Method for stabilizing ph of aqueous composition comprising drug

Abstract

To provide a method for stabilizing the pH of an aqueous composition comprising a drug which is prone to oxidation.SOLUTION: Provided is a method that comprises the addition of an additive to prevent oxidation of a drug that is prone to oxidation. In particular, the present disclosure relates to a method for stabilizing the pH of an aqueous composition comprising a corticosteroid, the method comprising the addition of an additive to prevent oxidation of the corticosteroid. The present disclosure also relates to a composition comprising a corticosteroid and an additive to prevent oxidation of the corticosteroid.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to a method for stabilizing the pH of an aqueous composition containing a drug, the method including the addition of an additive for preventing oxidation of the drug. In particular, the present disclosure relates to a method for stabilizing the pH of an aqueous composition containing a corticosteroid, the method including the addition of an additive for preventing oxidation of the corticosteroid. The present disclosure also relates to a composition containing a corticosteroid and an additive for preventing oxidation of the corticosteroid.

Background Art

[0002] Eye conditions are a global problem, and it is estimated that approximately 285 million people worldwide are visually impaired. In the United States, 2.1 million Americans have age-related macular degeneration (AMD), 2.7 million Americans have glaucoma, 7.7 million Americans have diabetic retinopathy, and 24 million Americans have been diagnosed with cataracts.

[0003] Most eye conditions can be treated and / or managed to reduce negative effects, including total blindness. However, current treatments for eye conditions are limited because it is difficult to deliver effective doses of drugs to the target tissues within the eye. In current treatments, topical administration of eye drops is the preferred means of drug administration to the eye compared to other ophthalmic drug administration routes, such as intravitreal injection and infusion, due to the convenience and safety of eye drops (Le Souriais, C., Acar, L., Zia, H., Sado, P.A., Needham, T., Leverge, R., 1998. Ophthalmic drug delivery systems - Recent advances. Progress in Retinal and Eye Research 17, 33 - 58). The drug is mainly transported by passive diffusion from the eye surface to the eye and surrounding tissues. According to Fick's law, the drug is driven into the eye by the gradient of dissolved drug molecules. Passive drug diffusion into the eye is hindered by three main obstacles (Gan, L., Wang, J., Jiang, M., Bartlett, H., Ouyang, D., Eperjesi, F., Liu, J., Gan, Y., 2013. Recent advances in topical ophthalmic drug delivery with lipid - based nanocarriers. Drug Discov. Today 18, 290 - 297; Loftsson, T., Sigurdsson, H.H., Konradsdottir, F., Gisladottir, S., Jansook, P., Stefansson, E., 2008. Topical drug delivery to the posterior segment of the eye: anatomical and physiological considerations. Pharmazie 63, 171 - 179; Urtti, A, 2006. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv. Drug Del. Rev. 58, 1131 - 1135).

[0004] In recent years, the applicant has described the preparation and testing of cyclodextrin-based eye drops containing dexamethasone (WO2018 / 100434, Johannesson, G., Moya- Ortega, M.D., Asgrimsdottir, G.M., Lund, S.H., Thorsteinsdottir, M., Loftsson, T., Stefansson, E., 2014. Kinetics of y-cyclodextrin nanoparticle suspension eye drops in tear fluid. Acta Ophthalmologica 92, 550-556; Thorsteinn Loftsson and Einar Stefansson, Cyclodextrin nanotechnology for ophthalmic drug delivery, US Pat. No. 7,893,040 (Feb. 22, 2011); Thorsteinn Loftsson and Einar Stefansson, Cyclodextrin nanotechnology for ophthalmic drug delivery, US Pat. No. 8,633, 172 (Jan. 21, 2014); Thorsteinn Loftsson and Einar Stefansson, Cyclodextrin nanotechnology for ophthalmic drug delivery US Pat. No. 8,999,953 (Apr. 7, 2015)).

[0005] These studies indicate that cyclodextrin-based eye drops containing the active ingredient are promising for the treatment of eye conditions.

[0006] However, under certain storage conditions, for example, when stored in low-density polyethylene (LDPE) vials for several months, the pH of cyclodextrin-based ophthalmic solutions containing the active ingredient is not stable and decreases over time. Therefore, in order to prevent pH drop, it is desirable to develop a method for stabilizing the pH of these aqueous compositions. SUMMARY OF THE INVENTION

[0007] A first object of the present disclosure is a method for stabilizing the pH of an aqueous composition containing a drug, the method comprising adding an additive that prevents oxidation of the drug.

[0008] The inventors have surprisingly found that adding an additive for preventing oxidation of a drug to an aqueous solution can prevent a decrease in pH, particularly during a long storage period.

[0009] A second object of the present disclosure is an aqueous composition containing a corticosteroid, a cyclodextrin, and an additive that prevents oxidation of the corticosteroid, the additive being present in the composition at a concentration of 0.15% (w / v) to 0.6% (w / v), for example, at a concentration of 0.15% (w / v) to 0.45% (w / v), preferably at a concentration of 0.2% (w / v) to 0.4% (w / v).

[0010] A third object of the present disclosure is the use of the additive that prevents oxidation of a corticosteroid for stabilizing the pH of an aqueous composition containing the corticosteroid.

[0011] A fourth object of the present disclosure is a method for stabilizing the pH of an aqueous composition containing a drug, the method comprising using an oxygen absorber for preventing oxidation of the drug. DETAILED DESCRIPTION OF THE INVENTION

[0012] [Definitions] As used herein, the term "weight % of compound X based on the volume of the composition" is also abbreviated as "% w / v" and corresponds to the amount of compound X in grams introduced into 100 mL of the composition.

[0013] As used herein, "ocular condition" is a disease, disorder, or other condition that affects or involves the eye, a part or region of the eye, or surrounding tissues such as the lacrimal gland. Broadly speaking, the eye includes the eyeball, as well as the tissues and body fluids that make up the eyeball, the muscles surrounding the eyeball (such as the oblique and rectus muscles), the lacrimal gland, and a portion of the optic nerve that is inside or near the eyeball and surrounding tissues such as the eyelid.

[0014] As used herein, "anterior ocular condition" is a disease, disorder, or other condition that affects or involves the anterior (i.e., front) ocular region or site, such as the muscles surrounding the eye, the eyelid, the lacrimal gland, or the ocular tissue or body fluid located in the posterior wall of the lens capsule or the anterior portion of the ciliary muscle.

[0015] Thus, anterior ocular conditions mainly affect or involve the following: the conjunctiva, the cornea, the anterior chamber of the eye, the iris, the lens, or the lens capsule, and the blood vessels and nerves that form or innervate blood vessels in the anterior ocular region or site. Anterior ocular conditions are also considered in this specification to extend to the lacrimal apparatus. In particular, the lacrimal gland that secretes tears and the ducts that carry the tears to the surface of the eye.

[0016] Furthermore, anterior ocular conditions affect or involve the posterior chamber of the eye, which is behind the retina and in front of the posterior wall of the lens capsule.

[0017] Anterior ocular conditions include diseases, disorders, or conditions such as aphakia; pseudophakia; astigmatism; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcer; dry eye syndrome; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupillary disorders; refractive disorders and strabismus. Since the clinical goal of glaucoma treatment is to reduce the high pressure of the water in the anterior chamber of the eye (i.e., lower intraocular pressure), glaucoma can also be considered an anterior ocular condition.

[0018] The state of the anterior eye includes inflammation in the anterior eye after cataract surgery, glaucoma, inflammation of the anterior chamber of the eye, and anterior eye inflammation such as central macular edema.

[0019] The "state of the posterior eye" is a disease, illness, or condition that mainly affects or involves the posterior eye region or the choroid or sclera (located behind the plane passing through the posterior wall of the lens capsule), vitreous body, vitreous chamber, retina, optic nerve (i.e., optic nerve head), and blood vessels and nerves that vascularize or innervate the posterior eye region or site.

[0020] Accordingly, the state of the posterior eye is a disease, ailment, or condition, such as macular degeneration (including non-exudative age-related macular degeneration and exudative age-related macular degeneration), choroidal neovascularization, acute macular neuroretinopathy, macular edema (such as cystoid macular edema and diabetic macular edema), Behçet's disease, retinal disorders, diabetic retinopathy (including proliferative diabetic retinopathy), retinal artery occlusive diseases, central retinal vein occlusive disease (CRVO), uveitis retinal diseases, retinal detachment, ocular trauma affecting the posterior eye or posterior eye position, the state of the eye caused by or affected by ocular laser treatment, the state of the posterior eye caused by or affected by photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, retinal vein branch occlusive diseases, anterior ischemic optic neuropathy, non-retinopathic diabetic retinal dysfunction, retinitis pigmentosa, and glaucoma. Glaucoma can be considered a state of the posterior eye because its treatment goal is to eliminate or prevent the occurrence of vision loss due to damage or loss of retinal cells or optic nerve cells (i.e., neuroprotection).

[0021] As used herein, the term "microparticle" refers to particles having a diameter D of about 1 μm to about 200 μm. 50 The term "nanoparticle" refers to particles having a diameter D of less than 1 μm. 50 In an exemplary embodiment, D 50Possible diameters range from 1 μm to about 200 μm, and the term "nanoparticle" refers to particles with a D less than about 1 μm. 50 having.

[0022] The term "micro-suspension" is intended to mean a composition containing solid composite microparticles suspended in a liquid phase.

[0023] As used herein, the expression "preventing oxidation of a drug" is intended to mean preventing or delaying the oxidation of the drug.

[0024] <Method for Stabilizing the pH of a Water-Soluble Composition Containing a Drug> The present disclosure relates first to a method for stabilizing the pH of an aqueous composition containing a drug, the method comprising adding an additive for preventing oxidation of the drug. The present invention also relates to an aqueous composition comprising a drug and an additive for preventing oxidation of the drug obtained by this method.

[0025] The additive for preventing oxidation of the drug can be added to the aqueous composition before or after the drug.

[0026] (Drug) The aqueous composition of the present disclosure contains a drug. In the context of the present disclosure, a drug is a compound that exhibits a therapeutic effect when administered in a sufficient amount to a patient suffering from an eye condition.

[0027] In one embodiment, the drug is a corticosteroid, and corticosteroids include glucocorticoids and mineralocorticoids. Advantageously, the drug is selected from betamethasone-type corticosteroids that are glucocorticoids having a C 16 methyl substitution. Betamethasone-type corticosteroids include alclometasone, beclomethasone, betamethasone, clobetasone, clocortolone, dexamethasone, diflucortolone, flumethasone, flucortolone, fluprednidene, fluticasone, halomethasone, and mometasone. Preferably, the drug is dexamethasone.

[0028] In a specific embodiment, the drug is susceptible to oxidation. This means that the drug can be decomposed via an oxidation pathway. In some cases, the decomposition product of this oxidation is an acidic decomposition product, and the addition of an additive to prevent the oxidation of the drug prevents the formation of the acidic decomposition product.

[0029] The concentration of the drug in the aqueous composition of the present disclosure can be from about 0.1 mg / ml to about 100 mg / ml, particularly from about 1 mg / ml to about 100 mg / ml, particularly from about 1 mg / ml to about 50 mg / ml, more specifically from about 1 mg / ml to about 40 mg / ml, even more specifically from about 5 mg / ml to about 35 mg / ml, and more specifically still from about 10 mg / ml to about 30 mg / ml. The concentration of the drug in the aqueous composition of the present disclosure can be from about 5 mg / ml to about 30 mg / ml, particularly from about 10 mg / ml to about 25 mg / ml.

[0030] The amount of the drug in the aqueous composition can be 0.5 to 5% by weight, particularly 1 to 4% by weight, more particularly 1.5 to 3% by weight of the drug, based on the volume of the composition.

[0031] (Cyclodextrin) The aqueous composition can contain cyclodextrin. The amount of cyclodextrin in the aqueous composition can be 1 to 35% by weight, particularly 5 to 30% by weight, more particularly 10 to 27% by weight, and even more particularly 12 to 25% by weight of cyclodextrin, based on the volume of the composition. The amount of cyclodextrin in the aqueous composition can be 10 to 25% by weight, particularly 12 to 20% by weight of cyclodextrin, based on the volume of the composition.

[0032] Cyclodextrin is a cyclic oligosaccharide containing 6 (α-cyclodextrin), 7 (β-cyclodextrin), and 8 (γ-cyclodextrin) glucopyranose monomers linked via α-1,4-glycosidic bonds. α-Cyclodextrin, β-cyclodextrin, and γ-cyclodextrin are natural products formed by the microbial degradation of starch. The outer surface of the donut-shaped cyclodextrin molecule is hydrophilic and has a large number of hydroxy groups, while their central cavities are somewhat lipophilic (Kurkov, S.V., Loftsson, T., 2013. Cyclodextrins. Int J Pharm 453, 167-180; Loftsson, T., Brewster, M.E., 1996. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. Journal of Pharmaceutical Sciences 85, 1017-1025). In addition to the three natural cyclodextrins, a number of water-soluble cyclodextrin derivatives have been synthesized and tested as drug carriers, including cyclodextrin polymers (Stella, V.J., He, Q., 2008. Cyclodextrins. Tox. Pathol. 36, 30-42).

[0033] Cyclodextrins can enhance the solubility and bioavailability of hydrophobic compounds. In aqueous solution, cyclodextrins form inclusion complexes with many drugs by incorporating the drug molecule or, more frequently, some of the lipophilic moieties of the molecule into the central cavity. This property has been used for the purposes of pharmaceutical formulation and drug delivery. The formation of drug / cyclodextrin inclusion complexes, their effects on the physicochemical properties of drugs, their effects on the ability of drugs to permeate biological membranes, and the use of cyclodextrins in pharmaceutical products have been reviewed (Loftsson, T., Brewster, M.E., 2010. Pharmaceutical applications of cyclodextrins: basic science and product development. Journal of Pharmacy and Pharmacology 62, 1607-1621; Loftsson, T., Brewster, M.E., 2011. Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes. J. Pharm. Pharmacol. 63, 1119-1135; Loftsson, T., Jarvinen, T., 1999. Cyclodextrins in ophthalmic drug delivery. Advanced Drug Delivery Reviews 36, 59-79).

[0034] Cyclodextrins and drug / cyclodextrin complexes can self-assemble in aqueous solution to form nano-sized and micro-sized aggregates and micelle-like structures, which can also solubilize poorly soluble drugs by non-complexation and micelle-like solubilization (Messner, M., Kurkov, S.V., Jansook, P., Loftsson, T., 2010. Self- assembled cyclodextrin aggregates and nanoparticles. Int J Pharm 387, 199-208). Generally, the tendency of cyclodextrins to self- assemble and form aggregates increases during the formation of drug / cyclodextrin complexes, and 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, and their complexes dissolve freely in water. On the other hand, natural α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, and their complexes had limited solubility in pure water at 25 °C, i.e., 129.5 ± 0.7, 18.4 ± 0.2 and 249.2 ± 0.2 mg / ml, respectively (Sabadini E., Cosgrovea T. and do Carme Egidio F., 2006. Solubility of cyclomaltooligosaccharides (cyclodextrins) in H2O and D2O: a comparative study. Carbohydr Res 341, 270-274). Their solubility is known to increase to some extent with increasing temperature (Jozwiakowski, M. J., Connors, K. A, 1985. Aqueous solubility behavior of three cyclodextrins. Carbohydr. Res., 143, 51-59). Due to the limited solubility of their complexes, natural cyclodextrins most frequently exhibit Bs-type or Bi-type phase solubility diagrams (Brewster M. E., Loftsson T., 2007, Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev., 59, 645-666). The solubility of native cyclodextrins has been observed to decrease below their solubility in pure water upon formation of drug / cyclodextrin complexes (Jansook, P., Maya-Ortega, M.D., Loftsson, T., 2010. Effect of self-aggregation of y-cyclodextrin on drug solubilization. Journal of Inclusion Phenomena and Macrocyclic Chemistry 68, 229-236). Low concentrations of dissolved drug / cyclodextrin complexes prevent the formation of nanoparticles and microparticles containing the drug / cyclodextrin complex. Furthermore, other excipients such as water-soluble polymers used to stabilize nanosuspensions and microsuspensions can form complexes with cyclodextrin. Thus, the formation of drug / cyclodextrin complexes can be further hindered.

[0035] Previously, the applicant has described the preparation and testing of cyclodextrin-based eye drops containing dexamethasone, dorzolamide, irbesartan, telmisartan, and cyclosporine A in cyclodextrin nanoparticles. The literature described for dexamethasone is Johannesson, G., Moya-Ortega, M.D., Asgrimsdottir, G.M., Lund, S.H., Thorsteinsdottir, M., Loftsson, T., Stefansson, E., 2014. Kinetics of γ-cyclodextrin nanoparticle suspension eye drops in tear fluid. Acta Ophthalmologica 92, 550-556; Thorsteinn Loftsson and Einar Stefansson, Cyclodextrin nanotechnology for ophthalmic Drug delivery, US Pat. No. 7,893,040 (Feb. 22, 2011); Thorsteinn Loftsson and Einar Stefansson, Cyclodextrin nanotechnology for ophthalmic drug delivery, US Pat. No. 8,633, 172 (Jan. 21, 2014); Thorsteinn Loftsson and Einar Stefansson, Cyclodextrin nanotechnology for ophthalmic drug delivery US Pat. No. 8,999,953 (Apr. 7, 2015. The literature that described dorzolamide is Johannesson, G., Maya-Ortega, M.D., Asgrimsdottir, G.M., Lund, S.H., Thorsteinsdottir, M., Loftsson, T., Stefansson, E., 2014. Kinetics of γ-cyclodextrin nanoparticle suspension eye drops in tear fluid. Acta Ophthalmologica 92, 550-556; Gudmundsdottir, B.S., Petursdottir, D., Asgrimsdottir, G.M., Gottfredsdottir, M.S., Hardarson, S.H., Johannesson, G., Kurkov, S.V., Jansook, P., Loftsson, T., Stefansson, E., 2014. γ-Cyclodextrin nanoparticle eye drops with dorzolamide: effect on intraocular pressure in man. J. Ocul. Pharmacol. Ther. 30, 35-41.The literature on irbesartan is Muankaew, C., Jansook, P., Stefansson, E., Loftsson, T., 2014. Effect of γ-cyclodextrin on solubilization and complexation of irbesartan: influence of pH and excipients. Int J Pharm 474, 80-90. The literature on telmisartan is C. Muankaew, P. Jansook, H. H. Sigurdsson, T. Loftsson, 2016, Cyclodextrin-based telmisartan ophthalmic. suspension: Formulation development for water-insoluble drugs. Int. J. Pharm. 507, 21-31. The literature on cyclosporine A is S. Johannsdottir, P. Jansook, E. Stefansson, T. Loftsson, 2015, Development of a cyclodextrin-based aqueous cyclosporin A eye drop formulation. Int. J. Pharm. 493(1-2), 86-95. These studies show that nanoparticles increase the drug contact time with the ocular surface and the ocular bioavailability of the drug. Drug / cyclodextrin nanoparticles and microparticles not only remain on the ocular surface but also enhance the drug solubility in aqueous tears. Nanoparticles and microparticles composed of drug / γ-cyclodextrin complexes have been shown to be particularly effective drug carriers for the topical delivery of drugs to the eye.

[0036] The composition of the present disclosure can include a solid complex containing a drug and cyclodextrin. The complex of a drug and cyclodextrin is referred to as a "drug / cyclodextrin complex". When the drug is a corticosteroid, the complex of the corticosteroid and cyclodextrin is referred to as a "corticosteroid / cyclodextrin complex". When the drug is dexamethasone and the cyclodextrin is γ-cyclodextrin, the complex of dexamethasone and γ-cyclodextrin is referred to as a "dexamethasone / γ-cyclodextrin complex".

[0037] The solid complex of the composition of the present disclosure may be a complex aggregate. The complex aggregate may correspond to an aggregate of a plurality of complexes, particularly a plurality of inclusion complexes containing a drug and cyclodextrin, typically a complex containing a drug and γ-cyclodextrin.

[0038] According to one embodiment, the aqueous composition of the present disclosure is a micro-suspension.

[0039] In particular, the aqueous composition of the present disclosure contains a solid complex having a diameter D of less than about 100 μm, particularly about 1 μm to about 100 μm. 50 In one embodiment, the diameter D 50 may be about 1 μm to about 25 μm, particularly about 1 μm to about 20 μm, more specifically about 1 μm to about 10 μm, even more specifically about 2 μm to about 10 μm, even more specifically about 2 μm to about 5 μm, or about 3 μm to about 8 μm. The diameter and / or size of the particulate or complex can be measured according to any method known to those skilled in the art. For example, the diameter D 50It is measured by laser diffraction particle size analysis. Generally, there are only a limited number of techniques for measuring / evaluating the diameter and / or size of cyclodextrin / drug particles or complexes. In particular, those skilled in the art in this field know that physical properties (such as particle size, diameter, average diameter, average particle size, etc.) are typically evaluated / measured using such limited typical known techniques. For example, such known techniques are described in Int. J. Pharm. 493 (2015), 86-95, which is hereby incorporated by reference in its entirety. Furthermore, such limited known measurement / evaluation techniques were known in the art, as evidenced by other technical references such as 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. These documents are also hereby incorporated by reference in their entirety.

[0040] The European Pharmacopoeia (01 / 2008:1163) teaches that eye drops in the form of a suspension should comply with the following: for every 10 μg of solid active substance, there are at most about 20 particles having a maximum diameter greater than about 25 μm, and at most about 2 of these particles have a maximum diameter greater than about 50 μm. None of the particles can have a maximum diameter exceeding about 90 μm. The aqueous compositions of the present disclosure comply with the requirements of the European Pharmacopoeia (01 / 2008:1163).

[0041] Generally, the particle size in an aqueous ophthalmic suspension is recommended to be maintained at a minimum, preferably less than about 10 μm, in order to prevent eye irritation. Further, the sedimentation rate in an aqueous suspension is proportional to the particle diameter, and the sedimentation rate of large particles is faster than that of small particles, assuming that all other factors remain constant.

[0042] In particular, 60 to 95% by weight, more specifically 70 to 90% by weight, of the drug in the composition can be in the form of a solid complex of the drug and cyclodextrin.

[0043] Even more specifically, 5 to 40% by weight, particularly 10 to 30% by weight, of the drug in the composition can be in dissolved form. The dissolved form includes uncomplexed drug dissolved in the liquid phase, complexes of the drug and cyclodextrin dissolved in the liquid phase, and water-soluble nanoparticles composed of drug / cyclodextrin complex aggregates.

[0044] Preferably, 0 to 0.5% by weight of the drug in the composition may be in an uncomplexed solid form. Thus, the composition of the present disclosure may not substantially contain uncomplexed solid particles of the drug.

[0045] In one embodiment, the micro-suspension may contain about 70% to about 99% of the drug in microparticles and about 1% to about 30% of the drug in nanoparticles. More specifically, the micro-suspension may contain about 80% to about 95% of the drug in microparticles having a diameter of about 1 μm to about 10 μm and about 20% to about 5% of the drug in nanoparticles. The micro-suspension may contain about 80% of the drug in microparticles having a diameter of about 1 μm to about 10 μm and about 20% of the drug in nanoparticles.

[0046] In another embodiment, the micro-suspension may contain from about 40% to about 99% of the drug in the microparticles and from about 1% to about 60% of the drug in the nanoparticles or water-soluble drug / cyclodextrin complexes. In particular, the micro-suspension may contain from about 80% to about 95% of the drug in microparticles having a diameter of about 1 μm to about 10 μm and from about 5% to about 20% of the drug in nanoparticles or water-soluble active pharmaceutical ingredient / cyclodextrin complexes.

[0047] According to a preferred embodiment, the aqueous composition comprises a drug / cyclodextrin complex, preferably a corticosteroid / cyclodextrin complex, more preferably a dexamethasone / γ-cyclodextrin complex.

[0048] Examples of compositions containing drug / cyclodextrin complexes are disclosed in International Publication No. WO 2018 / 100434, which is incorporated herein by reference.

[0049] (Additives for preventing oxidation of the drug) The aqueous composition contains an additive for preventing oxidation of the drug. The Applicants have surprisingly found that the addition of an additive for preventing oxidation of the drug stabilizes the pH of the aqueous composition and prevents a decrease in pH.

[0050] In a preferred embodiment, the additive for preventing oxidation of the drug is selected from antioxidants, oxygen scavengers, and mixtures thereof.

[0051] Antioxidants typically include phenolic antioxidants and reducing agents. Phenolic antioxidants are sterically hindered phenols that react with free radicals to block oxidation reactions. Among phenolic antioxidants, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), or 3,4-dihydroxybenzoic acid, dodecyl 3,4,5-trihydroxybenzoate (lauryl gallate) can be mentioned. Reducing agents are compounds that have a lower redox potential than the agents intended to prevent oxidation. Reducing agents capture oxygen from the solvent and thus delay or prevent oxidation. Among reducing agents, sodium thiosulfate (STS) or other industrial food preservatives with antioxidant properties can be mentioned. Examples of antioxidants further include water-soluble natural antioxidants such as ascorbic acid, malic acid, citric acid, tartaric acid, lactic acid, and other organic acids and their derivatives. Other antioxidants can be further selected from among known food antioxidants.

[0052] In certain embodiments, the additive for preventing oxidation of the agent is sodium thiosulfate.

[0053] In another specific embodiment, the additive for preventing oxidation of the drug is 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., trisodium citrate anhydrous), 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 even more preferably the additive is selected from sodium thiosulfate, methionine, and 3,4-dihydroxybenzoic acid. Of course, the mixture of the antioxidants may be added as an additive for preventing oxidation of the drug.

[0054] An additive for preventing oxidation of the drug, typically sodium thiosulfate, methionine, or 3,4-dihydroxybenzoic acid, can be added at a concentration of at least 0.05% (w / v), preferably 0.05% (w / v) to 1% (w / v), more preferably 0.1 to 0.5%, and even more preferably 0.2% (w / v) to 0.4% (w / v). An additive for preventing oxidation of the drug, typically sodium thiosulfate, can be added at a concentration of 0.2% (w / v) to 0.3% (w / v).

[0055] As used herein, a concentration of 0.3% (w / v) sodium thiosulfate corresponds to sodium thiosulfate without water. This corresponds to 0.471 g / 100 mL of sodium thiosulfate pentahydrate. For other antioxidants, typically the molar equivalent of 0.3% sodium thiosulfate can be used in the aqueous composition.

[0056] (pH of the composition) Advantageously, the pH of the aqueous composition containing the drug is from 4 to 9, preferably from 5 to 8. Typically, the pH of the aqueous composition containing the drug is the physiological pH.

[0057] Advantageously, the pH of the aqueous composition containing the corticosteroid is from 4 to 8, preferably from 4.5 to 6.

[0058] In certain embodiments, the pH of the aqueous composition is stabilized for more than 6 months, preferably more than 9 months, between 4 and 8, preferably between 4.5 and 6, when stored at 25 °C and 40% relative humidity in accordance with the ICH guidelines.

[0059] (aqueous composition) Advantageously, the aqueous composition is an ophthalmically acceptable solvent. The term "ophthalmically acceptable solvent" is intended to mean a solvent suitable for ophthalmic administration of the composition. The ophthalmically acceptable solvent is preferably a liquid.

[0060] The aqueous composition can contain an organic solvent. In this case, it is preferred that the aqueous composition does not contain an organic solvent.

[0061] In certain embodiments, the ophthalmically acceptable solvent does not contain any other solvent other than water. Thus, the ophthalmically acceptable solvent can correspond to an aqueous eye drop vehicle. In a specific embodiment, the aqueous composition is an unbuffered aqueous eye drop vehicle.

[0062] According to a specific embodiment, the aqueous composition comprises water and, optionally, additives selected from the group consisting of preservatives, stabilizers, electrolytes, and combinations thereof. In particular, the ophthalmically acceptable solvent can contain a preservative.

[0063] Preservatives can be used to limit bacterial growth in the composition. Examples of preservatives are benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, phenylethyl alcohol, and combinations thereof. The amount of preservative in the composition of the present disclosure may be 0 to 1% by weight, particularly 0.001 to 0.5% by weight, more particularly 0.005 to 0.1% by weight, and even more particularly 0.01 to 0.04% by weight of the preservative, based on the volume of the composition. In a preferred embodiment, the aqueous composition does not contain a preservative.

[0064] In particular, the aqueous composition can contain a stabilizer. An example of a suitable stabilizer is disodium edetate. The amount of stabilizer in the composition of the present disclosure can be 0 to 1% by weight, specifically 0.01 to 0.5% by weight, and more specifically 0.08 to 0.2% by weight of the stabilizer, based on the volume of the composition.

[0065] In particular, an ophthalmically acceptable solvent can contain an electrolyte. The electrolyte can be particularly used 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 composition of the present disclosure can be 0 to 2% by weight, specifically 0.1 to 1.5% by weight, and more specifically 0.2 to 1% by weight of the electrolyte, based on the volume of the composition.

[0066] The aqueous composition may further contain a polymer. In particular, the polymer may be a water-soluble polymer. Further, the polymer may be a viscosity-enhancing polymer. The term "viscosity-enhancing polymer" is intended to mean a polymer that increases the viscosity of a liquid. The polymer increases the viscosity of the composition of the present disclosure. The increase in viscosity results in enhancing the physical stability of the composition. Thus, when the composition contains a polymer, the tendency of the solid composite to settle is low. Thus, the polymer can be regarded as a polymer stabilizer. In particular, the polymer may be a surfactant polymer. The term "surfactant polymer" is intended to mean a polymer that exhibits surfactant properties. A surfactant polymer may include, for example, a hydrophobic chain grafted to a hydrophilic backbone polymer; a hydrophilic chain grafted to a hydrophobic backbone; or alternating hydrophilic and hydrophobic segments. The first two types are called graft copolymers, and the third type is called a block copolymer.

[0067] In one embodiment, the ophthalmic composition of the present disclosure contains a polymer selected from the group consisting of polyoxyethylene fatty acid esters; polyoxyethylene alkyl phenyl ethers; polyoxyethylene alkyl ethers; cellulose derivatives such as alkyl cellulose, hydroxyalkyl cellulose and hydroxyalkyl alkyl cellulose; carboxyvinyl polymers such as carbomers such as Carbopol 971 and Carbopol 974; polyvinyl polymers; polyvinyl alcohol; polyvinyl pyrrolidone; copolymers of polyoxypropylene and polyoxyethylene; tyloxapol; and combinations thereof.

[0068] Examples of suitable polymers include polyethylene glycol monostearate, polyethylene glycol distearate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, 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 Carbide)), polyoxyethylene stearate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, cellulose, polyvinyl alcohol (PVA), poloxamer (e.g., Pluronic F68 and FI08 which are block copolymers of ethylene oxide and propylene oxide); poloxamine (e.g., Tetronic 908 known as poloxamine 908, a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508 (T - 1508) (BASF Wyandotte Corporation), Tritons X - 200 which is an alkylaryl polyether sulfonate (Rohm and Haas); PEG - derivatized lipids, PEG - derivatized cholesterol, PEG - derivatized cholesterol derivatives, PEG - derivatized vitamin A, PEG - derivatized vitamin E, random copolymers of vinyl pyrrolidone and vinyl acetate, combinations thereof, etc., but are not limited thereto.

[0069] Particularly preferred examples of the polymers according to the present disclosure are tyloxapol and copolymers of polyoxypropylene and polyoxyethylene.

[0070] More specifically, the copolymer of polyoxypropylene and polyoxyethylene may be a triblock copolymer including a hydrophilic block-hydrophobic block-hydrophilic block configuration.

[0071] In one embodiment, the composition of the present disclosure includes a polymer that is a poloxamer. The poloxamer can 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, 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. The poloxamer is also known by the trade name Pluronic. Examples of Pluronics include 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 L 121, Pluronic L31, Pluronic L3S, Pluronic L43, Pluronic L44, Pluronic L61, Pluronic L62, Pluronic L62 LF, Pluronic L620, Pluronic L64, Pluronic L81, Pluronic L92, Pluronic L44, Pluronic N3, Pluronic P103, Pluronic P104, Pronic P85, Pluronic P123, Pluronic P65, Pluronic P84, Pluronic P85, and combinations thereof, etc.

[0072] Particularly useful polymers as stabilizers are poloxamers. Poloxamers can 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, 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. Poloxamers are also known by the trade name Pluronic. Pluronic includes, for example, Pluronic 10R5, Pluronic 17R2, Pluronic 17R4, Pluronic 25R2, Pluronic 25R4, Pluronic 31R1, Pluronic F108 Cast Solid Surfacta, Pluronic F108 NF, Pluronic F108 Pastille, Pluronic F 108 NF Prill Poloxamer 338, Pluronic F 127, Pluronic F 127 NF, Pluronic F 127 NF 500 BHT Prill, Pluronic F 127 NF Prill Poloxamer 407, Pluronic F 38, Pluronic F 38 Pastille, Pluronic F 68, Pluronic F 68 Pastille, Pluronic F 68 LF Pastille, Pluronic F 68NF, Pluronic F 68 NF Prill Poloxamer 188, Pluronic F 77, Pluronic F 77 Micropastille, Pluronic F 87, Pluronic F 87 NF Prill Poloxamer 237, Pluronic F 88, Pluronic F 88 Pastille, Pluronic F 98, Pluronic L 10, Pluronic L 101, Pluronic L 121, Pluronic L 31, Pluronic L 35, Pluronic L 43, Pluronic L 44 NF Poloxamer 124, Pluronic L 61, Pluronic L 62, Pluronic L 62 LF, Pluronic L 620, Pluronic L 64, Pluronic L 81, Pluronic L 92, Pluronic L44 NF INH Surfactant Poloxamer 124 View, Pluronic N 3, Pluronic P 103, Pluronic P 104, Pluronic P 105, Pluronic P 123 Surfactant, Pluronic P 65, Pluronic P 84, Pluronic P 85, and combinations thereof, etc. In particular, the polymer is Poloxamer 407.

[0073] A further polymer stabilizer compatible with the compositions and methods described herein is tyloxapol. In a preferred embodiment, the stabilizer and co-solubilizer is tyloxapol, and tyloxapol is tyloxapol, a 4-(1,1,3,3-tetramethylbutyl)phenol polymer containing formaldehyde and oxirane.

[0074] The present disclosure also relates to a method for stabilizing the pH of an aqueous composition comprising a corticosteroid / cyclodextrin complex, for example, the addition of an antioxidant, typically one or more of sodium thiosulfate, to prevent oxidation of the corticosteroid as described in the above sections.

[0075] The present disclosure also relates to a method for stabilizing the pH of an aqueous composition comprising a drug, the method comprising the use of an oxygen absorber to prevent oxidation of the drug. The aqueous composition comprising the drug can be stored in a vial, and the vial can be packaged in a sealed pouch containing an oxygen absorber, typically an aluminum pouch. Advantageously, the oxygen absorber contains iron particles.

[0076] (Aqueous composition containing corticosteroid) The present disclosure also relates to an aqueous composition comprising a corticosteroid, a cyclodextrin, and an additive for preventing oxidation of the corticosteroid. Here, the additive is, for example, a reducing agent, a water-soluble natural antioxidant, or a phenolic antioxidant as described in the above sections, typically sodium thiosulfate, and is present in the composition at a concentration of 0.15% (w / v) to 0.45% (w / v), preferably 0.2% (w / v) to 0.4% (w / v). The additive for preventing oxidation of the corticosteroid can be, for example, a reducing agent, a water-soluble natural antioxidant, or a phenolic antioxidant as described in the above sections, typically sodium thiosulfate, and can be present at a concentration between 0.2% (w / v) and 0.3% (w / v).

[0077] (Corticosteroid) Examples of corticosteroids include glucocorticoids and mineralocorticoids. Advantageously, the corticosteroid is C 16It is selected from betamethasone-type corticosteroids which are glucocorticoids having a methyl substitution. Betamethasone-type corticosteroids include alclometasone, beclometasone, betamethasone, clobetasone, clocortolone, dexamethasone, diflucortolone, flumethasone, fluocortolone, fluprednidene, fluticasone, halometasone, and mometasone. Preferably, the agent is dexamethasone.

[0078] In a specific embodiment, the corticosteroid is easily oxidized, which means that the corticosteroid can be decomposed via an oxidation pathway. In some cases, the decomposition product of this oxidation is an acidic decomposition product, and the addition of an additive to prevent the oxidation of the agent prevents the formation of the acidic decomposition product.

[0079] The concentration of the corticosteroid in the aqueous composition of the present disclosure can be about 0.1 mg / ml to about 100 mg / ml, particularly about 1 mg / ml to about 100 mg / ml, particularly about 1 mg / ml to about 50 mg / ml, more specifically about 1 mg / ml to about 40 mg / ml, even more specifically about 5 mg / ml to about 35 mg / ml, more specifically about 10 mg / ml to about 30 mg / ml. The concentration of the corticosteroid in the aqueous composition of the present disclosure can be about 5 mg / ml to about 30 mg / ml, specifically about 10 mg / ml to about 25 mg / ml.

[0080] The amount of the corticosteroid in the aqueous composition can be 0.5 to 5% by weight, particularly 1 to 4% by weight, more particularly 1.5 to 3% by weight of the corticosteroid based on the volume of the composition.

[0081] (Cyclodextrin) The aqueous composition contains cyclodextrin. The amount of cyclodextrin in the aqueous composition can be 1 to 35% by weight, specifically 5 to 30% by weight, more specifically 10 to 27% by weight, and even more specifically 12 to 25% by weight of cyclodextrin, based on the volume of the composition. The amount of cyclodextrin in the aqueous composition can be 10 to 25% by weight, specifically 12 to 20% by weight of cyclodextrin, based on the volume of the composition. In a specific embodiment using dexamethasone as the drug, the amount of cyclodextrin, typically gamma-cyclodextrin, in the aqueous composition is 10 to 25%, and the amount of dexamethasone is 1.5%. In other embodiments, the amount of cyclodextrin, typically gamma-cyclodextrin, in the aqueous composition may be 20 to 25%, for example, 23%, and may be combined with an amount of dexamethasone of 2.0 to 3.5%, preferably about 3% of dexamethasone.

[0082] As described above, the corticosteroid can form a corticosteroid / cyclodextrin complex.

[0083] (Additives for preventing oxidation of corticosteroids) The aqueous composition contains an additive for preventing oxidation of the corticosteroid. The applicants have surprisingly found that the addition of an additive for preventing oxidation stabilizes the pH of the aqueous composition and prevents a decrease in pH.

[0084] In a preferred embodiment, the additive for preventing oxidation of the corticosteroid is selected from antioxidants, oxygen scavengers, and mixtures thereof.

[0085] Antioxidants include phenolic antioxidants and reducing agents, such as water-soluble natural antioxidants or other known food antioxidants.

[0086] Among phenolic antioxidants, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ) or 3,4-dihydroxybenzoic acid, dodecyl 3,4,5-trihydroxybenzoate (lauryl gallate) can be mentioned. A reducing agent is a compound having a lower redox potential than the agent intended to prevent oxidation. The reducing agent captures oxygen from the solvent and thus delays or prevents oxidation. Among reducing agents, sodium thiosulfate (STS) can be mentioned. Examples of antioxidants further include water-soluble natural antioxidants such as ascorbic acid, malic acid, citric acid, tartaric acid, lactic acid, and other organic acids and their derivatives.

[0087] Other antioxidants may be selected from known food or cosmetic antioxidants.

[0088] In certain embodiments, the additive for preventing oxidation of the agent is sodium thiosulfate.

[0089] In another specific embodiment, the additive for preventing oxidation of the agent is 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. More preferably, the additive is selected from sodium thiosulfate, methionine (typically L-methionine), 3,4-dihydroxybenzoic acid, sodium citrate (e.g., trisodium citrate anhydrous), malic acid (typically DL-malic acid), sodium ascorbate (e.g., (+)-L-sodium ascorbate), tartaric acid (typically DL-tartaric acid), α-monothioglycerol, and butylated hydroxyanisole. Even more preferably, the additive is selected from sodium thiosulfate, methionine, and 3,4-dihydroxybenzoic acid. Of course, a mixture of the antioxidants may be added as an additive for preventing oxidation of the agent.

[0090] (pH of the composition) Preferably, the pH of the aqueous composition containing corticosteroid is 4 to 8, preferably 4.5 to 6.

[0091] In certain embodiments, when stored at 25 °C and 40% relative humidity in accordance with the ICH guidelines, the pH of the aqueous composition is stabilized between 4 and 8, preferably between 4.5 and 6, for longer than 6 months, preferably longer than 9 months.

[0092] (Aqueous composition) Preferably, the aqueous composition is an ophthalmically acceptable solvent as described above.

[0093] In particularly preferred embodiments, the aqueous composition is: 1 - 4% dexamethasone, such as 1.5 - 3% dexamethasone; 1 - 35% γ - cyclodextrin, such as 5 - 25% γ - cyclodextrin; 2.2 - 2.8% or 2.8 - 3.2% polymer, such as 2.5% or 3.0% polymer, typically poloxamer; 0 - 0.2% stabilizer, such as 0.1% stabilizer, typically sodium edetate; 0.15 - 0.45% additive for preventing oxidation of corticosteroid, such as 0.2 - 0.4% or 0.2 - 0.3% additive for preventing oxidation of corticosteroid, typically, for example, a water - soluble natural antioxidant, more preferably a phenolic antioxidant or reducing agent such as sodium thiosulfate, L - methionine, or 3,4 - dihydroxybenzoic acid; 0 - 1% electrolyte, such as 0.57% electrolyte, typically sodium chloride; and water; and wherein %, is % by weight based on the volume of the composition.

[0094] An aqueous composition containing a corticosteroid, cyclodextrin, and an additive for preventing oxidation of the corticosteroid can be stored in a plastic vial, typically an LDPE vial, or a glass vial.

[0095] (Preferred aqueous composition containing dexamethasone) In certain embodiments, the aqueous composition is; 1 - 4% dexamethasone, for example 1.5 - 3% dexamethasone; 1 - 35% γ - cyclodextrin, for example 5 - 25% γ - cyclodextrin; 0 - 0.2% stabilizer, for example 0.1% stabilizer, typically sodium edetate; 0 - 1% electrolyte, for example 0.57% electrolyte, typically sodium chloride; and water; and contains or consists essentially of these, wherein % is weight % based on the volume of the composition.

[0096] In certain embodiments, an aqueous composition for use as described herein is 1 - 4% dexamethasone, for example 1.5 - 3% dexamethasone; 1 - 35% γ - cyclodextrin, for example 5 - 25% γ - cyclodextrin; Optionally, 2.2 - 2.8% polymer or 2.8% - 3.2% polymer, for example 2.5% polymer or 3.0% polymer, typically poloxamer; 0 - 0.2% stabilizer, for example 0.1% stabilizer, typically sodium edetate; 0% - 0.8% additive for preventing oxidation of dexamethasone, for example 0.1% - 0.5%, or 0.2% - 0.4%, an additive for preventing oxidation of corticosteroid, typically, for example, a water - soluble natural antioxidant, more preferably a phenolic antioxidant or reducing agent such as sodium thiosulfate, L - methionine, or 3,4 - dihydroxybenzoic acid; 0 - 1% electrolyte, for example 0.57% electrolyte, typically sodium chloride; and water; comprising or consisting essentially of these, wherein % is % by weight based on the volume of the composition.

[0097] More specifically, a particularly preferred embodiment is an eye drop preparation, Dexamethasone 1.5%; γ-Cyclodextrin 14%; Poloxamer 2.5%; Stabilizer 0 - 0.2%, for example sodium edetate 0.1%; Electrolyte 0 - 1%, for example sodium chloride 0.57%; Additive for preventing oxidation of dexamethasone 0% - 0.6%, for example 0.2% - 0.4%, additive for preventing oxidation of corticosteroids, typically, for example, water-soluble natural antioxidants, more preferably phenolic antioxidants or reducing agents such as sodium thiosulfate, L-methionine, or 3,4-dihydroxybenzoic acid; and Water; comprising or consisting essentially of these, wherein % is % by weight based on the volume of the composition.

[0098] Typically, the eye drop preparation has the following components: Dexamethasone 1.5%; γ-Cyclodextrin 14%; Poloxamer 2.5%; Sodium edetate 0.1%; Sodium chloride 0.57%; and Sodium thiosulfate 0.2 - 0.4%; Water.

[0099] Another specific embodiment is an eye drop preparation, Dexamethasone 3%; γ-Cyclodextrin 1 - 35%, for example γ-cyclodextrin 20 - 25%; Optionally, polymer 2.8 - 3.2%, for example polymer 3.0%, typically poloxamer; Stabilizer 0 - 0.2%, for example, stabilizer 0.1%, typically sodium edetate; Additive for preventing oxidation of dexamethasone 0% - 0.6%, for example 0.1% - 0.5%, or 0.2% - 0.4%, additive for preventing oxidation of corticosteroids, typically, for example, water-soluble natural antioxidants, more preferably sodium thiosulfate, L-methionine, or phenolic antioxidants or reducing agents such as 3,4-dihydroxybenzoic acid; Electrolyte 0 - 1%, for example electrolyte 0.57%, typically sodium chloride; and Water; comprising or consisting essentially of these, wherein % is weight % based on the volume of the composition.

[0100] Another specific embodiment is an eye drop formulation, Dexamethasone 3%; γ-Cyclodextrin 20 - 25%; Optionally, poloxamer 2.8 - 3.2%; for example 3.0% poloxamer; Stabilizer 0 - 0.2%, for example sodium edetate 0.1%; Electrolyte 0 - 1%, for example sodium chloride 0.57%; Additive for preventing oxidation of dexamethasone 0% - 0.6%, for example 0.1% - 0.5%, or 0.2% - 0.4%, additive for preventing oxidation of corticosteroids, typically, for example, water-soluble natural antioxidants, more preferably sodium thiosulfate, L-methionine, or phenolic antioxidants or reducing agents such as 3,4-dihydroxybenzoic acid,; and Water; comprising or consisting essentially of these, wherein % is weight % based on the volume of the composition.

[0101] Typically, the eye drop formulation has the following components: Dexamethasone 3%; γ-Cyclodextrin 20 - 25%, for example γ-cyclodextrin 23%; Poloxamer 2.8 - 3.2%; 0.1% disodium edetate; 0.57% sodium chloride, and 0.2 - 0.4% sodium thiosulfate, typically 0.3% sodium thiosulfate, water.

[0102] All of the above formulations or aqueous compositions advantageously do not contain preservatives.

[0103] The final formulation for use as an eye drop is a micro - suspension containing a complex aggregate of dexamethasone and γ - cyclodextrin. Typically, 60 - 95% by weight, more specifically 70 - 90% by weight of dexamethasone in the composition may be in the form of a solid complex of dexamethasone and γ - cyclodextrin.

[0104] A method for preparing such a formulation includes the following steps: a) Mix dexamethasone with other excipients in an ophthalmologically acceptable solvent and heat (e.g., at 80°C - 110°C for at least 60 minutes) until dexamethasone is substantially dissolved in the ophthalmologically acceptable solvent; b) Suspend gamma - cyclodextrin in an ophthalmologically acceptable solvent to form a suspension and heat the suspension until cyclodextrin is substantially dissolved in the ophthalmologically acceptable solvent; c) Mix the compositions of steps a) and b) at a temperature T1 below 120°C and heat the mixture at a temperature T1 below 120°C for a time t; and d) Cool the resulting solution to a temperature T2 to obtain an aqueous composition containing a solid complex of dexamethasone and cyclodextrin (preferably gamma - cyclodextrin).

[0105] In the above manufacturing method, dexamethasone may be suspended in an ophthalmically acceptable solvent that does not contain cyclodextrin, and may optionally be suspended together with other excipients. The resulting suspension can have a milky white appearance. Independently of this, gamma-cyclodextrin can be suspended in an ophthalmically acceptable solvent that does not contain an active pharmaceutical ingredient. The resulting suspension can have a milky white appearance. The two suspensions can be heated or sterilized, for example, by heating in an autoclave at 121 °C for 20 minutes. Next, the two suspensions or hot solutions can be mixed together and the mixture can be heated until a complex of dexamethasone and gamma-cyclodextrin is formed. The resulting solution can be cooled at a rate sufficient to produce a micro-suspension containing the solid active pharmaceutical ingredient / gamma-cyclodextrin complex.

[0106] A detailed method for manufacturing the micro-suspension is also described in WO2018100434.

[0107] The micro-suspension as described above is stable and can be used as an eye drop formulation.

[0108] In certain embodiments, the aqueous composition containing 1.5% (w / v) is an ophthalmic micro-suspension that does not contain a preservative. They may be provided in unit dosages of a fill volume of 0.5 ml and may be provided, for example, in an LDPE plastic material. The resulting suspension can be stored at an ambient temperature of less than 25 °C and can be stored for at least 2, 3, 6, 12, 18 or 24 months.

[0109] (Use of an aqueous composition containing a corticosteroid) The aqueous composition of the present disclosure can be used for the treatment of eye conditions, particularly anterior segment eye conditions or posterior segment eye conditions, particularly uveitis, macular edema, macular degeneration, retinal detachment, eye tumors, fungal or viral infections, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal dissemination, and vascular occlusion. The aqueous composition of the present disclosure can be particularly useful for treating uveitis, macular edema, diabetic retinopathy, proliferative vitreoretinopathy (PVR), and vascular occlusion.

[0110] The aqueous composition containing dexamethasone according to the present disclosure can be used particularly for the treatment of macular edema. In this case, the aqueous composition containing dexamethasone according to the present disclosure can be topically administered to the eye three times a day in an amount of one drop of the composition. The amount of dexamethasone in the composition can be 1 to 5% by weight, particularly 1.5 to 3% by weight, based on the volume of the composition.

[0111] The composition of the present disclosure containing dexamethasone does not need to be administered as frequently as known topical dexamethasone compositions, i.e., it is not necessary to administer one drop of the composition six times a day. In fact, due to the viscosity of the composition, the solid complex of the composition of the present disclosure exhibits a higher contact time on the eye surface compared to known compositions that increase the bioavailability of the drug.

[0112] The present disclosure also encompasses the use of the aqueous composition of the present disclosure as an eye drop solution.

[0113] In one embodiment, the aqueous composition containing dexamethasone according to the present disclosure can be used particularly for the treatment of eye inflammations such as central retinal vein occlusion disease, or inflammation after cataract surgery, glaucoma, anterior chamber inflammation, central macular edema, etc.

[0114] The present disclosure also relates to the use of the aqueous composition of the present disclosure for the preparation of a pharmaceutical agent for the treatment of an eye condition, particularly an anterior eye condition or a posterior eye condition. The aqueous composition of the present disclosure may be particularly effective for the manufacture of a pharmaceutical agent for the treatment of central retinal vein occlusion disease, or inflammation after cataract surgery, glaucoma, anterior chamber inflammation, and eye inflammation such as central macular edema.

[0115] The present disclosure also relates to a method for treating an eye condition, particularly an anterior eye condition or a posterior eye condition. This method includes administering to a subject in need thereof, preferably a human, a therapeutically effective amount of the aqueous solution of the present disclosure.

[0116] As used herein, the term "treat" includes reversing, alleviating, inhibiting, or preventing the progression of, or reducing the likelihood of, a disease, disorder, or condition to which such term applies, or one or more symptoms or manifestations of such disease, disorder, or condition. Prevention refers to not causing a disease, disorder, condition, or such symptom or manifestation, or not causing an exacerbation of such severity. Thus, the compounds of the present disclosure can be administered prophylactically to prevent or reduce the occurrence or recurrence of a disease, disorder, or disorder.

[0117] As used herein, the term "therapeutically effective amount" refers to the amount of an agent that elicits a biological or medical response in a subject. For example, it refers to the amount of an agent that improves symptoms, alleviates a condition, slows or delays the progression of a disease, or prevents a disease.

[0118] (Preferred use of ophthalmic preparations with dexamethasone) The ophthalmic preparation of the aqueous composition as described above and dexamethasone preferably diabetic macular edema; inflammation after ophthalmic surgery (typically after cataract surgery); Cystoid macular edema after ophthalmic surgery; Acute anterior uveitis; Dry eye disease and blepharitis; Other acute or chronic ocular inflammatory diseases such as graft-versus-host disease (GVHD), vernal catarrh, pterygium, chalazion, allergic conjunctivitis, etc.; After corneal transplantation to control inflammation and prevent rejection; or, Treatment of non-infectious uveitis affecting the posterior segment of the eye It is used for the treatment or prevention of.

[0119] Specific embodiments of such use are described in more detail in the following section.

[0120] (Method for treating diabetic macular edema) The ophthalmic preparation of the present disclosure has been tested in clinical trials in patients suffering from such disorders, and the results are shown in the examples. In particular, efficacy has been shown in the treatment of diabetic macular edema with an ophthalmic preparation of 1.5% (w / v) dexamethasone.

[0121] More specifically, the present specification provides a method for treating diabetic macular edema in a subject in need thereof. The method includes topically administering to the affected eye of the subject. In the method, an ophthalmic preparation containing a therapeutically effective amount of 1.5% (w / v) dexamethasone (typically one of the above preferred preparations) is preferably dosed 1, 2, 3, 4, 5, or 6 drops per day, for a period of, for example, at least 6, 7, 8, 9, 10, 11, or 12 weeks.

[0122] In a preferred embodiment of the method, the ophthalmic preparation for use in the above method is Dexamethasone 1.5%; γ-Cyclodextrin 14%; Poloxamer 2.5%; Stabilizer 0 - 0.2%, for example 0.1% sodium edetate; Electrolyte 0 - 1%, for example 0.57% sodium chloride; Additives for preventing the oxidation of dexamethasone, 0% to 0.6%, for example additives for preventing the oxidation of corticosteroids, 0.1% to 0.5%, or 0.2% to 0.4%, typically sodium thiosulfate; and Water; comprises or consists essentially of these, where % is weight % based on the volume of the composition.

[0123] In a preferred embodiment of the method, the ophthalmic preparation for use in the above method is 3% of dexamethasone; 20 - 25% of γ-cyclodextrin, for example 23% of γ-cyclodextrin; 2.5% of poloxamer; Stabilizer 0 - 0.2%, for example 0.1% of disodium edetate; Electrolyte 0 - 1%, for example 0.57% of sodium chloride; Additives for preventing the oxidation of dexamethasone, 0% to 0.6%, for example additives for preventing the oxidation of corticosteroids, 0.1% to 0.5%, or 0.2% to 0.4%, typically sodium thiosulfate; and Water; comprises or consists essentially of these, where % is weight % based on the volume of the composition.

[0124] Typically, the central macular thickness (CMT) evaluated by SD - OCT can be significantly reduced in patients suffering from DME after 12 weeks of such treatment as described above. For example, for CMT exceeding 10% measured from baseline, the CMT is determined as described in the following examples.

[0125] In addition, the pinhole visual acuity can be improved by at least 3 ETDRS letters from baseline in patients suffering from DME after 12 weeks of the above treatment. The pinhole visual acuity can be determined as described in the following examples.

[0126] This treatment is particularly effective in patients who have no response or an inadequate response to VEGF inhibitor treatment (VEGF-naïve patients) and / or do not support invasive treatment for diabetic macular edema.

[0127] Thus, in certain embodiments of the above method of treating diabetic macular edema, the patient is selected from among VEGF-naïve patients who have increased retinal thickening in the eye affected by diabetic macular edema.

[0128] Typically, the patient is a human patient, more specifically an adult human patient.

[0129] (Method for treating inflammation after ophthalmic surgery) Efficacy has been shown against inflammation and / or pain after ophthalmic surgery, particularly when an ophthalmic preparation of 1.5% (w / v) dexamethasone is administered after cataract surgery (postoperative cataract).

[0130] Accordingly, provided herein is a method for treating inflammation after ophthalmic surgery, particularly after cataract surgery (postoperative cataract) in a subject in need of surgery. The method includes topically administering to the affected eye of the subject. The ophthalmic preparation in a therapeutically effective amount includes 1.5% or 3% (w / v) dexamethasone (typically the preferred preparation described above), preferably administered 1 or 2 drops per day, for example, for a period of at least 1 to 6 weeks.

[0131] In a preferred embodiment of the method, the ophthalmic preparation for use in the above method is Dexamethasone 1.5%; γ-Cyclodextrin 14%; Poloxamer 2.5%; Stabilizer 0 to 0.2%, for example sodium edetate 0.1%; Electrolyte 0 to 1%, for example sodium chloride 0.57%; Additives for preventing the oxidation of dexamethasone, 0% to 0.6%, for example, additives for preventing the oxidation of corticosteroids, 0.1% to 0.5%, or 0.2% to 0.4%, typically sodium thiosulfate; and Water; comprises, or consists essentially of these, wherein % is weight % based on the volume of the composition.

[0132] Typically, in patients suffering from pain and inflammation after ophthalmic surgery, the pain and inflammation of the eye can be significantly reduced or eliminated after 15 days of the above treatment. For example, after cataract surgery, the pain can be determined by numerical pain evaluation as described in the following examples. Inflammation can be determined by the number of cells and flare of the anterior chamber cells as described in the following examples.

[0133] Typically, the patient is a human patient, more specifically an adult human patient.

[0134] (Use of an additive for preventing the oxidation of corticosteroids) The present disclosure also relates to the use of the above additive for preventing the oxidation of corticosteroids to stabilize the pH of an aqueous composition containing corticosteroids. 〔Example〕 <Example 1: Formulation of an aqueous dexamethasone eye drop> An aqueous dexamethasone eye drop having the composition according to Table 1 was prepared.

[0135]

Table 1

[0136] The eye drop was prepared as follows: Part A: Disodium edetate, poloxamer 407 and sodium chloride were dissolved in pure water at 80°C. Dexamethasone was added to the excipient mixture immediately before sterilization.

[0137] Part B: γ-Cyclodextrin was separately suspended in pure water at 80 °C.

[0138] Parts A and B were sterilized at 121 °C for 15 minutes. After sterilization, Part B was added to Part A at 95 °C. After stirring for 15 minutes, the solution was rapidly cooled to room temperature (for 20 minutes or more) to form a turbid suspension solution.

[0139] Next, the suspension was filled into glass vials or low-density polyethylene (LDPE) vials and sealed.

[0140] The pH of the eye drops in the glass vials and LDPE vials was measured during storage at 25 °C. The results are shown in Table 2.

[0141] [Table 2]

[0142] These results indicate that when the eye drops are stored in LDPE vials, the pH decreases over time, while in glass vials, the pH remains stable.

[0143] <Example 2: Formulation of an aqueous dexamethasone eye drop containing sodium thiosulfate (STS)> Eye drops containing different percentages of sodium thiosulfate were prepared. The composition of the eye drops is shown in Table 3. Sodium thiosulfate was added to the aqueous eye drop formulation described in Table 1 (Example 2A), or during the preparation of the aqueous eye drop formulation (Example 2B). In this case, the eye drops were prepared according to the protocol described in Example 1, and sodium thiosulfate was added to Part A together with disodium edetate, poloxamer 407, and sodium chloride.

[0144] [Table 3] Eye drops containing 0.3% sodium thiosulfate (corresponding to 0.471 g of sodium thiosulfate pentahydrate), as well as different percentages of dexamethasone and γ-cyclodextrin were also prepared. The compositions of the eye drops are shown in Tables 4 and 5. Sodium thiosulfate was added during the preparation of the aqueous eye drop formulation: the eye drops were prepared according to the protocol described in Example 1, and sodium thiosulfate was added to Part A together with disodium edetate, poloxamer 407, and sodium chloride.

[0145] [Table 4]

[0146] [Table 5]

[0147] <Example 3: Stability Test of Aqueous Dexamethasone Eye Drops Containing STS> (1. Stress Test by Oxygen and Heat) The pH of the eye drop formulation containing STS was measured after the stress test by oxygen and heat. The eye drops of Examples 2A and 2B were transferred to 10 mL glass vials, where they were purged with nitrogen or oxygen, or stored in air. All vials were placed in an autoclave and subjected to 0 to 4 heating cycles (each heating cycle: 20 minutes at 121 °C). The pH was measured for all vials after each cycle, and the results are shown in Table 6 (Example 2A) and Table 7 (Example 2B).

[0148] [Table 6]

[0149] [Table 7]

[0150] These results indicate that the addition of STS, an antioxidant, prevents the pH of the ophthalmic preparation from decreasing. Therefore, the ophthalmic preparation is more stable.

[0151] (Measured pH values over 2.12 months) The pH of the ophthalmic preparation containing 0.3% STS (Example 2B), filled in LDPE vials and placed in a sealed aluminum pouch containing air or oxygen, was also measured for 12 months at temperatures and humidities controlled according to the ICH guidelines (25°C / 40% RH and 40°C / NMT 25% RH). The results are shown in Table 8.

[0152]

Table 8

[0153] These tests indicate that the addition of STS, an antioxidant, prevents the pH of the ophthalmic preparation from decreasing. Therefore, the ophthalmic preparation is stable for at least 6 months.

[0154] (Example 4: Formulation of an aqueous dexamethasone ophthalmic solution containing a phenolic antioxidant) 0.02% butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) was added to the aqueous ophthalmic preparation described in Table 1.

[0155] After dissolving 0.005 g of BHA in 10 μL of ethanol, it was added to the preparation until a concentration of 0.02% (w / v) was reached. After dissolving 0.005 g of BHT in 50 μL of ethanol, it was added to the preparation to make it 0.02% (w / v).

[0156] The ophthalmic solution was transferred to 10 mL glass vials and purged with either nitrogen or oxygen there, or stored in the atmosphere. All vials were placed in an autoclave and operated with 0 - 3 heating cycles (each heating cycle: 121°C, 20 minutes). The pH of all vials after each cycle was measured, and the results are shown in Table 9.

[0157]

Table 9

[0158] These results indicate that the addition of phenolic antioxidants prevents the pH drop of the ophthalmic preparation, thus making the ophthalmic preparation more stable.

[0159] <Example 5: Clinical trial using the ophthalmic preparation of the present disclosure (containing 1.5% w / v dexamethasone)> Abbreviations AC: Anterior chamber AE: Adverse event ANCOVA: Analysis of covariance BCVA: Best corrected visual acuity BID: Twice a day (from Latin "bis in die") CMT: Central macular thickness ETDRS: Early Treatment Diabetic Retinopathy Study HbA1c: Glycated hemoglobin IOP: Intraocular pressure LogMAR: Logarithm of the minimum angle of resolution QD: Once a day (from Latin "quaque die") SD-OCT: Spectral domain optical coherence tomography TEAEs: Treatment-emergent adverse events USP: United States Pharmacopeia <Grading and measurement scales and methods> (Anterior chamber cells and flare) The number of cells in the anterior chamber is recorded as the actual number of cells observed when ≤ 10 cells are seen (only white blood cells should be counted; red blood cells and pigment cells should not be counted). (Jabs, D. A., R. B. Nussenblatt, J. T. Rosenbaum and G. Standardization of Uveitis Nomenclature Working (2005). “Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop.” Am J Ophthalmol 140(3): 509-516)

[0160]

Table 10

[0161] (Eye pain) Eye pain is evaluated by the patient using a numerical pain rating scale ranked from 0 to 10 (McCaffery, M. and A. Beebe (1994). “Pain: clinical manual for nursing practice.” Nurs Stand 9(11): 55).

[0162] The examiner asks the patient the following question: “On a scale of 0 to 10 (0 being no pain and 10 being the worst or intolerable pain), please enter the number that best represents the pain or discomfort you are feeling in the * eye that was operated on this time. The middle of the scale (about 5) can be used to describe'moderate pain'. Only integer scores are permitted.” <Clinical Trial 1: Use of an Aqueous Pharmaceutical Preparation of Dexamethasone (1.5% w / v) in the Treatment of Diabetic Macular Edema> This was a prospective, multi - center, randomized, double - blind, parallel - group, vehicle - suspension controlled trial. 144 eligible subjects were randomly assigned at a ratio of 2:1. Subjects in one group were instilled with an ophthalmic micro - suspension containing 1.5% (w / v) dexamethasone, one drop once, three times a day (every 8 hours) for 12 weeks (99 cases). Subjects in the other group were instilled with vehicle eye drops three times a day (every 8 hours) for 12 weeks (45 cases). The primary efficacy endpoint was the mean change at 12 weeks compared to baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) best - corrected visual acuity (BCVA). The secondary endpoints included the mean changes at 2, 4, 8, 12, and 16 weeks compared to baseline in the central macular thickness (CMT) evaluated by spectral - domain optical coherence tomography (SD - OCT). The safety endpoints included adverse events (AEs), safety laboratory tests, slit - lamp microscopic parameters indicating ocular toxicity to the investigational drug, intraocular pressure, and dilated indirect ophthalmoscopy.

[0163] <Results of Efficacy> (Best - corrected visual acuity) The mean change from baseline in the ETDRS BCVA letter score at 12 weeks was higher in the investigational drug - administered group using the eye - drop formulation of the present disclosure than in the vehicle group, 2.9 (70% confidence interval: 2.13, 3.65) vs. 1.7 (70% confidence interval: 0.66, 2.72). The results of the ANCOVA proved the alternative hypothesis and confirmed the superiority of the eye - drop formulation containing dexamethasone described in the present disclosure over the vehicle eye drops at an α of 0.15.

[0164] (Central macular thickness) In the test group using the eye - drop formulation of the present disclosure, a greater decrease in the mean CMT from baseline was observed up to 12 weeks compared to the vehicle group.

[0165] From the second week to the twelfth week, a statistically highly significant difference in the LS mean from the baseline of the study was observed in the reduction of CMT in the tested eyes, with the test group being better; LS mean difference at the twelfth week: -36.77 (70% CI: -53.58, -19.95), p-value = 0.01.

[0166] Also, from the results of the covariance analysis of the baseline corrected using the multiple imputation method, the superiority of the eyedrop formulation over the vehicle group was shown for the improvement of CMT at the twelfth week (α was 0.15).

[0167] (Results of safety) AEs that occurred during treatment were reported at a higher rate in the subjects in the group instilled with dexamethasone ophthalmic micro-suspension than in the subjects in the vehicle group (70 subjects [70.0%] developed 134 TEAE, while 24 subjects [53.3%] developed 50 TEAE).

[0168] Serious TEAE were reported at a higher rate in the subjects in the dexamethasone ophthalmic micro-suspension group than in the subjects in the vehicle group (11 subjects [11.1%] developed 14 serious TEAE, while 1 subject [2.2%] developed 1 serious TEAE). These serious TEAE in both treatment groups were not related to the investigational drug.

[0169] (Trial 2: Use of an aqueous pharmaceutical formulation (1.5% w / v) of dexamethasone in the treatment of pain and inflammation after cataract surgery) This study was a multi-center study, a randomized study, a double-blind study, and a placebo (vehicle) controlled study. This study was designed to evaluate the efficacy and safety of the eyedrop formulation disclosed in this disclosure (1.5% w / v dexamethasone) compared to placebo in the treatment of inflammation and pain after cataract surgery.

[0170] Subjects were randomly assigned in a 1:1:1 ratio and instilled with ophthalmic formulations of dexamethasone QD (once daily) and placebo QD, BID (twice daily), or placebo BID. Subjects were administered 1 drop to the tested eye BID starting from the first postoperative day of the operated eye for 14 days. The hierarchical primary efficacy measures were: 1) no anterior chamber cells were observed at the 6th visit (day 15) (i.e., a score of "0"), and 2) no pain was observed at the 4th visit (day 4) (i.e., a score of "0"). Safety measures included changes from baseline in pinhole VA measured with an ETDRS chart (no other correction), changes from baseline in IOP, and the adverse event (AE) rate.

[0171] (Results of efficacy) At the 6th visit (day 15), the number of anterior chamber cell defects was significantly higher in QD (26 subjects [51.0%] with AC cell defects, p = 0.0009) and BID (34 subjects [66.7%] with AC cell defects, p < 0.0001) compared to placebo (10 subjects [19.6%] with absent AC cells). At the 4th visit, the number of subjects without observed pain was significantly higher in QD (37 subjects [72.5%], p = 0.0049) and BID (32 subjects [62.7%], p = 0.0738) compared to placebo (23 subjects [45.1%]).

[0172] Overall, the primary efficacy endpoint was reached, and the results showed that both QD and BID administrations were significantly superior to placebo in reducing the number of subjects with anterior chamber cells and the number of subjects with pain after cataract surgery.

[0173] (Results of safety) Overall, the proportion of TEAEs including ocular TEAEs was higher in the placebo group compared to both test groups. The results showed that the ophthalmic formulations containing dexamethasone were safe and well-tolerated.

[0174] <Example 6: Screening study for the use of alternative antioxidants> For the purpose of this study, a set of test formulations containing different amounts of antioxidants were prepared. The test formulations were prepared by adding specific antioxidants as listed in Table XX to the formulation as described in Table 1 of Example 1.

[0175] The concentration of the antioxidant was fixed as equimolar to 0.3% w / v sodium thiosulfate.

[0176] The prepared test formulations were adjusted to pH 5 (4.9 - 5.1) and autoclaved twice with ambient air (without oxygen insertion). After the second cycle of autoclaving, the pH of the samples was measured. Information on the antioxidants used, their concentrations, and the results of the pH measurements are shown in Table 11.

[0177]

Table 11

[0178] The antioxidants considered can be divided into several groups based on their effectiveness in stabilizing the formulation (see Table 12).

[0179]

Table 12

[0180] The antioxidants in Group A, Group B, and Group C showed a positive effect on the pH stability of the formulation, while the representative of Group D was ineffective.

[0181] <Discussion of Test Results> To facilitate the interpretation of the results obtained, the stress conditions of the described tests should be converted to the conditions of the current ongoing long - term stability program for ophthalmic formulations. For this purpose, the value of the pH decrease of the stock formulation stored in a glass container from the time of the test was compared with the pH decrease profile of the clinical batch stored at 25℃ in an LDPE plastic container without antioxidant (STS).

[0182] The inventors have found that the results of different heat stress tests reveal alternative antioxidants that can be used to inhibit the pH decrease of the OCS-01 formulation during long-term storage.

[0183] Antioxidants such as L-methionine, 3,4-dihydroxybenzoic acid, sodium citrate, DL-malic acid, sodium (+)-L-ascorbate, DL-tartaric acid, α-monothioglycerol, lauryl gallate, lactic acid, and tert-butylhydroquinone can stabilize the formulation during a storage period of at least one year at 25°C.

[0184] Covitol® 1100 EU, butylated hydroxyanisole, butylated hydroxytoluene, and sodium thiosulfate can function as suitable antioxidants for the formulation in storage up to two years at 25°C.

[0185] The maximum storage time for which the antioxidants mentioned above remain effective has not been studied and can exceed the storage times concluded above.

[0186] In conclusion, among the antioxidants screened, sodium thiosulfate was the best antioxidant for stabilizing the pH of the 1.5% dexamethasone ophthalmic suspension.

[0187] Additional antioxidants exhibit a stabilization profile for dexamethasone 1.5% ophthalmic suspension. These may be less effective than STS at stabilizing the pH, but may achieve two-year stability when stored at 25 °C in plastic / LDPE containers. These antioxidants include L-methionine, 3,4-dihydroxybenzoic acid, sodium citrate, DL-malic acid, sodium (+)-L-ascorbate, DL-tartaric acid, α-monothioglycerol, lauryl gallate, lactic acid, and tert-butylhydroquinone, Covitol® 1100 EU (d-α-tocopheryl acetate), butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

Claims

1. A method for stabilizing the pH of an aqueous composition comprising dexamethasone and gamma-cyclodextrin, comprising: The method includes adding an additive that prevents oxidation of dexamethasone; the additive that prevents oxidation is selected from the group consisting of 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; The aqueous composition is stored in a plastic vial. method.

2. The additive that prevents oxidation is selected from the group consisting of methionine, 3,4-dihydroxybenzoic acid, sodium citrate, malic acid, sodium ascorbate, tartaric acid, α-monothioglycerol, and butylated hydroxyanisole. The method of claim 1.

3. The additive that prevents oxidation is methionine or 3,4-dihydroxybenzoic acid. The method of claim 1.

4. The additive that prevents oxidation of dexamethasone is added to the aqueous composition at a concentration of at least 0.05% (w / v), preferably 0.05% (w / v) to 1% (w / v), more preferably 0.1 to 0.5%, and even more preferably 0.2% (w / v) to 0.4% (w / v). The method of claim 1.

5. The aqueous composition containing dexamethasone has a pH of 4 to 6, preferably 4.5 to 6, for more than 6 months. The method of claim 1.

6. An aqueous composition comprising dexamethasone, gamma-cyclodextrin, and an additive that prevents oxidation of dexamethasone, the additive is selected from the group consisting of 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; The aqueous composition is stored in a plastic vial. Aqueous composition.

7. The additive that prevents oxidation is selected from the group consisting of methionine, 3,4-dihydroxybenzoic acid, sodium citrate, malic acid, sodium ascorbate, tartaric acid, α-monothioglycerol, and butylated hydroxyanisole. The aqueous composition of claim 6.

8. The additive that prevents oxidation is methionine or 3,4-dihydroxybenzoic acid. The aqueous composition of claim 6.

9. The additive that prevents oxidation is present at a concentration of at least 0.05% (w / v), preferably 0.05% (w / v) to 1% (w / v), more preferably 0.1 to 0.5%, and even more preferably 0.2% (w / v) to 0.4% (w / v). The aqueous composition of claim 6.

10. The pH of the aqueous composition is maintained at 4 to 6, preferably 4.5 to 6, for more than 6 months. The aqueous composition of claim 6.

11. A microsuspension comprising 80% to 95% dexamethasone in microparticles having a diameter of 1 μm to 10 μm. The aqueous composition of claim 6.

12. - Dexamethasone 1-4%; 1-35% gamma-cyclodextrin; optionally 2.2-2.8% polymer, for example 2.5% or 3.0% polymer, typically a poloxamer; stabilizers 0-0.2%, e.g., edetate disodium 0.1%; - Electrolytes 0-1%, e.g. sodium chloride 0.57%; an additive to prevent oxidation of dexamethasone at a concentration not exceeding 0.6%, e.g., an additive to prevent oxidation of a corticosteroid at a concentration of 0.1% to 0.5%, or 0.2% to 0.4%; and water; where % is weight % based on the volume of the composition. The aqueous composition of claim 6.

13. The method of claim 12, wherein the dexamethasone is present at a concentration of 1.5% (w / v), and / or the gamma-cyclodextrin is present at a concentration of 10 to 25% (w / v). The aqueous composition of claim 6.

14. - Dexamethasone 1.5%; γ-cyclodextrin 14%; Poloxamer 2.5%; edetate disodium 0.1%; sodium chloride 0.57%; an additive to prevent oxidation of dexamethasone at a concentration not exceeding 0.6%, e.g., an additive to prevent oxidation of a corticosteroid at a concentration of 0.1% to 0.5%, or 0.2% to 0.4%; and water; where % is weight % based on the volume of the composition. The aqueous composition of claim 6.

15. A composition for use in the treatment of an ophthalmic condition, particularly an anterior or posterior ophthalmic condition, comprising: The aqueous composition of claim 6.

16. A compound for use in the treatment of central retinal vein occlusion disease or ocular inflammation, The aqueous composition of claim 6.

17. Diabetic macular edema; or for use in the treatment of inflammation following ophthalmic surgery, typically following cataract surgery; The aqueous composition of claim 6.

18. A method for stabilizing the pH of an aqueous composition comprising dexamethasone and gamma-cyclodextrin over time using an additive that prevents oxidation of dexamethasone, comprising: the additive that prevents oxidation of dexamethasone is selected from the group consisting of 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; The aqueous composition is stored in a plastic vial. method.