Topical formulations containing cyclosporin and uses thereof

Abstract

Provided herein are topical ophthalmic formulations containing 0.087 to 0.093% by weight of cyclosporin, as well as methods of making and using such formulations. In certain aspects and embodiments, the formulations may include polyoxyethylene lipids or fatty acids and / or polyalkoxylated alcohols, and may include nanomicelles. Also included herein are methods of treating or preventing a disease or condition, such as an ocular disease or condition.

Description

Technical Field

[0001] The present disclosure relates to the field of cyclosporin-containing formulations for topical administration thereof, such as ophthalmic formulations containing 0.087-0.093% cyclosporin, and methods of making and using such formulations. Background Art

[0002] The information provided and references cited herein are provided solely to aid the reader's understanding and do not constitute an admission that any reference or information is prior art to the present invention.

[0003] US Patent Application Nos. US2010 / 0310462 and US2009 / 0092665 disclose drug delivery systems for ophthalmic applications having nanomicelles including Vitamin E TPGS.

[0004] Travoprost is an ophthalmic solution preparation for reducing elevated intraocular pressure in patients with glaucoma or ocular hypertension. It contains 0.5% HCO-40, 0.004% of the prostaglandin analog travoprost as an active ingredient, and propylene glycol as an organic solvent (on the World Wide Web, nlm.nih.gov / dailymed / lookup.cfm?setid=338e7ff4-0d91-4208-a45d-bfa2be52334d). However, the composition is not in the form of nanomicelles (on the World Wide Web, ema.europa.eu / docs / en_GB / document_library / EPAR_-_Product_Information / hu man / 000665 / WC500038389.pdf).

[0005] US Patent No. 8,980,839 discloses an aqueous ophthalmic solution comprising cyclosporin, a polyoxyethylene lipid or fatty acid and a polyalkoxylated alcohol. The patent considers HCO-40 as the polyoxyethylene lipid and octoxynol-40 as the polyalkoxylated alcohol.

[0006] In use (0.05% cyclosporine ophthalmic emulsion) The most common adverse effect after was burning of the patient's eyes reported in 17% of cases. Other adverse reactions included conjunctival hyperemia, epiphora, eye pain, discharge, foreign body sensation, itching, stinging, and visual disturbances (in 1-5% of patients). Summary of the invention

[0007] The present disclosure relates to topical ophthalmic formulations comprising 0.087-0.093 wt % cyclosporin. In certain aspects and embodiments, the formulations comprising 0.087-0.093 wt % cyclosporin as described herein do not produce the same ophthalmic effects as those observed in other ophthalmic formulations such as Side effects such as decreased visual acuity, blurred vision, increased tearing, ocular discharge, and taste disturbance reported in LIFIGRAST® (lifitegrast ophthalmic solution) provide a better safety profile.

[0008] The formulations of the present disclosure are based, at least in part, on the surprising and unexpected discovery that formulations comprising 0.087-0.093 wt % cyclosporin can have greater efficacy and can be unexpectedly stable, e.g., in large-scale manufacturing. Features and advantages of the formulations of the present disclosure that were not anticipated prior to the present disclosure include improved handling thereof after industrial-scale preparation, i.e., the various aspects and embodiments of the formulations of the present disclosure remain sufficiently fluid in transport vehicles and thus resist a tendency to precipitate after handling thereof.

[0009] In certain embodiments, formulations of the present disclosure are surprisingly stable at elevated temperatures (eg, temperatures above about 40°C).

[0010] In certain aspects and embodiments, the formulations of the present disclosure further comprise polyoxyethylene lipids or fatty acids, and / or polyalkoxylated alcohols, and may comprise nanomicelles.

[0011] Nanomicelles contemplated by the present disclosure typically have a particle size in the range of about 1-100 nm; in certain embodiments, the particle size falls within the range of about 5-50 nm; in certain embodiments, the particle size falls within the range of about 10-40 nm; in certain embodiments, the particle size is about 15 nm.

[0012] In one aspect, the topical ophthalmic formulations of the present disclosure comprise 0.087-0.093% by weight cyclosporin and one or more additional formulation ingredients.

[0013] In one embodiment of the above aspects, the formulations contemplated herein are stable at temperatures above 40°C.

[0014] In another embodiment of the above aspects, the formulation of the present disclosure is a clear aqueous solution.

[0015] In another embodiment of the above aspects, the formulation of the present disclosure is substantially free of organic solvents.

[0016] In another embodiment of the above aspects, the formulation of the present disclosure does not contain a preservative.

[0017] In another embodiment of the above aspects, the formulation of the present disclosure comprises one or more additional formulation ingredients.

[0018] In another embodiment of the above aspects, the formulation of the present disclosure is a mixed nanomicelle formulation.

[0019] In another embodiment of the above aspects, the formulation of the present disclosure comprises cyclosporine encapsulated in the core of mixed nanomicelles.

[0020] In another embodiment of the above aspect, the nanomicelles have a particle size of about 5-100 nm.

[0021] In another embodiment of the above aspects, the formulation of the present disclosure comprises one or more additional ingredients.

[0022] In another embodiment of the above aspect, the additional ingredient is selected from polyoxyethylene lipids or fatty acids and polyalkoxylated alcohols.

[0023] In another embodiment of the above aspect, the polyoxyethylene lipid is polyoxyethylene castor oil.

[0024] In another embodiment of the above aspect, the polyoxyethylene lipid is selected from HCO-40, HCO-60, HCO-80 and HCO-100.

[0025] In another embodiment of the above aspect, the polyoxyethylene lipid or fatty acid is present in an amount of about 0.1-5% by weight of the formulation.

[0026] In another embodiment of the above aspect, the polyalkoxylated alcohol is octoxynol 40.

[0027] In another embodiment of the above aspect, the polyalkoxylated alcohol is present in an amount of about 0.002-4% by weight of the formulation.

[0028] In another embodiment of the above aspects, the formulation of the present disclosure comprises additional formulation ingredients further selected from additives, adjuvants, buffers, tonicity agents, bioadhesive polymers and preservatives.

[0029] In another embodiment of the above aspect, the buffer is selected from the group consisting of phosphates, borates, acetates, citrates, carbonates, and borate-polyol complexes.

[0030] In another embodiment of the above aspect, the tonicity agent is selected from mannitol, sodium chloride, sodium nitrate, sodium sulfate, dextrose, xylitol, or a combination thereof.

[0031] In another embodiment of the above aspect, the bioadhesive polymer is selected from carbopol, carbophils, cellulose derivatives, gums such as xanthan gum, karaya gum, guar gum, tragacanth gum, agarose and other polymers such as povidone, polyethylene glycol, poloxamer, hyaluronic acid or combinations thereof.

[0032] In another embodiment of the above aspects, the bioadhesive polymer is povidone.

[0033] In certain aspects and embodiments, the formulations of the present disclosure comprise additional active agents.

[0034] In one embodiment of the above aspects, the other active ingredient is selected from a resolvin, a resolvin-like compound, a steroid, an antibiotic, an antiviral agent, a hormone, a cytokine, a toxin, a vitamin, or a combination thereof.

[0035] In certain aspects and embodiments, the formulations of the present disclosure comprise 0.087-0.093 wt % cyclosporin, wherein the formulation demonstrates a clinically significant improvement in tear production compared to vehicle, with an increase of ≥ 10 mm from baseline in the Schimer test score.

[0036] In one embodiment of the above aspects, the formulation of the present disclosure exhibits an early onset compared to other formulations of cyclosporin A.

[0037] In certain aspects and embodiments, the formulations of the present disclosure comprise:

[0038] 0.087-0.093 wt% cyclosporine,

[0039] about 0.1-6 weight percent hydrogenated 40 polyoxyethylene castor oil, and

[0040] About 0.002-4 wt. % octoxynol-40.

[0041] In certain aspects and embodiments, the formulations of the present disclosure comprise:

[0042] 0.087-0.093 wt% cyclosporine,

[0043] about 1.0 weight percent hydrogenated 40 polyoxyethylene castor oil, and

[0044] About 0.05 wt.% Octoxynol-40 (Igepal).

[0045] In certain aspects and embodiments, the formulations of the present disclosure further comprise:

[0046] about 0.20-0.405% by weight sodium dihydrogen phosphate,

[0047] about 0.23-0.465 wt.% disodium hydrogen phosphate,

[0048] about 0.05% by weight sodium chloride,

[0049] About 0.3 wt% Povidone K90,

[0050] Sodium hydroxide / hydrochloric acid and

[0051] Water for injection.

[0052] As used herein in connection with numerical values, the terms "about" and "approximately" mean ±10% of the specified value, inclusive of the specified value.

[0053] In certain aspects, formulations contemplated herein comprise 0.088-0.093% cyclosporin by weight.

[0054] In certain aspects, the formulations contemplated herein comprise 0.089-0.093% by weight cyclosporin. In certain embodiments of such aspects, the formulations of the present disclosure comprise:

[0055] 0.089-0.093 wt% cyclosporine,

[0056] about 1.0 weight percent hydrogenated 40 polyoxyethylene castor oil, and

[0057] About 0.05 wt.% Octoxynol-40 (Igepal).

[0058] In certain aspects and embodiments, the formulations of the present disclosure further comprise:

[0059] About 0.20% by weight of sodium dihydrogen phosphate,

[0060] About 0.23% by weight of disodium hydrogen phosphate,

[0061] about 0.05% by weight sodium chloride,

[0062] About 0.3 wt% Povidone K90,

[0063] Sodium hydroxide / hydrochloric acid and

[0064] Water for injection.

[0065] In certain embodiments of such aspects, the formulations of the present disclosure comprise:

[0066] 0.09-0.093 wt% cyclosporin,

[0067] about 1.0 weight percent hydrogenated 40 polyoxyethylene castor oil, and

[0068] About 0.05 wt.% Octoxynol-40 (Igepal).

[0069] In certain aspects and embodiments, the formulations of the present disclosure further comprise:

[0070] About 0.405% by weight sodium dihydrogen phosphate,

[0071] About 0.465% by weight of disodium hydrogen phosphate,

[0072] about 0.05% by weight sodium chloride,

[0073] About 0.3 wt% Povidone K90,

[0074] Sodium hydroxide / hydrochloric acid and

[0075] Water for injection.

[0076] In certain aspects, formulations contemplated herein comprise 0.091-0.093% cyclosporin by weight.

[0077] In certain aspects, formulations contemplated herein comprise 0.092-0.093% cyclosporin by weight.

[0078] In certain aspects, formulations contemplated herein comprise 0.087-0.092% cyclosporin by weight.

[0079] In certain aspects, formulations contemplated herein comprise 0.087-0.091 wt % cyclosporin.

[0080] In certain aspects, the formulations contemplated herein comprise 0.087-0.09% by weight cyclosporin. In certain embodiments of such aspects, the formulations of the present disclosure comprise:

[0081] 0.087-0.09 wt% cyclosporin,

[0082] about 1.0 weight percent hydrogenated 40 polyoxyethylene castor oil, and

[0083] About 0.05 wt.% Octoxynol-40 (Igepal).

[0084] In certain aspects and embodiments, the formulations of the present disclosure further comprise:

[0085] About 0.20% by weight of sodium dihydrogen phosphate,

[0086] About 0.23% by weight of disodium hydrogen phosphate,

[0087] about 0.05% by weight sodium chloride,

[0088] About 0.3 wt% Povidone K90,

[0089] Sodium hydroxide / hydrochloric acid and

[0090] Water for injection.

[0091] In certain embodiments of such aspects, the formulations of the present disclosure comprise:

[0092] 0.087-0.089 wt% cyclosporine,

[0093] about 1.0 weight percent hydrogenated 40 polyoxyethylene castor oil, and

[0094] About 0.05 wt.% Octoxynol-40 (Igepal).

[0095] In certain aspects and embodiments, the formulations of the present disclosure further comprise:

[0096] About 0.405% by weight sodium dihydrogen phosphate,

[0097] About 0.465% by weight of disodium hydrogen phosphate,

[0098] about 0.05% by weight sodium chloride,

[0099] About 0.3 wt% Povidone K90,

[0100] Sodium hydroxide / hydrochloric acid and

[0101] Water for injection.

[0102] In certain aspects, formulations contemplated herein comprise 0.087% cyclosporin by weight.

[0103] In certain aspects, formulations contemplated herein comprise 0.088% cyclosporin by weight.

[0104] In certain aspects, formulations contemplated herein comprise 0.089% cyclosporin by weight.

[0105] In certain aspects, formulations contemplated herein comprise 0.09% cyclosporin by weight.

[0106] In certain aspects, formulations contemplated herein comprise 0.091% by weight cyclosporin.

[0107] In certain aspects, formulations contemplated herein comprise 0.092% cyclosporin by weight.

[0108] In certain aspects, formulations contemplated herein comprise 0.093% by weight cyclosporin.

[0109] In certain aspects and embodiments, the formulations as described herein are particularly suitable for anterior ocular delivery, or posterior ocular delivery, or both anterior and posterior ocular delivery.

[0110] In certain aspects and embodiments, the formulations of the present disclosure consist essentially of the following components:

[0111] 0.087-0.093 wt% cyclosporine,

[0112] about 1.0 weight percent hydrogenated 40 polyoxyethylene castor oil, and

[0113] about 0.05 wt. % octoxynol-40 (Igepal), and

[0114] Optionally further consists essentially of the following components:

[0115] about 0.20-0.405% by weight sodium dihydrogen phosphate,

[0116] about 0.23-0.465 wt.% disodium hydrogen phosphate,

[0117] about 0.05% by weight sodium chloride,

[0118] About 0.3 wt% Povidone K90,

[0119] NaOH / HCl, and

[0120] Water for injection.

[0121] In certain embodiments, the formulation comprises nanomicelles having a relatively increased capture efficiency; in such embodiments, the cyclosporin may be at least about 0.087%, or at least about 0.088%, or at least about 0.089%, or at least about 0.09%, or at least about 0.091%; or at least about 0.092%; or at least about 0.093%; or no more than 0.087%; or between 0.087 and 0.093%; or between 0.088 and 0.093%; or between 0.089 and 0.093%; or about 0.087%, or about 0.088%, or about 0.089%; or about 0.09%; or about 0.091%; or about 0.092%; or about 0.093% of the formulation and is present in the nanomicelles of the formulation.

[0122] Therefore, in one aspect, an ophthalmic preparation is provided, comprising 0.087-0.093 wt % cyclosporin, a polyoxyethylene lipid or fatty acid, and a polyalkoxylated alcohol. In certain embodiments, the preparation comprises nanomicelles. In certain embodiments, the polyoxyethylene lipid or fatty acid is polyoxyethylene castor oil. In certain embodiments, the polyoxyethylene lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80, or HCO-100. In certain embodiments, the polyoxyethylene lipid or fatty acid (such as polyoxyethylene castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) is present at 0.5 to 5%, or 0.6 to 5%, or 0.7 to 5%, or 0.8 to 5%, or 0.9 to 5%, or 1 to 5%, or 1 to 4%, or 1 to 3%, or 1 to 2%, or about 1%, or greater than 0.5%, or greater than 0.6%, or greater than 0.7%, or greater than 0.8%, or greater than 0.9%, or greater than 1% by weight of the formulation. In certain embodiments, the polyoxyethylene lipid is HCO-60. In certain embodiments, the polyoxyethylene lipid is HCO-80. In certain embodiments, the polyoxyethylene lipid is HCO-100. In certain embodiments, the formulation includes a polyalkoxylated alcohol that is octoxynol-40. In certain embodiments, the formulation includes a polyalkoxylated alcohol (such as octoxynol-40) present at between 0.01 and 1%, or between 0.02 and 1%, or between 0.03 and 1%, or between 0.04 and 1%, or between 0.05 and 1%, or between 0.06 and 1%, or between 0.07 and 1%, or between 0.08 and 1%, or about 1%, by weight of the formulation.

[0123] As used herein, the term "polyoxyethylene lipid or fatty acid" represents the monoester and diester of lipid or fatty acid and polyoxyethylene glycol. As fully understood in the art, according to the average polymer length (for example, 40, 60, 80, 100) of oxyethylene units, polyoxyethylene lipid or fatty acid can be numbered (" n "). The term "n ≥ 40 polyoxyethylene lipids" refers to that polyoxyethylene lipid or fatty acid has an average oxyethylene polymer length equal to or greater than 40 units. Stearate hydrogenated castor oil and castor oil are commercially available common lipids / fatty acids as polyoxyethylene lipid or fatty acid, but it should be understood that any lipid or fatty acid can be polyoxyethyleneized to become the polyoxyethylene lipid or fatty acid considered in this article. The example of polyoxyethylene lipid or fatty acid includes, but is not limited to HCO-40, HCO-60, HCO-80, HCO-100, polyoxyethylene 40 stearates, polyoxyethylene 35 castor oils.

[0124] In certain embodiments of any of the compositions and methods described herein, the average polymer length of the oxyethylene units of the polyoxyethylene lipid or fatty acid is longer for relatively larger active ingredients and shorter for relatively smaller active ingredients; for example, in certain embodiments in which the active ingredient is a resolvin or a resolvin-like compound, the polyoxyethylene lipid is HCO-60, and in certain embodiments in which the active ingredient is cyclosporine A (which is larger than resolvin), the polyoxyethylene lipid is HCO-80 or HCO-100.

[0125] As used herein, the term "micelle" or "nano-micelle" refers to an aggregate (or cluster) of surfactant molecules. Micelles are formed only when the concentration of the surfactant is greater than the critical micelle concentration (CMC). Surfactants are amphipathic chemical substances, which means that they contain hydrophobic groups and hydrophilic groups. Micelles can exist in different shapes, including spherical, cylindrical and disc-shaped. Micelles containing at least two different molecular species are mixed micelles. In certain embodiments, the ophthalmic compositions of the present disclosure include aqueous, clear, mixed micellar solutions.

[0126] In another aspect, an ophthalmic preparation is provided, comprising 0.087-0.093 wt % cyclosporin and n≥40 polyoxyethylene lipids or fatty acids. In certain embodiments, the preparation comprises nanomicelles. In certain embodiments, the polyoxyethylene lipids or fatty acids are polyoxyethylene castor oil. In certain embodiments, the polyoxyethylene lipids or fatty acids are selected from one or more of HCO-40, HCO-60, HCO-80 or HCO-100. In certain embodiments, the polyoxyethylene lipid or fatty acid (such as polyoxyethylene castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) is present at between 0.1 and 2%, or between 0.2 and 2%, or between 0.3 and 2%, or between 0.4 and 2%, or between 0.5 and 2%, or between 0.6 and 2%, or between 0.7 and 2%, or between 0.8 and 2%, or between 0.9 and 2%, or between 1 and 2%, or between 0.1 and 6%, or about 4%, or greater than 0.4%, or greater than 1%, or greater than 1.5%, or greater than 2%, or greater than 3%, or greater than 4% by weight of the formulation. In certain embodiments, the polyoxyethylene lipid is HCO-60. In certain embodiments, the polyoxyethylene lipid is HCO-80. In certain embodiments, the polyoxyethylene lipid is HCO-100. In certain embodiments, the formulation further comprises a polyalkoxylated alcohol. In certain embodiments, the formulation further comprises a polyalkoxylated alcohol that is octoxynol-40. In certain embodiments, the formulation comprises a polyalkoxylated alcohol (such as octoxynol-40) present at between 0.002 and 4%, or between 0.005 and 3%, or between 0.005 and 2%, or between 0.005 and 1%, or between 0.005 and 0.5%, or between 0.005 and 0.1%, or between 0.005 and 0.05%, or between 0.008 and 0.02%, or between 0.01 and 0.1%, or between 0.02 and 0.08%, or between 0.005 and 0.08%, or about 0.05%, or about 0.01%, by weight of the formulation.

[0127] In another aspect, an ophthalmic preparation is provided, comprising 0.087-0.093% by weight cyclosporin and a polyoxyethylene lipid or fatty acid; wherein the polyoxyethylene lipid or fatty acid is present in an amount equal to or greater than 1% of the preparation. In a similar aspect, an ophthalmic preparation is provided, comprising 0.087-0.093% by weight cyclosporin and a polyoxyethylene lipid or fatty acid; wherein the polyoxyethylene lipid or fatty acid is present in an amount equal to or greater than 0.05% of the preparation. In certain embodiments, the preparation comprises nanomicelles. In certain embodiments, the polyoxyethylene lipid or fatty acid is polyoxyethylene castor oil. In certain embodiments, the polyoxyethylene lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-100. In certain embodiments, the polyoxyethylene lipid or fatty acid (such as polyoxyethylene castor oil such as HCO-60, HCO-80 or HCO-100) is present at 0.5 to 2% by weight of the formulation, or 0.7 to 2%, or 1 to 6%, or 2 to 6%, or 2 to 6%, or 3 to 6%, or 4 to 6%, or 2 to 5%, or 3 to 5%, or 3 to 5%, or 2 to 6%, or about 4%, or greater than 1.5%, or greater than 2%, or greater than 3%, or greater than 4%. In certain embodiments, the polyoxyethylene lipid is HCO-40. In certain embodiments, the polyoxyethylene lipid is HCO-60. In certain embodiments, the polyoxyethylene lipid is HCO-80. In certain embodiments, the polyoxyethylene lipid is HCO-100. In certain embodiments, the formulation further comprises a polyalkoxylated alcohol. In certain embodiments, the formulation further comprises a polyalkoxylated alcohol that is octoxynol-40. In certain embodiments, the formulation comprises a polyalkoxylated alcohol such as octoxynol-40 present at between 0.002 and 4%, or between 0.005 and 3%, or between 0.005 and 2%, or between 0.005 and 1%, or between 0.005 and 0.5%, or between 0.005 and 0.1%, or between 0.005 and 0.05%, or between 0.008 and 0.02%, or between 0.01 and 0.1%, or between 0.02 and 0.08%, or between 0.005 and 0.08%, or about 0.05%, or about 0.01%, by weight of the formulation.

[0128] In another aspect, an ophthalmic preparation is provided, comprising 0.087-0.093 wt % cyclosporin and a polyoxyethylene lipid or fatty acid; wherein the preparation comprises nanomicelles. In certain embodiments, the polyoxyethylene lipid or fatty acid is polyoxyethylene castor oil. In certain embodiments, the polyoxyethylene lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-100. In certain embodiments, the polyoxyethylene lipid or fatty acid (such as polyoxyethylene castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) is present at between 0.5 and 2% by weight of the formulation, or between 0.7 and 2%, or between 1 and 6%, or between 2 and 6%, or between 2 and 6%, or between 3 and 6%, or between 4 and 6%, or between 2 and 5%, or between 3 and 5%, or between 3 and 5%, or between 2 and 6%, or about 4%, or greater than 0.7%, or greater than 1%, or greater than 1.5%, or greater than 2%, or greater than 3%, or greater than 4%. In certain embodiments, the polyoxyethylene lipid is HCO-40. In certain embodiments, the polyoxyethylene lipid is HCO-60. In certain embodiments, the polyoxyethylene lipid is HCO-80. In certain embodiments, the polyoxyethylene lipid is HCO-100. In certain embodiments, the formulation further comprises a polyalkoxylated alcohol. In certain embodiments, the formulation further comprises a polyalkoxylated alcohol that is octoxynol-40. In certain embodiments, the formulation comprises a polyalkoxylated alcohol (such as octoxynol-40) present at between 0.002 and 4%, or between 0.005 and 3%, or between 0.005 and 2%, or between 0.005 and 1%, or between 0.005 and 0.5%, or between 0.005 and 0.1%, or between 0.005 and 0.05%, or between 0.008 and 0.02%, or between 0.01 and 0.1%, or between 0.02 and 0.08%, or between 0.005 and 0.08%, or about 0.05%, or about 0.01%, by weight of the formulation.

[0129] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093 wt % cyclosporin, 1-5% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.05% octoxynol-40.

[0130] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093 wt % cyclosporin, 1-5% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.05% octoxynol-40.

[0131] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093 wt % cyclosporin, 1-5% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.05% octoxynol-40.

[0132] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093 wt % cyclosporin, 1-5% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.05% octoxynol-40.

[0133] In another aspect, an ophthalmic formulation is provided comprising 0.087-0.093 wt % cyclosporine, about 4 % HCO-60, and about 0.01-0.05 % octoxynol-40.

[0134] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093 wt % cyclosporine, 0.7-1.5% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05-0.1% octoxynol-40.

[0135] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093 wt % cyclosporine, 0.7-1.5% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05-0.1% octoxynol-40.

[0136] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093 wt % cyclosporine, 0.7-1.5% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05-0.1% octoxynol-40.

[0137] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093 wt % cyclosporine, 0.7-1.5% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05-0.1% octoxynol-40.

[0138] In another aspect, an ophthalmic formulation is provided comprising 0.087-0.093 wt % cyclosporine, about 1 % HCO-60, and about 0.05-0.1 % octoxynol-40.

[0139] In various embodiments of any of the aspects and embodiments described herein, the formulation comprises nanomicelles.

[0140] In certain embodiments of aspects and embodiments described herein, the preparation includes polyoxyethylene lipid or fatty acid. In certain embodiments, the polyoxyethylene lipid or fatty acid is polyoxyethylene castor oil. In certain embodiments, the polyoxyethylene lipid or fatty acid is selected from one or more of HCO-40, HCO-60, HCO-80 or HCO-100. In certain embodiments, the polyoxyethylene lipid or fatty acid (such as polyoxyethylene castor oil such as HCO-60, HCO-80 or HCO-100) is present in 0.5 to 2% of the preparation weight, or between 0.7 to 2%, or between 1 to 6%, or between 2 to 6%, or between 2 to 6%, or between 3 to 6%, or between 4 to 6%, or between 2 to 5%, or between 3 to 5%, or between 3 to 5%, or between 2 to 6%, or about 4%, or greater than 0.7%, or greater than 1%, or greater than 1.5%, or greater than 2%, or greater than 3%, or greater than 4%. In certain embodiments, the polyoxyethylene lipid is HCO-40. In certain embodiments, the polyoxyethylene lipid is HCO-60. In certain embodiments, the polyoxyethylene lipid is HCO-80. In certain embodiments, the polyoxyethylene lipid is HCO-100.

[0141] In certain embodiments of the aspects and embodiments disclosed herein, polyalkoxylated alcohols are included. In certain embodiments, the formulation includes a polyalkoxylated alcohol that is octoxynol-40. In certain embodiments, the formulation includes a polyalkoxylated alcohol (such as octoxynol-40) present at between 0.002 and 4%, or between 0.005 and 3%, or between 0.005 and 2%, or between 0.005 and 1%, or between 0.005 and 0.5%, or between 0.005 and 0.1%, or between 0.005 and 0.05%, or between 0.008 and 0.02%, or between 0.01 and 0.1%, or between 0.02 and 0.08%, or between 0.005 and 0.08%, or about 0.05%, or about 0.01% by weight of the formulation.

[0142] In certain aspects and embodiments, the present disclosure contemplates a stable emulsion comprising:

[0143] 0.087-0.093 wt% cyclosporine,

[0144] about 1.0 weight percent hydrogenated 40 polyoxyethylene castor oil, and

[0145] about 0.05 wt. % octoxynol-40 (Igepal), and

[0146] Optionally further comprising:

[0147] 0.20-0.405% by weight sodium dihydrogen phosphate,

[0148] 0.23-0.465 wt% disodium hydrogen phosphate,

[0149] about 0.05% by weight sodium chloride,

[0150] About 0.3 wt% Povidone K90,

[0151] Sodium hydroxide / hydrochloric acid, and

[0152] Water for injection.

[0153] In certain aspects, the present disclosure contemplates a method of preparing a topical ophthalmic formulation of cyclosporine, the method comprising the steps of:

[0154] (1) Melt the required amount of polyoxyethylene lipid,

[0155] (2) slowly adding cyclosporine to step (1) and substantially homogenizing the mixture,

[0156] (3) adding the polyalkoxylated alcohol to step (2) and continuing stirring until a uniform homogeneous solution is obtained,

[0157] (4) adding the buffer system and tonicity agent to the solution obtained from step (3) and continuing stirring to achieve good dissolution,

[0158] (5) adding the required amount of bioadhesive polymer to the solution of the above step,

[0159] (6) if necessary, adjust the pH of the solution and make up to the final volume with water for injection; and

[0160] (7) The solution is sterile filtered and filled into unit dose vials.

[0161] In certain aspects, the present disclosure contemplates a melt-based process for preparing a cyclosporine-containing formulation, including the formulations described above, comprising:

[0162] Melted hydrogenated 40 polyoxyethylene castor oil,

[0163] slowly adding cyclosporin thereto, and thereafter substantially mixing the ingredients,

[0164] Octoxynol-40 (Igepal) was added to the resulting homogenous mixture and stirred until substantially homogenous, and thereafter

[0165] This mixture is added to water for injection, and then the excipients (eg, sodium dihydrogen phosphate, sodium hydrogen phosphate, and sodium chloride) are added individually with stirring sufficient to achieve good dissolution of each.

[0166] An exemplary melt-based preparation method contemplated for use herein includes the following steps:

[0167] Step 1: Melt the required amount of HCO-40 in a flask while heating to about 60°C with stirring. When liquefied, add the required amount of cyclosporine and mix until dissolved. Then add the octoxynol-40 and mix the entire solution until homogeneous.

[0168] Step 2: Charge the required amount of water for injection into a stainless steel container and stir until the temperature is 25°C.

[0169] Step 3: Transfer the contents from Step 1 to the stainless steel container and stir until dissolved.

[0170] Step 4: Add the required amount of sodium chloride and phosphate buffer to the stainless steel container and mix the contents until dissolved.

[0171] Step 5: Add the required amount of povidone to the container and stir until dissolved.

[0172] Step 6: Measure the pH of the solution in Step 5, adjust (if necessary), and bring to final volume with water for injection.

[0173] Step 7: The solution from Step 6 was sterile filtered and aseptically filled into blow / fill / seal (BFS) unit dose vials with a nominal fill volume of 0.3 mL.

[0174] Step 8: Package the vials in strips of four (4) BFS units in heat-sealed foil bags.

[0175] In certain aspects, the present disclosure contemplates a method of preparing an ophthalmic topical formulation of cyclosporine, the method comprising the steps of:

[0176] (1) dissolving the required amount of cyclosporin, polyalkoxylated alcohol and polyoxyethylene lipid in a suitable solvent,

[0177] (2) the solution obtained in step (1) is placed in a round-bottom flask of suitable size,

[0178] (3) removing the solvent by rotary evaporation until a thin film is obtained,

[0179] (4) Add the required amount of water for injection to the flask containing the membrane of step (3) and mix;

[0180] (5) adding a buffer system and a tonicity agent to the solution of step (4);

[0181] (6) adding the required amount of bioadhesive polymer to the solution of the above step,

[0182] (7) if necessary, adjust the pH of the solution and make up to the final volume with water for injection; and

[0183] (8) The solution is sterile filtered and filled into unit dose vials.

[0184] An exemplary solvent-based preparation method contemplated for use herein comprises the following steps:

[0185] (1) dissolving the required amount of cyclosporine, octoxynol-40 and hydrogenated 40 polyoxyethylene castor oil in a suitable solvent,

[0186] (2) the solution obtained in step (1) is placed in a round-bottom flask of suitable size,

[0187] (3) removing the solvent by rotary evaporation until a thin film is obtained,

[0188] (4) Add the required amount of water for injection to the flask containing the membrane of step (3) and mix;

[0189] (5) adding phosphate buffer and sodium chloride to the solution of step (4);

[0190] (6) Add the required amount of povidone to the solution of the above step,

[0191] (7) if necessary, adjust the pH of the solution and make up to the final volume with water for injection; and

[0192] (8) The solution is sterile filtered and filled into unit dose vials.

[0193] The present disclosure further relates to treating or preventing ocular diseases or disorders, for example, by topical administration of a formulation as described herein.

[0194] The patient or subject to be treated by any of the compositions or methods of the present disclosure may refer to a human or non-human animal. In one embodiment, the present disclosure provides a method for treating an eye disease in a human patient in need thereof. In one embodiment, the present disclosure provides a method for treating an inflammatory eye disease in a human patient in need thereof. In another embodiment, the present disclosure provides a method for treating an eye disease in a veterinary patient in need thereof, including, but not limited to, dogs, horses, cats, rabbits, gerbils, hamsters, rodents, avian species, aquatic mammals, cattle, pigs, camelids, and other zoological animals.

[0195] In certain embodiments of the compositions and methods disclosed herein, the cyclosporin further comprises one or more additional active ingredients, for example, an active agent selected from resolvin or resolvin-like compounds, steroids (such as corticosteroids), etc. In certain embodiments, the additional active agent includes resolvin. In certain embodiments, the additional active agent includes corticosteroids. In certain embodiments, the additional active agent includes resolvin and corticosteroids. In certain embodiments, the additional active agent includes antibiotics, for example, one or more selected from azithromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin and levofloxacin. In certain embodiments, the additional active agent includes antibiotics, for example, one or more selected from azithromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin and levofloxacin antibiotics; and the second of such agents is a resolvin such as described herein (including but not limited to compound 1001). In certain embodiments, the active agent includes two or more active agents, and one of the active agents is an antiviral agent, such as one or more selected from ganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir and cidofovir. In certain embodiments, the active agent includes two or more active agents, and one of the active agents is an antibiotic, such as one or more selected from ganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir and cidofovir antiviral agents; and the second of the active agents is a resolvogen such as described herein (including but not limited to compound 1001).

[0196] The term "treat," ...

[0197] As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to an untreated control sample.

[0198] As used herein, the terms "ocular disease," "ocular disorder," "eye disease," and "ocular disorder" refer to diseases / disorders of the eye that can threaten vision, cause eye discomfort, and may signal systemic health problems.

[0199] As used herein, the term "anterior segment disease" refers to all disorders that affect the ocular surface, anterior chamber, iris and ciliary body and lens of the eye. The ocular surface consists of the cornea, conjunctiva, eyelids, lacrimal and meibomian glands, and interconnecting nerves.

[0200] As used herein, the terms "posterior segment ocular disease" and "posterior ocular disease" refer to all disorders that affect the posterior segment of the eye. Posterior ocular disease is a disease that primarily affects the posterior ocular parts, such as the choroid or sclera, vitreous body, vitreous cavity, retina, optic nerve and blood vessels, and nerves that vascularize or innervate the posterior ocular parts.

[0201] Thus, in another aspect, a method of treating or preventing an eye disease or condition is provided, comprising topically administering a formulation of any aspect or embodiment as disclosed herein. In certain embodiments, the eye disease is an anterior segment disease. In certain embodiments, the eye disease is a posterior segment disease. In certain embodiments, the ocular disease is selected from one or more of the following: dry eye syndrome, Sjögren's syndrome, uveitis, anterior uveitis (iritis), chorioretinitis, posterior uveitis, conjunctivitis, allergic conjunctivitis, keratitis, keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis, systemic immune-mediated diseases such as cicatricial conjunctivitis and other autoimmune disorders of the surface of the eye, blepharitis, scleritis, age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), ocular neovascularization, age-related macular degeneration (ARMD), proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV) retinitis, optic neuritis, retrobulbar neuritis and macular pucker. In one embodiment, the ocular disease is dry eye. In one embodiment, the ocular disease is allergic conjunctivitis. In one embodiment, the ocular disease is age-related macular degeneration (AMD). In one embodiment, the ocular disease is diabetic retinopathy. BRIEF DESCRIPTION OF THE DRAWINGS

[0202] Figure 1 The results of Schirmer tests using vehicle, formulations containing 0.05 wt % cyclosporin, and 0.09 wt % cyclosporin are summarized. DETAILED DESCRIPTION

[0203] Active Agent

[0204] According to various aspects and embodiments of the methods and compositions provided herein, when present in addition to cyclosporin, the active agent can be any agent capable of affecting a biological process. Active agents other than cyclosporin (the term active ingredient is used interchangeably with the term active agent herein) include drugs, hormones, cytokines, toxins, therapeutic agents, vitamins, and the like. In certain embodiments, the active agent according to the aspects and embodiments disclosed herein is an agent capable of or approved for use in treating or preventing a disease or condition, for example, in certain embodiments, the active agent is capable of or approved for use in treating or preventing an eye disease or condition.

[0205] In certain embodiments, the active agent other than cyclosporin is an antibiotic, such as one or more selected from azithromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin and levofloxacin. In certain embodiments, the active agent is an antiviral agent, such as one or more selected from ganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir and cidofovir.

[0206] In certain embodiments of any of the aspects and embodiments disclosed herein, the active agent is cyclosporin A, an analog thereof, or a pharmaceutically acceptable salt thereof.

[0207] Cyclosporins (originally extracted from the soil fungus Potypaciadium infilatum) have a cyclic 11-amino acid structure and include, for example, cyclosporins A to I, such as cyclosporins A, B, C, D and G. Cyclosporins bind to the cytosolic protein cyclophilin of immunocompetent lymphocytes (particularly T-lymphocytes), forming a complex. The complex inhibits calcineurin, which normally induces transcription of interleukin-2 (IL-2). Cyclosporins also inhibit lymphokine production and interleukin release, resulting in reduced effector T-cell function.

[0208] Eye diseases

[0209] In various aspects and embodiments, the formulations disclosed herein can be used to treat or prevent ocular diseases or disorders. Ocular diseases and disorders contemplated herein include anterior segment diseases and posterior segment diseases. Exemplary ocular diseases that can be treated with the formulations disclosed herein in certain embodiments include the following.

[0210] Dry eye syndrome (DES, chronic dry eyes, keratitis sicca; dry eye disease; keratoconjunctivitis sicca) can be defined as a condition that includes multiple disorders that result in the loss or altered composition of the natural tear film that remains on the surface of the eye. Without this tear film, vision is impaired and patients may suffer from severe ocular discomfort. DES can be caused by excessive tear evaporation or by a decrease in tear production in the lacrimal glands (the site of tear production). Although the exact cause of the condition is unknown, there is evidence to support an association between reduced tear production and inflammation of one or more components of the lacrimal apparatus. The currently available drugs for DES leave a lot of room for the development of more effective and better tolerated products.

[0211] DES can also be a manifestation of Sjögren's syndrome, an autoimmune disorder in which the glands that produce tears and saliva are destroyed. This results in dry mouth, decreased tear production, and other dry mucous membranes.

[0212] Non-infectious uveitis is a chronic inflammatory, presumed Th1 / Th17-mediated autoimmune disease associated with a high incidence of visual acuity and may cause blindness. Blindness caused by uveitis does not usually occur from a single inflammatory attack; instead, recurrent attacks of inflammation cause cumulative damage. Inflammatory sequelae leading to visual loss may include one or more of cystoid macular edema, cataracts, vitreous fragments, glaucoma, macular pathology (scarring and atrophy), optic neuropathy, and retinal detachment.

[0213] Anterior uveitis (iritis) occurs in the front of the eye and is the most common form of uveitis. Parplanitis is inflammation of the ciliary ring, which is the narrow area between the iris and the choroid. This condition occurs more often in young men, but is usually unrelated to other diseases. Posterior uveitis (chondroitis) mainly affects the choroid; the back of the uvea. If the retina is also involved, it is called chorioretinitis. Posterior uveitis can occur with autoimmune diseases or after systemic infection. In posterior uveitis, inflammation can last for several months to several years and can cause permanent visual impairment, even after treatment.

[0214] Uveitis can cause visual impairment, eye pain, and vision loss. It is estimated that approximately 10% of new cases of blindness in the United States are caused by uveitis. In the United States alone, approximately 300,000 people suffer from uveitis, most of whom are affected by anterior uveitis. The only class of therapeutic agents approved by the FDA for the treatment of uveitis is corticosteroids, which are known for a variety of side effects, such as high blood pressure, hyperglycemia, and hypercholesterolemia, as well as glaucoma and cataract formation in the eye.

[0215] Conjunctivitis (pink eye) describes a group of diseases that cause swelling, itching, burning, and redness of the conjunctiva, the protective membrane that lines the eyelids and covers the exposed areas of the sclera, or white of the eye.

[0216] Keratitis is an inflammation of the cornea (the clear front part of the eye). Keratitis can be caused by infectious agents (bacteria, fungi, viruses, parasites, etc.) or non-infectious agents (for example, certain types of autoimmune diseases are associated with various non-infectious keratitis).

[0217] Keratoconjunctivitis refers to inflammation of the cornea and conjunctiva.

[0218] Vernal keratoconjunctivitis (VKC) is a recurring inflammatory eye disease characterized by hard, raised, boulder-like bumps on the upper eyelid. There may also be swelling and thickening of the conjunctiva. The conjunctiva is the outermost membrane lining the eyelids and exposed parts of the eye, excluding the cornea.

[0219] Atopic keratoconjunctivitis is the result of a condition called atopy. Atopy is a genetic condition whereby the immune system produces a higher than normal antibody response to a given allergen.

[0220] Systemic immune-mediated diseases such as cicatricial conjunctivitis and other autoimmune disorders of the ocular surface represent a variety of clinical conditions in which acute and chronic autoreactive mechanisms can cause significant damage to the eye. When severe and affecting the epithelium and the intrinsic substance of the conjunctiva, scarring can ensue, resulting in significant mechanical changes as a result of fibrosis. Although these conditions are usually uncommon, they can be the cause of complex conditions and visual disabilities.

[0221] Blepharitis is a common condition that causes inflammation of the eyelids.

[0222] Scleritis is a serious inflammatory disease that affects the white outer layer of the eye, called the sclera.

[0223] Age-related macular degeneration (AMD) is a disease associated with aging that gradually destroys clear central vision. AMD affects the macula lutea located in the center of the retina. AMD occurs in two forms: wet and dry. When abnormal blood vessels behind the retina begin to grow under the macula lutea, wet AMD occurs. These new blood vessels are often very fragile and often leak blood and fluid. The blood and fluid raise the macula lutea from its normal position at the back of the eye. Damage to the macula lutea occurs rapidly. When the photosensitive cells in the macula lutea slowly decompose, the central vision of the affected eye is gradually blurred, dry AMD occurs.

[0224] Diabetes can affect the eyes in many ways. Diabetic retinopathy (DR) is a diabetic complication caused by damage to the blood vessels of the light-sensitive tissue at the back of the eye (retina). At first, diabetic retinopathy may cause no symptoms or only minor vision problems. However, eventually, diabetic retinopathy can lead to blindness. Diabetic macular edema (DME) is swelling of the retina in diabetes due to fluid leaking from blood vessels within the macula.

[0225] Ocular neovascularization is the abnormal or excessive formation of blood vessels within the eye. Ocular neovascularization has been demonstrated in diabetic retinopathy and age-related macular degeneration (AMD).

[0226] Proliferative vitreoretinopathy (PVR) is scar tissue formation inside the eye. "Proliferative" because the cells multiply, "vitreoretinopathy" because the problem involves both the vitreous and the retina. In PVR, scar tissue forms in a thin sheet over the shrinking retina. This dramatic shrinkage pulls the retina toward the center of the eye and can severely detach and deform the retina. PVR can occur in the back or front, and folding of the retina can also occur in the front or periphery.

[0227] Cytomegalovirus (CMV) is related to the herpes virus and is present in almost everyone. When a person's immune system is suppressed due to illness (HIV), an organ or bone marrow transplant, or chemotherapy, the CMV virus can cause damage and disease in the eyes and the rest of the body. CMV affects the eye in about 30% of cases by causing damage to the retina. This is called CMV retinitis.

[0228] Optic neuritis occurs when the optic nerve becomes inflamed and the myelin sheath becomes damaged or destroyed. Nerve damage that occurs in the segment of the optic nerve located at the back of the eye is called retrobulbar neuritis, which is another term sometimes used for optic neuritis.

[0229] Epiretinal membrane, also known as macular pucker, is a scar tissue-like membrane that forms over the macula. It usually develops slowly and affects central vision by causing blurriness and distortion. As it develops, the stretching of the membrane over the macula may cause swelling.

[0230] In one embodiment, the composition can be used to prevent transplant rejection of corneal allografts, for example, after transplantation. It is well known that in inflammation, T lymphocytes play a key role in mediating the rejection of foreign tissues. Preventing rejection is extremely important for maintaining the health of the transplanted cornea. Rejection may occur in any layer that constitutes the cornea, such as the corneal epithelium, corneal stroma or corneal endothelium. The function of the cornea may be impaired after endothelial rejection. The endothelial layer plays a role in keeping the cornea compact, thereby acting as a pump by removing water from the corneal stroma. If the function of the endothelial layer is impaired, the directional disorder of the collagen fibers can occur successively, and the transparency of the cornea can be lost. Human endothelial cells are non-replicable, so donor cell loss is irreversible in the case of rejection, and may lead to reduced graft function and survival. Therefore, the goal of preventing or treating rejection in corneal transplant recipients is to minimize the loss of endothelial cells. The composition of the present disclosure can be used to prevent rejection after corneal allograft transplantation.

[0231] Additional ingredients

[0232] The compositions of the present disclosure may also contain other components such as, but not limited to, additives, adjuvants, buffers, tonicity agents, bioadhesive polymers and preservatives. In any composition of the present disclosure for topical application to the eye, the mixture is preferably formulated at about pH 5 to about pH 8. This pH range can be achieved by adding a buffer to the composition, as described in the examples. In one embodiment, the pH range of the composition in the formulation is about pH 6.6 to about pH 7.0. It should be understood that the compositions of the present disclosure may be buffered by any conventional buffer system such as phosphate, borate, acetate, citrate, carbonate and borate-polyol complexes, with pH and osmotic pressure adjusted to suitable physiological values ​​according to well-known techniques. The mixed micellar compositions of the present disclosure are stable in buffered aqueous solutions. That is, there is no adverse interaction between the buffer and any other component that would cause the composition to be unstable.

[0233] Tonicity agents include, for example, mannitol, sodium chloride, sodium nitrate, sodium sulfate, dextrose, xylitol, or a combination thereof. These tonicity agents can be used to adjust the osmotic pressure of the composition. In one aspect, the osmotic pressure of the preparation is adjusted to within the range of about 250 to about 350 mOsmol / kg. In a preferred aspect, the osmotic pressure of the preparation is adjusted to between about 280 to about 300 mOsmol / kg.

[0234] Additives such as sugar, glycerol and other sugar alcohols can be included in the composition of the present disclosure. Pharmaceutical additives can be added to enhance the effectiveness or efficacy of other ingredients in the composition. For example, pharmaceutical additives can be added to the composition of the present disclosure to improve the stability of calcineurin inhibitors, adjust the osmotic pressure of the composition, adjust the viscosity of the composition, or for other reasons such as completing drug delivery. Non-limiting examples of pharmaceutical additives of the present disclosure include sugars, for example, trehalose, mannose, D-galactose and lactose. In one embodiment, the sugar can be incorporated into the composition before the film is hydrated (i.e., internal addition method). In another embodiment, the sugar can be incorporated into the composition in the hydration step (i.e., external addition method). In one embodiment, the aqueous, clear, mixed micellar solution of the present disclosure includes additives such as sugars.

[0235] In one embodiment, the composition of the present disclosure further comprises one or more bioadhesive polymers. Bioadhesion represents the ability of some synthetic and biological macromolecules and hydrocolloids to adhere to biological tissues. Bioadhesion is a complex phenomenon, which depends in part on the properties, biological tissues and surroundings of the polymer. It has been found that several factors can contribute to the bioadhesive ability of the polymer: the presence of the functional groups (-OH, COOH) that can form hydrogen bridges, the presence and intensity of anionic charges, the elasticity of the polymer chain are enough to insert mucosal layers and high molecular weight. Bioadhesive systems have been used in dentistry, orthopedics, ophthalmology and surgical applications. However, recently in other fields such as artificial replacement based on soft tissue and in the controlled release system for local release of bioactive agents, significant interest has occurred in the application of bioadhesive materials. Such applications include systems for releasing drugs in the oral cavity or nasal cavity and systems for intestinal or rectal administration.

[0236] In one embodiment, the composition of the present disclosure includes at least one bioadhesive polymer. The bioadhesive polymer can increase the viscosity of the composition and thereby increase the residence time in the eye. The bioadhesive polymers of the present disclosure include, for example, carboxylic acid polymers such as Carbopol RTM (carbomers), (polycarbophils); cellulose derivatives, including alkyl and hydroxyalkyl celluloses such as methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose; gums, such as locust bean, xanthan gum, agarose, karaya gum, guar gum; and other polymers, including, but not limited to, polyvinyl alcohol, povidone, polyethylene glycol, (Poloxamers), tragacanth and hyaluronic acid; phase change polymers that provide sustained and controlled delivery of encapsulated drugs to the eye (e.g., alginic acid, carrageenan (e.g., Eucheuma), xanthan gum and locust bean gum mixture, pectin, cellulose acetate phthalate, alkyl hydroxyalkyl cellulose and its derivatives, hydroxyalkylated polyacrylic acid and its derivatives, poloxamers and their derivatives, etc. Changes in environmental factors (such as ionic strength, pH or temperature alone or in combination with other factors) can mediate the physical characteristics of these polymers. In one embodiment, the presence of The optional one or more bioadhesive polymers comprise about 0.01 wt % to about 10 wt % / volume, preferably about 0.1 to about 5 wt % / volume. In one embodiment, the composition of the present disclosure further comprises at least one hydrophilic polymer excipient selected from, for example, PVP-K-30, PVP-K-90, HPMC, HEC and polycarbophil. In one embodiment, the polymer excipient is selected from PVP-K-90, PVP-K-30 or HPMC. In one embodiment, the polymer excipient is selected from PVP-K-90 or PVP-K-30.

[0237] In one embodiment, if a preservative is desired, the composition may optionally be preserved with any of a number of well-known preservatives, including benzyl alcohol (with or without EDTA), benzalkonium chloride, chlorhexidine, Cosmocil RTM CQ, or Dowicil RTM 200. In certain embodiments, it may be desirable that the formulations described herein do not include any preservatives. In this regard, in certain embodiments, a preservative may not be necessary or desirable in a formulation contained within a single-use container. In other embodiments, it may be advantageous to include a preservative, such as in certain embodiments in which the formulation is contained within a multiple-use container.

[0238] The ophthalmic composition can be topically administered to the eye as a biocompatible, aqueous, clear mixed micellar solution. The composition has the drug incorporated and / or encapsulated in micelles dispersed in an aqueous medium.

[0239] Non-limiting list of exemplary embodiments

[0240] In addition to the aspects and embodiments described and provided elsewhere in this disclosure, the following non-limiting list of specific embodiments is specifically contemplated.

[0241] 1. An ophthalmic preparation comprising 0.087-0.093 wt% cyclosporin, a polyoxyethylene lipid or fatty acid and a polyalkoxylated alcohol.

[0242] 2. An ophthalmic preparation comprising 0.087-0.093 wt% cyclosporin and n≥40 polyoxyethylene lipids or fatty acids.

[0243] 3. An ophthalmic formulation comprising 0.087-0.093 wt% cyclosporin and a polyoxyethylene lipid or fatty acid; wherein the polyoxyethylene lipid or fatty acid is present in an amount equal to or greater than 0.5% of the formulation.

[0244] 4. An ophthalmic formulation comprising 0.087-0.093 wt% cyclosporin and a polyoxyethylene lipid or fatty acid; wherein the formulation comprises nanomicelles.

[0245] 5. An ophthalmic preparation comprising 0.087-0.093 wt% cyclosporin, 0.5-5% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.1% octoxynol-40.

[0246] 6. An ophthalmic preparation comprising 0.087-0.093 wt% cyclosporin, 0.6-2% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% octoxynol-40.

[0247] 7. An ophthalmic preparation comprising about 0.09% cyclosporine, 0.5-5% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% octoxynol-40.

[0248] 8. An ophthalmic preparation comprising 0.087-0.093 wt% cyclosporin, 0.6-4% of one or more polyoxyethylene lipids selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% octoxynol-40.

[0249] 9. An ophthalmic formulation comprising 0.087-0.093% by weight cyclosporine, 0.7-4% polyoxyethylene lipid or fatty acid; and about 0.02-0.1% octoxynol-40.

[0250] 10. An ophthalmic formulation comprising 0.087-0.093% by weight cyclosporine, 0.8-4% polyoxyethylene lipid or fatty acid; and about 0.02-0.1% octoxynol-40; wherein the formulation comprises nanomicelles.

[0251] 11. An ophthalmic formulation comprising 0.087-0.093% by weight cyclosporine, 0.9-4% polyoxyethylene lipid or fatty acid; and about 0.02-0.1% octoxynol-40; wherein the formulation comprises nanomicelles.

[0252] 12. An ophthalmic preparation comprising 0.087-0.093 wt% cyclosporine, about 1% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% octoxynol-40.

[0253] 13. An ophthalmic formulation comprising 0.087-0.093 wt% cyclosporine, about 1% HCO-60 and about 0.02-0.1% octoxynol-40.

[0254] 14. An ophthalmic preparation comprising 0.087-0.093 wt% cyclosporin, 0.5-4% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05% octoxynol-40.

[0255] 15. An ophthalmic preparation comprising 0.087-0.093 wt% cyclosporine, 0.5-4% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.

[0256] 16. An ophthalmic preparation comprising about 0.09% cyclosporine, 0.5-4% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05% octoxynol-40.

[0257] 17. An ophthalmic preparation comprising 0.087-0.093 wt% cyclosporin, 0.6-2% of one or more polyoxyethylene lipids selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05% octoxynol-40.

[0258] 18. An ophthalmic formulation comprising 0.087-0.093% by weight cyclosporine, 0.6-2% polyoxyethylene lipid or fatty acid; and about 0.05% octoxynol-40.

[0259] 19. An ophthalmic formulation comprising 0.087-0.093% by weight cyclosporine, 0.6-2% polyoxyethylene lipid or fatty acid; and about 0.05% octoxynol-40; wherein the formulation comprises nanomicelles.

[0260] 20. An ophthalmic formulation comprising 0.087-0.093% by weight cyclosporine, 0.6-2% polyoxyethylene lipid or fatty acid; and about 0.05% octoxynol-40; wherein the formulation comprises nanomicelles.

[0261] 21. An ophthalmic formulation comprising 0.087-0.093 wt% cyclosporine, about 1% of one or more selected from HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05% octoxynol-40.

[0262] 22. An ophthalmic formulation comprising 0.087-0.093 wt% cyclosporine, about 1% HCO-60 and about 0.05% octoxynol-40.

[0263] 23. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.6 to 2% by weight of the formulation.

[0264] 24. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.8 to 2% by weight of the formulation.

[0265] 25. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.9 to 1.5% by weight of the formulation.

[0266] 26. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 1 to 1.5% by weight of the formulation.

[0267] 27. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.5 to 5% by weight of the formulation.

[0268] 28. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.6 to 5% by weight of the formulation.

[0269] 29. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.6 to 4% by weight of the formulation.

[0270] 30. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.6 to 3% by weight of the formulation.

[0271] 31. The formulation of any of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.6 to 2% by weight of the formulation.

[0272] 32. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.6 to 1% by weight of the formulation.

[0273] 33. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.8 to 5% by weight of the formulation.

[0274] 34. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.8 to 4% by weight of the formulation.

[0275] 35. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.8 to 3% by weight of the formulation.

[0276] 36. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.8 to 2% by weight of the formulation.

[0277] 37. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.9 to 2% by weight of the formulation.

[0278] 38. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid comprises 0.9 to 1.5% by weight of the formulation.

[0279] 39. The formulation of any of the above embodiments, wherein the polyoxyethylene lipid or fatty acid is about 1% by weight of the formulation.

[0280] 40. The formulation of any of the above embodiments, wherein the polyoxyethylene lipid or fatty acid is greater than about 0.6% by weight of the formulation.

[0281] 41. The formulation of any of the above embodiments, wherein the polyoxyethylene lipid or fatty acid is greater than about 0.7% by weight of the formulation.

[0282] 42. The formulation of any of the above embodiments, wherein the polyoxyethylene lipid or fatty acid is greater than about 0.8% by weight of the formulation.

[0283] 43. The formulation of any of the above embodiments, wherein the polyoxyethylene lipid or fatty acid is greater than about 0.9% by weight of the formulation.

[0284] 44. The formulation of any of the above embodiments, wherein the polyoxyethylene lipid or fatty acid is greater than about 1% by weight of the formulation.

[0285] 45. The formulation of any of the above embodiments, wherein the polyalkoxylated alcohol, if present, comprises from 0.005 to 4% by weight of the formulation.

[0286] 46. ​​The formulation of any of the above embodiments, wherein the polyalkoxylated alcohol, if present, comprises from 0.005 to 3% by weight of the formulation.

[0287] 47. The formulation of any of the above embodiments, wherein the polyalkoxylated alcohol, if present, comprises from 0.005 to 2% by weight of the formulation.

[0288] 48. The formulation of any of the above embodiments, wherein the polyalkoxylated alcohol, if present, comprises from 0.005 to 1% by weight of the formulation.

[0289] 49. The formulation of any of the above embodiments, wherein the polyalkoxylated alcohol, if present, comprises from 0.005 to 0.5% by weight of the formulation.

[0290] 50. The formulation of any of the above embodiments, wherein the polyalkoxylated alcohol, if present, comprises from 0.005 to 0.1% by weight of the formulation.

[0291] 51. The formulation of any of the above embodiments, wherein the polyalkoxylated alcohol, if present, comprises from 0.005 to 0.05% by weight of the formulation.

[0292] 52. The formulation of any of the above embodiments, wherein the polyalkoxylated alcohol, if present, comprises from 0.008 to 0.02% by weight of the formulation.

[0293] 53. The formulation of any of the above embodiments, wherein the polyalkoxylated alcohol, if present, is about 0.05% by weight of the formulation.

[0294] 54. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid is polyoxyethylene castor oil.

[0295] 55. The formulation of any one of the above embodiments, wherein the polyoxyethylene lipid or fatty acid is one or more selected from HCO-60, HCO-80 or HCO-100.

[0296] 56. The formulation of any of the above embodiments, wherein the polyoxyethylene lipid or fatty acid is HCO-60.

[0297] 57. The formulation of any one of the above embodiments, wherein the active agent comprises a combination of two different agents.

[0298] 58. The formulation of any of the above embodiments, wherein the active agent comprises two or more active agents selected from resolvins or resolvin-like compounds, steroids (such as corticosteroids), cyclosporine A and cyclosporine.

[0299] 59. The formulation of any one of the above embodiments, wherein the active agent further comprises a resolvin and a corticosteroid.

[0300] 60. The formulation of any one of the above embodiments, wherein the active agents comprise cyclosporine A and a corticosteroid.

[0301] 61. The formulation of any one of the above embodiments, wherein the active agents comprise resolvins, cyclosporin A, and a corticosteroid.

[0302] 62. The formulation of any one of the above embodiments, wherein the formulation does not include a preservative.

[0303] 63. The formulation of any of the above embodiments, wherein the formulation does not include benzyl alcohol (with or without EDTA), benzalkonium chloride, chlorhexidine, or

[0304] 64. A method of treating or preventing an ocular disease or condition comprising topically administering a formulation according to any one of the above embodiments.

[0305] 65. A method of treating or preventing an ocular disease or condition, the method comprising topically administering a formulation of any one of the above embodiments; wherein the disease is an anterior segment disease.

[0306] 66. A method of treating or preventing an ocular disease or condition, the method comprising topically administering a formulation of any one of the above embodiments; wherein the disease is a posterior segment disease.

[0307] 67. A method of treating or preventing an ocular disease or condition, the method comprising topically administering the formulation of any one of the above embodiments; wherein the disease is one or more selected from the group consisting of dry eye syndrome, Sjögren's syndrome, uveitis, anterior uveitis (iritis), chorioretinitis, posterior uveitis, conjunctivitis, allergic conjunctivitis, keratitis, keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis, systemic immune-mediated diseases such as cicatricial conjunctivitis and other autoimmune disorders of the ocular surface, blepharitis, scleritis, age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), ocular neovascularization, age-related macular degeneration (ARMD), proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV) retinitis, optic neuritis, retrobulbar neuritis, and macular pucker.

[0308] 68. A method of treating or preventing an ocular disease or condition, the method comprising topically administering the formulation of any one of the above embodiments; wherein the disease is dry eye syndrome.

[0309] 69. A method of treating or preventing an ocular disease or condition, the method comprising topically administering the formulation of any one of the above embodiments; wherein the disease is allergic conjunctivitis.

[0310] 70. A method of treating or preventing an ocular disease or condition, the method comprising topically administering the formulation of any one of the above embodiments; wherein the disease is age-related macular degeneration (AMD).

[0311] The following examples are provided to further illustrate aspects of the present invention. These examples are non-limiting and should not be construed as limiting any aspect of the present invention.

[0312] Example 1

[0313] Preparation of cyclosporin-containing formulations of mixed nanomicelles

[0314] The mixed nanomicelle formulation of cyclosporin was prepared as follows:

[0315] Melted hydrogenated 40 polyoxyethylene castor oil,

[0316] slowly adding cyclosporin thereto, and thereafter substantially homogenizing the ingredients,

[0317] Octoxynol-40 was added to the resulting homogenous mixture and stirred until substantially homogenous, and thereafter

[0318] Excipients (eg, sodium dihydrogen phosphate, sodium hydrogen phosphate, and sodium chloride) are added individually with stirring sufficient to achieve good dissolution of each.

[0319] The prepared formulations were subjected to various tests such as entrapment efficiency, loading efficiency, mixed nanomicelle size and polydispersity index.

[0320] Hybrid Nanomicelle Size and Polydispersity Index: The size and polydispersity index of the preparations were determined using a Zetasizer, Malvern Instruments, NJ. In short, approximately 1 ml of each preparation was transferred to a cuvette and placed in the instrument. A laser beam was used to determine the size of the mixed nanomicelles. The nanomicelles contemplated by the present disclosure typically have a particle size in the range of about 1-100 nm; in certain embodiments, the particle size falls within the range of about 5-50 nm; in certain embodiments, the particle size falls within the range of about 10-40 nm; in certain embodiments, the particle size is about 15 nm.

[0321] Capture efficiency: In order to determine the capture efficiency of the preparation, the capture efficiency test was performed on all the prepared preparations. In short, the preparation was vortexed and mixed evenly, and 1 mL was transferred to a new (1.5 mL) eppendorf tube. Each preparation was lyophilized to obtain a solid at the bottom of the eppendorf tube. The resulting solid was suspended in 1 mL of an organic solvent (ether) to produce reverse micelles, and the drug was released into an external organic solvent. The organic solvent was evaporated overnight in a high-speed vacuum. The resulting reverse micelles were resuspended in 1 mL of 2-propanol (considering the dilution factor), and further diluted to determine the concentration of cyclosporin captured in each micellar preparation with HPLC. The capture efficiency of the preparation was calculated using the following formula (wherein MNF=mixed nanomicelle preparation):

[0322]

[0323] Drug Quantification by HPLC Methods:In vitro analysis of cyclosporin was performed as follows: Reverse phase high performance liquid chromatography (RP-HPLC) method, using Shimadzu HPLC (Shimadzu, Shimadzu Scientific instruments, Columbia, MD), Alcott autosampler (model 718AL), Shimadzu UV / visible detector (Shimadzu, SPD-20A / 20AV, USA), ODS column (5 μm, 150 x 4.6 mm) thermostated at 40 ± 1 ° C, and Hewlett Packard HPLC integrator (Hewlett Packard, Palo Alto, CA). The mobile phase contained methanol (MeOH), water and trifluoroacetic acid (TFA) (70:30:0.05% v / v), which was set at a flow rate of 0.5 mL / min. The detection wavelength was set at 272 nm. The sample tray temperature was maintained at 4 ° C. A calibration curve (0.5-5 μg / mL) of cyclosporin was prepared by preparing appropriate dilutions from the stock solution in 2-propanol. An injection volume of 10 μl was injected into the HPLC column for analysis. All prepared standards and samples were stored at 4°C before and during analysis.

[0324] Example 2

[0325] Preparation of cyclosporine-containing formulations of mixed nanomicelles using a solvent-based method or a melt-based method

[0326] The mixed nanomicelle formulation encapsulating cyclosporin was prepared in two steps by a solvent evaporation method:

[0327] preparing bulk ophthalmic solutions; and

[0328] The bulk ophthalmic solution was filled into blow / fill / seal (BFS) unit doses and strips of four (4) BFS units were subsequently packaged into individual foil pouches.

[0329] An exemplary solvent-based preparation method contemplated for use herein is described in more detail as follows:

[0330] Step 1: Dissolve the required amount of cyclosporin, octoxynol-40 and HCO-40 in ethanol and load into a round bottom flask of appropriate size. Connect the flask to a rotary evaporator and start rotating to mix the contents of the flask.

[0331] Step 2: Remove the ethanol by rotary evaporation until a thin film is obtained.

[0332] Step 3: Fill the flask containing the membrane from step 2 with the required amount of water for injection and dissolve the contents by mixing with rotation (laminar flow).

[0333] Step 4: Add the required amount of sodium chloride and pre-prepared phosphate buffer to a stainless steel container and mix the contents.

[0334] Step 5: Transfer the contents from step 3 to the tank containing the buffer and stir until dissolved.

[0335] Step 6: Add the required amount of Povidone to the jar and stir until dissolved.

[0336] Step 7: Measure the pH of the solution in Step 6, adjust (if necessary), and bring to final volume with water for injection.

[0337] Step 8: The solution from Step 7 was sterile filtered and aseptically filled into blow / fill / seal (BFS) unit dose vials with a nominal fill volume of 0.25 mL.

[0338] Step 9: Package the vials in strips of four (4) BFS units in heat-sealed foil bags.

[0339] An exemplary melt-based preparation method contemplated for use herein is described in more detail as follows:

[0340] Step 1: Melt the required amount of HCO-40 in a flask while heating to about 60°C with stirring. When liquefied, add the required amount of cyclosporine and mix until dissolved. Then add the octoxynol-40 and mix the entire solution until homogeneous.

[0341] Step 2: Charge the required amount of water for injection into a stainless steel container and stir until the temperature is 25°C.

[0342] Step 3: Transfer the contents from Step 1 to the stainless steel container and stir until dissolved.

[0343] Step 4: Add the required amount of sodium chloride and phosphate buffer to the stainless steel container and mix the contents until dissolved.

[0344] Step 5: Add the required amount of povidone to the container and stir until dissolved.

[0345] Step 6: Measure the pH of the solution in Step 5, adjust (if necessary), and bring to final volume with water for injection.

[0346] Step 7: The solution from Step 6 was sterile filtered and aseptically filled into blow / fill / seal (BFS) unit dose vials with a nominal fill volume of 0.3 mL.

[0347] Step 8: Package the vials in strips of four (4) BFS units in heat-sealed foil bags.

[0348] Example 3

[0349] Preparation of cyclosporine-containing formulations of mixed nanomicelles using an ethanol solvent evaporation method

[0350] The mixed nanomicelle formulation encapsulating cyclosporine was prepared in two steps by a solvent evaporation method:

[0351] preparing bulk ophthalmic solutions; and

[0352] The bulk ophthalmic solution was filled into blow / fill / seal (BFS) unit doses and strips of four (4) BFS units were subsequently packaged into individual foil pouches.

[0353] The preparation method employed in this article is described in more detail as follows:

[0354] Step 1: Dissolve the required amount of cyclosporine, octoxynol-40 and vitamin E polyethylene glycol succinate in ethanol and load into a round bottom flask of appropriate size. Connect the flask to a rotary evaporator and start rotating to mix the contents of the flask.

[0355] Step 2: Remove the ethanol by rotary evaporation until a waxy solid is obtained.

[0356] Step 3: Charge the required amount of water for injection into the flask containing the waxy residue from Step 2 and dissolve the contents by rotating (laminar flow) mixing.

[0357] Step 4: Transfer the contents from step 3 to a stainless steel container containing the required amount of povidone solution and mix the contents until homogeneous.

[0358] Step 5: Add required amount of sodium chloride and pre-prepared phosphate buffer to the solution of step 4 and mix the contents.

[0359] Step 6: Measure the pH of the solution in Step 5, adjust (if necessary), and bring to final volume with water for injection.

[0360] Step 7: The solution from Step 6 was sterile filtered and aseptically filled into blow / fill / seal (BFS) unit dose vials with a nominal fill volume of 0.25 mL.

[0361] Step 8: Package the vials in strips of four (4) BFS units in heat-sealed foil bags.

[0362] Example 4

[0363] Preparation of cyclosporine-containing formulations of mixed nanomicelles using an alternative order of addition using a melt-based approach

[0364] Step 1: Melt the required amount of HCO-40 in a flask while heating to about 60°C with stirring. When liquefied, add the required amount of cyclosporine and mix until dissolved and homogeneous.

[0365] Step 2: Heat the required amount of Octoxynol-40 to about 60°C and when liquefied, add the Cyclosporine HCO-40 mixture.

[0366] Step 3: Charge the required amount of water for injection into the flask containing the dissolved cyclosporin at about 25°C and stir until dissolved.

[0367] Step 4: Add required amounts of sodium chloride and phosphate buffer to the flask and mix the contents.

[0368] Step 5: Weigh PVP-K90, add to the solution and mix until dissolved.

[0369] Step 6: Measure the pH of the solution in Step 5, adjust (if necessary), and bring to final volume with water for injection.

[0370] Example 5

[0371] Any of the protocols described herein can be performed with the following reagents:

[0372] 0.09 wt% cyclosporine,

[0373] 1.0 wt% hydrogenated 40 polyoxyethylene castor oil, and

[0374] 0.05 wt% Octoxynol-40 (Igepal),

[0375] 0.405 wt% sodium dihydrogen phosphate, and optionally

[0376] 0.465 wt% disodium hydrogen phosphate,

[0377] 0.05 wt% sodium chloride,

[0378] 0.3 wt% Povidone K90, and

[0379] Water for injection.

[0380] A randomized, multicenter, double-blind, vehicle-controlled, dose-ranging study was designed to evaluate two concentrations of OTX-101 ophthalmic solution, 0.09% and 0.05%, relative to vehicle in approximately 420 subjects with keratoconjunctivitis sicca (KCS). Subjects who met eligibility criteria at screening (patient-reported history of KCS ≥ 6 months, clinical diagnosis of bilateral KCS, lissamine green staining score ≥ 3 and ≤ 9, and total symptom score ≥ 40 based on a modified "Symptom Assessment iN Dry Eye" (SANDE) questionnaire) entered the run-on phase, in which vehicle was topically applied to both eyes twice daily (BID) for 14 days. After the run-in period, subjects who continued to meet the inclusion criteria for lissamine green staining score and total symptom score in at least one eye were randomized to 1 of 3 treatment groups and received treatment for 12 weeks (84 days):

[0381] 1 drop of OTX-101 0.05% in both eyes twice a day (BID),

[0382] 1 drop of OTX-101 0.09% in both eyes twice daily (BID), and

[0383] 1 drop of vehicle in both eyes twice daily (BID).

[0384] Subjects' symptoms were assessed with the SANDE questionnaire, subjects' signs were assessed with lissamine green conjunctival staining, corneal fluorescein staining, Schirmer's test (without anesthesia), and tear breakup time, and subjects' treatment satisfaction was assessed using a 5-point ordinal scale. Safety was assessed by Snellen visual acuity (VA), slit lamp examination, intraocular pressure (IOP) tonometry, dilated ophthalmoscopy / fundus examination, adverse event (AE) collection, and concomitant medication review. Safety and efficacy evaluations were performed at study visits on Days 14, 28, 42, 56, and 84. Both eyes were assessed at each visit.

[0385] The results are presented in Figure 1 , in which it can be seen that the formulation according to the present disclosure (containing 0.09 wt % cyclosporin) is significantly more effective than the placebo or the formulation containing only 0.05 wt % cyclosporin.

[0386] The formulation according to the present disclosure containing 0.09 wt% cyclosporin was not only superior to vehicle in Schirmer's test (p=0.007), such formulation was also superior to vehicle in conjunctival staining (composite observation, p=0.008) and corneal staining (p<0.001). The formulation of the present disclosure (containing 0.09 wt% cyclosporin) demonstrated clinically meaningful improvement in tear production in subjects, with an increase of ≥10 mm in Schirmer's test score from baseline based on data from both eyes.

[0387] The invention exemplarily described herein can be practiced without any one or more elements, one or more limitations not specifically disclosed herein. The terms and expressions that have been adopted are used as descriptive rather than limiting terms, and any equivalents of the features shown and described or parts thereof are not intended to be excluded in the application of such terms and expressions, but it should be recognized that multiple changes are possible within the scope of the claimed invention. Thus, it should be understood that although the preferred embodiments and optional features have specifically disclosed the present invention, those skilled in the art may make modifications and changes to the concepts disclosed herein, and such modifications and changes are considered to be within the scope of the invention defined in the appended claims.

[0388] The contents of articles, patents and patent applications, and all other documents and electronically available information mentioned or cited herein are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. Applicants reserve the right to physically incorporate into this application any and all materials and information from any such article, patent, patent application or other document.

[0389] The invention exemplarily described herein can be appropriately practiced in the absence of any one or more elements, one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprise", "include", "contain", etc. should be read broadly and without restriction. In addition, the terms and expressions used herein have been used as terms of description rather than limitation, and any equivalents of the features shown and described or parts thereof are not intended to be excluded in the application of such terms and expressions, but it should be recognized that multiple changes are possible within the scope of the claimed invention. Thus, it should be understood that although the preferred embodiments and optional features have specifically disclosed the present invention, modifications and changes of the invention embodied therein disclosed herein can be made by those skilled in the art, and such modifications and changes are considered to be within the scope of the present invention.

[0390] The invention has been described generally and generically herein. Each narrower genus and subgroup falling within the generic disclosure also forms a part of the invention. This includes the general invention specification having a proviso or negative limitation excluding any subject matter from the genus, regardless of whether the excluded material is expressly mentioned herein.

[0391] In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0392] Other embodiments are set forth within the following claims.

Claims

1. A topical preparation for eye use, comprising: 0.087-0.093 wt% cyclosporin; about 1.0 wt. % hydrogenated 40 polyoxyethylene castor oil; about 0.05% by weight of octoxynol-40; about 0.20-0.405% by weight of sodium dihydrogen phosphate, about 0.23-0.465% by weight of disodium hydrogen phosphate, about 0.05% by weight sodium chloride; about 0.3% by weight of povidone; Sodium hydroxide / hydrochloric acid; and Water for injection.

2. The topical ophthalmic formulation of claim 1, wherein cyclosporine is present in an amount of 0.09% by weight of the formulation.

3. The topical ophthalmic formulation of claim 1, wherein the formulation is substantially free of organic solvents.

4. The topical ophthalmic formulation according to claim 1, wherein the formulation is free of preservatives.

5. The topical ophthalmic formulation of claim 1, wherein the formulation is a clear aqueous solution.

6. The topical ophthalmic formulation according to claim 1, wherein the formulation is a mixed nanomicelle solution.

7. The topical ophthalmic formulation according to claim 6, wherein the mixed nanomicelle solution comprises nanomicelles having a particle size of about 5-100 nanometers.

8. The topical ophthalmic formulation according to any one of claims 1 to 7, for use in treating or preventing an ocular disease or disorder.

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