Therapeutic uses of topical ophthalmic formulations of cyclosporine.

Description

1 / 49 “THERAPEUTIC USES OF TOPICAL OPHTHALMIC FORMULATIONS OF CYCLOSPORINE” FIELD OF THE INVENTION

[001] The present invention relates to the field of cyclosporine-containing formulations for topical administration thereof, such as ophthalmic formulations containing 0.087-0.093% cyclosporine, and methods of manufacturing and using such formulations. BACKGROUND OF THE INVENTION

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

[003] U.S. Patent Applications Nos. US2010 / 0310462 and US2009 / 0092665 describe drug delivery systems for ophthalmic use that have nanomycells that include vitamin E TPGS.

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

[005] U.S. Patent No. 8,980,839 describes an aqueous ophthalmic solution, said solution comprising cyclosporine, a polyoxyl lipid or fatty acid, and a polyalkoxylated alcohol. The patent contemplates HCO-40 as the polyoxyl lipid and Octoxinol-40 as the polyalkoxylated alcohol.

[006] The most common adverse effect following the use of RESTATIS® Petition 870260043159, dated 07 / 05 / 2026, page 11 / 67 2 / 49 (cyclosporine ophthalmic emulsion 0.05%) is ocular burning in patients as reported in 17% of cases. Other adverse reactions include conjunctival hyperemia, epiphora, eye pain, discharge, foreign body sensation, itching, burning, and visual disturbance (in 1-5% of patients). SUMMARY OF THE INVENTION

[007] The present disclosure relates to topical ophthalmic formulations comprising 0.087-0.093% by weight of cyclosporine. In certain aspects and embodiments, formulations comprising 0.087-0.093% by weight of cyclosporine as described herein do not produce the side effects such as reduced visual acuity, blurred vision, increased lacrimation, ocular discharge and dysgeusia as reported in other ophthalmic formulations such as Xiidra® (Lifitegrast ophthalmic solution), thus providing a better safety profile.

[008] The formulations of the present disclosure are based, at least in part, on the surprising and unexpected findings that formulations comprising 0.087-0.093% by weight of cyclosporine may have greater efficacy and may be unexpectedly stable, for example, in large-scale manufacturing. The features and advantages of formulations of the present disclosure that could not have been foreseen prior to the present disclosure include improved handling thereof by means of preparation on an industrial scale, i.e., various aspects and embodiments of formulations of the present disclosure remain fully fluid in the vehicle, therefore, and resist the propensity to precipitate upon handling thereof.

[009] The formulations of the present disclosure in certain embodiments are surprisingly stable at high temperatures, for example, temperatures above about 40 degrees C.

[0010] In certain aspects and embodiments, the formulations of the present disclosure further include a polyoxyl lipid or fatty acid, and / or an alcohol. Petition 870260043159, dated 07 / 05 / 2026, p. 12 / 67 3 / 49 polyalkoxylated and may include nanomycells.

[0011] Nanomicelles contemplated by the present disclosure typically have a particle size in the range of about 1-100 nm; in some embodiments, the particle size is in the range of about 5-50 nm; in some embodiments, the particle size is in the range of about 10-40 nm; in some 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 of cyclosporine and one or more additional formulation ingredients.

[0013] In one embodiment of the above aspect, the formulations contemplated here are stable at temperatures above 40 degrees C.

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

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

[0016] In another embodiment of the above aspect, the formulation of the present disclosure is preservative-free.

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

[0018] In another embodiment of the above aspect, the formulation of the present disclosure are mixed nanomicellar formulations.

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

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

[0021] In another embodiment of the above aspect, the formulation of the present disclosure comprises one or more additional ingredients. Petition 870260043159, dated 07 / 05 / 2026, p. 13 / 67 4 / 49

[0022] In another embodiment of the above aspect, the additional ingredients are selected from the group consisting of a polyoxyl lipid or a fatty acid and a polyalkoxylated alcohol.

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

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

[0025] In another embodiment of the above aspect, the polyoxyl 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 octoxinol 40.

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

[0028] In another embodiment of the above aspect, the formulations of the present disclosure comprising additional formulation ingredients are further selected from the group consisting of additives, adjuvants, buffers, tonicity agents, bioadhesive polymers and preservatives.

[0029] In another embodiment of the above aspect, buffer is selected from the group consisting of phosphate, borate, acetate, citrate, carbonate and borate-polyol complexes.

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

[0031] In another embodiment of the above aspect, the bioadhesive polymer is selected from the group consisting of carbopol, carbophils, cellulose derivatives, gums such as xanthan, karaya, guar, tragacanth, agarose and other such polymers. Petition 870260043159, dated 07 / 05 / 2026, page 14 / 67 5 / 49 such as povidone, polyethylene glycol, poloxamers, hyaluronic acid, or combinations thereof.

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

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

[0034] In one embodiment of the above aspect, additional active ingredients are selected from the group consisting of resolvin, resolvin-like compounds, steroids, antibiotics, antivirals, hormones, cytokines, toxins, vitamins, or combinations thereof.

[0035] In certain aspects and embodiments, the formulations of the present disclosure comprise 0.087-0.093% by weight of cyclosporine, wherein said formulation demonstrates a clinically significant improvement when compared to the vehicle in tear production with > 10 mm increase in Schimer test score from reference.

[0036] In one embodiment of the above aspect, the formulations of the present disclosure demonstrate an earlier onset when compared with other cyclosporine A formulations.

[0037] In certain aspects and modalities, the formulations of the present disclosure comprise: 0.087-0.093% by weight of cyclosporine, approximately 0.1-6% by weight of hydrogenated polyoxyl 40 castor oil, and approximately 0.002-4% by weight of octoxinol-40.

[0038] In certain aspects and modalities, the formulations of the present disclosure comprise: 0.087-0.093% by weight of cyclosporine, approximately 1.0% by weight of hydrogenated polyoxyl 40 castor oil, and Petition 870260043159, dated 07 / 05 / 2026, page 15 / 67 6 / 49 approximately 0.05% by weight of octoxinol-40 (Igepal). In certain aspects and modalities, the formulations of the present disclosure also include: approximately 0.20-0.405% by weight of monobasic sodium phosphate, approximately 0.23-0.465% by weight of dibasic sodium phosphate, approximately 0.05% by weight of sodium chloride, approximately 0.3% by weight of povidone K90, sodium hydroxide / hydrochloric acid and water for injection.

[0039] As used herein in connection with numerical values, the terms approximately and about mean + / - 10% of the stated value, including the stated value.

[0040] In some respects, the formulations contemplated herein comprise 0.088-0.093% by weight of cyclosporine.

[0041] In some aspects, the formulations contemplated herein comprise 0.089–0.093% by weight of cyclosporine. In some embodiments of such aspects, the formulations of the present disclosure comprise: 0.089-0.093% by weight of cyclosporine, approximately 1.0% by weight of hydrogenated polyoxyl 40 castor oil, and approximately 0.05% by weight of octoxinol-40 (Igepal). In certain aspects and modalities, the formulations of the present disclosure also include: approximately 0.20% by weight of monobasic sodium phosphate, approximately 0.23% by weight of dibasic sodium phosphate, approximately 0.05% by weight of sodium chloride, approximately 0.3% by weight of povidone K90, sodium hydroxide / hydrochloric acid and Petition 870260043159, dated 07 / 05 / 2026, page 16 / 67 7 / 49 water for injection.

[0042] In some modalities of such aspects, the formulations of the present disclosure comprise: 0.09-0.093% by weight of cyclosporine, approximately 1.0% by weight of hydrogenated polyoxyl 40 castor oil, and approximately 0.05% by weight of octoxinol-40 (Igepal). In certain aspects and modalities, the formulations of the present disclosure also include: approximately 0.405% by weight of monobasic sodium phosphate, approximately 0.465% by weight of dibasic sodium phosphate, approximately 0.05% by weight of sodium chloride, approximately 0.3% by weight of povidone K90, sodium hydroxide / hydrochloric acid and water for injection.

[0043] In some aspects, the formulations contemplated herein comprise 0.091-0.093% by weight of cyclosporine.

[0044] In some aspects, the formulations contemplated herein comprise 0.092-0.093% by weight of cyclosporine.

[0045] In some aspects, the formulations contemplated herein comprise 0.087-0.092% by weight of cyclosporine.

[0046] In some aspects, the formulations contemplated herein comprise 0.087-0.091% by weight of cyclosporine.

[0047] In some aspects, the formulations contemplated herein comprise 0.087–0.09% by weight of cyclosporine. In some embodiments of such aspects, the formulations of the present disclosure comprise: 0.087-0.09% by weight of cyclosporine, approximately 1.0% by weight of hydrogenated polyoxyl 40 castor oil, and Petition 870260043159, dated 07 / 05 / 2026, page 17 / 67 8 / 49 approximately 0.05% by weight of octoxinol-40 (Igepal). In certain aspects and modalities, the formulations of the present disclosure also include: approximately 0.20% by weight of monobasic sodium phosphate, approximately 0.23% by weight of dibasic sodium phosphate, approximately 0.05% by weight of sodium chloride, approximately 0.3% by weight of povidone K90, sodium hydroxide / hydrochloric acid and water for injection.

[0048] In some modalities of such aspects, the formulations of the present disclosure comprise: 0.087-0.089% by weight of cyclosporine, approximately 1.0% by weight of hydrogenated polyoxyl 40 castor oil, and approximately 0.05% by weight of octoxinol-40 (Igepal). In certain aspects and modalities, the formulations of the present disclosure also include: approximately 0.405% by weight of monobasic sodium phosphate, approximately 0.465% by weight of dibasic sodium phosphate, approximately 0.05% by weight of sodium chloride, approximately 0.3% by weight of povidone K90, sodium hydroxide / hydrochloric acid and water for injection.

[0049] In some respects, the formulations contemplated herein comprise 0.087% by weight of cyclosporine.

[0050] In some respects, the formulations contemplated herein comprise 0.088% by weight of cyclosporine.

[0051] In some respects, the formulations contemplated herein Petition 870260043159, dated 07 / 05 / 2026, page 18 / 67 9 / 49

[0052] In some respects, the formulations contemplated herein comprise 0.09% by weight of cyclosporine.

[0053] In some respects, the formulations contemplated herein comprise 0.091% by weight of cyclosporine.

[0054] In some respects, the formulations contemplated herein comprise 0.092% by weight of cyclosporine.

[0055] In some respects, the formulations contemplated herein comprise 0.091% by weight of cyclosporine. They comprise 0.093% by weight of cyclosporine.

[0056] In certain aspects and modalities, formulations as described here are particularly suitable for application to the anterior eye, or application to the posterior eye, or application to both the anterior and posterior eye.

[0057] In certain aspects and modalities, the formulations of the present disclosure consist essentially of: 0.087-0.093% by weight of cyclosporine, about 1.0% by weight of hydrogenated polyoxyl 40 castor oil, and about 0.05% by weight of octoxinol-40 (Igepal), and optionally further consist essentially of: about 0.20-0.405% by weight of monobasic sodium phosphate, about 0.23-0.465% by weight of dibasic sodium phosphate, about 0.05% by weight of sodium chloride, about 0.3% by weight of povidone K90, NaOH / HCl, and water for injection.

[0058] In some embodiments, the formulation has nanomicelles with a relatively increased trapping efficiency; in such embodiments, cyclosporine may be at least about 0.087%, or at least about Petition 870260043159, dated 07 / 05 / 2026, page 19 / 67 10 / 49 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 not 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 between 0.09 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 nanomycells of the formulation.

[0059] Consequently, in one aspect an ophthalmic formulation is provided that includes 0.087-0.093% by weight of cyclosporine, a polyoxyl lipid or fatty acid, and a polyalkoxylated alcohol. In some embodiments, the formulations include nanomycells. In some embodiments, the polyoxyl lipid or fatty acid is a polyoxyl castor oil. In some embodiments, the polyoxyl lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80, or HCO-100. In some embodiments, the polyoxyl lipid or fatty acid (such as a polyoxyl castor oil such as HCO-40, HCO-60, HCO-80, or HCO-100) is present between 0.5 and 5%; or 0.6 and 5%; or 0.7 and 5%; or 0.8 and 5%; or 0.9 and 5%; or 1 and 5%; or 1 and 4%; or 1 and 3%; or 1 and 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 some embodiments, the polyoxyl lipid is HCO-60. In some embodiments, the polyoxyl lipid is HCO-80.In some embodiments, the polyoxyl lipid is HCO-100. In some embodiments, the formulation includes a polyalkoxylated alcohol that is octoxinol-40. In some embodiments, the formulation includes a polyalkoxylated alcohol (as octoxinol-40) present between 0.01 and 1%; or between 0.02 and 1%; or 0.03 and 1%; or 0.04 and 1%; or 0.05 and 1%; or 0.06 and 1%; or 0.07 and 1%; or 0.08 and 1%; or about 1% by weight of the formulation.

[0060] As used herein, the term polyoxyl lipid or fatty acid refers to mono- and diesters of lipids or fatty acids and polyoxyethylene diols. Polyoxyl lipids Petition 870260043159, dated 07 / 05 / 2026, p. 20 / 67 11 / 49 or fatty acids can be numbered (n) according to the average polymer length of the oxyethylene units (e.g., 40, 60, 80, 100) as is well understood in the art. The term n > 40 polyoxyl lipid means that the polyoxyl lipid or fatty acid has an average oxyethylene polymer length equal to or greater than 40 units. Hydrogenated castor oil stearate and castor oil are common lipids / fatty acids commercially available as polyoxyl lipids or fatty acids; however, it is understood that any lipid or fatty acid could be polyoxylated to become a lipid or fatty acid as contemplated herein. Examples of polyoxyl lipids or fatty acids include, without limitation, HCO-40, HCO-60, HCO-80, HCO-100, polyoxyl stearate 40, polyoxyl 35 castor oil.

[0061] In some embodiments of any of the compositions and methods described herein, the average polymer length of the oxyethylene units of a polyoxyl lipid or fatty acid is longer for a relatively larger active ingredient and shorter for a relatively smaller active ingredient; for example, in some embodiments where the active ingredient is a resolvin or resolvin-like compound, the polyoxyl lipid is HCO-60 and in some embodiments where the active ingredient is cyclosporine A (which is larger than a resolvin) the polyoxyl lipid is HCO-80 or HCO-100.

[0062] As used herein, the term micelle or nanomicelle refers to an aggregate (or agglomeration) of surfactant molecules. Micelles only form when the surfactant concentration is greater than the critical micelle concentration (CMC). Surfactants are chemicals that are amphipathic, meaning they contain both hydrophobic and hydrophilic groups. Micelles can exist in different shapes, including spherical, cylindrical, and discoidal. A micelle comprising at least two different molecular species is a mixed micelle. In some embodiments, the ophthalmic compositions of the present disclosure include a clear, aqueous mixed micelle solution. Petition 870260043159, dated 07 / 05 / 2026, page 21 / 67 12 / 49

[0063] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093% by weight of cyclosporine, and an n>40 polyoxyl lipid or fatty acid. In some embodiments, the formulations include nanomycells. In some embodiments, the polyoxyl lipid or fatty acid is a polyoxyl castor oil. In some embodiments, the polyoxyl lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-100. In some embodiments, the polyoxyl lipid or fatty acid (such as a polyoxyl castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) is present between 0.1 and 2%, or 0.2 and 2%, or 0.3 and 2%; or 0.4 and 2%; or 0.5 and 2%; or 0.6 and 2%; or 0.7 and 2%; or 0.8 and 2%; or 0.9 and 2%; or 1 and 2%; or 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 some embodiments, the polyoxyl lipid is HCO-60. In some embodiments, the polyoxyl lipid is HCO-80.In some embodiments, the polyoxyl lipid is HCO-100. In some embodiments, a formulation also includes polyalkoxylated alcohol. In some embodiments, a formulation also includes polyalkoxylated alcohol that is octoxinol-40. In some embodiments, a formulation includes a polyalkoxylated alcohol (such as octoxinol-40) present 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 approximately 0.05%, or approximately 0.01% by weight of the formulation.

[0064] In another aspect, an ophthalmic formulation is provided, which includes 0.087-0.093% by weight of cyclosporine and a polyoxyl lipid or fatty acid; wherein said polyoxyl lipid or fatty acid is present in an amount equal to or greater than 1% of said formulation. In a similar aspect, an ophthalmic formulation is provided, which includes 0.087-0.093% by weight of cyclosporine and a polyoxyl lipid or fatty acid; wherein said polyoxyl lipid or fatty acid is present Petition 870260043159, dated 07 / 05 / 2026, p. 22 / 67 13 / 49 in an amount equal to or greater than 0.05% of said formulation. In some embodiments, the formulations include nanomicelles. In some embodiments, the polyoxyl lipid or fatty acid is a polyoxyl castor oil. In some embodiments, the polyoxyl lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80, or HCO-100. In some embodiments, the polyoxyl lipid or fatty acid (such as a polyoxyl castor oil such as HCO-60, HCO-80, or HCO-100) is present between 0.5 and 2%, or 0.7 and 2%, or between 1 and 6%; or 2 and 6%; or 2 and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and 5%; or 3 and 5%; or 2 and 6%; or about 4%; or greater than 1.5%; or greater than 2%; or greater than 3%; or greater than 4% by weight of the formulation. In some embodiments, the polyoxyl lipid is HCO-40. In some embodiments, the polyoxyl lipid is HCO-60. In some embodiments, the polyoxyl lipid is HCO-80. In some embodiments, the polyoxyl lipid is HCO-100.In some embodiments, a formulation also includes polyalkoxylated alcohol. In some embodiments, a formulation further includes polyalkoxylated alcohol that is octoxinol-40. In some embodiments, a formulation includes a polyalkoxylated alcohol (such as octoxinol-40) present in concentrations 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 approximately 0.05%, or approximately 0.01% by weight of the formulation.

[0065] In another aspect, an ophthalmic formulation is provided, which includes 0.087-0.093% by weight of cyclosporine and a polyoxyl lipid or fatty acid; wherein said formulation comprises nanomicelles. In some embodiments, the polyoxyl lipid or fatty acid is a polyoxyl castor oil. In some embodiments, the polyoxyl lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-100. In some embodiments, the polyoxyl lipid or fatty acid (such as a polyoxyl castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) is selected from HCO-40, HCO-60, HCO-80 or HCO-100. 14 / 49 The presence of polyoxyl lipid (HCO-100) is between 0.5 and 2%, or 0.7 and 2%, or between 1 and 6%; or 2 and 6%; or 2 and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and 5%; or 3 and 5%; or 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% by weight of the formulation. In some embodiments, the polyoxyl lipid is HCO-40. In some embodiments, the polyoxyl lipid is HCO-60. In some embodiments, the polyoxyl lipid is HCO-80. In some embodiments, the polyoxyl lipid is HCO-100. In some embodiments, a formulation also includes polyalkoxylated alcohol. In some embodiments, a formulation further includes polyalkoxylated alcohol that is octoxinol-40.In some embodiments, a formulation includes a polyalkoxylated alcohol (such as octoxinol-40) present in concentrations ranging from 0.002 to 4%; or from 0.005 to 3%; or from 0.005 to 2%; or from 0.005 to 1%; or from 0.005 to 0.5%; or from 0.005 to 0.1%; or from 0.005 to 0.05%; or from 0.008 to 0.02%; or from 0.01 to 0.1%; or from 0.02 to 0.08%; or from 0.005 to 0.08%; or approximately 0.05%, or approximately 0.01% by weight of the formulation.

[0066] In a further aspect, an ophthalmic formulation is provided, comprising 0.087-0.093% by weight of cyclosporine, 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.05% of octoxinol-40.

[0067] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093% by weight of cyclosporine, 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.05% of octoxinol-40.

[0068] In yet another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093% by weight of cyclosporine, 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.05% of octoxinol-40.

[0069] In another aspect, an ophthalmic formulation is provided, Petition 870260043159, dated 07 / 05 / 2026, p. 24 / 67 15 / 49 comprising 0.087-0.093% by weight of cyclosporine, 1-5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.05% of octoxinol-40.

[0070] In a further aspect, an ophthalmic formulation is provided, comprising 0.087-0.093% by weight of cyclosporine, about 4% of HCO-60 and about 0.01-0.05% of octoxinol-40.

[0071] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093% by weight of cyclosporine, 0.7-1.5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05-0.1% of octoxinol-40.

[0072] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093% by weight of cyclosporine, 0.7-1.5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05-0.1% of octoxinol-40.

[0073] In yet another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093% by weight of cyclosporine, 0.7-1.5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05-0.1% of octoxinol-40.

[0074] In another aspect, an ophthalmic formulation is provided, comprising 0.087-0.093% by weight of cyclosporine, 0.7-1.5% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05-0.1% of octoxinol-40.

[0075] In a further aspect, an ophthalmic formulation is provided, comprising 0.087-0.093% by weight of cyclosporine, about 1% of HCO-60 and about 0.05-0.1% of octoxinol-40.

[0076] In various embodiments of any of the aspects and embodiments described herein, one formulation includes nanomicels. Petition 870260043159, dated 07 / 05 / 2026, p. 25 / 67 16 / 49

[0077] In some embodiments of the aspects and embodiments described herein, a formulation includes a polyoxyl lipid or fatty acid. In some embodiments, the polyoxyl lipid or fatty acid is a polyoxyl castor oil. In some embodiments, the polyoxyl lipid or fatty acid is one or more selected from HCO-40, HCO-60, HCO-80, or HCO-100. In some embodiments, the polyoxyl lipid or fatty acid (such as a polyoxyl castor oil such as HCO-60, HCO-80, or HCO-100) is present in concentrations of 0.5 to 2%, 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 approximately 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% by weight of the formulation. In some embodiments, the polyoxyl lipid is HCO-40. In some embodiments, the polyoxyl lipid is HCO-60. In some embodiments, the polyoxyl lipid is HCO-80. In some embodiments, the polyoxyl lipid is HCO-100.

[0078] In some embodiments of the aspects and embodiments described herein, it includes a polyalkoxylated alcohol. In some embodiments, a formulation includes a polyalkoxylated alcohol that is octoxinol-40. In some embodiments, a formulation includes a polyalkoxylated alcohol (such as octoxinol-40) present 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 approximately 0.05%, or approximately 0.01% by weight of the formulation.

[0079] In certain aspects and embodiments, the present disclosure contemplates stable emulsions comprising: 0.087-0.093% by weight of cyclosporine, approximately 1.0% by weight of hydrogenated polyoxyl 40 castor oil, and approximately 0.05% by weight of octoxinol-40 (Igepal), and optionally further comprising: Petition 870260043159, dated 07 / 05 / 2026, p. 26 / 67 17 / 49 0.20-0.405% by weight of monobasic sodium phosphate, 0.23-0.465% by weight of dibasic sodium phosphate, approximately 0.05% by weight of sodium chloride, approximately 0.3% by weight of povidone K90, sodium hydroxide / hydrochloric acid, and water for injection.

[0080] In some respects, the present disclosure contemplates a process for preparing the topical ophthalmic formulation of cyclosporine, said method comprising the steps of: (1) melting the required amount of polyoxyl lipid, (2) slow addition of cyclosporine to step (1) and substantial homogenization of the mixture, (3) addition of polyalkoxylated alcohol to step (2) and continuous stirring until a uniform homogeneous solution is obtained, (4) addition of the buffer system and tonicity agent to the solution obtained from step (3) and continuous stirring to achieve good dissolution, (5) addition of the required amount of bioadhesive polymer to the solution from the above step, (6) adjustment of the solution pH, if necessary, and making up the final volume with water for injection; and (7) filtration and aseptic filling of the solution into unit dose vials.

[0081] In some respects, the present disclosure contemplates fusion-based methods for the manufacture of cyclosporine-containing formulations, including the formulations described above, said methods comprising: Fusion of hydrogenated polyoxyl 40 castor oil, slow addition of cyclosporine to the same and, after that, substantially Petition 870260043159, dated 07 / 05 / 2026, page 27 / 67 18 / 49 Mix the ingredients, add octoxinol-40 (Igepal) to the resulting homogeneous mixture and stir until substantially homogeneous, then add this mixture to the water for injection, followed by the individual addition of excipients (e.g., monobasic sodium phosphate, dibasic sodium phosphate, and sodium chloride) with sufficient stirring to achieve good dissolution of each.

[0082] An exemplary melt-based manufacturing process contemplated for use herein comprises the following steps: Step 1: The required amount of HCO-40 is melted in a flask heated to approximately 60°C with stirring. Once liquefied, the required amount of cyclosporine is added and mixed until dissolved. Octoxinol-40 is then added and the entire solution is mixed until uniform. Step 2: The required amount of water for injection is loaded into a stainless steel vessel and stirred until the temperature reaches 25°C. Step 3: The contents of step 1 are transferred to the stainless steel vessel and stirred until dissolved. Step 4: The required amounts of sodium chloride and phosphate buffer are added to the stainless steel vessel and the contents are mixed until dissolved. Step 5: The required amount of Povidone is added to the container and stirred until dissolved. Step 6: The pH of the solution from Step 5 is measured, adjusted (if necessary), and brought to the final volume with water for injection. Step 7: The solution from Step 6 is aseptically filtered and aseptically filled into blow-fill-seal (BFS) unit-dose vials with a nominal fill volume of 0.3 mL. Step 8: The vials are packaged in strips of four (4) units of Petition 870260043159, dated 07 / 05 / 2026, page 28 / 67 19 / 49 BFS in thermally sealed aluminum pouches.

[0083] In some respects, the present disclosure contemplates the process of preparing the topical ophthalmic formulation of cyclosporine, said method comprising the steps of: (1) Dissolving the required amounts of cyclosporine, polyalkoxylated alcohol and polyoxyl lipid in a suitable solvent, (2) Loading the solution obtained from step (1) into a round-bottom flask of suitable size, (3) Removing the solvent by rotary evaporation until a thin film is obtained, (4) Adding and mixing the required amount of water for injection to the flask containing the film from step (3); (5) addition of buffer system and tonicity agent to the solution from step (4); (6) adding the required amount of bioadhesive polymer to the solution from the step above, (7) adjusting the pH of the solution, if necessary, and making up the final volume with water for injection; and (8) filtering and aseptically filling the solution into unit-dose vials.

[0084] An exemplary solvent-based manufacturing process contemplated for use herein comprises the following steps: (1) Dissolving the required quantities of cyclosporine, octoxinol-40 and hydrogenated polyoxyl 40 castor oil in a suitable solvent, (2) Loading the solution obtained from step (1) into a round-bottom flask of suitable size, (3) Removing the solvent by rotary evaporation until a thin film is obtained, Petition 870260043159, dated 07 / 05 / 2026, page 29 / 67 20 / 49 (4) addition and mixing of the required amount of water for injection to the vial containing the film from step (3); (5) addition of phosphate buffer and sodium chloride to the solution from step (4); (6) adding the required amount of povidone to the solution from the step above, (7) adjusting the pH of the solution, if necessary, and making up the final volume with water for injection; and (8) filtering and aseptically filling the solution into unit-dose vials.

[0085] The present disclosure also relates to the treatment or prevention of eye diseases or disorders, for example, by local administration of the formulations as described herein.

[0086] A patient or individual to be treated by any of the compositions or methods of the present disclosure may mean a human or a non-human animal. In one embodiment, the present disclosure provides methods for treating an eye disease in a human patient in need thereof. In one embodiment, the present disclosure provides methods for treating an inflammatory eye disease in a human patient in need thereof. In another embodiment, the present disclosure provides methods for treating an eye disease in a veterinary patient in need thereof, including but not limited to dogs, horses, cats, rabbits, gerbils, hamsters, rodents, birds, aquatic mammals, cattle, pigs, camelids, and other zoo animals.

[0087] In some embodiments of the compositions and methods described herein, cyclosporine further comprises one or more additional active ingredients, for example, active agents selected from the group consisting of a resolvin or resolvin-like compound, a steroid (such as a corticosteroid), and the like. In some embodiments, the additional active agent includes a resolvin. Petition 870260043159, dated 07 / 05 / 2026, p. 30 / 67 21 / 49 In some embodiments, the additional active agent includes a corticosteroid. In some embodiments, the additional active agent includes a resolvin and a corticosteroid. In some embodiments, the additional active agent includes an antibiotic, for example, one or more antibiotics selected from the group consisting of azithromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin, and levofloxacin. In some embodiments, the additional active agent includes an antibiotic, for example, one or more antibiotics selected from the group consisting of azithromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin, and levofloxacin; and a second such agent is a resolvin as described herein (including without limitation compound 1001).In some embodiments, the active agent includes two or more active agents, and one of the so-called active agents is an antiviral, for example, one or more antivirals selected from the group consisting of ganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir, and cidofovir. In some embodiments, the active agent includes two or more active agents, and one of the active agents is an antibiotic, for example, one or more antivirals selected from the group consisting of ganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir, and cidofovir; and a second of the active agents is a resolvin as described herein (including without limitation compound 1001).

[0088] The term treatment refers to: preventing a disease, disorder or condition from occurring in a cell, tissue, system, animal or human that may be predisposed to the disease, disorder and / or condition, but has not yet been diagnosed as having it; stabilizing a disease, disorder or condition, that is, halting its development; and / or relieving one or more symptoms of the disease, disorder or condition, that is, causing regression of the disease, disorder and / or condition.

[0089] As used herein, a therapeutic product that prevents a disorder. Petition 870260043159, dated 07 / 05 / 2026, page 31 / 67 22 / 49 or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the 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 the untreated control sample.

[0090] As used herein, the terms eye disease, eye condition, eye ailment, and eye condition refer to diseases / conditions of the eye(s) that may threaten vision, lead to eye discomfort, and may signal systemic health problems.

[0091] As used herein, the term anterior segment disease refers to all disorders affecting the surface of the eyes, anterior chamber, iris and ciliary body, and lens of the eyes. The surface of the eye is composed of the cornea, conjunctiva, eyelids, lacrimal and meibomian glands, and the interconnecting nerves.

[0092] As used herein, the terms posterior segment eye disease and back eye disease refer to all disorders affecting the posterior segment of the eye. A posterior eye disease is a disease that primarily affects a posterior ocular site such as the choroid or sclera, vitreous, vitreous chamber, retina, optic nerve, and blood vessels and nerves that vascularize or innervate a posterior ocular site.

[0093] Consequently, in another aspect, a method of treatment or prevention of an eye disease or condition is provided, which includes the local administration of a formulation of any of the aspects or modalities as described herein. In some modalities, the eye disease is an anterior segment disease. In some modalities, the eye disease is a posterior segment disease. In some modalities, the eye 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), Petition 870260043159, dated 07 / 05 / 2026, p. 32 / 67 23 / 49 atopic keratoconjunctivitis, systemic immune-mediated diseases such as cicatrizing conjunctivitis and other autoimmune disorders of the ocular surface, blepharitis, scleritis, age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), ocular neurovascularization, age-related macular degeneration (ARMD), proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV) retinitis, optic neuritis, retrobulbar neuritis, and macular pucker. In one modality, the eye disease is dry eye. In one modality, the eye disease is allergic conjunctivitis. In one modality, the eye disease is age-related macular degeneration (AMD). In one modality, the eye disease is diabetic retinopathy. BRIEF DESCRIPTION OF THE FIGURE

[0094] Figure 1 summarizes the results of the Schirmer test with vehicle, formulation containing 0.05% by weight of cyclosporine and 0.09% by weight of cyclosporine. DETAILED DESCRIPTION OF PREFERRED MODALITIES Active agents

[0095] According to various aspects and embodiments of the methods and compositions provided herein, an active agent, when present in addition to cyclosporine, may be any agent capable of affecting a biological process. Active agents in addition to cyclosporine (the term active ingredient is used herein interchangeably with the term active agent) include drugs, hormones, cytokines, toxins, therapeutic agents, vitamins, and the like. In some embodiments, an active agent according to the aspects and embodiments described herein is an agent capable of or approved for the treatment or prevention of a disease or condition, for example, in some embodiments, an active agent is capable of or approved for the treatment or prevention of an eye disease or condition. Petition 870260043159, dated 07 / 05 / 2026, p. 33 / 67 24 / 49

[0096] In some embodiments, the active agent in addition to cyclosporine is an antibiotic, for example, one or more antibiotics selected from the group consisting of azithromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin and levofloxacin. In some embodiments, the active agent is an antiviral, for example, one or more antivirals selected from the group consisting of ganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir and cidofovir.

[0097] In some embodiments of any of the aspects and embodiments described herein, the active agent is cyclosporine A, an analogue thereof, or a pharmaceutically acceptable salt thereof.

[0098] Cyclosporine, originally extracted from the soil fungus Potypaciadium infilatum, has a structure of 11 cyclic amino acids and includes, for example, Cyclosporines A to I, such as Cyclosporine A, B, C, D, and G. Cyclosporine binds to the cytosolic protein cyclophilin of immunocompetent lymphocytes, especially T lymphocytes, forming a complex. The complex inhibits calcineurin which, under normal circumstances, induces the transcription of interleukin-2 (IL-2). Cyclosporine also inhibits lymphokine production and interleukin release, leading to reduced effector T cell function. Eye diseases

[0099] In various aspects and modalities, the formulations as described herein can be used to treat or prevent an eye disease or disorder. The eye diseases and disorders contemplated herein include anterior segment diseases and posterior segment diseases. Exemplary eye diseases that can be treated, in certain modalities, with formulations as described herein include the following.

[00100] Dry eye syndrome (DES, Chronic dry eye, Keratitis sicca; Xerophthalmia; Keratoconjunctivitis sicca) can be defined as a condition that Petition 870260043159, dated 07 / 05 / 2026, page 34 / 67 25 / 49 encompasses a variety of disorders that result in a loss of, or altered composition of, the natural tear film that maintains the surface of the eye. Without this tear film, vision is impaired, and patients may suffer severe eye discomfort. DES can be caused by excessive tear evaporation or by a reduction in tear production in the lacrimal gland, which is the site of tear production. Although the exact causes of this condition are unknown, there is evidence supporting a link between reduced tear production and inflammation of one or more components of the lacrimal apparatus. Currently, available medications for DES are leaving substantial room for more effective and better-tolerated products.

[00101] DES can also be a manifestation of Sjögren's syndrome, which is an autoimmune disorder in which the glands that produce tears and saliva are destroyed. This leads to dry mouth, decreased tear production, and other dry mucous membranes.

[00102] Non-infectious uveitis is a putative, inflammatory, chronic Th1 / Th17-mediated autoimmune disease associated with substantial visual morbidity and is potentially blinding. Uveitis blindness generally does not occur from a single inflammatory episode; instead, cumulative damage results from recurrent episodes of inflammation. Inflammatory sequelae resulting in vision loss may include one or more cystoid macular edema, cataracts, vitreous residue, glaucoma, macular pathology (scarring and atrophy), optic neuropathy, and retinal detachment.

[00103] Anterior uveitis (iritis) occurs in the front of the eyes and is the most common form of uveitis. Pars planitis is an inflammation of the pars plana, a narrow area between the iris and the choroid. This condition occurs most frequently in young men but is usually not associated with another disease. Posterior uveitis (chondroitis) primarily affects the choroid; the back portion of the uveal tract. If the Petition 870260043159, dated 07 / 05 / 2026, page 35 / 67 26 / 49 If the retina is also involved, it is called chorioretinitis. Posterior uveitis can occur in association with an autoimmune disease or follow a systemic infection. In posterior uveitis, the inflammation can last from months to years and can cause permanent vision damage, even with treatment.

[00104] Uveitis can cause impaired vision, eye pain, and vision loss. It is estimated that about 10% of new cases of blindness in the United States are caused by uveitis. Approximately 300,000 people suffer from uveitis in the United States alone, most of whom are affected by anterior uveitis. The only FDA-approved therapeutic class for the treatment of uveitis is corticosteroids, which are observed for multiple side effects such as hypertension, hyperglycemia, and hypercholesterolemia, and in the eye, glaucoma and cataract formation.

[00105] 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 exposed areas of the sclera or white of the eyes.

[00106] Keratitis is an inflammation of the cornea (the clear portion at the front of the eyes). Keratitis can be caused by an infection (bacterial, fungal, viral, parasitic, etc.) or a non-infectious agent (for example, certain types of autoimmune diseases are associated with a variety of non-infectious keratitis).

[00107] Keratoconjunctivitis refers to inflammation of the cornea and conjunctiva.

[00108] Vernal keratoconjunctivitis (VKC) is a recurrent inflammatory eye disease characterized by raised, hard, stone-like lumps on the upper eyelid. There may also be swelling and thickening of the conjunctiva. The conjunctiva is the outermost membrane that lines the eyelids as well as the exposed parts of the eye, except for the cornea.

[00109] Atopic keratoconjunctivitis is the result of a condition Petition 870260043159, dated 07 / 05 / 2026, p. 36 / 67 27 / 49 called atopy. Atopy is a genetic condition in which the immune system produces more than normal antibodies in response to a given allergen.

[00110] Systemic immune-mediated diseases such as scarring conjunctivitis and other autoimmune disorders of the ocular surface represent a clinically heterogeneous group of conditions where acute and chronic autoreactive mechanisms can cause significant damage to the eye. When severe and affecting the epithelium and conjunctival substance, scarring may occur, leading to significant mechanical changes as a result of fibrosis. These conditions, although generally infrequent, can be the cause of profound pathology and visual impairment.

[00111] Blepharitis is a common condition that causes inflammation of the eyelids.

[00112] Scleritis is a serious inflammatory disease that affects the white outer lining of the eye, known as the sclera.

[00113] Age-related macular degeneration (AMD) is a disease associated with aging that gradually destroys sharp, central vision. AMD affects the macula, which is located in the center of the retina. AMD occurs in two forms: wet and dry. Wet AMD occurs when abnormal blood vessels behind the retina begin to grow under the macula. These new blood vessels tend to be very fragile and often leak blood and fluid. The blood and fluid lift the macula from its normal place behind the eye. Damage to the macula occurs rapidly. Dry AMD occurs when the light-sensitive cells in the macula slowly break down, gradually blurring central vision in the affected eye.

[00114] Diabetes can affect the eye in several ways. Diabetic retinopathy (DR) is a complication of diabetes that results from damage to the blood vessels of the light-sensitive tissue at the back of the eye (the retina). First, diabetic retinopathy may cause no symptoms or only Petition 870260043159, dated 07 / 05 / 2026, page 37 / 67 28 / 49 mild vision problems. Eventually, however, diabetic retinopathy can result in blindness. Diabetic macular edema (DME) is swelling of the retina in diabetes mellitus due to fluid leakage from blood vessels within the macula.

[00115] Ocular neurovascularization is the abnormal or excessive formation of blood vessels in the eye. Ocular neurovascularization has been shown in diabetic retinopathy and age-related macular degeneration (AMD).

[00116] Proliferative vitreoretinopathy (PVR) is the formation of scar tissue within the eye. Proliferative because the cells proliferate and vitreoretinopathy because the problems involve both the vitreous and the retina. In PVR, scar tissue forms in layers on the retina that contract. This marked contraction pulls the retina toward the center of the eye and severely detaches and distorts the retina. PVR can occur both posteriorly and anteriorly with retinal folding both anteriorly and circumferentially.

[00117] Cytomegalovirus (CMV) is related to the herpes virus and is present in almost everyone. When a person's immune system is suppressed because of illness (HIV), bone marrow or organ transplantation, or chemotherapy, the CMV virus can cause damage and disease to the eye 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.

[00118] Optic neuritis occurs when the optic nerve becomes inflamed and the myelin sheath becomes damaged or destroyed. Nerve damage that occurs in the section of the optic nerve located behind the eye is called retrobulbar neuritis, which is another term sometimes used for optic neuritis.

[00119] Also known as macular pucker, epiretinal membrane is a type of scar tissue that forms over the macula. It typically progresses slowly and affects central vision by causing blurring and Petition 870260043159, dated 07 / 05 / 2026, page 38 / 67 29 / 49 distortion. As it progresses, the dragging of the membrane over the macula can cause swelling.

[00120] In one embodiment, the compositions can be used for the prevention of transplant rejection of, for example, corneal allografts after transplantation. It is well known that in inflammation, T lymphocytes play a critical role in mediating the rejection of foreign tissues. Preventing rejection is of utmost importance in maintaining the health of transplanted corneas. Rejection can occur in any of the layers comprising the cornea, for example, the corneal epithelium, the corneal stroma, or the corneal endothelium. Corneal function can be compromised after endothelial rejection. The endothelial layer serves to maintain the cornea in a compact state, acting as a pump by removing water from the corneal stroma. If the function of the endothelial layer is compromised, disorientation of collagen fibers may occur and corneal transparency may be lost.Human endothelial cells are non-replicative and, as a consequence, the loss of donor cells in a rejection setting is irreversible and can lead to decreased graft function and survival. Thus, the goal of preventing or treating rejection in corneal transplant recipients is to minimize endothelial cell loss. The compositions of the present disclosure can be used for the prevention of rejection after corneal allograft transplantation. Additional formulation ingredients

[00121] 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 of the compositions of this description for topical use in the eye, the mixtures are preferably formulated at about pH 5 to about pH 8. This pH range can be achieved by adding buffers to the composition as described in the examples. In Petition 870260043159, dated 07 / 05 / 2026, page 39 / 67 30 / 49 In one embodiment, the pH range in the composition in a formulation is about pH 6.6 to about pH 7.0. It should be appreciated that the compositions of the present disclosure can be buffered by any common buffer system such as phosphate, borate, acetate, citrate, carbonate and borate-polyol complexes, with the pH and osmolarity adjusted according to well-known techniques to appropriate physiological values. The mixed micellar compositions of the present disclosure are stable in buffered aqueous solution. That is, there is no adverse interaction between the buffer and any other component that would cause the compositions to be unstable.

[00122] Tonicity agents include, for example, mannitol, sodium chloride, sodium nitrate, sodium sulfate, dextrose, xylitol, or combinations thereof. These tonicity agents can be used to adjust the osmolarity of the compositions. In one aspect, the osmolarity of the formulation is adjusted to be in the range of about 250 to about 350 mOsmol / kg. In a preferred aspect, the osmolarity of the formulation is adjusted to be between about 280 and about 300 mOsmol / kg.

[00123] An additive such as a sugar, glycerol, and other sugar alcohols may be included in the compositions of the present disclosure. Pharmaceutical additives may be added to increase the efficacy or potency of other ingredients in the composition. For example, a pharmaceutical additive may be added to a composition of the present disclosure to improve the stability of the calcineurin inhibitor, to adjust the osmolarity of the composition, to adjust the viscosity of the composition, or for another reason, such as to effect drug delivery. Non-limiting examples of pharmaceutical additives of the present disclosure include sugars such as trehalose, mannose, D-galactose, and lactose. In one embodiment, the sugars may be incorporated into a composition prior to thin film hydration (i.e., internally). In another embodiment, the sugars Petition 870260043159, dated 07 / 05 / 2026, p. 40 / 67 31 / 49 can be incorporated into a composition during the hydration step (i.e., externally). In one embodiment, a clear, aqueous, mixed micellar solution of the present disclosure includes additives such as sugar.

[00124] In one embodiment, the compositions of the present disclosure further comprise one or more bioadhesive polymers. Bioadhesion refers to the ability of certain synthetic and biological macromolecules and hydrocolloids to adhere to biological tissues. Bioadhesion is a complex phenomenon, depending in part on the properties of polymers, biological tissue, and the surrounding environment. Several factors have been found to contribute to a polymer's bioadhesive capacity: the presence of functional groups capable of forming hydrogen bonds (--OH, COOH), the presence and strength of anionic charges, sufficient elasticity for the polymer chains to interpenetrate the mucosal layer, and high molecular weight. Bioadhesion systems have been used in dentistry, orthopedics, ophthalmology, and surgical applications.However, significant interest has recently emerged in the use of bioadhesive materials in other areas such as soft tissue-based artificial replacements and controlled-release systems for local delivery of active bioagents. Such applications include systems for drug delivery in the oral or nasal cavity and for intestinal or rectal administration.

[00125] In one embodiment, a composition of the present disclosure includes at least one bioadhesive polymer. The bioadhesive polymer can enhance the viscosity of the composition and thereby increase its residence time in the eye. The bioadhesive polymers of the present disclosure include, for example, carboxylic polymers such as CarbopolRTM (carbomers), NoveonRTM (polycarbophiles), cellulose derivatives including alkyl and hydroxyalkyl cellulose such as methylcellulose, hydroxypropylcellulose, carboxymethylcellulose, gums such as locust bean gum, xanthan gum, agarose gum, karaya gum, guar gum, and other polymers including, but not limited to, polyvinyl alcohol, Petition 870260043159, dated 07 / 05 / 2026, page 41 / 67 32 / 49 povidone, polyethylene glycol, PluronicRTM (Poloxamers), tragacanth, and hyaluronic acid; phase transition polymers to provide sustained and controlled application of eye-closed medications (e.g., alginic acid, carrageenans (e.g., Eucheuma), mixtures of xanthan gum and locust bean gum, pectins, cellulose acetate phthalate, alkylhydroxyalkyl cellulose and derivatives thereof, hydroxyalkylated polyacrylic acids and derivatives thereof, poloxamers and their derivatives, etc. The physical characteristics in these polymers may be mediated by changes in environmental factors such as ionic strength, pH, or temperature alone or in combination with other factors. In one embodiment, one or more optional bioadhesive polymers are present in the composition from about 0.01% by weight to about 10% by weight / volume, preferably from about 0.1% to about 5% by weight / volume.In one embodiment, the compositions of the present disclosure further comprise at least one hydrophilic polymeric excipient selected from, for example, PVP-K-30, PVP-K-90, HPMC, HEC, and polycarbophil. In one embodiment, the polymeric excipient is selected from PVP-K-90, PVP-K-30, or HPMC. In another embodiment, the polymeric excipient is selected from PVP-K-90 or PVP-K-30.

[00126] In one embodiment, if a preservative is desired, the compositions may optionally be preserved with any of the many well-known preservatives, including benzyl alcohol with / without EDTA, benzalkonium chloride, chlorhexidine, Cosmocil.RTMCQ or Dowicil.RTM200. In certain embodiments, it may be desirable that a formulation as described herein not include any preservatives. In this respect, preservatives, in some embodiments, may not be necessary or desirable in formulations contained in single-use containers. In other embodiments, it may be advantageous to include preservatives, such as in certain embodiments where the formulations are contained in a multi-use container. Petition 870260043159, dated 07 / 05 / 2026, p. 42 / 67 33 / 49

[00127] Ophthalmic compositions can be administered topically to the eye as clear, aqueous, biocompatible mixed micellar solutions. The compositions have the drugs incorporated and / or encapsulated in micelles that are dispersed in an aqueous medium. Non-limiting list of exemplary modalities.

[00128] In addition to the aspects and modalities described and provided elsewhere in this description, the following non-limiting list of particular modalities is specifically contemplated. 1. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, a polyoxyl lipid or fatty acid and a polyalkoxylated alcohol. 2. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, and an n>40 polyoxyl lipid or fatty acid. 3. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine and a polyoxyl lipid or fatty acid; wherein said polyoxyl lipid or fatty acid is present in an amount equal to or greater than 0.5% of said formulation. 4. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine and a polyoxyl lipid or fatty acid; wherein said formulation comprises nanomycells. 5. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.5-5% of one or more selected from the group consisting of HCO40, HCO-60, HCO-80 and HCO-100; and about 0.01-0.1% of octoxinol-40. 6. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.6-2% of one or more selected from the group consisting of HCO40, HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% of octoxinol-40. 7. An ophthalmic formulation comprising approximately 0.09% cyclosporine, 0.5-5% of one or more selected from the group consisting of HCO- Petition 870260043159, dated 07 / 05 / 2026, page 43 / 67 34 / 49 40, HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% octoxynol-40. 8. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.6-4% of one or more polyoxyl lipids selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% of octoxinol-40. 9. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.7-4% of polyoxyl lipids or fatty acids; and about 0.02-0.1% of octoxinol-40. 10. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.8-4% of polyoxyl lipids or fatty acids; and about 0.02-0.1% of octoxinol-40; wherein the formulation comprises nanomycells. 11. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.9-4% of polyoxyl lipids or fatty acids; and about 0.02-0.1% of octoxinol-40; wherein the formulation comprises nanomycells. 12. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, approximately 1% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and approximately 0.02-0.1% of octoxinol-40. 13. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, approximately 1% of HCO-60 and approximately 0.02-0.1% of octoxinol-40. 14. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.5-4% of one or more selected from the group consisting of HCO40, HCO-60, HCO-80 and HCO-100; and about 0.05% of octoxinol-40. 15. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.5-4% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01% of octoxinol-40. 16. An ophthalmic formulation comprising approximately 0.09% cyclosporine, 0.5-4% of one or more selected from the group consisting of HCO- Petition 870260043159, dated 07 / 05 / 2026, p. 44 / 67 35 / 49 40, HCO-60, HCO-80 and HCO-100; and about 0.05% octoxynol-40. 17. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.6-2% of one or more polyoxyl lipids selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05% of octoxinol40. 18. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.6-2% of polyoxyl lipids or fatty acids; and about 0.05% of octoxinol-40. 19. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.6-2% of polyoxyl lipids or fatty acids; and about 0.05% of octoxinol-40; wherein the formulation comprises nanomycells. 20. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, 0.6-2% of polyoxyl lipids or fatty acids; and about 0.05% of octoxinol-40; wherein the formulation comprises nanomycells. 21. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, approximately 1% of one or more selected from the group consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and approximately 0.05% of octoxinol-40. 22. An ophthalmic formulation comprising 0.087-0.093% by weight of cyclosporine, approximately 1% of HCO-60 and approximately 0.05% of octoxinol-40. 23. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.6 and 2% by weight of said formulation. 24. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.8 and 2% by weight of said formulation. 25. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.9 and 1.5% by weight of said formulation. 26. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 1 and 1.5% by weight of said formulation. Petition 870260043159, dated 07 / 05 / 2026, page 45 / 67 36 / 49 27. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.5 and 5% by weight of said formulation. 28. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.6 and 5% by weight of said formulation. 29. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.6 and 4% by weight of said formulation. 30. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.6 and 3% by weight of said formulation. 31. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.6 and 2% by weight of said formulation. 32. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.6 and 1% by weight of said formulation. 33. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.8 and 5% by weight of said formulation. 34. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.8 and 4% by weight of said formulation. 35. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.8 and 3% by weight of said formulation. 36. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.8 and 2% by weight of said formulation. 37. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.9 and 2% by weight of said formulation. 38. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is between 0.9 and 1.5% by weight of said formulation. 39. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is about 1% by weight of said formulation. 40. The formulation of any of the previous modalities, in which the said Petition 870260043159, dated 07 / 05 / 2026, pp. 46 / 67 37 / 49 polyoxyl lipid or fatty acid is greater than about 0.6% by weight of said formulation. 41. Any formulation of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is greater than about 0.7% by weight of said formulation. 42. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is greater than about 0.8% by weight of said formulation. 43. Any formulation of the foregoing embodiments in which said polyoxyl lipid or fatty acid is greater than about 0.9% by weight of said formulation. 44. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is greater than about 1% by weight of said formulation. 45. The formulation of any of the preceding embodiments, in which said polyalkoxylated alcohol is present, is between 0.005 and 4% by weight of said formulation. 46. ​​The formulation of any of the above embodiments, in which said polyalkoxylated alcohol is present, is between 0.005 and 3% by weight of said formulation. 47. The formulation of any of the foregoing embodiments, in which said polyalkoxylated alcohol is present, is between 0.005 and 2% by weight of said formulation. 48. The formulation of any of the preceding embodiments, in which said polyalkoxylated alcohol is present, is between 0.005 and 1% by weight of said formulation. 49. The formulation of any of the preceding embodiments, in which said polyalkoxylated alcohol is present, is between 0.005 and 0.5% by weight of said formulation. 50. The formulation of any of the foregoing embodiments, in which said polyalkoxylated alcohol is present, is between 0.005 and 0.1% by weight of said formulation. 51. The formulation of any of the previous modalities, in which the said Petition 870260043159, dated 07 / 05 / 2026, page 47 / 67 38 / 49 polyalkoxylated alcohol, if present, is between 0.005 and 0.05% by weight of said formulation. 52. The formulation of any of the foregoing embodiments, in which said polyalkoxylated alcohol is present, is between 0.008 and 0.02% by weight of said formulation. 53. The formulation of any of the foregoing embodiments, in which said polyalkoxylated alcohol is present, is approximately 0.05% by weight of said formulation. 54. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is a polyoxyl castor oil. 55. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is one or more selected from HCO-60, HCO-80 or HCO-100. 56. The formulation of any of the foregoing embodiments, in which said polyoxyl lipid or fatty acid is HCO-60. 57. The formulation of any of the previous modalities, in which the said active agent comprises a combination of two different agents. 58. A formulation of any of the foregoing embodiments, in which the active agent comprises two or more active agents selected from the group consisting of a resolvin or resolvin-like compound, a steroid (such as a corticosteroid), cyclosporine A, and voclosporin. 59. The formulation of any of the above modalities, in which the active agent also comprises a resolvin and a corticosteroid. 60. The formulation of any of the above modalities, in which the active agent comprises cyclosporine A and a corticosteroid. 61. The formulation of any of the above modalities, in which the active agent comprises a resolvin, cyclosporine A, and a corticosteroid. 62. The formulation of any of the above forms, in which said formulation does not include preservatives. 63. The formulation of any of the previous modalities, in which the said Petition 870260043159, dated 07 / 05 / 2026, pp. 48 / 67 The 39 / 49 formulation does not include benzyl alcohol with / without EDTA, benzalkonium chloride, chlorhexidine, Cosmocil.RTM.CQ or Dowicil.RTM.200. 64. A method of treating or preventing an eye disease or condition, said method comprising topical administration of a formulation of any of the preceding modalities. 65. A method of treating or preventing an eye disease or condition, said method comprising topical administration of a formulation of any of the preceding modalities; wherein said disease is a disease of the anterior segment. 66. A method of treating or preventing an eye disease or condition, said method comprising topical administration of a formulation of any of the preceding modalities; wherein said disease is a disease of the posterior segment. 67. A method of treating or preventing an eye disease or condition, said method comprising topical administration of a formulation of any of the preceding modalities; wherein said 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 cicatrizing conjunctivitis and other autoimmune disorders of the ocular surface, blepharitis, scleritis, age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), ocular neurovascularization, age-related macular degeneration (ARMD), proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV) retinitis, optic neuritis, retrobulbar neuritis, and macular pucker. 68. A method of treating or preventing an eye disease or condition, said method comprising topical administration of a formulation. Petition 870260043159, dated 07 / 05 / 2026, page 49 / 67 40 / 49 of any of the previous modalities; in which the said disease is dry eye syndrome. 69. A method of treating or preventing an eye disease or condition, said method comprising topical administration of a formulation of any of the preceding modalities; wherein said disease is allergic conjunctivitis. 70. A method of treating or preventing an eye disease or condition, said method comprising topical administration of a formulation of any of the preceding modalities; wherein said disease is age-related macular degeneration (AMD).

[00129] The following examples are provided to further illustrate aspects of the invention. These examples are non-limiting and should not be construed as limiting any aspect of the invention. EXAMPLE 1 Preparation of Mixed Nanomicellar Formulations Containing Cyclosporine

[00130] Mixed cyclosporine nanomicellar formulations are prepared as follows: hydrogenated polyoxyl 40 castor oil melt; Slow addition of cyclosporine to the same and, after that, substantial homogenization of the ingredients; Add octoxinol-40 to the resulting homogeneous mixture and stir until substantially homogeneous, followed by the individual addition of excipients (e.g., monobasic sodium phosphate, dibasic sodium phosphate, and sodium chloride) with sufficient stirring to achieve good dissolution of each.

[00131] The prepared formulations are subjected to various tests such as trapping efficiency, loading efficiency, size Petition 870260043159, dated 07 / 05 / 2026, pp. 50 / 67 41 / 49 mixed nanomicellar and polydispersity index.

[00132] Mixed nanomicellar size and polydispersity index: The size and polydispersity index of the formulation are determined with a Zetasizer, Malvern Instruments, NJ. In summary, approximately 1 ml of each formulation was transferred to a container and placed in the instrument. A laser light beam was used to determine the mixed nanomicellar size. Nanomicells contemplated by the present disclosure typically have a particle size in the range of about 1-100 nm; in some embodiments, the particle size falls in the range of about 5-50 nm; in some embodiments, the particle size falls in the range of about 10-40 nm; in some embodiments, the particle size is about 15 nm.

[00133] Trapping efficiency: To determine the trapping efficiency of the formulation, all prepared formulations are subjected to a trapping efficiency test. In summary, the formulations are vortex-mixed for homogeneity, and 1 mL is transferred to a fresh Eppendorf tube (1.5 mL). Each formulation is lyophilized to obtain a solid at the bottom of the Eppendorf tube. The resulting solid is suspended in 1 mL of organic solvent (diethyl ether) to generate reverse micelles and release the drug into the external organic solvent. The organic solvent is evaporated overnight at vacuum speed. The resulting reverse micelles are resuspended in 1 mL of 2-propanol (the dilution factor was considered) and further diluted to determine the concentration of cyclosporine trapped in each micellar preparation using HPLC. The trapping efficiency of the formulation is calculated using the following formula (where MNF = mixed nanomicellar formulation): Trapping efficiency = (amount of drug quantified in MNF) x 100 / amount of drug added to the MNF

[00134] Drug Quantification by an HPLC Method: In vitro analysis of cyclosporine is performed by a high-performance liquid chromatography method. Petition 870260043159, dated 07 / 05 / 2026, pp. 51 / 67 42 / 49 reverse-phase HPLC performance with a Shimadzu HPLC pump (Shimadzu, Shimadzu Scientific Instruments, Columbia, MD), Alcott autosampler (model 718 AL), 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 comprises methanol (MeOH), water, and trifluoroacetic acid (TFA) (70:30:0.05% v / v) which is set at a flow rate of 0.5 mL / min. The detection wavelength is set at 272 nm. The sample tray temperature is maintained at 4°C. The calibration curve (0.5 to 5 μg / mL) for cyclosporine is prepared by making appropriate dilutions of the stock solution in 2-propanol. A 10 μL injection volume is injected into the HPLC column for analysis. All prepared standards and samples are stored at 4°C before and during analysis. EXAMPLE 2 Preparation of a Mixed Nanomicellin Cyclosporine-Containing Formulation Using a Solvent-Based Method or a Fusion-Based Method

[00135] The mixed nanomicellar formulation encapsulating cyclosporine is prepared by a two-step solvent evaporation method: Composition of the sinus ophthalmic solution (bulk); and Filling of sinus ophthalmic solution in unit doses of blow / fill / seal (BFS) with subsequent packaging of strips of four (4) BFS units into individual aluminum pouches.

[00136] An exemplary solvent-based manufacturing process contemplated for use herein is described in more detail as follows: Step 1: The required quantities of cyclosporine, octoxinol-40, and HCO40 are dissolved in ethanol and loaded into a round-bottom flask of appropriate size. The flask is attached to a rotary evaporator, and rotation is started to mix the contents of the flask. Petition 870260043159, dated 07 / 05 / 2026, pp. 52 / 67 43 / 49 Step 2: The ethanol is removed by rotary evaporation until a thin film is obtained. Step 3: The required amount of water for injection is added to the vial containing the film from step 2, and the contents are dissolved by rotational mixing (laminar flow). Step 4: The required quantities of sodium chloride and previously prepared phosphate buffer are added to a stainless steel vessel, and the contents are mixed. Step 5: The contents of Step 3 are transferred to the tank containing the buffer and stirred until dissolved. Step 6: The required amount of Povidone is added to the tank and stirred until dissolved. Step 7: The pH of the solution from Step 6 is measured, adjusted (if necessary), and brought to the final volume with water for injection. Step 8: The solution from Step 7 is aseptically filtered and aseptically filled into blow-fill-seal (BFS) unit-dose vials with a nominal fill volume of 0.25 mL. Step 9: The vials are packaged in strips of four (4) BFS units in heat-sealed aluminum pouches.

[00137] An exemplary melt-based manufacturing process contemplated for use herein is described in more detail below: Step 1: The required amount of HCO-40 is melted in a flask heated to approximately 60°C with stirring. Once liquefied, the required amount of cyclosporine is added and mixed until dissolved. Octoxinol 40 is then added and the entire solution is mixed until uniform. Step 2: The required amount of water for injection is loaded into a stainless steel vessel and stirred until the temperature reaches 25°C. Petition 870260043159, dated 07 / 05 / 2026, pp. 53 / 67 44 / 49 Step 3: The contents of Step 1 are transferred to the stainless steel vessel and stirred until dissolved. Step 4: The required amounts of sodium chloride and phosphate buffer are added to the stainless steel vessel and the contents are mixed until dissolved. Step 5: The required amount of Povidone is added to the container and stirred until dissolved. Step 6: The pH of the solution from Step 5 is measured, adjusted (if necessary), and brought to the final volume with water for injection. Step 7: The solution from Step 6 is aseptically filtered and aseptically filled into blow-fill-seal (BFS) unit-dose vials with a nominal fill volume of 0.3 mL. Step 8: The vials are packaged in strips of four (4) BFS units in heat-sealed aluminum pouches. EXAMPLE 3 Preparation of a formulation containing mixed nanomicellar cyclosporine using an ethanol solvent evaporation method.

[00138] The mixed nanomicellar formulation encapsulating cyclosporine is prepared by the two-step solvent evaporation method: Composition of the sinus ophthalmic solution; and Filling of sinus ophthalmic solution in unit doses of blow / fill / seal (BFS) with subsequent packaging of strips of four (4) BFS units into individual aluminum pouches.

[00139] The manufacturing process employed here is described in more detail below: Step 1: The required quantities of cyclosporine, octoxinol-40, and vitamin E polyethylene glycol succinate are dissolved in ethanol and loaded into a vial. Petition 870260043159, dated 07 / 05 / 2026, pages 54 / 67 A 45 / 49 round-bottomed flask of suitable size. The flask is attached to a rotary evaporator and rotation is started to mix the contents of the flask. Step 2: The ethanol is removed by rotary evaporation until a waxy solid is obtained. Step 3: The required amount of water for injection is added to the vial containing the waxy residue from Step 2, and the contents are dissolved by rotational mixing (laminar flow). Step 4: The contents of Step 3 are transferred to a stainless steel vessel containing the required amount of povidone solution, and the contents are mixed until uniform. Step 5: The required amounts of sodium chloride and phosphate buffer prepared previously are added to the solution in Step 4, and the contents are mixed. Step 6: The pH of the solution from Step 5 is measured, adjusted (if necessary), and brought to the final volume with water for injection. Step 7: The solution from Step 6 is aseptically filtered and aseptically filled into blow-fill-seal (BFS) unit-dose vials with a nominal fill volume of 0.25 mL. Step 8: The vials are packaged in strips of four (4) BFS units in heat-sealed aluminum pouches. EXAMPLE 4 Preparation of mixed nanomicellar formulations containing cyclosporine using an alternative order of addition-based method. Step 1: The required amount of HCO-40 is melted in a flask heated to approximately 60°C with stirring. Once liquefied, the required amount of cyclosporine is added and mixed until dissolved and uniform. Petition 870260043159, dated 07 / 05 / 2026, pp. 55 / 67 46 / 49 Step 2: The required amount of Octoxinol-40 is heated to approximately 60°C and, once liquefied, is added to the cyclosporine HCO-40 mixture. Step 3: The required amount of water for injection at approximately 25°C is added to the vial containing the dissolved cyclosporine and shaken until dissolved. Step 4: The required amounts of sodium chloride and phosphate buffer are added to the flask and the contents are mixed. Step 5: PVP-K90 is weighed, added to the solution, and mixed until dissolved. Step 6: The pH of the solution from Step 5 is measured, adjusted (if necessary), and brought to the final volume with water for injection. EXAMPLE 5

[00140] Any of the protocols described here can be performed with the following reagents: 0.09% by weight of cyclosporine, 1.0% by weight of hydrogenated polyoxyl 40 castor oil, and 0.05% by weight of octoxinol-40 (Igepal), 0.405% by weight of monobasic sodium phosphate and optionally 0.465% by weight of dibasic sodium phosphate, 0.05% by weight of sodium chloride, 0.3% by weight of povidone K90, and water for injection.

[00141] A multicenter, randomized, dual-mask, vehicle-controlled, dose-ranging, vehicle-controlled study was designed to evaluate 2 concentrations of OTX-101 ophthalmic solution, 0.09% and 0.05%, versus vehicle in approximately 420 individuals with keratoconjunctivitis sicca (KCS). Individuals who met the eligibility criteria at screening (patient-reported history of KCS for > 6 months, clinical diagnosis of KCS) were eligible. Petition 870260043159, dated 07 / 05 / 2026, pages 56 / 67 Individuals with bilateral 47 / 49, lissamine green staining score > 3 to < 9, and global symptom score > 40 based on a modified Symptom Assessment in Dry Eye (SANDE) questionnaire) entered a trial period with vehicle administered topically twice daily (BID) to both eyes for 14 days. After the trial period, individuals who continued to meet the inclusion criteria for lissamine green staining score and global symptom score in at least one eye were randomized into 1 of 3 treatment groups and received treatment for 12 weeks (84 days): OTX-101 0.05% 1 drop in both eyes BID, OTX-101 0.09% 1 drop in both eyes BID, and Vehicle: 1 drop in both eyes twice daily.

[00142] Individuals' symptoms were assessed using the SANDE questionnaire, individual signs were evaluated using lissamine green conjunctival staining, corneal fluorescein staining, Schirmer test (non-anesthetized), and tear breakup time, and individual satisfaction with treatment was assessed using a 5-point ordinal scale. Safety was assessed by Snellen visual acuity (VA), slit-light examination, intraocular pressure (IOP) tonometry, dilated ophthalmoscopy / fundus examination, adverse event (AE) collection, and review of concomitant medication. Safety and efficacy assessments were conducted at study visits on days 14, 28, 42, 56, and 84. Both eyes were evaluated at each visit.

[00143] The results are presented in Figure 1, where it can be seen that the formulations according to the present disclosure (containing 0.09% by weight of cyclosporine) are substantially more effective than placebo or formulations containing only 0.05% by weight of cyclosporine.

[00144] The formulations according to the present disclosure containing 0.09% by weight of cyclosporine were not only superior to the vehicle with Petition 870260043159, dated 07 / 05 / 2026, pages 57 / 67 48 / 49 in relation to the Schirmer test (p=0.007), these formulations were also superior to the vehicle with respect to conjunctival staining (co-primary, p=0.008) and corneal staining (p<0.001). The formulations of the present disclosure (containing 0.09% by weight of cyclosporine) showed clinically significant improvement in tear production in individuals with > 10 mm increase in Schirmer test score from baseline based on data for both eyes.

[00145] The invention described in an illustrative manner herein can be practiced in the absence of any element or elements, limitation or limitations not specifically described herein. The terms and expressions employed are used as terms of description and not of limitation, and there is no intention that the use of such terms and expressions excludes any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed invention. Thus, it should be understood that although the present invention has been specifically described by preferred embodiments and optional features, those skilled in the art may resort to modifying and varying the concepts described herein, and such modifications and variations are considered within the scope of this invention as defined by the appended claims.

[00146] The contents of articles, patents and patent applications and all other electronically available documents and information mentioned or cited herein are hereby incorporated by reference in their entirety to the same extent as if each individual publication were specifically and individually indicated as being incorporated by reference. The applicants reserve the right to physically incorporate into this application any and all materials and information from any such articles, patents, patent applications or other documents.

[00147] The inventions described in an illustrative manner herein can be practiced. Petition 870260043159, dated 07 / 05 / 2026, pp. 58 / 67 49 / 49 appropriately in the absence of any element or elements, limitation or limitations not specifically described herein. Thus, for example, the terms comprising, including, “containing, etc.” should be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed invention. Thus, it should be understood that although the present invention has been specifically described by preferred embodiments and optional features, those skilled in the art may resort to modification and variation of the incorporated inventions described herein, and such modifications and variations are considered within the scope of this invention.

[00148] The invention has been described broadly and generically herein. Each of the more restricted subgeneric species and groupings found within the generic description is also part of the invention. This includes the generic description of the invention with a negative condition or limitation of removing any subject matter of the genus, regardless of whether the excised material is specifically recited herein or not.

[00149] In addition, where features and aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also hereby described in terms of any individual member or subgroup of members of the Markush group.

[00150] Other modalities are presented within the following claims. Petition 870260043159, dated 07 / 05 / 2026, pp. 59 / 67

Claims

1 / 2 CLAIMS 1. Use of an aqueous topical ophthalmic formulation CHARACTERIZED in that it is for the manufacture of a medicament to treat an inflammatory eye disease in an individual, wherein the aqueous topical ophthalmic formulation consists essentially of: 0.087 to 0.093% by weight of cyclosporine, 1.0% by weight of hydrogenated polyoxyl 40 castor oil, 0.05% by weight of octoxinol-40, 0.3% by weight of povidone, 0.05% by weight of sodium chloride, phosphate buffer, adjusted to a pH of 5 to 8 with sodium hydroxide and / or hydrochloric acid; and water.

2. Use, according to claim 1, CHARACTERIZED by the fact that the inflammatory eye disease is keratoconjunctivitis sicca.

3. Use according to claim 1, CHARACTERIZED in that cyclosporine is 0.09% by weight of the formulation.

4. Use according to claim 1, CHARACTERIZED in that the pH of the formulation is 6.6 to 7.

0.

5. Use of a topical ophthalmic formulation CHARACTERIZED by the fact that it is in the manufacture of a medicament to treat keratoconjunctivitis sicca in an individual, the formulation being defined as consisting essentially of 0.09% by weight of cyclosporine, 1.0% by weight of hydrogenated polyoxyl 40 castor oil, 0.05% by weight of octoxinol-40, 0.3% by weight of povidone, 0.05% by weight of sodium chloride, phosphate buffer, and sodium hydroxide and / or hydrochloric acid, and having a pH of 5 to 8, wherein the individual has: Petition 870260043159, dated 07 / 05 / 2026, page 60 / 67 2 / 2 i) a history of keratoconjunctivitis sicca (KCS) for at least 6 months; ii) a clinical diagnosis of bilateral KCS; iii) a lissamine green staining score of 3 to 9; and iv) a global symptom score greater than 40 based on a modified “Symptom Assessment in Dry Eye” (SANDE) questionnaire.

6. Use according to claim 5, CHARACTERIZED in that the formulation has a pH of 6.6 to 7.

7. Use, according to claim 5, CHARACTERIZED in that cyclosporine is present in one or more mixed nanomycells in the formulation.

8. Use, according to claim 7, CHARACTERIZED in that the mixed nanomicelles have a particle size of 5 to 50 nm.

9. Use, according to claim 7, CHARACTERIZED in that the mixed nanomicelles have a particle size of 10 to 40 nm.

10. Use according to claim 7, CHARACTERIZED in that the mixed nanomicelles have a particle size of 15 nm. Petition 870260043159, dated 07 / 05 / 2026, pp. 61 / 67

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