eye at a dose of 6 drops per day.

[0102] In a particular embodiment, the maintenance phase includes the step of topically administering an eye drop formulation containing 1.5% (w / v) dexamethasone to the affected eye at a dose of 1 to 3 drops per day.

[0103] In a particular embodiment, the maintenance phase includes the step of topically administering an eye drop formulation containing 1.5% (w / v) dexamethasone to the affected eye at a dose of 3 drops per day.

[0104] In a preferred embodiment, the administration regimen is: (i) The loading phase involves topical administration of an eye drop formulation containing 1.5% (w / v) dexamethasone to the affected eye at a dose of 6 drops per day for 6 weeks, followed by... (ii) During the maintenance phase, administer the eye drop formulation topically at a dose of 3 drops per day. Includes.

[0105] In a particularly preferred embodiment, the administration regimen is: (i) An induction phase in which a 1.5% (w / v) dexamethasone eye drop formulation is administered topically to the affected eye at a dose of 6 drops per day for 6 weeks, followed by... (ii) A maintenance period in which the eye drop formulation is administered topically at a dose of 3 drops per day for at least 6 weeks, for example, at least 46 weeks, and for as long as necessary for the patient. Includes.

[0106] The eye drop formulations described herein have been tested in clinical trials involving patients with diabetic macular edema, and the results are described in the examples. In particular, the efficacy of 1.5% (w / v) dexamethasone eye drop formulations for the treatment of diabetic macular edema has been demonstrated with specific dosing regimens having induction and maintenance phases as described above.

[0107] In the human clinical trials described in further detail in Example 2, the use of an induction dose of 6 drops per day resulted in a potent and rapid improvement in efficacy, as shown below: • The mean change in BCVA / ERDTS character score from baseline at week 6 was 7.2. • The mean change in central subfield thickness (CST) as evaluated by optical coherence tomography at the end of the induction phase in week 6 was -63.6 μm from baseline. • 25.3% of patients showed improvement of more than 3 lines (15 characters) in BCVA. A maintenance dose of 3 drops per day was sufficient to maintain these improvements (and further improvements) in visual acuity at 12 weeks, with a mean change of 7.6 letters in BCVA / ERDTS compared to baseline (see Figure 1), and a mean change of -61.6 mm in CST at 12 weeks from baseline. Furthermore, no unexpected safety findings were observed at week 12.

[0108] In certain embodiments, the average ETDRS best corrected visual acuity at the end of the introductory phase of the above treatment in patients with DME is improved by, for example, at least 4, 5, or 6 ETDRS characters, preferably at least 7 ETDRS characters, from baseline. The ETDRS best corrected visual acuity is determined as described in the following embodiments.

[0109] In one embodiment, the mean ETDRS best corrected visual acuity during the maintenance phase is maintained at at least 6 ETDRS characters, preferably at least 7 ETDRS characters, measured from baseline.

[0110] In a preferred embodiment, the mean best corrected visual acuity in ETDRS after 6 weeks of maintenance is maintained at at least 6 ETDRS characters, preferably at least 7 ETDRS characters, measured from baseline. In a particular embodiment, in the subject with DME, the mean change in central subfield thickness (CST) in LS after 6 weeks of induction is greater than -50 μm, preferably greater than -60 μm, measured from baseline. In one embodiment, the decrease in the mean change in central subfield thickness (CST) in LS is maintained at a value greater than -50 μm CST, measured from baseline, during the maintenance phase, preferably after 6 weeks of maintenance.

[0111] In some embodiments, the dosing regimens described herein result in an improvement of at least 3 lines (15 characters or more) from baseline in the BCVA / ETDRS character count assessment at 12 months in at least 25%, at least 27%, at least 30%, at least 35%, or more than 35% of the treated patient population.

[0112] In a preferred embodiment of the above method, the eye drop formulation for use in the method is: - 1.5% dexamethasone; - 14% γ-cyclodextrin; - 2.5% poloxamer (e.g., poloxamer 407); - 0-0.2% chelating agent, e.g., 0.1% disodium edetate; - 0-1% electrolyte, for example, 0.57% sodium chloride; - An additive to prevent oxidation of dexamethasone, in an amount of 0% to 0.6%, for example, an additive to prevent oxidation of corticosteroids, in an amount of 0.05% to 0.45%, or 0.05% to 0.3%, typically sodium thiosulfate; and, - water, This includes, or essentially consists of, Here, % represents weight % based on the volume of the composition.

[0113] In certain embodiments, this treatment is useful for mitigating or resolving problems associated with intravitreal injection therapy in DME patients requiring such treatment. Such treatments include, but are not limited to, anti-VEGF drugs such as ranibizumab (Lucentis; Genentech, South San Francisco, CA, USA), approved in August 2012, and aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY, USA), approved in July 2014.

[0114] This treatment is particularly useful for patients who do not respond to or respond poorly to VEGF inhibitor therapy (VEGF-naïve patients) and / or who cannot tolerate invasive treatment for diabetic macular edema.

[0115] Therefore, in a particular embodiment of the above method for treating diabetic macular edema, the patient is selected from VEGFi-naïve patients who present with retinal thickening in the affected eye due to diabetic macular edema.

[0116] Typically, the patient is a human patient, and more specifically, an adult human patient.

[0117] [Specific Embodiments] Embodiment E1: A method for treating diabetic macular edema in a human subject requiring such treatment, wherein the method is (i) An induction phase in which an eye drop formulation containing 1.5% (w / v) dexamethasone is administered topically to the affected eye in a dose of 5 to 7 drops per day, followed by, (ii) During the maintenance phase, the eye drop formulation containing 1.5% (w / v) dexamethasone is administered locally to the affected eye at a frequency less frequent than that of the induction phase. Methods that include...

[0118] Embodiment E2: The eye drop preparation is a micro-suspension containing a solid complex of dexamethasone, γ-cyclodextrin, and poloxamer, The method according to Embodiment E1.

[0119] Embodiment E3: The eye drop preparation is a micro-suspension containing microparticles with a diameter D 50 in the range of about 1 μm to 90 μm, The method according to Embodiment E1 or E2.

[0120] Embodiment E4: The induction phase comprises the step of topically administering to the affected eye of a subject an eye drop preparation containing 1.5% (w / v) dexamethasone at a dose of 5 to 7 drops per day for a period ranging from 5 days to 6 weeks, The method according to any one of Embodiments E1 to E3.

[0121] Embodiment E5: The induction phase comprises the step of topically administering to the affected eye of a subject an eye drop preparation containing 1.5% (w / v) dexamethasone at a dose of 5 to 7 drops per day over a period of 6 weeks, The method according to any one of Embodiments E1 to E4.

[0122] Embodiment E6: The induction phase comprises the step of topically administering to the affected eye of a subject an eye drop preparation containing 1.5% (w / v) dexamethasone at a dose of 6 drops per day over a period of 6 weeks, The method according to any one of Embodiments E1 to E4.

[0123] Embodiment E7: The maintenance phase comprises the step of topically administering to the affected eye of a subject an eye drop preparation containing 1.5% (w / v) dexamethasone at a dose of 1, 2, or 3 drops per day, The method according to any one of Embodiments E1 to E5.

[0124] Embodiment E8: The maintenance phase comprises the step of topically administering to the affected eye of a subject an eye drop preparation containing 1.5% (w / v) dexamethasone at a dose of 3 drops per day, The method according to any one of embodiments E1 to E7.

[0125] Embodiment E9: The administration regimen is, (i) An induction phase in which a 1.5% (w / v) dexamethasone eye drop formulation is administered topically to the affected eye at a dose of 6 drops per day, followed by... (ii) A maintenance period in which the eye drop formulation is administered topically at a dose of 1, 2, or 3 drops per day for at least 6 weeks. The method according to any one of embodiments E1 to E8, including the method described above.

[0126] Embodiment E10: The administration regimen is, (i) An induction phase in which a 1.5% (w / v) dexamethasone eye drop formulation is administered topically to the affected eye at a dose of 6 drops per day for 6 weeks, followed by... (ii) During the maintenance phase, the eye drop formulation is administered locally at a dose of 3 drops per day. The method according to any one of embodiments E1 to E9, including the method described above.

[0127] Embodiment E11: The administration regimen is, (i) An induction phase in which a 1.5% (w / v) dexamethasone eye drop formulation is administered topically to the affected eye at a dose of 6 drops per day for 6 weeks, followed by... (ii) During the maintenance phase, the eye drop formulation is administered locally at a dose of 3 drops per day. Includes, Here, the eye drop formulation is a microsuspension containing a solid complex of dexamethasone, γ-cyclodextrin, and poloxamer. The method according to any one of embodiments E1 to E10.

[0128] Embodiment E12: The eye drop formulation contains γ-cyclodextrin in an amount of 12-16% by weight of cyclodextrin based on the volume of the composition. The method according to any one of embodiments E1 to E11.

[0129] Embodiment E13: The administration regimen is, (i) An induction phase in which a 1.5% (w / v) dexamethasone eye drop formulation is administered topically to the affected eye at a dose of 6 drops per day for 6 weeks, followed by... (ii) During the maintenance phase, the eye drop formulation is administered locally at a dose of 3 drops per day. Includes, Here, the eye drop formulation is a microsuspension containing a solid complex of dexamethasone and γ-cyclodextrin, and the microsuspension is: - 1.5% dexamethasone; - 12% to 16% γ-cyclodextrin; - 2% to 2.7% polymer; - 0-0.1% chelating agent, e.g., 0.1% disodium edetate; - 0-1% electrolyte, for example, 0.57% sodium chloride; - An additive to prevent oxidation of the dexamethasone, in an amount of 0% to 0.6%; and, - water, This includes, or essentially consists of, Here, the pH is between 4.7 and 6.0. Here, % is weight % based on the volume of the composition. The method according to any one of embodiments E1 to E12.

[0130] Embodiment E14: The maintenance phase includes the step of topically administering the eye drop formulation at a dose of 3 drops per day for at least 6 weeks or at least 12 weeks. The method according to any one of embodiments E1 to E13.

[0131] Embodiment E15: The maintenance phase includes the step of topically administering the eye drop formulation at a dose of 3 drops per day for at least 46 weeks. The method according to any one of embodiments E1 to E14.

[0132] Embodiment E16: The maintenance phase includes the step of locally administering the eye drop formulation at a dose of 3 drops per day for the period required by the patient. The method according to any one of embodiments E1 to E15.

[0133] Embodiment E17: The maintenance phase includes the step of administering the eye drop formulation locally at a dose of 3 drops per day indefinitely. The method according to any one of embodiments E1 to E15.

[0134] Embodiment E18: The maintenance phase includes the step of locally administering the eye drop formulation at a dose of 3 drops per day for a certain period, followed by locally administering a reduced daily dose. The method according to any one of embodiments E1 to E17.

[0135] Embodiment E19: The eye drop formulation is: - 1.5% dexamethasone; - 14% γ-cyclodextrin; - 2.5% poloxamer; - 0-0.1% chelating agent, e.g., 0.1% disodium edetate; - 0-1% electrolyte, for example, 0.57% sodium chloride; - Additives to prevent oxidation of the dexamethasone, such as sodium thiosulfate, in an amount of 0.05% to 0.3%; and, - water, This includes, or essentially consists of, Here, % is weight % based on the volume of the composition. The method according to any one of embodiments E1 to E18.

[0136] Embodiment E20: The subject does not respond to VEGF inhibitor therapy, or responds insufficiently, and / or cannot tolerate invasive treatment for diabetic macular edema. The method according to any one of embodiments E1 to E19.

[0137] Embodiment E21: The subjects are selected from patients who have not received VEGFi treatment and exhibit retinal thickening in the affected eye due to diabetic macular edema. The method according to any one of Embodiments E1 to E20.

[0138] Embodiment E22: The subject is an adult human subject. The method according to any one of embodiments E1 to E21.

[0139] Embodiment E23: At the end of the introductory phase, in subjects with DME, the mean ETDRS best corrected visual acuity improves by at least 6 ETDRS characters compared to baseline. The method according to any one of embodiments E1 to E22.

[0140] Embodiment E24: After 6 weeks of maintenance, in subjects with DME, the mean ETDRS best corrected visual acuity is maintained at least 6 ETDRS letters compared to baseline. The method according to any one of embodiments E1 to E23.

[0141] Embodiment E25: In a subject suffering from DME, after 6 weeks of treatment, the mean change in central subfield thickness (CST) measured from baseline decreases by more than -50 μm CST. The method according to any one of embodiments E1 to E24.

[0142] Embodiment E26: In the ETDRS character count evaluation, an improvement of at least 3 lines (15 characters) from baseline is observed in at least 25%, at least 27%, at least 30%, at least 35%, or more than 35% of the treated patient population at 12 months. The method according to any one of embodiments E1 to E25.

[0143] Embodiment E27: After 12 weeks of treatment, the percentage of subjects whose intraocular pressure increased by more than 10 mmHg does not exceed 20%. The method according to any one of embodiments E1 to E26.

[0144] Embodiment E28: After 12 weeks of treatment, the percentage of subjects whose intraocular pressure increased by more than 35 mmHg does not exceed 5%. The method according to any one of embodiments E1 to E27.

[0145] Embodiment E29: The eye drop formulation is free of preservatives. The method according to any one of embodiments E1 to E28.

[0146] Embodiment E30: An eye drop formulation for use in a method for treating diabetic macular edema in human subjects requiring such treatment, wherein the method is (i) An induction phase in which an eye drop formulation containing 1.5% (w / v) dexamethasone is administered topically to the affected eye in a dose of 5 to 7 drops per day, followed by, (ii) During the maintenance phase, the eye drop formulation containing 1.5% (w / v) dexamethasone is administered locally to the affected eye at a frequency less frequent than that of the induction phase. An eye drop formulation containing [this ingredient].

[0147] Embodiment E31: The eye drop formulation is a microsuspension containing a solid complex of dexamethasone, γ-cyclodextrin, and poloxamer. An eye drop formulation for use as described in Embodiment E30.

[0148] Embodiment E32: The eye drop formulation has a diameter D 50 It is a microsuspension containing microparticles in the range of approximately 1 μm to 90 μm. An eye drop formulation for use as described in Embodiment E30 or E31.

[0149] Embodiment E33: The induction phase includes the step of topically administering an eye drop formulation containing 1.5% (w / v) dexamethasone to the target affected eye at a dose of 5 to 7 drops per day for a period ranging from 5 days to 6 weeks. An eye drop formulation for use according to any one of embodiments E30 to E32.

[0150] Embodiment E34: The induction phase includes the step of topically administering an eye drop formulation containing 1.5% (w / v) dexamethasone to the target affected eye at a dose of 5 to 7 drops per day for a period of 6 weeks. An eye drop formulation for use according to any one of embodiments E30 to E33.

[0151] Embodiment E35: The induction phase includes the step of topically administering a 1.5% (w / v) dexamethasone eye drop formulation to the target affected eye at a dose of 6 drops per day for a period of 6 weeks. An eye drop formulation for use according to any one of embodiments E30 to E34.

[0152] Embodiment E36: ​​The maintenance phase includes the step of topically administering an eye drop formulation containing 1.5% (w / v) dexamethasone to the affected eye at a dose of 1, 2, or 3 drops per day. An eye drop formulation for use according to any one of embodiments E30 to E35.

[0153] Embodiment E37: The maintenance phase includes the step of topically administering an eye drop formulation containing 1.5% (w / v) dexamethasone to the affected eye at a dose of 3 drops per day. An eye drop formulation for use according to any one of embodiments E30 to E36.

[0154] Embodiment E38: The administration regimen is, (i) An induction phase in which a 1.5% (w / v) dexamethasone eye drop formulation is administered topically to the affected eye at a dose of 6 drops per day, followed by... (ii) A maintenance period in which the eye drop formulation is administered topically at a dose of 1, 2, or 3 drops per day for at least 6 weeks. An eye drop formulation for use according to any one of embodiments E29 to E36, including the one described above.

[0155] Embodiment E39: The administration regimen is, (i) An induction phase in which a 1.5% (w / v) dexamethasone eye drop formulation is administered topically to the affected eye at a dose of 6 drops per day for 6 weeks, followed by... (ii) During the maintenance phase, the eye drop formulation is administered locally at a dose of 3 drops per day. An eye drop formulation for use according to any one of embodiments E30 to E38, including the one described above.

[0156] Embodiment E40: The administration regimen is, (i) An induction phase in which a 1.5% (w / v) dexamethasone eye drop formulation is administered topically to the affected eye at a dose of 6 drops per day for 6 weeks, followed by... (ii) During the maintenance phase, the eye drop formulation is administered locally at a dose of 3 drops per day. Includes, Here, the eye drop formulation is a microsuspension containing a solid complex of dexamethasone, γ-cyclodextrin, and poloxamer. An eye drop formulation for use according to any one of embodiments E30 to E39.

[0157] Embodiment E41: The eye drop formulation contains γ-cyclodextrin in an amount of 12-16% by weight of cyclodextrin based on the volume of the composition. An eye drop formulation for use as described in any one of Embodiments E30 to E40.

[0158] Embodiment E42: The administration regimen is, (i) An induction phase in which a 1.5% (w / v) dexamethasone eye drop formulation is administered topically to the affected eye at a dose of 6 drops per day for 6 weeks, followed by... (ii) During the maintenance phase, the eye drop formulation is administered locally at a dose of 3 drops per day. Includes, Here, the eye drop formulation is a microsuspension containing a solid complex of dexamethasone and γ-cyclodextrin, and the microsuspension is: - 1.5% dexamethasone; - 12% to 16% γ-cyclodextrin; - 2% to 2.7% polymer; - 0-0.1% chelating agent, e.g., 0.1% disodium edetate; - 0-1% electrolyte, for example, 0.57% sodium chloride; - An additive to prevent oxidation of the dexamethasone, in an amount of 0% to 0.6%; and, - water, This includes, or essentially consists of, Here, the pH is between 4.7 and 6.0. Here, % is weight % based on the volume of the composition. An eye drop formulation for use according to any one of embodiments E30 to E41.

[0159] Embodiment E43: The maintenance phase includes the step of topically administering the eye drop formulation at a dose of 3 drops per day for at least 6 weeks or at least 12 weeks. An eye drop formulation for use according to any one of embodiments E30 to E42.

[0160] Embodiment E44: The maintenance phase includes the step of topically administering the eye drop formulation at a dose of 3 drops per day for at least 46 weeks. An eye drop formulation for use according to any one of embodiments E30 to E43.

[0161] Embodiment E45: The maintenance phase includes the step of locally administering the eye drop formulation at a dose of 3 drops per day for the period required by the patient. An eye drop formulation for use as described in any one of embodiments E30 to E44.

[0162] Embodiment E46: The maintenance phase includes the step of administering the eye drop formulation locally at a dose of 3 drops per day indefinitely. An eye drop formulation for use as described in any one of embodiments E30 to E45.

[0163] Embodiment E47: The maintenance phase includes the step of locally administering the eye drop formulation at a dose of 3 drops per day for a certain period of time, followed by locally administering a reduced daily dose. An eye drop formulation for use according to any one of embodiments E30 to E46.

[0164] Embodiment E48: The eye drop formulation is: - 1.5% dexamethasone; - 14% γ-cyclodextrin; - 2.5% poloxamer; - 0-0.1% chelating agent, e.g., 0.1% disodium edetate; - 0-1% electrolyte, for example, 0.57% sodium chloride; - Additives to prevent oxidation of the dexamethasone, such as sodium thiosulfate, in an amount of 0.05% to 0.3%; and, - water, This includes, or essentially consists of, Here, % is weight % based on the volume of the composition. An eye drop formulation for use according to any one of embodiments E30 to E47.

[0165] Embodiment E49: The subject does not respond to VEGF inhibitor therapy, or responds insufficiently, and / or cannot tolerate invasive treatment for diabetic macular edema. An eye drop formulation for use as described in any one of embodiments E30 to E48.

[0166] Embodiment E50: The subjects are selected from patients who have not received VEGFi treatment and exhibit retinal thickening in the affected eye due to diabetic macular edema. An eye drop formulation for use as described in any one of embodiments E30 to E49.

[0167] Embodiment E51: The subject is an adult human subject. An eye drop formulation for use as described in any one of embodiments E30 to E50.

[0168] Embodiment E52: At the end of the introductory phase, in subjects with DME, the mean ETDRS best corrected visual acuity improves by at least 6 ETDRS characters compared to baseline. An eye drop formulation for use according to any one of embodiments E30 to E51.

[0169] Embodiment E53: Six weeks after the maintenance phase, the mean ETDRS best corrected visual acuity is maintained at least 6 ETDRS letters compared to baseline in subjects with DME. An eye drop formulation for use according to any one of embodiments E30 to E52.

[0170] Embodiment E54: In a subject suffering from DME, after 6 weeks of treatment, the mean change in central subfield thickness (CST) measured from baseline decreases by more than -50 μm CST. An eye drop formulation for use according to any one of embodiments E30 to E53.

[0171] Embodiment E55: In the ETDRS character count evaluation, an improvement of at least 3 lines (15 characters) from baseline is observed in at least 25%, at least 27%, at least 30%, at least 35%, or more than 35% of the treated patient population at 12 months. The method according to any one of embodiments E30 to E54.

[0172] Embodiment E56: After 12 weeks of treatment, the percentage of subjects whose intraocular pressure increased by more than 10 mmHg does not exceed 20%. An eye drop formulation for use according to any one of embodiments E30 to E55.

[0173] Embodiment E57: After 12 weeks of treatment, the percentage of subjects whose intraocular pressure increased by more than 35 mmHg does not exceed 5%. An eye drop formulation for use according to any one of embodiments E30 to E56.

[0174] Embodiment E58: An eye drop formulation that does not contain preservatives. An eye drop formulation for use according to any one of embodiments E30 to E57.

[0175] [Legend for the drawing] Figure 1: Trial DX219, Stage 1, mean change from baseline in BCVA (Best Corrected Visual Acuity) ETDRS better score at each follow-up visit - entire trial (ITT). BCVA: Best Corrected Visual Acuity; ITT: Intention-to-treat; SE: Standard Error.

[0176] Figure 2: Test 219, Stage 1, Change in CST compared to baseline - All Tests (ITT). CST: Central subfield thickness; LS: Least squares; SE: Standard error. The interpolation rule is applied based on the pattern mixed model approach.

[0177] Figure 3: Minimal change in intraocular pressure (IOP) was observed throughout Study 219, Stage 1, induction and maintenance phases. The Y-axis shows the mean change from baseline in millimeters of mercury (mmHg) at each time point in weeks since the start of treatment, shown on the X-axis, for OCS-01 (dark gray bars) or vehicle (light gray bars) (standard deviation (SD) is shown in parentheses). The mean IOP (SD) at baseline was 15.3 (3.1) mmHg for OCS-01 and 14.7 (3.0) mmHg for vehicle.

[0178] [Examples] [OCS-01 eye drop formulation] Dexamethasone eye drops having the composition shown in the table below were prepared.

[0179] [Table 1]

[0180] The formulations for each example are prepared as described below: The manufacturing process for the final bulk formulation is divided into two parts, A and B. Part A contains sterile water for injection, sodium chloride, disodium edetate dihydrate, poloxamer 407, sodium thiosulfate pentahydrate, and dexamethasone, while Part B contains sterile water for injection and gamma cyclodextrin. After sterilizing each suspension by heating, Part B is aseptically transferred to a tank containing Part A. The resulting solution is then cooled to room temperature under gentle agitation. The bulk product is then aseptically filled into single-dose units using blow-fill-seal technology.

[0181] [Example 1: Phase I Clinical Trial - A prospective, single-center, open-label study on the plasma pharmacokinetics and safety of OCS-01 ophthalmic suspension after local administration in healthy adults - Study DX217] Background and Evidence To evaluate the plasma pharmacokinetic (PK) and safety profile of OCS-01 ophthalmic suspension in healthy adults, a prospective, single-center, open-label Phase I trial was designed, following a two-day topical ophthalmic administration regimen using once-daily, three-daily, or six-daily doses to the test eye. This clinical trial utilized inclusion criteria designed to appropriately identify healthy subjects while minimizing concomitant therapies, procedures, or medical conditions that could pose a risk to or interfere with the study parameters. Participants were questioned about potential adverse events (AEs), and ocular safety was assessed at each visit.

[0182] In this clinical trial, the OCS-01 ophthalmic suspension consisted of dexamethasone (1.5% w / v), γ-cyclodextrin, sodium thiosulfate pentahydrate, disodium edetate, poloxamer 407, sodium chloride, and sterile water for injection. Dexamethasone is a corticosteroid that has been used in the form of eye drops (Maxidex®, Alcon) to treat inflammation caused by surgery, infection, or trauma. The OCS-01 ophthalmic suspension is a novel formulation consisting of nanoparticle aggregates of the active ingredients dexamethasone and γ-cyclodextrin, which significantly improves the solubility of the active ingredient and delivers high concentrations of dexamethasone to target tissues in the anterior and posterior segments of the eye after topical ophthalmic administration.

[0183] the purpose To clarify the characteristics of the plasma pharmacokinetics and safety profile of OCS-01 ophthalmic suspension following a 2-day topical ophthalmic administration regimen using once-daily, three-times-daily, or six-times-daily doses in a test eye in healthy adults.

[0184] methodology This study was a prospective, single-center, open-label Phase I trial in healthy adults to evaluate the plasma pharmacokinetics and safety profile of OCS-01 ophthalmic suspension, following a two-day topical ophthalmic administration regimen using once-daily, three-times-daily, or six-times-daily doses in the test eye.

[0185] Number of subjects (planned and analyzed subjects) The plan was to randomize a total of 18 healthy adult subjects into one of three treatment groups (administering OCS-01 ophthalmic suspension once daily, three times daily, or six times daily) in a 1:1:1 ratio. A total of 53 subjects underwent screening, and 19 healthy adult subjects were enrolled in the study and randomized into one of the three treatment groups. In the OCS-01 ophthalmic suspension administration regimens, 6 subjects were randomized into the once-daily dose group, 6 subjects into the three-times-daily dose group, and 7 subjects into the six-times-daily dose group.

[0186] Test product / control product, dosage, administration method OCS-01 ophthalmic suspension (dexamethasone 1.5%) was administered topically to the test eye for two days by trained research staff at the study site. Participants were randomly assigned to one of three treatment groups and received one drop (approximately 30 μL, equivalent to 0.45 mg of dexamethasone per drop) of OCS-01 once daily, three times daily, or six times daily. This dosing regimen was equivalent to 0.45 mg, 1.35 mg, or 2.7 mg of dexamethasone per day, and 0.9 mg, 2.7 mg, or 5.4 mg of dexamethasone per day over the entire study period, respectively. No control product was used in this study.

[0187] Treatment period The trial participation period per participant ranged from 6 to 31 days, with a treatment period of 2 days.

[0188] Evaluation items (Pharmacokinetic evaluation) OCS-01 is a 1.5% (w / v) suspension, equivalent to 1.5 g of dexamethasone per 100 mL of suspension. One drop from the eye drop bottle is approximately 30 μL and contains approximately 0.45 mg of dexamethasone. The pharmacokinetic (PK) of OCS-01 was evaluated based on plasma dexamethasone concentration.

[0189] To measure the pharmacokinetics of dexamethasone after administration of the OCS-01 ophthalmic suspension, consecutive plasma samples were collected after the first dose on day 1 and after the final dose on day 2. For each of the three treatment groups, the following plasma pharmacokinetic parameters were calculated to the greatest extent possible: Cmax (maximum plasma concentration), Tmax (time to reach maximum plasma concentration), Tlast (time to obtain the final measurable plasma concentration), Ke (apparent elimination rate constant estimated by log-linear regression of the concentration-time profile toward the terminal phase), T1 / 2 (apparent elimination half-life; calculated as ln(2) / Ke), and AUC0-∞ (area under the plasma concentration-time curve from 0 to infinity; calculated using the linear rising / log-falling trapezoid rule). AUC0-3 (Area under the plasma concentration-time curve from 0 to 3 hours; calculated using the linear rising / logarithmic falling trapezoid rule), AUC0-6 (Area under the plasma concentration-time curve from 0 to 6 hours; calculated using the linear rising / logarithmic falling trapezoid rule), AUC0-24 (Area under the plasma concentration-time curve from 0 to 24 hours; calculated using the linear rising / logarithmic falling trapezoid rule), AUClast (AUC up to the final measurable concentration), ARCmax (Accumulation rate of Cmax; calculated as Cmax at the last dose on day 2 / Cmax at the first dose on day 1), AR AUC (The accumulation rate of AUC is calculated as follows: for once-daily administration, AUC0-24 on day 2 / AUC0-24 on day 1; for three-times-daily administration, AUC0-6 from the final dose on day 2 / AUC0-6 from the first dose on day 1; for six-times-daily administration, AUC0-3 from the final dose on day 2 / AUC0-3 from the first dose on day 1), CL / F (clearance divided by bioavailability), and Vz / F (volume of distribution based on the terminal phase divided by bioavailability).

[0190] (Safety assessment) • Adverse events (reported, induced, and observed); • Best Corrected Visual Acuity (BCVA) at Distance; • Slit-lamp microscopy; • Physical examination; • Vital signs (resting blood pressure and heart rate); · Mydriatic fundus examination; • Intraocular pressure (IOP); and, • Blood tests, blood biochemistry tests, and urine tests.

[0191] (Other evaluations) • Urinary pregnancy test; • Illegal drug urine tests (including alcohol, amphetamines, barbiturates, benzodiazepines, cocaine (metabolites), cannabinoids, methadone, methamphetamine, opiates, and phencyclidine); and, • Blood tests for alcohol, hepatitis B surface antigen, hepatitis C antibody, and antigens and antibodies for HIV types 1 and 2.

[0192] result There were no substantial differences in the mean concentration-time profiles among the three treatment groups after the initial dose. In contrast, the mean dexamethasone concentration after the final dose increased with increasing dosing frequency (i.e., concentrations were higher in the 6-times-daily group than in the 3-times-daily group, and higher in the 3-times-daily group than in the once-daily group). Inter-subject variability in plasma dexamethasone concentrations after OCS-01 ocular administration was large (CV% ranged from 31.3% to 119.2%). This is consistent with the generally greater variability observed in PK studies when dexamethasone is administered topically compared to systemically, and with the small sample sizes within each treatment group.

[0193] No significant effect of repeated dosing or dosing regimens was observed on dexamethasone Tmax and T1 / 2. The mean (SD) T1 / 2 after the final dose was 5.97 (1.91), 5.74 (1.33), and 6.23 (1.28) hours for the once-daily, three-times-daily, and six-times-daily groups, respectively. Mean Cmax and AUC0-3 values ​​after the first dose were inconsistent across all three cohorts, although the ranges of these parameter values ​​overlapped among the cohorts. The differences in mean plasma exposure observed among the cohorts after the first dose are likely due to the large inter-subject variability observed across all three cohorts.

[0194] In subjects administered OCS-01 once daily, little to no dexamethasone accumulation was observed after two doses (mean (SD) ARCmax and ARAUC were 1.00 (0.48) and 1.04 (0.40), respectively). However, accumulation based on mean Cmax and AUC0-6, or AUC0-3 values, was observed in subjects administered three times daily and six times daily. The mean (SD) values ​​of ARCmax and ARAUC in the three times daily cohort were 1.70 (0.60) and 1.94 (0.78), respectively, and in the six times daily cohort they were 4.18 (3.04) and 6.28 (4.57).

[0195] This suggests that dexamethasone accumulation increases with increasing frequency of OSC-01 administration. Based on the T1 / 2 of dexamethasone, steady-state concentrations are expected to be reached by day 3 after repeated administration. The total plasma volume in the mean subject (71.4 kg) was estimated to be approximately 3060 mL, and the achievable maximum plasma concentration of dexamethasone after administration of one drop (0.45 mg of dexamethasone) was 147 ng / mL. The mean Cmax after the first OSC-01 administration on day 1 in the entire treatment group was 794 pg / mL, and the concentration present in the plasma at Tmax was approximately 0.54% of the theoretical maximum concentration (assuming 100% bioavailability).

[0196] Discussion and Summary (Pharmacokinetics of OCS-01) No effect of the administration regimen on dexamethasone Tmax or T1 / 2 was observed. Dexamethasone accumulation was minimal in subjects receiving OCS-01 once daily, but accumulation was observed with repeated administration in cohorts receiving OCS-01 three times daily and six times daily. This suggests that dexamethasone accumulation gradually increases with increasing frequency of OCS-01 administration.

[0197] The bioavailability of dexamethasone after ocular administration is T max At that time, the concentration was approximately 0.54% of the theoretical maximum concentration present in plasma.

[0198] For comparison, the systemic bioavailability of topically administered 1% atropine ophthalmic solution was measured to be 63.5 ± 28.6% (Timo Kaila, Juha-Matti Korte and K. Matti Saari, Acta Ophthalmol. Scand. 1999: 77: 193-196). Generally, only a small portion (less than 5%) of a topically administered drug is absorbed into the eye, while up to 80% enters the systemic blood circulation (Marc Labetoulle, Eric Frau, Claire Le Jeune, Systemic adverse effects of topical ocular treatments, Presse Med 2005; 34: 589-95).

[0199] Therefore, this study demonstrates that despite the large amount of dexamethasone administered to the eye, even at a dose of 6 drops per day, the amount of dexamethasone entering the bloodstream is surprisingly small, thereby reducing the risk of safety problems.

[0200] (Comparison with published pharmacokinetic results for dexamethasone) Plasma dexamethasone C after the first and final doses of OSC-01 max The values ​​were compared to those reported by other researchers after dexamethasone administration via various routes. These data are presented in the clinical trial report below.

[0201] The peak plasma concentrations of dexamethasone after single or repeated administration of OCS-01 were lower compared to those after oral, intramuscular (IM), or intravenous (IV) administration. max The values ​​were 1%–11% and 1%–25% respectively after a single oral administration of 0.5–6 mg; 2%–3% and 2%–6% respectively after a single intramuscular administration of 3 mg; and 0.1%–0.2% and 0.1%–0.4% respectively after a single intravenous bolus administration of 6.7 mg.

[0202] Compared with the single bilateral administration of Ciprodex® (ciprofloxacin 0.3% / dexamethasone 0.1%) in pediatric patients, the maximum plasma concentration of dexamethasone in this study was 21% to 44% lower after a single administration or once-daily administration of OCS-01, and 21% to 79% higher after multiple administrations of OCS-01 (three times daily and six times daily).

[0203] When comparing the single administration of ophthalmic preparations, the C of dexamethasone after administration of OCS-01 (dexamethasone 1.5%) max value was 1.6 to 2.2 times higher than after single bilateral administration of Tobradex® (tobramycin 0.3% / dexamethasone 0.1%). In terms of multiple administrations, the C of dexamethasone 2 days after OCS-01 was administered once daily, three times daily, and six times daily max value was 1.5 to 3.6 times higher than 2 days after Tobradex® was administered bilaterally to both eyes four times daily. When adjusted for dexamethasone, the plasma concentration of dexamethasone during OCS-01 administration resulted in approximately 60% lower levels than during Tobradex® administration.

[0204] Based on these results, OCS-01 has a much lower potential to cause systemic side effects than would be expected with other eye drop formulations having equivalent doses.

[0205] [Example 2: Phase II / III Clinical Trial in Patients with Diabetic Macular Edema - Study DX219 (DIAMOND)] Study DX219 (DIAMOND) is a multicenter, randomized, double-masked, 2-stage Phase II / III trial designed to evaluate the efficacy and safety of the OCS-01 ophthalmic formulation in patients with diabetic macular edema. This study consists of two stages, and patients enrolled in Stage 1 will not participate in Stage 2.

[0206] Stage 1 was conducted at 39 sites in the United States and Europe, where 148 patients were randomly assigned at a ratio of 2:1, and administered OCS-01 (n=100) or vehicle (n=48) 6 times daily during the 6-week induction phase, followed by 3 times daily during the subsequent 6-week maintenance phase.

[0207] The main eligibility criteria for this study are as follows: · Age 18 to 85 years · Type 1 or type 2 diabetes mellitus · BCVA (Best Corrected Visual Acuity) of 65 to 24 ETDRS (equivalent to 20 / 50 to 20 / 320 in Snellen conversion) · Central Subfield Thickness (CST) of more than 310 μm as measured by SD-OCT Previous treatment history is allowed (with a washout period).

[0208] The endpoints of the Phase 1 trial of DX219 are as follows: · Primary endpoint: Mean change from baseline in BCVA at Week 6 · Mean change from baseline in BCVA at Week 12 · Proportion (%) of patients who achieved an improvement of 3 lines or more in BCVA at Week 6 and Week 12 · Mean change in CST as assessed by SD-OCT · AUC of the change in BCVA · Proportion (%) of patients who achieved an improvement of 1 line or more or 2 lines or more in BCVA at each post-baseline visit · Adverse events.

[0209] Subjects were randomized at a ratio of 2:1 (OCS-01 vs. vehicle), and administered the drug or vehicle 6 times daily during the 6-week induction phase, and 3 times daily during the 6-week maintenance phase.

[0210] A total of 148 patients were randomized, with 100 in the OCS-01 group and 48 in the vehicle group. Of these patients, 85 in the OCS-01 group and 39 in the vehicle group completed the 12-week study.

[0211] This study achieved the primary endpoint, the mean change in LS from baseline in BCVA character count at week 6, with statistical significance (p=0.007, 95% CI, 1.1–7.0), demonstrating a significant improvement in visual acuity in the treatment group compared to the vehicle group (OCS-01: 7.2 characters vs. vehicle group: 3.1 characters, p=0.007). This effect persisted statistically significantly until week 12 (OCS-01: 7.6 characters vs. vehicle group: 3.7 characters, p=0.016). Furthermore, the proportion of patients who achieved an improvement of 15 letters or more from baseline in BCVA at week 6 was higher in the OCS-01 group compared to the vehicle group (OCS-01: 25.3% vs. vehicle group: 9.8%, p=0.015), and this trend continued until week 12 (OCS-01: 27.4% vs. vehicle group: 7.5%, p=0.009). (See Table 1). Figure 1 shows the mean change in LS from baseline in BCVA at each visit.

[0212] [Table 2]

[0213] This study also achieved a statistically significant secondary endpoint, the mean change from baseline in CST, and Figure 2 shows the change in CST at each visit after baseline.

[0214] The most frequent adverse events were diabetic macular edema, elevated IOP, hypertension, ocular hypertension, and macular edema. IOP-related events are shown in Table 2, and Figure 3 shows the mean increase in IOP from baseline (mmHg) at each time point during the study period. Serious adverse events that occurred during treatment (≥2.0% in the OCS-01 group or ≥4.0% in the vehicle group) are shown in Table 3.

[0215] [Table 3]

[0216]

Table 4

[0217] One fatal adverse event occurred in the OCS-01 group. This event was determined to be unrelated to the investigational drug.

[0218] Table 4 summarizes, for illustrative purposes, clinically relevant ophthalmic outcome data derived from the DX-219, Stage 1 trial and the OZURDEX clinical trials.

[0219]

Table 5

[0220] Conclusion In this 3-month study, OCS-01, administered according to a specific dosing regimen (6 drops per day for 6 weeks, followed by 3 drops per day for the subsequent 6 weeks), met all of the clinical efficacy endpoints required for regulatory approval (the main change from baseline in BCVA, and the proportion of patients showing an improvement of 3 lines or more).

[0221] OCS-01 was well tolerated, and no unexpected adverse events were observed. This is a necessary condition to promote patient treatment compliance.

[0222] As a non-invasive treatment that has shown such favorable results, OCS-01 has the potential to benefit a large number of DME patients.

Brief Description of the Drawings

[0223] [Figure 1] Figure 1: Mean change from baseline in BCVA (Best Corrected Visual Acuity) ETDRS better score at each follow-up visit in Trial DX219, Stage 1 - All Subjects (ITT). BCVA: Best Corrected Visual Acuity; ITT: intention-to-treat; SE: standard error. [Figure 2]Figure 2: Test 219, Stage 1, Change in CST compared to baseline - All Tests (ITT). CST: Central subfield thickness; LS: Least squares; SE: Standard error. Interpolation rules are applied based on the pattern mixed model approach. [Figure 3] Figure 3: Minimal change in intraocular pressure (IOP) was observed throughout Study 219, Stage 1, induction and maintenance phases. The Y-axis shows the mean change from baseline in millimeters of mercury (mmHg) at each time point in weeks since the start of treatment, shown on the X-axis, for OCS-01 (dark gray bars) or vehicle (light gray bars) (standard deviation (SD) is shown in parentheses). The mean IOP (SD) at baseline was 15.3 (3.1) mmHg for OCS-01 and 14.7 (3.0) mmHg for vehicle.

Claims

1. A method for treating diabetic macular edema in human subjects requiring such treatment, wherein the method is (i) An induction phase in which an eye drop formulation containing 1.5% (w / v) dexamethasone is administered topically to the affected eye in doses of 5, 6, or 7 drops per day, followed by, (ii) During the maintenance phase, the eye drop formulation containing 1.5% (w / v) dexamethasone is administered topically to the affected eye in a dose selected from 1, 2, or 3 drops per day. Methods that include...

2. The eye drop formulation is a microsuspension containing a solid complex of dexamethasone, γ-cyclodextrin, and poloxamer. The method according to claim 1.

3. The eye drop formulation has a diameter of D ５０ This is a microsuspension containing microparticles in the range of approximately 1 μm to 20 μm. The method according to claim 1 or 2.

4. The aforementioned introductory phase includes the step of locally administering the eye drop formulation at a dose of 5, 6, 7, or 8 drops per day for a period ranging from 5 days to 3, 4, 5, or 6 weeks. The method according to any one of claims 1 to 3.

5. The aforementioned introductory phase includes the step of locally administering the eye drop formulation at a dose of 6 drops per day for a period of up to 3 weeks, 4 weeks, 5 weeks, or 6 weeks. The method according to any one of claims 1 to 4.

6. The aforementioned introductory phase includes the step of locally administering the eye drop formulation at a dose of 6 drops per day for a period of up to 6 weeks. The method according to any one of claims 1 to 5.

7. The maintenance period includes the step of topically administering the eye drop formulation at a dose of one, two, or three drops per day for at least three weeks, at least six weeks, at least twelve weeks, at least twenty-four weeks, at least thirty-six weeks, at least forty-six weeks, for a period required by the patient, or indefinitely. The method according to any one of claims 1 to 6.

8. The maintenance period includes the step of topically administering the eye drop formulation at a dose of one, two, or three drops per day for a period of at least 46 weeks. The method according to any one of claims 1 to 6.

9. The maintenance period includes the step of topically administering the eye drop formulation at a dose of three drops per day for at least three weeks, at least six weeks, at least twelve weeks, at least twenty-four weeks, at least thirty-six weeks, at least forty-six weeks, for a period required by the patient, or indefinitely. The method according to any one of claims 1 to 6.

10. The maintenance period includes the step of administering the eye drop formulation topically at a dose of three drops per day for a period of at least 46 weeks. The method according to any one of claims 1 to 6.

11. The maintenance phase includes the step of topically administering a 1.5% (w / v) dexamethasone eye drop formulation to the affected eye at a dose of 1, 2, or 3 drops per day. The method according to any one of claims 1 to 6.

12. The maintenance phase includes the step of locally administering a 1.5% (w / v) dexamethasone eye drop formulation to the affected eye at a dose of 3 drops per day. The method according to any one of claims 1 to 6.

13. The administration regimen is, (i) An induction phase in which an eye drop formulation containing 1.5% (w / v) dexamethasone is administered topically to the affected eye of the subject at a dose of 6 drops per day, followed by, (ii) A maintenance period in which the eye drop formulation is administered topically at a dose of 1, 2, or 3 drops per day for at least 6 weeks. The method according to any one of claims 1 to 3, including the method described in any one of claims 1 to 3.

14. The maintenance period includes the step of administering the eye drop formulation at a dose of three drops per day for at least six weeks. The method according to claim 13.

15. The administration regimen is, (i) An induction phase in which an eye drop formulation containing 1.5% (w / v) dexamethasone is administered topically to the affected eye for six weeks at a dose of six drops per day, followed by, (ii) During the maintenance phase, the eye drop formulation is administered topically at a dose of 3 drops per day. The method according to any one of claims 1 to 3, including the method described in any one of claims 1 to 3.

16. The eye drop formulation contains γ-cyclodextrin in an amount of 10 to 25% by weight of cyclodextrin based on the volume of the composition. The method according to any one of claims 1 to 15.

17. The aforementioned eye drop formulation: - 1.5% dexamethasone; - 12-16% γ-cyclodextrin; - 2-2.7% poloxamer; - 0-0.1% chelating agent, e.g., 0.1% disodium edetate; - 0-1% electrolyte, for example, 0.57% sodium chloride; - An additive to prevent oxidation of the dexamethasone, in an amount of 0% to 0.6%; and, - water, It includes, or essentially consists of, Here, the pH is between 4.7 and 6.

0. Here, % is a weight percentage based on the volume of the composition. The method according to any one of claims 1 to 16.

18. The aforementioned subjects either do not respond to VEGF inhibitor treatment or respond only insufficiently, and / or cannot tolerate invasive treatment for diabetic macular edema. The method according to any one of claims 1 to 17.

19. The subjects are selected from among VEGF-naïve patients who exhibit retinal thickening in the affected eye due to diabetic macular edema. The method according to any one of claims 1 to 18.

20. The subject is an adult human subject. The method according to any one of claims 1 to 19.

21. At the end of the aforementioned introductory period, the mean ETDRS best corrected visual acuity in subjects with DME improves by at least 5 ETDRS characters compared to baseline. The method according to any one of claims 1 to 20.

22. At the end of the aforementioned introductory period, the mean ETDRS best corrected visual acuity in subjects with DME improves by at least 6 ETDRS characters compared to baseline. The method according to claim 21.

23. At the end of the aforementioned introductory period, the mean ETDRS best corrected visual acuity in subjects with DME improves by at least 7 ETDRS characters compared to baseline. The method according to claim 22.

24. In subjects suffering from the aforementioned DME, after 6 weeks of treatment, the mean change in central subfield thickness (CST) measured from baseline decreases by more than -50 μm CST. The method according to any one of claims 1 to 23.

25. After 12 weeks of treatment, the percentage of subjects whose intraocular pressure rose above 35 mmHg did not exceed 5%. The method according to any one of claims 1 to 24.

26. The aforementioned eye drop formulation does not contain preservatives. The method according to any one of claims 1 to 25.

27. The administration regimen is, (iii) An induction phase in which an eye drop formulation containing 1.5% (w / v) dexamethasone is administered topically to the affected eye for six weeks at a dose of six drops per day, followed by, (iv) During the maintenance phase, administer the eye drop formulation locally at a dose of 3 drops per day. including, and, Here, the eye drop formulation is: - 1.5% dexamethasone; - 14% γ-cyclodextrin; - 2.5% poloxamer; - 0-0.2% chelating agent; - 0-1% electrolytes; - An additive to prevent oxidation of the aforementioned dexamethasone, in an amount of 0% to 0.6%; And, - water, This includes, or essentially consists of, The percentage is a weight percentage based on the volume of the composition. The method according to any one of claims 1 to 3.

28. The chelating agent is 0.1% (w / v) disodium edetate. The method according to claim 27.

29. The electrolyte is 0.57% (w / v) sodium chloride. The method according to claim 27 or 28.

30. The aforementioned additive is sodium thiosulfate. The method according to any one of claims 27 to 29.

31. The aforementioned additive is 0.3% (w / v) sodium thiosulfate. The method according to any one of claims 27 to 30.

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