Cyclosporine formulations for use in patients undergoing cataract surgery

Abstract

A method for preparing a subject for cataract surgery includes topical administration of a cyclosporine solution. Administration may be twice daily and may be for 28 days. The method results in improved error prediction for monthly spherical equivalent and improvement of ocular surface irregularities.

Description

[Background technology]

[0001] Patient satisfaction after cataract surgery in today's world depends on minimizing refractive errors and optimizing the quality of the visual image (see D1, D2). Ocular surface irregularities can adversely affect the consistency of preoperative keratometric measurements and subsequently affect the quality of postoperative vision (see D3-D5). These inconsistent preoperative keratometric measurements directly impact the cataract surgeon's ability to select the appropriate intraocular lens (IOL) implant. Thus, for example, in patients with dry eye disease (DED), improving the ocular surface will lead to greater refractive accuracy of lens selection preoperatively (see D6-D8).

[0002] It is well established that management of ocular surface disease is critical to the success of cataract surgery for several reasons. Not only can cataract surgery exacerbate signs and symptoms of dry eye, even in patients who self-report asymptomatic, but ocular surface irregularities can compromise the accuracy of preoperative biometry and corneal topography / tomography, leading to inaccurate IOL calculations, suboptimal postoperative outcomes, and patient dissatisfaction (see D9, D10). High-order aberrations (HOAs) are also associated with postoperative patient dissatisfaction, especially when multifocal IOLs are implanted. Given the generally high postoperative expectations of patients (see D11), cataract surgeons must prioritize minimizing these issues in order to meet their patients' needs. References

[0003] D1. Monestam E. Long-term outcomes of cataract surgery:15-year results of a prospective study. J Cataract Refract Surg.Jan 2016;42(1):19-26.doi:10.1016 / j.jcrs.2015.07.040

[0004] D2. Gollogly HE,Hodge DO,St Sauver JL,Erie JC. Increasing incidence of cataract surgery:population-based study. J Cataract Refract Surg.Sep 2013;39(9):1383-9.doi:10.1016 / j.jcrs.2013.03.027

[0005] D3. Lee AC,Qazi MA,Pepose JS. Biometry and intraocular lens power calculation. Current opinion in ophthalmology. Jan 2008;19(1):13-7.doi:10.1097 / ICU.0b013e3282f1c5ad

[0006] D4. Jeong J,Song H,Lee JK,Chuck RS,Kwon BMS. The effect of ocular biometric factors on the accuracy of various IOL power calculation formulas. BMC Ophthalmol. May 2 2017;17(1):62.doi:10.1186 / s12886-017-0454-y

[0007] D5. Norrby S. Sources of error in intraocular lens power calculation. J Cataract Refract Surg.Mar 2008;34(3):368-76.doi:10.1016 / j.jcrs.2007.10.031

[0008] D6. Sheard R.Optimising biometry for best outcomes in cataract surgery. Eye. Feb 2014;28(2):118-25. doi:10.1038 / eye.2013.248

[0009] D7. Sahin A,Hamrah P.Clinically relevant biometry. Current opinion in ophthalmology. Jan 2012;23(1):47-53.doi:10.1097 / ICU.0b013e32834cd63e

[0010] D8. Hovanesian J,Epitropoulos A,Donnenfeld ED,Holladay JT. The Effect of Lifitegrast on Refractive Accuracy and Symptoms in Dry Eye Patients Undergoing Cataract Surgery. Clin Ophthalmol.2020;14:2709-2716.doi:10.2147 / opth.S264520

[0011] D9. Li XM,Hu L,Hu J,Wang W.Investigation of dry eye disease and analysis of the pathogenic factors in patients after cataract surgery. Cornea. Oct 2007;26(9 Suppl 1):S16-20.doi:10.1097 / ICO.0b013e31812f67ca00003226-200710001-00005[pii]

[0012] D10. Epitropoulos AT,Matossian C,Berdy GJ,Malhotra RP,Potvin R.Effect of tear osmolarity on repeatability of keratometry for cataract surgery planning. J Cataract Refract Surg. Aug 2015;41(8):1672-7. doi:10.1016 / j.jcrs.2015.01.016

[0013] D11. Addisu Z,Solomon B.Patients'preoperative expectation and outcome of cataract surgery at jimma university specialized hospital -department of ophthalmology. Ethiop J Health Sci. Mar 2011;21(1):47-55.doi:10.4314 / ejhs.v21i1.69044 Summary of the Invention

[0014] The present invention relates to a method of preparing a subject for cataract surgery, the method comprising administering a solution comprising cyclosporine to the eye in which cataract surgery is to be performed.

[0015] In one embodiment of the method, the cyclosporine solution is administered topically.

[0016] In another embodiment of the invention, the cyclosporine solution is administered twice daily.

[0017] In yet another embodiment of the invention, the cyclosporine solution is administered for 28 days immediately prior to cataract surgery.

[0018] In yet another embodiment of the present invention, the solution containing cyclosporine is an aqueous topical ophthalmic formulation consisting of about 0.087-0.093% by weight cyclosporine, about 1.0% by weight hydrogenated 40 polyoxyl castor oil, about 0.05% by weight octoxynol-40, about 0.3% by weight povidone, about 0.05% by weight sodium chloride, about 0.20-0.405% by weight monobasic sodium phosphate, and about 0.23-0.465% by weight dibasic sodium phosphate, adjusted to a pH of about 5 to about 8 with sodium hydroxide / hydrochloric acid, and made up to a final volume with water. In one aspect of the above embodiment, about 0.20-0.405% by weight monobasic sodium phosphate is equivalent to about 0.26-0.53% by weight monobasic sodium phosphate dihydrate. In another aspect of the above embodiment, the dibasic sodium phosphate is in anhydrous form.

[0019] In one embodiment of the invention, cyclosporine is present in an amount of about 0.09% by weight of the formulation.

[0020] In another embodiment of the invention, the pH of the solution of cyclosporine is about 6.6 to 7.0.

[0021] In yet another embodiment of the present invention, the cyclosporine-containing solution is an aqueous transparent nanomicellar ophthalmic formulation comprising about 0.05-0.5% by weight of cyclosporine, a polyalkoxylated alcohol, and one or more polymers including HCO-40, HCO-60, HCO-80, HCO-100, polyoxyl 35 castor oil, or combinations thereof.

[0022] In still yet another embodiment of the invention, the one or more polymers comprise HCO-40, HCO-60, HCO-80, HCO-100, or combinations thereof.

[0023] In one embodiment of the present invention, the aforementioned polymer comprises polyoxyl 35 castor oil.

[0024] In another embodiment of the invention, the polymer is HCO-40.

[0025] In one embodiment of the invention, the polymer is about 0.5-1.5% by weight of the cyclosporine formulation.

[0026] In another embodiment of the invention, the polymer comprises HCO-40, HCO-60, HCO-80, or a combination thereof, and is about 0.5-1.5% by weight of the formulation.

[0027] In yet another embodiment of the invention, the polyalkoxylated alcohol used in the solution of cyclosporine comprises octoxynol-40.

[0028] In yet another embodiment of the invention, the polyalkoxylated alcohol comprises octoxynol-40 and is about 0.02-4% by weight of the formulation.

[0029] In another embodiment of the invention, the polyalkoxylated alcohol comprises octoxynol-40 and is about 0.02-0.1% by weight of the formulation.

[0030] In another embodiment of the invention, the method employs a solution of cyclosporine, the cyclosporine being about 0.05-0.2% by weight of the formulation.

[0031] In yet another embodiment of the method, the polymer used in the solution of cyclosporine comprises HCO-40, HCO-60, HCO-80, HCO-100, or a combination thereof, and said polyalkoxylated alcohol is octoxynol-40.

[0032] In yet another embodiment of the method, the polymer used in the solution of cyclosporine is about 0.5-1.5% by weight of the formulation and said polyalkoxylated alcohol is octoxynol-40 and is about 0.02-0.1% by weight of the formulation.

[0033] In yet another embodiment of the method, the polymer used in the solution of cyclosporine is about 0.5-1.5% by weight of the formulation, said polyalkoxylated alcohol comprises octoxynol-40 in an amount of about 0.02-0.1% by weight of the formulation, and the cyclosporine is about 0.05-0.2% by weight of the formulation.

[0034] The present invention further provides a method of reducing ocular surface irregularities, the method comprising administering to the eye a solution comprising cyclosporine.

[0035] In one embodiment of the invention, the cyclosporine solution is administered topically.

[0036] In another embodiment, the cyclosporine solution is administered twice daily.

[0037] In yet another embodiment, the cyclosporine solution is administered for 28 days.

[0038] In yet another embodiment, the solution containing cyclosporine is an aqueous ophthalmic topical formulation consisting of about 0.087-0.093% by weight cyclosporine, about 1.0% by weight hydrogenated 40 polyoxyl castor oil, about 0.05% by weight octoxynol-40, about 0.3% by weight povidone, about 0.05% by weight sodium chloride, about 0.20-0.405% by weight sodium phosphate monobasic, and about 0.23-0.465% by weight sodium phosphate dibasic, adjusted to a pH of about 5 to about 8 with sodium hydroxide / hydrochloric acid, and made up to final volume with water.

[0039] In one embodiment of the invention, cyclosporine is present in an amount of about 0.09% by weight of the formulation.

[0040] In another embodiment of the invention, the pH of the solution of cyclosporine is about 6.6 to 7.0.

[0041] In yet another embodiment of the present invention, a method for reducing ocular surface irregularities comprises administering a cyclosporine solution comprising an aqueous transparent nanomicellar ophthalmic formulation comprising about 0.05-0.5% by weight cyclosporine, a polyalkoxylated alcohol, and one or more polymers including HCO-40, HCO-60, HCO-80, HCO-100, polyoxyl 35 castor oil, or combinations thereof.

[0042] In yet another embodiment of the invention, the polymer comprises HCO-40, HCO-60, HCO-80, HCO-100, or combinations thereof.

[0043] In yet another embodiment of the present invention, the polymer comprises polyoxyl 35 castor oil.

[0044] In yet another embodiment of the present invention, the polymer is HCO-40.

[0045] In yet another embodiment of the invention, the polymer is about 0.5-1.5% by weight of the formulation.

[0046] In one embodiment of the present invention, a method for reducing ocular surface irregularities comprises administering a cyclosporine solution comprising an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, wherein the polymer comprises HCO-40, HCO-60, HCO-80, or a combination thereof, at about 0.5-1.5% by weight of the formulation.

[0047] In another embodiment of the invention, a method for reducing ocular surface irregularities comprises administering a cyclosporine solution comprising an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, wherein the polyalkoxylated alcohol comprises octoxynol-40.

[0048] In yet another embodiment, a method for reducing ocular surface irregularities comprises administering a cyclosporine solution comprising an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, wherein the polyalkoxylated alcohol comprises octoxynol-40 and is at 0.02-4% by weight of the formulation.

[0049] In yet another embodiment of the invention, the polyalkoxylated alcohol comprises octoxynol-40 and is at 0.02-0.1% by weight of the formulation.

[0050] In one embodiment of the present invention, the method of reducing ocular surface irregularities employs a solution of cyclosporine, the cyclosporine being 0.05-0.2% by weight of the formulation.

[0051] In another embodiment of the invention, a method of reducing ocular surface irregularities uses a solution of cyclosporine solution, said solution comprising a polymer comprising HCO-40, HCO-60, HCO-80, HCO-100, or combinations thereof, and said polyalkoxylated alcohol is octoxynol-40.

[0052] In yet another embodiment of the invention, said polymer is about 0.5-1.5% by weight of the formulation and said polyalkoxylated alcohol is octoxynol-40 and is about 0.02-0.1% by weight of the formulation.

[0053] In yet another embodiment of the invention, the polymer is present at about 0.5-1.5% by weight of the formulation, the polyalkoxylated alcohol comprises octoxynol-40 and is present at about 0.02-0.1% by weight of the formulation, and the cyclosporine is present at 0.05-0.2% by weight of the formulation.

[0054] The present invention also provides a method for reducing conjunctival erythema, the method comprising administering to the eye a solution comprising cyclosporine.

[0055] In one embodiment of the invention, the cyclosporine solution is administered topically.

[0056] In another embodiment of the invention, the cyclosporine solution is administered twice daily.

[0057] In one embodiment of the invention, the cyclosporine solution is administered for 28 days.

[0058] In one embodiment, the invention provides a method of reducing conjunctival erythema, the method comprising administering to the eye a solution comprising cyclosporine, the cyclosporine-containing solution being an aqueous ophthalmic topical formulation consisting of about 0.087-0.093% by weight cyclosporine, about 1.0% by weight hydrogenated 40 polyoxyl castor oil, about 0.05% by weight octoxynol-40, about 0.3% by weight povidone, about 0.05% by weight sodium chloride, about 0.20-0.405% by weight sodium phosphate monobasic, and about 0.23-0.465% by weight sodium phosphate dibasic, adjusted to a pH of about 5 to about 8 with sodium hydroxide / hydrochloric acid, and made up to a final volume with water.

[0059] In another embodiment of the invention, the cyclosporine is present in an amount of about 0.09% by weight of the formulation.

[0060] In yet another embodiment of the invention, the pH of the formulation is about 6.6 to 7.0.

[0061] In one embodiment, the present invention provides a method for reducing conjunctival erythema comprising administering to an eye a solution comprising cyclosporine, the cyclosporine-containing solution being an aqueous transparent nanomicellar ophthalmic formulation comprising about 0.05-0.5% by weight cyclosporine, a polyalkoxylated alcohol, and one or more polymers including HCO-40, HCO-60, HCO-80, HCO-100, polyoxyl 35 castor oil, or combinations thereof.

[0062] In one embodiment of the invention, the polymer comprises HCO-40, HCO-60, HCO-80, HCO-100, or a combination thereof.

[0063] In another embodiment of the invention, the polymer comprises polyoxyl 35 castor oil.

[0064] In yet another embodiment, the polymer is HCO-40.

[0065] In one embodiment of the invention, the polymer is about 0.5-1.5% by weight of the formulation.

[0066] In one embodiment, the present invention provides a method of reducing conjunctival erythema comprising administering to the eye a solution comprising cyclosporine, the solution comprising cyclosporine being an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, the polymer comprising HCO-40, HCO-60, HCO-80, or a combination thereof, at about 0.5-1.5% by weight of the formulation.

[0067] In one embodiment, the present invention provides a method of reducing conjunctival erythema comprising administering to the eye a solution comprising cyclosporine, the solution comprising cyclosporine being an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, wherein the polyalkoxylated alcohol comprises octoxynol-40.

[0068] In one embodiment, the present invention provides a method for reducing conjunctival erythema comprising administering to an eye a solution comprising cyclosporine, the solution comprising cyclosporine being an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, the polyalkoxylated alcohol comprising octoxynol-40, being at about 0.02-4% by weight of the formulation.

[0069] In one embodiment, the present invention provides a method of reducing conjunctival erythema comprising administering to an eye a solution comprising cyclosporine, the solution comprising cyclosporine being an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, the polyalkoxylated alcohol comprising octoxynol-40 being at about 0.02-0.1% by weight of the formulation.

[0070] In one embodiment, the present invention provides a method for reducing conjunctival erythema comprising administering to an eye a solution comprising cyclosporine, the solution comprising cyclosporine being an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, wherein the cyclosporine is about 0.05-0.2% by weight of the formulation.

[0071] In one embodiment, the present invention provides a method of reducing conjunctival erythema comprising administering to an eye a solution comprising cyclosporine, the solution comprising cyclosporine being an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, wherein the polymer comprises HCO-40, HCO-60, HCO-80, HCO-100, or a combination thereof, and the polyalkoxylated alcohol is octoxynol-40.

[0072] In another embodiment, the present invention provides a method of reducing conjunctival erythema comprising administering to an eye a solution comprising cyclosporine, wherein the solution comprising cyclosporine is an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, wherein the polymer is at about 0.5-1.5% by weight of the formulation, and the polyalkoxylated alcohol is octoxynol-40 and is at about 0.02-0.1% by weight of the formulation.

[0073] In one embodiment, the invention provides a method of reducing conjunctival erythema comprising administering to an eye a solution comprising cyclosporine, the solution comprising cyclosporine being an aqueous transparent nanomicellar ophthalmic formulation comprising cyclosporine, a polyalkoxylated alcohol, and one or more polymers, the polymer being at about 0.5-1.5% by weight of the formulation, the polyalkoxylated alcohol comprising octoxynol-40 being at about 0.02-0.1% by weight of the formulation, and the cyclosporine being at about 0.05-0.2% by weight of the formulation. [Brief description of the drawings]

[0074] [Figure 1] FIG. 1 is a graphical representation illustrating the study visit and testing process. [Diagram 2] Figure 2 is a graph showing that the predictive accuracy of corneal power measurements performed after cyclosporine was significantly higher than those performed before cyclosporine (n=64, P<0.03, paired t-test). [Diagram 3] Figure 3 is a graph showing that significantly more patients improved than declined in root mean square higher order aberrations after 28 days of cyclosporine (n=64, P<0.0001, McNemar's chi-square test). [Figure 4] FIG. 4 is a graph showing that SPEED scores improved significantly after 28 days of treatment with cyclosporine (P<0.00001, paired t-test). [Diagram 5] Figure 5 is a graph showing that corneal staining (Oxford scale) was measured before and after 28 days of treatment with cyclosporine and improved significantly after treatment, showing complete resolution in 56% of patients (P<0.000001, paired t-test). Note that all eyes (n=64) had at least grade 1 staining before treatment as a condition for enrollment in the study. [Figure 6] FIG. 6 is a graph showing tear film breakup time measured before and after 28 days of treatment with cyclosporine, which was significantly improved after treatment (n=64, P<0.00001, paired t-test). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0075] This disclosure shows improvement in surface regularity and predictive accuracy of preoperative corneal power measurements for topical administration of a solution containing cyclosporine, e.g., cyclosporine about 0.09% (CEQUA), for 28 days prior to surgery in patients presenting for cataract surgery. This disclosure also describes the effect of topical cyclosporine solution on ocular surface irregularity as measured by HOA, corneal staining, tear film breakup time (TBUT), and ocular redness.

[0076] 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 or fatty acids may be numbered ("n") according to the average polymer length in 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 of 40 units or more. Hydrogenated castor oil stearate and castor oil are common lipids / fatty acids commercially available as polyoxyl lipids or fatty acids, but it is understood that any lipid or fatty acid can be polyoxylated to become a polyoxyl lipid or fatty acid contemplated herein. Examples of polyoxyl lipids or fatty acids include, but are not limited to, HCO-40, HCO-60, HCO-80, HCO-100, polyoxyl 40 stearate, polyoxyl 35 castor oil.

[0077] As used herein, the terms sodium phosphate monobasic and / or sodium phosphate dibasic are used to refer to phosphate buffers and may also be used in different hydrated and anhydrous forms of the salt. For example, sodium phosphate monobasic may be used interchangeably with an equimolar amount of sodium phosphate monobasic dihydrate, and sodium phosphate dibasic may be used interchangeably with an equimolar amount of sodium phosphate dibasic anhydrous.

[0078] In some embodiments of any of the compositions and methods described herein, the average polymer length of the oxyethylene units of the polyoxyl lipid or fatty acid is longer for relatively large active ingredients and shorter for relatively small active ingredients, e.g., where the active ingredient is a resolvin or a resolvin-like compound, in some embodiments the polyoxyl lipid is HCO-60 and where the active ingredient is cyclosporin A (larger than a resolvin), in some embodiments the polyoxyl lipid is HCO-80 or HCO-100.

[0079] As used herein, the term "micelle" or "nanomicelles" refers to aggregates (or clusters) of surfactant molecules. Micelles form only when the concentration of surfactant is higher than the critical micelle concentration (CMC). Surfactants are chemicals that are amphiphilic, meaning that they contain both hydrophobic and hydrophilic groups. Micelles may exist in different shapes, including spherical, cylindrical, and discoidal. Micelles that contain at least two different molecular species are mixed micelles. In some embodiments, the ophthalmic compositions of the present disclosure comprise an aqueous, clear, mixed micellar solution.

[0080] As used throughout this specification, the term "about" is intended to include ±10% of the numerical value of the amount used in the formulations / compositions according to the present invention.

[0081] The patient or subject treated by any of the compositions or methods of the present disclosure may refer to either a human or a non-human animal. In one embodiment, the present disclosure provides a method for preparing a human subject for cataract surgery. In one embodiment, the present disclosure provides a method for reducing ocular surface irregularities in a human patient in need thereof. In one embodiment, the present disclosure provides a method for reducing conjunctival erythema in a human patient in need thereof. In another embodiment, the present disclosure provides the above method for a veterinary patient in need thereof, including but not limited to dogs, horses, cats, rabbits, gerbils, hamsters, rodents, birds, aquatic mammals, cows, pigs, camelids, and other zoological animals.

[0082] Cyclosporine 0.09% solution Cyclosporine solutions useful according to the present disclosure are those containing cyclosporine, for example, as disclosed in U.S. Pat. Nos. 8,980,839, 9,937,225, 10,441,630, and 10,918,694, the entire contents of each of which are incorporated by reference in their entirety.

[0083] In a preferred embodiment, the solution containing cyclosporine is as disclosed in U.S. Pat. No. 10,918,694 and comprises an aqueous topical ophthalmic formulation comprising about 0.087-0.093% by weight cyclosporine, about 1.0% by weight hydrogenated 40 polyoxyl castor oil, about 0.05% by weight octoxynol-40, about 0.3% by weight povidone, about 0.05% by weight sodium chloride, about 0.20-0.405% by weight sodium phosphate monobasic, and about 0.23-0.465% by weight sodium phosphate dibasic, adjusted to a pH of about 5 to about 8 with sodium hydroxide / hydrochloric acid, and made up to final volume with water. In a particular formulation of this embodiment, cyclosporine is present in an amount of about 0.09% by weight of the formulation. In another formulation of this embodiment, the pH of the formulation is about 6.6-7.0.

[0084] In certain preferred embodiments, the solution containing cyclosporine is CEQUA.

[0085] In another embodiment, the solution comprising cyclosporine may be as disclosed in U.S. Patent No. 9,937,225. In such an embodiment, the solution comprising cyclosporine may be an aqueous transparent nanomicellar ophthalmic formulation comprising about 0.05-0.5% by weight of cyclosporine, a polyalkoxylated alcohol, and one or more polymers comprising HCO-40, HCO-60, HCO-80, HCO-100, polyoxyl 35 castor oil, or combinations thereof. In a particular formulation of this embodiment, the polymer may comprise HCO-40, HCO-60, HCO-80, HCO-100, or combinations thereof. In another formulation of this embodiment, the polymer may comprise polyoxyl 35 castor oil. In yet another formulation of this embodiment, the polymer is HCO-40. In a particular formulation of this embodiment, the polymer may be present in an amount of about 0.5-1.5% by weight of the formulation. In certain formulations of this embodiment, the polymer may comprise HCO-40, HCO-60, HCO-80, or a combination thereof, and may be present in an amount of about 0.5-1.5% by weight of the formulation. In yet other formulations of this embodiment, the polyalkoxylated alcohol may comprise octoxynol-40, and in formulations in which the polyalkoxylated alcohol comprises octoxynol-40, the octoxynol-40 may be present in an amount of about 0.02-4% by weight, or about 0.02-0.1% by weight of the formulation. In certain formulations of this embodiment, the cyclosporine may be present in an amount of about 0.05-0.2% by weight of the formulation. In other formulations of this embodiment, the polymer may comprise HCO-40, HCO-60, HCO-80, HCO-100, or a combination thereof, and the polyalkoxylated alcohol may be octoxynol-40. In yet another formulation of this embodiment, the polymer may be present in an amount of about 0.5-1.5% by weight of the formulation and the polyalkoxylated alcohol may comprise octoxynol-40 in an amount of about 0.02-0.1% by weight of the formulation. In another formulation of this embodiment, the polymer may be present in an amount of about 0.5-1.5% by weight of the formulation, the polyalkoxylated alcohol may comprise octoxynol-40 in an amount of about 0.02-0.1% by weight of the formulation, and the cyclosporine may be present in an amount of about 0.05-0.2% by weight of the formulation.

[0086] Additional formulation ingredients 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 the present disclosure for topical administration to the eye, the mixture is preferably formulated at about pH 5 to about pH 8. This pH range may be achieved by the addition of a buffering agent to the composition described in the Examples. In one embodiment, the pH range in the composition in the formulation is about pH 6.4 to about pH 7.5. In yet another embodiment, the pH range in the composition in the formulation is about pH 6.6 to about pH 7.0. The compositions of the present disclosure may be buffered with any common buffer system, such as phosphate, borate, acetate, citrate, carbonate, and borate-polyol complexes, with the pH and osmolality adjusted according to well-known techniques to the appropriate physiological values. The mixed micelle compositions of the present disclosure are stable in buffered aqueous solutions. That is, there is no deleterious interaction between the buffer and any other components that would destabilize the composition.

[0087] Examples of isotonicity agents include mannitol, sodium chloride, xylitol, etc. These isotonicity agents may be used to adjust the osmotic pressure of the composition. In one embodiment, the osmolality of the formulation is adjusted to within the range of about 250 to about 350 mOsmol / kg. In a preferred embodiment, the osmolality of the formulation is adjusted to between about 280 to about 300 mOsmol / kg.

[0088] Additives such as sugars, glycerol, and other sugar alcohols may be included in the compositions of the present disclosure. Pharmaceutical additives may be added to increase the effectiveness or potency of other components in the composition. Pharmaceutical additives may be added to the compositions of the present disclosure for other reasons, such as to improve the stability of calcineurin inhibitors or mTOR inhibitors, to adjust the osmotic pressure of the composition, to adjust the viscosity of the composition, or to provide 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 aqueous transparent mixed micellar solution of the present disclosure includes an additive such as a sugar.

[0089] In one embodiment, the composition of the present disclosure further comprises one or more bioadhesive polymers. Bioadhesion refers to the ability of certain synthetic and biological macromolecules, as well as hydrocolloids, to adhere to biological tissues. Bioadhesion is a complex phenomenon that depends in part on the properties of the polymer, the biological tissue, and the surrounding environment. Several factors have been found to contribute to the bioadhesive ability of a polymer: the presence of functional groups capable of forming hydrogen bridges (--OH, COOH), the presence and strength of anionic charges, sufficient elasticity for the polymer chain to penetrate the mucosal layer, and high molecular weight. Bioadhesive systems have been used in dental, orthopedic, ophthalmic, and surgical applications. However, recently, significant interest has emerged in the use of bioadhesive materials in other areas, such as soft tissue-based artificial replacements and controlled release systems for the local release of bioactive agents. Such applications include systems for the release of drugs in the oral or nasal cavity, and systems for intestinal or rectal administration.

[0090] In one embodiment, the composition of the present disclosure includes at least one bioadhesive polymer. The bioadhesive polymer may increase the viscosity of the composition, thereby increasing its residence time in the eye. Bioadhesive polymers of the present disclosure include, for example, carboxylic acid polymers such as CARBOPOL (carbomer), NOVEON (polycarbophil), cellulose derivatives including alkyl and hydroxyalkyl celluloses such as methylcellulose, hydroxypropylcellulose, carboxymethylcellulose, gums such as locust bean, xanthan, agarose, karaya, guar, and other polymers such as, but not limited to, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, PLURONIC (poloxamer), tragacanth, and hyaluronic acid; phase transition polymers (e.g., alginate, glycerol, sorbitol ... Examples of suitable bioadhesive polymers include carrageenans (e.g., Eucheuma), xanthan, and locust bean gum mixtures, pectin, cellulose acetate phthalate, alkyl hydroxyalkyl cellulose and its derivatives, hydroxyalkylated polyacrylic acid and its derivatives, poloxamer and its derivatives, and the like. The physical properties of these polymers may be mediated by changing environmental factors such as ionic strength, pH, or temperature, alone or in combination with other factors. In one embodiment, the optional one or more bioadhesive polymers are , is present in the composition at about 0.01% to about 10% by weight / volume, preferably about 0.1 to about 5% by weight / volume. In one embodiment, the composition of the present disclosure further comprises at least one hydrophilic polymer excipient, e.g., selected from 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.

[0091] In one embodiment, if a preservative is desired, the composition may be optionally preserved with any of a number of well-known preservatives, including benzyl alcohol with or without EDTA, benzalkonium chloride, chlorhexidine, COSMOCIL CQ, or DOWICIL 200. In certain embodiments, it may be desirable for the formulations described herein to be free of any preservatives. In this regard, a preservative may not be necessary or desirable in some embodiments in formulations contained in single-use containers. In other embodiments, including a preservative may be advantageous, such as in certain embodiments in which the formulation is contained in a multi-use container.

[0092] In some embodiments of the compositions and methods disclosed herein, the cyclosporine further comprises one or more additional active ingredients, e.g., an active agent 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 comprises a resolvin. In some embodiments, the additional active agent comprises a corticosteroid. In some embodiments, the additional active agent comprises a resolvin and a corticosteroid. In some embodiments, the additional active agent comprises an antibiotic, e.g., 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 comprises an antibiotic, such as one or more antibiotics selected from the group consisting of azithromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin, and levofloxacin, and a second of such active agents is a resolvin. In some embodiments, the active agent comprises two or more active agents, and one of the active agents is an antiviral agent, such as one or more antiviral agents selected from the group consisting of ganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir, and cidofovir. In some embodiments, the active agent comprises two or more active agents, and one of the active agents is an antibiotic, such as one or more antiviral agents selected from the group consisting of ganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir, and cidofovir, and a second of the active agents is a resolvin.

[0093] Method of administration The cyclosporine-containing solution is preferably administered topically to the eye. Methods of administration may be as described, for example, in U.S. Patent Nos. 8,980,839, 9,937,225, 10,441,630, and 10,918,694.

[0094] In the experiment reported below, cyclosporine 0.09% solution (CEQUA) was administered to patients twice a day for 28 days.However, the administration method is not limited to the method shown.Administration may be given for a long or short period of time as needed to improve ocular surface irregularity.Dose may also be changed as may be necessary to achieve improvement of ocular surface irregularity.

[0095] experiment In the experiments reported below, cyclosporine 0.09% solution (CEQUA) was used.

[0096] Figure 1 generally illustrates the procedure used in the patient testing. The following experiment involved an open-label, multicenter, prospective study including 75 eyes (from 75 patients) presented for cataract surgery evaluation with signs of DED, including corneal staining with fluorescein and a TBUT of 10 seconds or less. Each patient underwent an identical set of preoperative diagnostics before and after treatment with cyclosporine 0.09%. Patients scheduled to undergo bilateral surgery had their first eye enrolled in the study.

[0097] Inclusion / exclusion criteria and the study protocol were published prospectively on D8. Exclusion criteria included previous ocular surgery within the past 3 months, ocular inflammation or corneal scarring, corneal dystrophies, or other defects or abnormalities of the ocular surface. Subjects were allowed to continue any baseline dry eye treatment (lubricant drops, warm compresses) unchanged, but did not make any modifications beyond the addition of topical cyclosporine 0.09%.

[0098] At the 1-month visit after treatment with cyclosporine 0.09%, patients were asked to report on their compliance, and noncompliant patients were excluded.

[0099] Patients were prescribed topical cyclosporine 0.09% twice daily (BID) for 28 days. Keratometry, slit lamp examination, and the Standard Patient Evaluation of Ocular Dryness (SPEED) questionnaire were assessed at the initial and follow-up visits as discussed below. Cataract surgery was performed 1 to 3 weeks after the second biometry visit. Refraction and corrected distance visual acuity measurements were performed 1 month postoperatively. The primary outcome was the difference in absolute predicted error of spherical equivalent refractive power 1 month before and after cyclosporine treatment. Secondary outcomes included the effect of topical cyclosporine 0.09% on ocular surface irregularities.

[0100] Keratometry was performed using an IOL Master 500 or 700 (CARL ZEISS MEDITEC, California, US) both at the first visit and after 28 days of cyclosporine 0.09%. Corneal topographies were collected with a ZEISS ATLAS 900 or newer topographer, and the root mean square (RMS) HOA was recorded in the central 6.0 mm of the cornea for each visit. Other evaluations included slit lamp examination (conjunctival injection according to the Schulze scale (see D3 and D5), corneal staining according to the Oxford Rating Scale, and TBUT). A Standard Patient Evaluation of Ocular Dryness (SPEED) survey was also performed, with a score of >10 considered abnormal. See D3, D6. After the initial evaluation, patients were prescribed cyclosporine 0.09% BID for 28 days. Biometry and test measurements were repeated at the end of the 28-day cycle. Cataract surgery was performed 1 to 3 weeks after the second evaluation, using the intraocular lens (IOL) power suggested by the biometry measurements from the latter evaluation.

[0101] Approximately one month after surgery, refraction and corrected distance visual acuity (CDVA) were measured.

[0102] Each set of biometry measurements was used to generate an IOL power calculation for the study eye using the Barrett-Universal II formula, and the predicted manifest refractive spherical equivalent of the IOL selected for surgery was calculated for each set of measurements. These predicted spherical equivalents were then compared to the actual final manifest refractive spherical equivalent measured 30 days after surgery to determine the absolute measurement error of each prediction.

[0103] SPEED questionnaire scores, conjunctival hyperemia scores, corneal staining, and TBUT were recorded for each visit and entered into a database for comparison before and after surgery. Paired t-tests were used to assess statistical significance of differences at 95% confidence. RMS HOA measurements were also compared before and after cyclosporine 0.09% treatment using paired t-tests.

[0104] A total of 75 patients were initially enrolled. Of these, 8 (11%) withdrew due to updated SARS-CoV-2-related stay-at-home orders by canceling surgery or withdrawing from study participation to reduce clinic visits. Two (3%) withdrew due to insurance or scheduling conflicts, and 1 (1%) withdrew due to inability to tolerate the study medication. Of the 64 patients who completed the study, 34 (53%) were female and 30 (47%) were male. A total of 36 (56%) patients had their right eye studied and 28 (44%) had their left eye studied. The mean age was 70.5 ± 7.4 years (range 50–84 years). Patients were enrolled at Harvard Eye Associates (n=27), Opthalmology Associates (n=20), and Ophthalmic Surgeons and Consultants of Ohio State (n=17).

[0105] Measurement of primary endpoint Figure 2 is a graph showing the prediction accuracy of corneal power measurements performed before and after cyclosporine treatment. The absolute prediction error of the 1-month equivalent spherical refractive power was 0.39 ± 0.30 D vs. 0.33 ± 0.25 D based on biometry performed before and after treatment with cyclosporine 0.09%, respectively. This difference was statistically significant (P < 0.03, paired t-test). The proportion of eyes that would have achieved the target refractive power was greater after cyclosporine 0.09%: within 0.25 D, 41% vs. 47% (P < 0.05, McNemar's chi-square test), within 0.5 D, 72% vs. 73% (P < 0.31), and within 0.75 D, 88% vs. 95% (P < 0.03). These differences were statistically significant for accuracy within 0.25 D to 0.75 D.

[0106] Secondary endpoint measurements Figure 3 shows the results of RMS HOA measurements and indicates that after 28 days of treatment with cyclosporine, more patients showed improvement compared to a decline in RMS HOA. As shown in Figure 3, cyclosporine 0.09% treatment caused a change in total HOA measured within the central 6.0 mm of the cornea with a mean improvement of 0.28 ± 0.27 μ in 28 eyes (44%), no change in 18 eyes (28%), and a mean worsening of 0.17 ± 0.15 μ in 18 eyes (28%). These differences were statistically significant in favor of improvement (P < 0.0001, McNemar's chi-square test). The overall mean magnitude of corneal HOA was also significantly improved by cyclosporine 0.09%, with values ​​of 0.68 ± 0.32 μ before treatment and 0.60 ± 0.22 μ after treatment (P < 0.02, paired t-test).

[0107] The presence of a total corneal HOA greater than 0.5μ preoperatively is associated with suboptimal patient subjective perception postoperatively. Using this cutoff as a measure of the probability of success with a multifocal IOL, 25 patients (39%) before cyclosporine 0.09% treatment and 29 patients (45%) after cyclosporine 0.09% treatment were considered candidates for a multifocal IOL. This difference was statistically significant (P<0.05, McNemar's chi-square test).

[0108] Figure 4 shows the results of the SPEED score. As seen in Figure 4, after 28 days of treatment with cyclosporine 0.09%, the SPEED score improved significantly, with a mean score of 7.9 ± 6.2 before treatment and 5.2 ± 5.3 after treatment (P < 0.00001, paired t-test). A score of 5 or less was observed in 25 patients (39%) before cyclosporine 0.09% treatment and 40 patients (63%) after cyclosporine 0.09% treatment, and a score of less than 10 was observed in 48 patients (75%) before cyclosporine 0.09% treatment and 56 patients (88%) after cyclosporine 0.09% treatment. These differences were statistically significant (P < 0.007 and P < 0.04, respectively, McNemar's chi-square test).

[0109] FIG. 5 shows the results of the corneal staining (Oxford scale) test, measured before and after 28 days of treatment with cyclosporine. FIG. 4 illustrates that corneal staining significantly improved (decreased) after treatment and disappeared in 56% of patients. In particular, corneal staining, as measured by the Oxford scale, significantly improved from a mean grade of 1.6±0.56 before cyclosporine 0.09% treatment to 0.5±0.62 after treatment (P<0.000001, paired t-test). All eyes had at least grade 1 staining before treatment, 36 eyes (56%) improved to grade 0 (no staining), 24 eyes (38%) improved to grade 1, and 4 eyes (6%) completed the study with grade 2 staining. Only 2 eyes (3%) showed no improvement in corneal staining, which remained at grade 2 after treatment.

[0110] FIG. 6 shows the results of tear film breakup time (TBUT) measurements taken 28 days before and after treatment with cyclosporine 0.09%. As can be seen in FIG. 6, tear film breakup time was significantly improved after treatment. In particular, TBUT improved significantly from a mean of 5.2±2.2 seconds before treatment to 7.0±2.9 seconds after treatment (P<0.000001, paired t-test). The mean improvement was 2.6±2.4 seconds. TBUT was 0-5 seconds in 37 eyes (59%) and 23 eyes (36%) before and after cyclosporine 0.09% treatment, respectively (P<0.002, McNemar's chi-square test), and was 6-10 seconds in 26 (41%) and 33 (52%) patients before and after cyclosporine 0.09% treatment, respectively (P<0.03, McNemar's chi-square test).

[0111] Conjunctival erythema, as measured by the Schulze scale, also improved significantly with cyclosporine 0.09% treatment (mean scores were 19.1 ± 8.9 before treatment and 15.3 ± 6.7 after treatment, respectively, P < 0.002, paired t test). The lowest grade of 10 was observed in 23 eyes (36%) before treatment and in 36 eyes (56%) after treatment (P < 0.02, McNemar's chi-square test). Other values ​​of conjunctival hyperemia are shown in Table 1.

[0112] [Table 1]

[0113] Sixty-four patients completed the study. The absolute prediction error of spherical equivalent at 1 month was 0.39 ± 0.30 D pretreatment vs. 0.33 ± 0.25 D posttreatment, respectively (P < 0.03). The proportion of eyes that achieved the target refraction based on measurements after topical cyclosporine 0.09% was greater than would have occurred using pretreatment measurements.

[0114] As can be seen from the results above, cataract surgery patients with dry eye who were prescribed topical cyclosporine 0.09% twice daily (BID) for 28 days prior to surgery showed a statistically significant improvement in the predicted error of surgical spherical equivalent. Other measures of dry eye severity showed significant improvement after treatment.

[0115] The study reported above enrolled patients with DED and evaluated the impact of a new cyclosporine formulation on the refractive accuracy of cataract surgery. We found a statistically significant improvement in the prediction error of the surgical spherical equivalent when measurements were used 28 days after cyclosporine 0.09% treatment was initiated, compared with measurements taken before treatment. Other measures of dry eye severity, including corneal RMS HOA, corneal staining, TBUT, conjunctival erythema, and SPEED score, also showed significant improvements after cyclosporine 0.09% treatment.

[0116] There was also a significant improvement in tear breakup time, providing evidence that treatment establishes a more stable tear breakup layer in preoperative dry eye. This is especially important for postoperative patients, because achieving satisfaction with surgery depends not only on establishing clarity, but also on the ability to support extended periods of reading and other visually intensive tasks.

[0117] Although many pharmacological treatments for dry eye exist, cyclosporine 0.09% is the highest dose of cyclosporine currently approved by the FDA, and only cyclosporine containing nanomicelle technology for better penetration and drug absorption is approved, as reported in Goldberg DF, Malhotra RP, Schechter BA, Justice A, Weiss SL, Sheppard JD. A Phase 3, Randomized, Double-Masked Study of OTX-101 Ophthalmic Solution 0.09% in the Treatment of Dry Eye Disease. Ophthalmology. Sep 2019;126(9):1230-1237. doi:10.1016 / j.ophtha.2019.03.050. Although there are some limitations to this disclosure, namely, the number of patients who initiated treatment and completed the study was lower than originally planned due to a high number of patients canceling their surgeries or wanting to withdraw to avoid office visits, one patient withdrew due to intolerance to the study drug, the discontinuation rate was slightly better than the 2.4% discontinuation rate reported in the Goldberg U.S. Food and Drug Administration Phase 3 approved trial of cyclosporine 0.09% mentioned above, and the primary endpoint measure - improvement in refractive accuracy - showed statistically significant results.

[0118] To the knowledge of the present invention, this is the first disclosure demonstrating improved refractive accuracy of cataract surgery using pre-treatment cyclosporine 0.09%. The results indicate that cyclosporine 0.09% has added benefit beyond common dry eye treatments.

[0119] The method may be combined with other treatments, such as artificial tears, warm compresses, diet and habit modifications, and therapies for DED.

[0120] A previous pivotal trial of cyclosporine 0.09% (Goldberg, supra) demonstrated the superiority of this formulation over vehicle alone in treating DED, and therefore it is envisioned that the improvements in refractive accuracy shown in this disclosure from cyclosporine 0.09% will be similarly superior to those of its vehicle.

[0121] Similar to DED, corneal HOA can be affected by many factors, including seasonality, body hydration, hormonal changes, and any other factors that affect ocular hydration. Each of these can act randomly and cause variations in the "smoothness" of the ocular surface. This may explain why 28% of patients treated with cyclosporine 0.09% in this study had a worsening of HOA. Despite these notable and random variations, a significantly higher percentage of eyes, 44%, showed improvement in this indicator.

[0122] Interestingly, all patients in this study had significant DED, but the majority were asymptomatic at baseline. 75% had a SPEED score of 10 or less, and nearly 40% had a score below 5. This supports previous studies, including the PHACO study (Trattler WB, Majmudar PA, Donnenfeld ED, McDonald MB, Nachcipher KG, Goldberg DF, The Prospective Health Assessment of Cataract Patients' Ocular Surface (PHACO) study: the effect of dry eye; poster. Clin Ophthalmol. 2017 March; 11: 1423-1430. doi:10.2147 / OPTH.S120159), which showed a similar proportion of asymptomatic patients and reinforces the common clinical procedure for screening cataract surgery candidates for DED.

[0123] Although certain specific embodiments are fully described in this application, it should be understood that the same concepts disclosed with respect to those specific embodiments are also applicable to other embodiments. Moreover, the individual elements of the formulations and methods disclosed herein are described only with reference to the specific embodiments for convenience. It should be understood that the individual elements of the formulations and methods disclosed herein are applicable to embodiments other than the specific embodiments for which they are described.

[0124] Additionally, the contents of all documents discussed in this disclosure are incorporated herein by reference in their entirety.

[0125] Furthermore, the scope of the present disclosure is not limited to the above-described embodiments, and those skilled in the art will understand that various modifications and changes can be made without departing from the scope of the present disclosure.

Claims

1. A solution containing cyclosporine for use in preparing a subject for cataract surgery, the solution being administered to the eye in which the cataract surgery is to be performed.

2. (i) Reduction of ocular surface irregularity, (ii) reduction of conjunctival erythema, (iii) improvement of refractive accuracy after cataract surgery, (iv) improvement of corneal staining after cataract surgery, or (v) any combination thereof A solution containing cyclosporine for use in

3. The solution for use according to claim 1 or 2, which is administered topically.

4. The solution for use according to claim 1 or 2, which is administered twice a day.

5. The solution for use according to claim 1, which is administered for 28 days immediately before cataract surgery.

6. The solution for use according to claim 2, which is administered for 28 days.

7. The solution is an ophthalmic aqueous topical formulation, and the ophthalmic aqueous topical formulation contains about 0.087 to 0.093 wt% of cyclosporine, about 1.0 wt% of hydrogenated castor oil 40, about 0.05 wt% of octoxynol-40, about 0.3 wt% of povidone, about 0.05 wt% of sodium chloride, about 0.20 to 0.405 wt% of monobasic sodium phosphate, about 0.23 to 0.465 wt% of dibasic sodium phosphate, sodium hydroxide / hydrochloric acid, and water, and the pH of the formulation is about 5 to about 8, The solution for use according to claim 1 or 2.

8. The solution for use according to claim 7, wherein cyclosporine is present in an amount of about 0.09 wt% of the formulation.

9. The solution for use according to claim 7, wherein the pH of the formulation is about 6.6 to 7.

0.

10. The solution for use according to claim 1 or 2, which is an aqueous transparent nanomicelle ophthalmic formulation containing about 0.05 to 0.5 wt% of cyclosporine, polyalkoxylated alcohol, and one or more polymers including HCO-40, HCO-60, HCO-80, HCO-100, and hydrogenated castor oil 35 or a combination thereof.

11. The solution for use according to claim 10, wherein the one or more polymers include HCO-40, HCO-60, HCO-80, HCO-100, or a combination thereof.

12. The solution for use according to claim 10, wherein the one or more polymers include hydrogenated castor oil 35.

13. The solution for use according to claim 10, wherein the one or more polymers are HCO-40.

14. The solution for use according to claim 10, wherein the one or more polymers are about 0.5 to 1.5% by weight of the formulation.

15. The solution for use according to claim 10, wherein the one or more polymers comprise HCO-40, HCO-60, HCO-80, or a combination thereof and are about 0.5 to 1.5% by weight of the formulation.

16. The solution for use according to claim 10, wherein the polyalkoxylated alcohol comprises octoxynol-40.

17. The solution for use according to claim 10, wherein the polyalkoxylated alcohol comprises octoxynol-40 and is about 0.02 to 4% by weight or about 0.02 to 0.1% by weight of the formulation.

18. The solution for use according to claim 10, wherein the cyclosporine is about 0.05 to 0.2% by weight of the formulation.

19. The solution for use according to claim 10, wherein the one or more polymers comprise HCO-40, HCO-60, HCO-80, HCO-100, or a combination thereof and the polyalkoxylated alcohol is octoxynol-40.

20. The solution for use according to claim 10, wherein the one or more polymers are about 0.5 to 1.5% by weight of the formulation, the polyalkoxylated alcohol is octoxynol-40, and is about 0.02 to 0.1% by weight of the formulation.

21. The solution for use according to claim 10, wherein the one or more polymers are about 0.5 to 1.5% by weight of the formulation, the polyalkoxylated alcohol comprises octoxynol-40 and is about 0.02 to 0.1% by weight of the formulation, and the cyclosporine is about 0.05 to 0.2% by weight of the formulation.

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