Ophthalmic composition for ophthalmic surgical preparation of ocular surface disease patients

Abstract

The present disclosure provides methods for (a) preparing a patient for an ocular surgery, (b) treating ocular surface diseases in a patient prepared for an ocular surgery, and (c) performing biometric measurements for preparing an ocular surgery, wherein the method comprises topically administering to the eye of the patient a composition comprising about 0.05%-0.1% (w / v) cyclosporin dissolved in a semi-fluorinated alkane, optionally with an alcoholic co-solvent, once to four times per day.

Description

BACKGROUND

[0001] Eye surgery includes cataract surgery, refractive surgery (including corneal abrasion, corneal transplantation, radial keratotomy, and intraocular lens implantation), glaucoma surgery (including canaloplasty, laser trabeculoplasty, iridotomy, iridectomy, sclerectomy, trabeculectomy, and viscocanalostomy), laser eye surgery (e.g., laser-assisted in situ keratomileusis or LASIK, and photorefractive keratectomy, also known as LASEK, laser-assisted sub-epithelial keratomileusis), and vitreoretinal surgery (e.g., vitrectomy, repair of retinal detachment). Because the eye is a particularly delicate organ, extreme care is required before, during, and after any eye surgery. It is also necessary to ensure that the patient is in the best possible state to undergo surgery beforehand.

[0002] One particularly important type of eye surgery is cataract surgery, which aims to restore vision in an eye affected by a cataract.

[0003] The lens is a structure in the human eye that is responsible for focusing incoming light onto the light-sensitive cells of the retina. The lens is part of the anterior segment of the eye, located behind the iris, and in front of the vitreous. All light perceived by the eye must pass through the lens, and therefore, maintaining the transparency of the lens to light is essential for vision.

[0004] The lens functions as part of a muscular and connective tissue integrated system that allows the shape of the lens to be adjusted to change the refractive index of the lens. This process is known as accommodation and allows people to adjust their visual focus from distant objects to near objects, and vice versa. However, as people age, the lens can become stiffer and the ability to adjust its shape decreases.

[0005] Cataracts are opacities of the lens. While some cataracts are small and do not require treatment, in many cases, cataracts are large enough to interfere with vision by blocking light from reaching the retina. Cataracts are usually part of the aging process, but they can also be congenital, and they can form in response to eye injuries, including trauma and radiation. Cataracts usually develop slowly, and they can affect one eye or both eyes. Symptoms of cataracts include color fading, blurred vision, double vision, halos around light sources, sensitivity to bright light, difficulty reading, and difficulty seeing at night.

[0006] Cataracts are a common problem, especially as the population ages. If left untreated, cataracts will progress to blindness. Cataracts are responsible for 51% of cases of blindness worldwide and 33% of cases of visual impairment worldwide. In the United States, approximately 68% of people over 80 years of age have cataracts.

[0007] Cataracts can be classified as partial or complete, static or progressive, and hard or soft. Cataracts are also classified into three main categories based on their location and pathology: nuclear, cortical, and posterior subcapsular. Nuclear cataracts affect the central region of the lens, the nucleus, starting with the gradual hardening and yellowing of the lens material. Over time, the affected region expands to other layers of the lens. Cortical cataracts start in the outer layer of the lens, the cortex, and gradually extend from the periphery to the center of the lens. Posterior subcapsular cataracts start on the posterior surface of the lens below the lens capsule. While nuclear and cortical cataracts progress slowly over years, posterior subcapsular cataracts can rapidly progress in a matter of months.

[0008] Cataracts can be classified according to the LOCS III system (Lens Opacities Classification System III; see Chylack et al., Arch. Ophthalmol. 111(6):831-36 (1993)). The system uses different criteria for different types of cataracts, providing scores ranging from trace to 4+. For nuclear cataracts, the degree of nuclear pigmentation (yellowing) and opalescence is evaluated. For cortical cataracts, the degree of cortical spoke-like opacities is evaluated (percentage of lens showing spoke-like opacities). For posterior subcapsular cataracts, the degree of opacity is evaluated (percentage of capsule showing opacity).

[0009] Lenses with cataracts cannot be repaired, so the only effective treatment for advanced cataracts is surgical removal of the damaged lens and replacement with an artificial lens, which is typically made of a polymer such as polymethyl methacrylate or silicone. Cataract surgery has become quite common, with approximately 6 million lenses implanted worldwide each year. The surgical procedure is typically performed on an outpatient basis using only local (eye) anesthesia. An experienced ophthalmologist can complete a cataract surgery in less than 30 minutes.

[0010] The most common cause of cataract surgery is age-related cataracts, primarily of the nuclear hardening type. Typically, surgery is needed when the cataract becomes 3+ or 4+. Once surgery is needed, it should be performed as soon as possible. If surgery is delayed, the lens will continue to become whiter and denser, and the surgery becomes more difficult to perform and the risk of complications is higher for the patient.

[0011] One of the major risk factors for cataract surgery (and other ocular surgeries, such as refractive surgery) is an undertreated or untreated ocular surface disease, such as corneal surface injury and tear film deficiency or breakdown. In fact, studies have shown that up to 50% of patients undergoing ocular surgery are incidentally found to have such pre-existing conditions that must be quickly treated in order to allow the patient to proceed with the ocular surgery necessary to save or restore their vision.

[0012] In some studies, it has been found that pre-existing undertreated or untreated ocular surface disease (particularly corneal surface injury and tear film deficiency or breakdown) is a major cause of post-operative discomfort, complications, or patient dissatisfaction. The invasive nature of ocular surgery can exacerbate such pre-existing conditions, even when the patient has not been previously aware of the conditions. Many undiagnosed systemic diseases can lead to ocular surface disease, including collagen vascular disease, rheumatoid arthritis, Graves' disease and other thyroid disorders, Sjogren's syndrome, vitamin A deficiency, and diabetes. Some very common medications can also lead to these pre-existing conditions, including antihistamines, tricyclic antidepressants, selective serotonin reuptake inhibitors, diuretics, and beta blockers. Some ocular diseases that can also lead to such pre-existing conditions include chronic conjunctivitis (such as allergic conjunctivitis, infectious conjunctivitis, or tobacco smoke-induced conjunctivitis), blepharitis, dry eye disease, meibomian gland dysfunction, keratoconjunctivitis sicca, and aqueous tear deficiency, as well as contact lens use or overuse.

[0013] Preoperative evaluation for many ocular surgeries (especially cataract surgery and refractive surgery) requires an accurate anatomical assessment of the eye (biometry measurements), including determination of axial length (AL), keratometry (corneal curvature), and anterior chamber depth (ACD). Biometry is an important step prior to cataract surgery and refractive intraocular lens implantation, as selecting the wrong lens size, shape, or curvature can significantly reduce the chances of a successful outcome. However, corneal surface abnormalities can lead to inaccurate keratometry assessments, which are necessary for proper calculation of the power of the intraocular lens required. Therefore, ensuring that the cornea is as healthy as possible prior to biometry measurements is critical to maximizing positive outcomes of ocular surgery.

[0014] There is no effective early-acting treatment to improve the ocular surface or corneal surface. Current treatment options have a fairly weak effect on the ocular surface and take a long time to take effect (e.g., about 4-6 months for Restasis® and about 3 months for Ikervis®). Corticosteroids can take effect more quickly, however, there is limited evidence in randomized controlled trials of their effect to improve the ocular surface. In addition, current treatment options have additional drawbacks, including instillation site irritation due to surfactants and preservatives in the formulation. Currently, the most common method to treat ocular surface disease prior to cataract surgery or prior to biometry measurements in cataract surgery is to use slow-acting dry eye disease medications (e.g., Restasis®), sometimes in combination with an ocular corticosteroid. However, as noted above, several months of treatment are required for effectiveness.

[0015] Accordingly, there is a need for an improved means and method for preoperatively treating a patient preparing for an ocular procedure to reduce ocular surface disease, particularly corneal surface damage. In particular, there is a need for an improved means and method for preoperatively improving ocular surface disease, particularly corneal surface damage, in a subject having ocular surface disease, such as a subject having corneal surface damage, prior to biometry measurements. There is a particular need to do so quickly with minimal side effects (e.g., irritation) so as to allow the patient to proceed to the ocular procedure quickly after the most accurate biometry measurements. Accordingly, it is an object of the present invention to provide compositions and methods that effectively meet these needs. Other objects of the present invention will become apparent from the following description of the invention, embodiments, and claims. SUMMARY

[0016] In a first aspect, the present disclosure provides a method for preparing a patient for an ocular procedure (e.g., cataract surgery), the method comprising topically administering to the eye of the patient a composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane optionally with an alcohol cosolvent, one to four times per day.

[0017] In a second aspect, the present disclosure provides a method for treating ocular surface disease (e.g., corneal surface damage, tear film deficiency, or tear film breakup) in a patient preparing for an ocular procedure (e.g., cataract surgery), the method comprising topically administering to the eye of the patient a composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane optionally with an alcohol cosolvent, one to four times per day.

[0018] In a third aspect, the present disclosure provides a method for performing biometry measurements for an ocular procedure (e.g., cataract surgery), the method comprising topically administering to the eye of the patient one to four times a day a composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane optionally with an alcohol cosolvent prior to the biometry measurements.

[0019] In particular embodiments of the first, second, and third aspects, the methods of the present disclosure achieve their objectives in a rapid onset of action (e.g., less than 2 weeks). DETAILED DESCRIPTION

[0020] In a first aspect, the present disclosure provides a method (Method 1) for preparing a patient for an ocular procedure (e.g., cataract surgery), the method comprising topically administering to the eye (e.g., the eye undergoing the ocular procedure) of the patient one to four times a day (e.g., twice a day) a composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane (e.g., 1-perfluorobutylpentane) optionally with an alcohol cosolvent (e.g., ethanol).

[0021] In further embodiments of the first aspect, the present disclosure provides:

[0022] 1.1 Method 1, wherein the ocular procedure is selected from the group consisting of cataract surgery, refractive surgery (including corneal abrasion, corneal transplantation, radial keratotomy, and intraocular lens implantation), glaucoma surgery (including canaloplasty, laser trabeculoplasty, iridotomy, iridectomy, sclerectomy, trabeculectomy, and viscoanastomosis), laser eye surgery (e.g., laser-assisted in situ keratomileusis or LASIK, and photorefractive keratectomy, also known as LASEK, laser-assisted sub-epithelial keratomileusis), and vitreoretinal surgery (e.g., vitrectomy, repair of retinal detachment);

[0023] 1.2 Method 1.1, wherein the ocular procedure is cataract surgery or refractive surgery;

[0024] 1.3 Method 1.2, wherein the ocular procedure is cataract surgery or refractive surgery via intraocular lens implantation;

[0025] 1.4 Method 1 or any of 1.1-1.3, wherein the method further comprises the step of determining the extent of ocular surface disease (e.g., corneal surface damage, tear film deficiency, and / or tear film break-up) in preparation for the ocular procedure;

[0026] 1.5 Method 1.4, wherein determining the extent of ocular surface disease comprises the step of determining the extent of corneal surface damage and / or tear film deficiency or break-up;

[0027] 1.6 Method 1.5, wherein the extent of the corneal surface damage is determined by a total corneal fluorescein staining score and / or a central corneal fluorescein staining score, and / or wherein the extent of the tear film deficiency or disruption is determined by a tear film break-up time (TFBUT) or a Schirmer’s test;

[0028] 1.7 Method 1 or any one of 1.1-1.6, wherein the method further comprises the step of performing biometry measurements in preparation for the eye surgery;

[0029] 1.8 Method 1.7, wherein the biometry measurements comprise corneal curvature measurements and / or optical biometry, such as measuring the corneal curvature (e.g., corneal anterior curvature, corneal posterior curvature), the axial length, the anterior chamber depth, the lens thickness, and / or the corneal power of the eye on which the eye surgery is to be performed;

[0030] 1.9 Method 1 or any one of 1.1-1.8, wherein the semifluorinated alkane is 1-perfluorobutylpentane;

[0031] 1.10 Method 1 or any one of 1.1-1.9, wherein the composition comprises 1- perfluorobutylpentane and 2-perfluorobutylpentane;

[0032] 1.11 Method any one of 1.9-1.10, wherein the composition comprises 1- perfluorobutylpentane and 2-perfluorobutylpentane in a weight ratio of about 95:5, or about 96:4, or about 97:3, or about 98:2, or about 99:1, or about 99.5:0.5, or about 99.6:0.4, or about 99.7:0.3, or about 99.8:0.2, or about 99.9:0.1;

[0033] 1.12 Method any one of 1.9-1.11, wherein the composition comprises at most 5% (w / w) of 2-perfluorobutylpentane, or at most 3% (w / w), or at most 2% (w / w), or at most 1% (w / w), or at most 0.5% (w / w), or at most 0.4% (w / w), or at most 0.3% (w / w), or at most 0.2% (w / w), or at most 0.1% (w / w) of 2- perfluorobutylpentane, optionally wherein the composition comprises at least 0.01% (w / w), or at least 0.1% (w / w), or at least 0.3% (w / w) of 2-perfluorobutylpentane;

[0034] 1.13 Method 1 or any of 1.1-1.12, wherein the composition is free or substantially free of water, e.g., less than 2 wt.%, or less than 1 wt.%, or less than 0.5 wt.%, or less than 0.2 wt.%, or less than 0.1 wt.% water by weight of the composition;

[0035] 1.14 Method 1 or any of 1.1-1.13, wherein the composition is free or substantially free of any preservative, e.g., less than 3 wt.%, or less than 2 wt.%, or less than 1 wt.%, or less than 0.5 wt.%, or less than 0.1 wt.% preservative by weight of the composition, or wherein the composition is formulated to not include any preservative;

[0036] 1.15 Method 1 or any of 1.1-1.14, wherein the composition further comprises an alcoholic co-solvent;

[0037] 1.16 Method 1.15, wherein the alcoholic co-solvent is ethanol;

[0038] 1.17 Method any of 1.15-1.16, wherein the composition comprises the alcoholic co-solvent in an amount of 0.01% to 5% (w / w), or 0.05% to 4% (w / w), or 0.1% to 3% (w / w), or 0.2% to 2% (w / w), or 0.2% to 1.5% (w / w), or 0.2% to 1.0% (w / w), or 0.5% to 1.2% (w / w), or about 0.5% (w / w), or about 1.0% (w / w);

[0039] 1.18 Method 1 or any of 1.1-1.17, wherein the composition comprises about 0.05-0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane;

[0040] 1.19 Method 1.18, wherein the composition comprises about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane;

[0041] 1.20 Method 1.19, wherein the composition comprises or consists essentially of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane with about 1% (w / w) ethanol;

[0042] 1.21 Method 1.20, wherein the composition comprises or consists essentially of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane with about 1% (w / w) ethanol and up to about 1% (w / w) 2-perfluorobutylpentane;

[0043] 1.22 Method 1.21, wherein the composition consists of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane with about 1% (w / w) ethanol and up to about 0.5% (w / w) 2-perfluorobutylpentane;

[0044] 1.23 Method 1 or any of 1.1-1.22, wherein the composition is administered four times per day;

[0045] 1.24 Method 1 or any of 1.1-1.22, wherein the composition is administered three times per day;

[0046] 1.25 Method 1 or any of 1.1-1.22, wherein the composition is administered twice per day;

[0047] 1.26 Method 1 or any of 1.1-1.22, wherein the composition is administered once per day;

[0048] 1.27 Method 1 or any of 1.1-1.26, wherein the amount of cyclosporine administered in a single dose per eye is about 8-12 µg, e.g., 9-11 µg, e.g., 9-10 µg, or about 9 µg, or about 10 µg cyclosporine;

[0049] 1.28 Method 1 or any of 1.1-1.27, wherein the volume administered in a single dose per eye is about 8-12 µL, e.g., 9-11 µL, e.g., 9-10 µL, or about 9 µl or about 10 µL;

[0050] 1.29 Method 1 or any of 1.1-1.28, wherein the composition is administered to the patient for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days;

[0051] 1.30 Method 1 or any of 1.1-1.29, wherein the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) precedes the step of performing a biomicroscopy measurement;

[0052] 1.31 Method 1 or any of 1.1-1.30, wherein the last day of administering the composition precedes the biomicroscopy measurement of the patient, e.g., by at least 1 day, or at least 2 days, or at least 3 days, or at least 5 days, or at least 7 days, or 1-7 days;

[0053] 1.32 Method 1 or any of 1.1-1.31, wherein the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) precedes the administration of the composition;

[0054] 1.33 The method of 1 or any of 1.1-1.32, wherein administration of the composition continues after the biomterics measurement, optionally until 1-3 days prior to the ocular surgery of the patient;

[0055] 1.34 The method of 1 or any of 1.1-1.33, wherein administration of the composition continues after the ocular surgery;

[0056] 1.35 The method of 1 or any of 1.1-1.34, wherein the method further comprises topical ocular administration of a corticosteroid;

[0057] 1.36 The method of 1 or any of 1.1-1.34, wherein the method does not further comprise topical ocular administration of a corticosteroid;

[0058] 1.37 The method of 1 or any of 1.1-1.36, wherein the method does not further comprise topical ocular administration of a drug that blocks LFA-1 binding to ICAM-1 (e.g., lifitegrast);

[0059] 1.38 The method of 1 or any of 1.1-1.37, wherein the composition is the only topical ophthalmic composition administered to the patient during the period of time in which the method is performed;

[0060] 1.39 The method of 1 or any of 1.1-1.38, wherein the patient has not been previously diagnosed with dry eye disease prior to evaluation for the ocular surgery;

[0061] 1.40 The method of 1 or any of 1.1-1.38, wherein the patient has been previously diagnosed with dry eye disease prior to evaluation for the ocular surgery;

[0062] 1.41 The method of 1 or any of 1.1-1.40, wherein the patient has ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film breakup);

[0063] 1.42 The method of 1 or any of 1.1-1.41, wherein the patient is first identified as having ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film breakup) at the time of evaluation for the ocular surgery or in preparation for the ocular surgery;

[0064] 1.43 The method of 1 or any of 1.1-1.41, wherein the method further comprises the step of measuring or evaluating the extent of the ocular surface disease prior to administration of the composition;

[0065] 1.44 The method of any one of 1 or 1.1-1.43, wherein the method comprises the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) after completion of administration of the composition (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), e.g., by total corneal fluorescein staining score and / or central corneal fluorescein staining score, for purposes of comparison to pre-treatment conditions;

[0066] 1.45 The method of 1.44, wherein the method further comprises the step of comparing the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) before and after administration of the composition (e.g., before and after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days) to determine whether the patient can undergo the biometrical measurement and / or the ocular procedure;

[0067] 1.46 The method of any one of 1 or 1.1-1.45, wherein the method further comprises the step of subjecting the patient to an ocular procedure after determining that the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) has been reduced to a level that is safe and suitable for biometrical measurement and / or performance of the ocular procedure;

[0068] 1.47 The method of any one of 1 or 1.1-1.46, wherein prior to initiating administration of the composition according to the method, the patient is characterized by an eye for which ocular surgery is anticipated that exhibits:

[0069] (a) a total corneal fluorescein staining score greater than or equal to 7 (e.g., greater than 8, 9, 10, 11, or 12), or greater than or equal to 10 (e.g., greater than 10, 11, 12, or 13), such as 7-15, 7-13, 10-15, or 10-13; and / or

[0070] (b) a central corneal fluorescein staining score equal to or greater than 1 (e.g., greater than 1, greater than 2), such as 1-2 or 1-3 or 2-3;

[0071] 1.48 The method of any one of 1 or 1.1-1.47, wherein after treatment of the patient with the composition according to the method for a period of time (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), the patient is characterized by the eye for which ocular surgery is anticipated that exhibits:

[0072] (a) a total corneal fluorescein staining score of less than 7 (e.g., less than or equal to 1, 2, 3, 4, 5, or 6) or less than 10 (e.g., less than or equal to 3, 4, 5, 6, 7, 8, or 9); and / or a total corneal fluorescein staining score has been reduced by at least 3 grades from a pre-treatment score; and / or

[0073] (b) a central corneal fluorescein staining score of less than or equal to 1; and / or a central corneal fluorescein staining score has been reduced by at least 1 grade from a pre-treatment score;

[0074] 1.49 The method of any one of 1 or 1.1-1.48, wherein the method improves the total corneal fluorescein staining score of the patient’s eye for which the ocular surgery is contemplated by at least 3 grades prior to performing the biometry measurement and / or prior to performing the ocular surgery;

[0075] 1.50 The method of any one of 1 or 1.1-1.49, wherein the method improves the central corneal fluorescein staining score of the patient’s eye for which the ocular surgery is contemplated by at least 1 grade prior to performing the biometry measurement and / or prior to performing the ocular surgery;

[0076] 1.51 The method of any one of 1 or 1.1-1.50, wherein the method further comprises the step of subjecting the patient to a biometry measurement after the total corneal fluorescein staining score of the patient’s eye for which the ocular surgery is contemplated has been reduced by at least 3 grades;

[0077] 1.52 The method of any one of 1 or 1.1-1.51, wherein the method further comprises the step of subjecting the patient to an ocular surgery after the total corneal fluorescein staining score of the patient’s eye for which the ocular surgery is contemplated has been reduced by at least 3 grades;

[0078] 1.53 The method of any one of 1 or 1.1-1.52, wherein the method improves tear quality in the patient’s eye for which the surgery is contemplated, e.g., as shown by an improved tear film break-up time (TFBUT) and / or an improved Schirmer’s test score;

[0079] 1.54 The method of any one of 1.48-1.53, wherein the patient achieves the level of improvement after less than 8 weeks of treatment, e.g., after 1 to 6 weeks of administration of the composition, or after 1 to 5 weeks of administration of the composition, or after 1 to 4 weeks of administration of the composition, or after 2 to 6 weeks of administration of the composition, or after 2 to 5 weeks of administration of the composition, or after 2 to 4 weeks of administration of the composition, or after 2 to 3 weeks of administration of the composition, or after less than 4 weeks of administration of the composition;

[0080] 1.55 The method of any one of 1 or 1.1-1.54, wherein the patient is subjected to biomterics after administration of the composition for a sufficient time to reduce the tCFS score of the eye for which the ocular procedure is intended by at least 3 grades;

[0081] 1.56 The method of any one of 1 or 1.1-1.55, wherein the patient is administered the composition until the total corneal fluorescein staining score of the patient’s eye for which the ocular procedure is intended is reduced by at least 3 grades;

[0082] 1.57 The method of any one of 1 or 1.1-1.56, wherein the patient has dry eye disease at the time of evaluation for or in preparation for the ocular procedure (e.g., cataract surgery), optionally wherein the patient has not been diagnosed with dry eye disease prior to the time of evaluation for or in preparation for the ocular procedure (e.g., cataract surgery);

[0083] 1.58 The method of 1.57, wherein the patient has ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) caused by the dry eye disease;

[0084] 1.59 The method of any one of 1 or 1.1-1.57, wherein the patient has ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) that is not caused by the dry eye disease;

[0085] 1.60 The method of 1.59, wherein the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) is caused by corneal abrasion, ocular chemical irritation, irritation due to contact lens wear (e.g., improper contact lens wear or sensitivity to contact lens care solutions), foreign body exposure, ultraviolet light damage, or ionizing radiation damage;

[0086] 1.61 The method of any one of 1 or 1.1-1.60, wherein the patient does not have Meibomian gland dysfunction;

[0087] 1.62 The method of any one of 1 or 1.1-1.61, wherein the patient does not have blepharitis or uveitis;

[0088] 1.63 The method of any one of 1 or 1.1-1.62, wherein the composition does not comprise latanoprost, tafluprost, bimatoprost, travoprost, unoprostone, tacrolimus, sirolimus, eprosartan, timolol, nebivolol, an antibacterial agent, an antifungal agent, an antiviral agent.

[0089] In a second aspect, the present disclosure provides a method (Method 2) for treating an ocular surface disease (e.g., corneal surface injury, tear film deficiency, or tear film breakup) in a patient being prepared for an ocular surgery (e.g., cataract surgery), the method comprising topically administering to the eye of the patient once to four times (e.g., twice) per day a composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane (e.g., 1-perfluorobutylpentane) optionally with an alcohol cosolvent (e.g., ethanol).

[0090] In further embodiments of the second aspect, the present disclosure provides:

[0091] 2.1. Method 2, wherein the ocular surgery is selected from cataract surgery, refractive surgery (including photorefractive keratectomy, corneal transplantation, radial keratotomy, and intraocular lens implantation), glaucoma surgery (including canaloplasty, laser trabeculoplasty, iridotomy, iridectomy, sclerectomy, trabeculectomy, and viscoanastomosis), laser eye surgery (e.g., laser-assisted in situ keratomileusis or LASIK, and photorefractive keratectomy also known as LASEK, laser-assisted sub-epithelial keratomileusis), and vitreoretinal surgery (e.g., vitrectomy, repair of retinal detachment);

[0092] 2.2. Method 2.1, wherein the ocular surgery is cataract surgery or refractive surgery;

[0093] 2.3. Method 2.2, wherein the ocular surgery is cataract surgery or refractive surgery via intraocular lens implantation;

[0094] 2.4. Method 2 or any of 2.1-2.3, wherein the method further comprises the step of determining the extent of ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film breakup) in preparation for the ocular surgery;

[0095] 2.5. Method 2.4, wherein determining the extent of ocular surface disease comprises the step of determining the extent of the corneal surface injury, and / or tear film deficiency or breakup;

[0096] 2.6. Method 2.5, wherein the extent of the corneal surface injury is determined by total corneal fluorescein staining score and / or central corneal fluorescein staining score, and / or wherein the extent of the tear film deficiency or breakup is determined by tear film breakup time (TFBUT) or Schirmer’s test;

[0097] 2.7. Method 2 or any of 2.1-2.6, wherein the method further comprises the step of performing biometry measurements in preparation for the ocular surgery;

[0098] 2.8. Method 2.7, wherein the biometry measurements comprise corneal curvature measurements and / or optical biometry, such as measuring the corneal curvature (e.g., corneal anterior curvature, corneal posterior curvature), axial length, anterior chamber depth, lens thickness, and / or corneal power of the eye on which the eye surgery is performed;

[0099] 2.9. Method 2 or any of 2.1-2.8, wherein the semifluorinated alkane is 1-perfluorobutyl-pentane;

[0100] 2.10. Method 2 or any of 2.1-2.9, wherein the composition comprises 1-perfluorobutyl-pentane and 2-perfluorobutyl-pentane;

[0101] 2.11. Method any of 2.9-2.10, wherein the composition comprises 1-perfluorobutyl-pentane and 2-perfluorobutyl-pentane in a weight ratio of about 95:5, or about 96:4, or about 97:3, or about 98:2, or about 99:1, or about 95.5:0.5, or about 99.6:0.4, or about 99.7:0.3, or about 99.8:0.2, or about 99.9:0.1;

[0102] 2.12. Method any of 2.9-2.11, wherein the composition comprises at most 5% (w / w) of 2-perfluorobutyl-pentane, or at most 3% (w / w), or at most 2% (w / w), or at most 1% (w / w), or at most 0.5% (w / w), or at most 0.4% (w / w), or at most 0.3% (w / w), or at most 0.2% (w / w), or at most 0.1% (w / w) of 2-perfluorobutyl-pentane, optionally wherein the composition comprises at least 0.01% (w / w), or at least 0.1% (w / w), or at least 0.3% (w / w) of 2-perfluorobutyl-pentane;

[0103] 2.13. Method 2 or any of 2.1-2.12, wherein the composition is free or substantially free of water, e.g., less than 2 wt.%, or less than 1 wt.%, or less than 0.5 wt.%, or less than 0.2 wt.%, or less than 0.1 wt.% of a preservative by weight of the composition;

[0104] 2.14. Method 2 or any of 2.1-2.13, wherein the composition is free or substantially free of any preservative, e.g., less than 3 wt.%, or less than 2 wt.%, or less than 1 wt.%, or less than 0.5 wt.%, or less than 0.1 wt.% of water by weight of the composition, or wherein the composition is formulated to not include any preservative;

[0105] 2.15. The method of 2 or any of 2.1-2.14, wherein the composition further comprises an alcohol co-solvent;

[0106] 2.16. The method of 2.15, wherein the alcohol co-solvent is ethanol;

[0107] 2.17. The method of any of 2.15-2.16, wherein the composition comprises the alcohol co-solvent in an amount of 0.01% to 5% (w / w), or 0.05% to 4% (w / w), or 0.1% to 3% (w / w), or 0.2% to 2% (w / w), or 0.2% to 1.5% (w / w), or 0.2% to 1.0% (w / w), or 0.5% to 1.2% (w / w), or about 0.5% (w / w), or about 1.0% (w / w);

[0108] 2.18. The method of 2 or any of 2.1-2.17, wherein the composition comprises about 0.05-0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane;

[0109] 2.19. The method of 2.18, wherein the composition comprises about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane;

[0110] 2.20. The method of 2.19, wherein the composition comprises or consists essentially of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane with about 1% (w / w) ethanol;

[0111] 2.21. The method of 2.20, wherein the composition comprises or consists essentially of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane with about 1% (w / w) ethanol and up to about 2% (w / w) or up to about 1% (w / w) 2-perfluorobutylpentane;

[0112] 2.22. The method of 2.21, wherein the composition consists of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane with about 1% (w / w) ethanol and up to about 2% (w / w) or up to about 0.5% (w / w) 2-perfluorobutylpentane;

[0113] 2.23. The method of 2 or any of 2.1-2.22, wherein the composition is administered four times per day;

[0114] 2.24. The method of 2 or any of 2.1-2.22, wherein the composition is administered three times per day;

[0115] 2.25. The method of 2 or any of 2.1-2.22, wherein the composition is administered two times per day;

[0116] 2.26. Method 2 or any of 2.1-2.22, wherein the composition is administered once daily;

[0117] 2.27. Method 2 or any of 2.1-2.26, wherein the amount of cyclosporine administered in a single dose per eye is about 8-12 pg, e.g., 9-11 pg, e.g., 9-10 pg, or about 9 pg, or about 10 pg cyclosporine;

[0118] 2.28. Method 2 or any of 2.1-2.27, wherein the volume administered in a single dose per eye is about 8-12 pL, e.g., 9-11 pL, e.g., 9-10 pL, or about 9 pL or about 10 pL;

[0119] 2.29. Method 2 or any of 2.1-2.28, wherein the composition is administered to the patient for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days;

[0120] 2.30. Method 2 or any of 2.1-2.29, wherein the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) precedes the step of performing a biomicroscopy measurement;

[0121] 2.31. Method 2 or any of 2.1-2.30, wherein the last day of administration of the composition precedes the biomicroscopy measurement of the patient by, e.g., at least 1 day, or at least 2 days, or at least 3 days, or at least 5 days, or at least 7 days, or 1-7 days;

[0122] 2.32. Method 1 or any of 2.1-2.31, wherein the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) precedes administration of the composition;

[0123] 2.33. Method 2 or any of 2.1-2.32, wherein administration of the composition continues after the biomicroscopy measurement, optionally until 1-3 days prior to ocular surgery of the patient;

[0124] 2.34. Method 2 or any of 2.1-2.33, wherein administration of the composition continues after the ocular surgery;

[0125] 2.35. Method 2 or any of 2.1-2.34, wherein the method further comprises topical ocular administration of a corticosteroid;

[0126] 2.36. Method 2 or any of 2.1-2.34, wherein the method does not further comprise topical ocular administration of a corticosteroid;

[0127] 2.37. Method 2 or any of 2.1-2.36, wherein the method does not further comprise topical ocular administration of a drug that blocks LFA-1 binding to ICAM-1 (e.g., niflumic acid);

[0128] 2.38. Method 2 or any of 2.1-2.37, wherein the composition is the only topical ocular composition administered to the patient during the time period in which the method is performed;

[0129] 2.39. Method 2 or any of 2.1-2.38, wherein the patient has not been previously diagnosed with dry eye disease prior to evaluation for the ocular procedure;

[0130] 2.40. Method 1 or any of 2.1-1.38, wherein the patient has been previously diagnosed with dry eye disease prior to evaluation for the ocular procedure;

[0131] 2.41. Method 2 or any of 2.1-2.40, wherein the patient has ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up);

[0132] 2.42. Method 2 or any of 2.1-2.41, wherein the patient is first identified as having ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) at the time of evaluation for the ocular procedure or in preparation for the ocular procedure;

[0133] 2.43. Method 2 or any of 2.1-2.41, wherein the method further comprises a step of measuring or evaluating the extent of the ocular surface disease prior to administration of the composition;

[0134] 2.44. Method 2 or any of 2.1-2.43, wherein the method comprises a step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up), e.g., by total corneal fluorescein staining score and / or central corneal fluorescein staining score, after completion of administration of the composition (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), e.g., for purposes of comparison to pre-treatment conditions;

[0135] 2.45. Method 2.44, wherein the method further comprises the step of comparing the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) before and after administration of the composition (e.g., before and after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days) to determine whether the patient can undergo the biometrical measurement and / or the ocular surgery;

[0136] 2.46. Method 2 or any of 2.1-2.45, wherein the method further comprises the step of subjecting the patient to ocular surgery after determining that the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) has been reduced to a level that is safe and suitable for biometrical measurement and / or performance of the ocular surgery;

[0137] 2.47. Method 2 or any of 2.1-2.46, wherein prior to initiating administration of the composition according to the method, the patient is characterized by an eye for which ocular surgery is anticipated that exhibits:

[0138] (a) a total corneal fluorescein staining score greater than or equal to 7 (e.g., greater than 8, 9, 10, 11, or 12), or greater than or equal to 10 (e.g., greater than 11, 12, or 13), such as 7-15, 7-13, 10-15, or 10-13; and / or

[0139] (b) a central corneal fluorescein staining score equal to or greater than 1 (e.g., greater than 1, greater than 2), such as 1-2 or 1-3 or 2-3;

[0140] 2.48. Method 2 or any of 2.1-2.47, wherein after treatment of the patient with the composition according to the method for a period of time (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), the patient is characterized by the eye for which ocular surgery is anticipated that exhibits:

[0141] (a) a total corneal fluorescein staining score less than 7 (e.g., less than or equal to 1, 2, 3, 4, 5, or 6) or less than 10 (e.g., less than or equal to 3, 4, 5, 6, 7, 8, or 9); and / or a total corneal fluorescein staining score that has been reduced by at least 3 grades from the pre-treatment score; and / or

[0142] (b) a central corneal fluorescein staining score less than or equal to 1; and / or a central corneal fluorescein staining score that has been reduced by at least 1 grade from the pre-treatment score;

[0143] 2.49. The method of 2 or any of 2.1-2.48, wherein the method improves the total corneal fluorescein staining score of the patient's eye for which ocular surgery is contemplated by at least 3 grades prior to performing the biometry measurement and / or prior to performing the ocular surgery.

[0144] 2.50. The method of 2 or any of 2.1-2.49, wherein the method improves the central corneal fluorescein staining score of the patient's eye for which ocular surgery is contemplated by at least 1 grade prior to performing the biometry measurement and / or prior to performing the ocular surgery.

[0145] 2.51. The method of 2 or any of 2.1-2.50, wherein the method further comprises the step of subjecting the patient to a biometry measurement after the total corneal fluorescein staining score of the patient's eye for which ocular surgery is contemplated is reduced by at least 3 grades.

[0146] 2.52. The method of 2 or any of 2.1-2.51, wherein the method further comprises the step of subjecting the patient to an ocular surgery after the total corneal fluorescein staining score of the patient's eye for which ocular surgery is contemplated is reduced by at least 3 grades.

[0147] 2.53. The method of 2 or any of 2.1-2.52, wherein the method improves tear quality in the patient's eye for which surgery is contemplated, e.g., as shown by an improved tear film break-up time (TFBUT) and / or an improved Schirmer's test score.

[0148] 2.54. The method of any of 2.48-2.53, wherein the patient achieves the level of improvement after less than 8 weeks of treatment, e.g., after 1 to 6 weeks of administration of the composition, or after 1 to 5 weeks of administration of the composition, or after 1 to 4 weeks of administration of the composition, or after 2 to 6 weeks of administration of the composition, or after 2 to 5 weeks of administration of the composition, or after 2 to 4 weeks of administration of the composition, or after 2 to 3 weeks of administration of the composition, or after less than 4 weeks of administration of the composition.

[0149] 2.55. The method of 2 or any of 2.1-2.54, wherein the patient is subjected to biometry after administration of the composition for a sufficient time to reduce the tCFS score of the patient's eye for which ocular surgery is contemplated by at least 3 grades.

[0150] 2.56. The method of 2 or any of 2.1-2.55, wherein the patient is administered the composition until the total corneal fluorescein staining score of the patient's eye for which ocular surgery is contemplated is reduced by at least 3 grades.

[0151] 2.57. The method of any one of 2 or 2.1-2.56, wherein the patient has dry eye disease at the time of evaluation for or preparation for the eye surgery, optionally wherein the patient has not been diagnosed with dry eye disease prior to the time of evaluation for or preparation for the eye surgery;

[0152] 2.58. The method of 2.57, wherein the patient has ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) caused by the dry eye disease;

[0153] 2.59. The method of any one of 2 or 2.1-2.57, wherein the patient has ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) that is not caused by the dry eye disease;

[0154] 2.60. The method of 2.59, wherein the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) is caused by corneal abrasion, ocular chemical irritation, irritation due to contact lens wear (e.g., improper contact lens wear or sensitivity to contact lens care solutions), foreign body exposure, ultraviolet light damage, or ionizing radiation damage;

[0155] 2.61. The method of any one of 2 or 2.1-2.60, wherein the patient does not have meibomian gland dysfunction;

[0156] 2.62. The method of any one of 2 or 2.1-2.61, wherein the patient does not have blepharitis or uveitis;

[0157] 2.63. The method of any one of 2 or 2.1-2.62, wherein the composition does not comprise latanoprost, tafluprost, bimatoprost, travoprost, unoprostone, tacrolimus, sirolimus, everolimus, timolol, nepafenol, an antibacterial agent, an antifungal agent, an antiviral agent.

[0158] In a third aspect, the present disclosure provides a method (Method 3) for performing biometry measurements for an eye surgery (e.g., cataract surgery), the method comprising topically administering to the eye of the patient once to four times (e.g., twice) per day a composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane (e.g., 1-perfluorobutylpentane) optionally with an alcoholic cosolvent (e.g., ethanol) prior to the biometry measurements.

[0159] In further embodiments of the third aspect, the present disclosure provides:

[0160] 3.1. Method 3, wherein the eye surgery is selected from the group consisting of cataract surgery, refractive surgery (including corneal abrasion, corneal transplantation, radial keratotomy and intraocular lens implantation), glaucoma surgery (including canaloplasty, laser trabeculoplasty, iridotomy, iridectomy, sclerectomy, trabeculectomy and viscoanastomosis), laser eye surgery (e.g. laser-assisted in situ keratomileusis or LASIK, and photorefractive keratectomy, also known as LASEK, laser-assisted sub-epithelial keratomileusis) and vitreoretinal surgery (e.g. vitrectomy, repair of retinal detachment);

[0161] 3.2. Method 3.1, wherein the eye surgery is cataract surgery or refractive surgery;

[0162] 3.3. Method 3.2, wherein the eye surgery is cataract surgery or refractive surgery via intraocular lens implantation;

[0163] 3.4. Method 3 or any one of 3.1 to 3.3, wherein the method further comprises the step of determining the extent of ocular surface disease (e.g. corneal surface damage, tear film deficiency and / or tear film break-up) in preparation for the eye surgery;

[0164] 3.5. Method 3.4, wherein determining the extent of ocular surface disease comprises the step of determining the extent of the corneal surface damage, and / or tear film deficiency or break-up;

[0165] 3.6. Method 3.5, wherein the extent of the corneal surface damage is determined by the total corneal fluorescein staining score and / or the central corneal fluorescein staining score, and / or wherein the extent of the tear film deficiency or break-up is determined by the tear film break-up time (TFBUT) or the Schirmer's test;

[0166] 3.7. Method 3 or any one of 3.1 to 3.6, wherein the biometry measurements comprise corneal curvature measurements and / or optical biometry, such as measuring the anterior corneal curvature, the posterior corneal curvature, the axial length of the eye, the anterior chamber depth, the lens thickness and / or the corneal power of the eye on which the eye surgery is performed;

[0167] 3.8. Method 3 or any one of 3.1 to 3.7, wherein the semifluorinated alkane is 1-perfluorobutyl-pentane;

[0168] 3.9. Method 3 or any one of 3.1 to 3.8, wherein the composition comprises 1- perfluorobutyl-pentane and 2-perfluorobutyl-pentane;

[0169] 3.10. Any of methods 3.8-3.9, wherein the composition comprises 1-perfluorobutylpentane and 2-perfluorobutylpentane in a weight ratio of about 95 : 5, or about 96:4, or about 97 : 3, or about 98 : 2, or about 99 : 1, or about 99.5 : 0.55, or about 99.6 : 0.4, or about 99.7: 0.3, or about 99.8 : 0.22, or about 99.9 : 0.1;

[0170] 3.11. Any of methods 3.8-3.10, wherein the composition comprises at most 2% (w / w) of 2- perfluorobutylpentane, or at most 1% (w / w), or at most 0.5% (w / w), or at most 0.2% (w / w), or at most 0.1% (w / w) of 2-perfluorobutylpentane, optionally wherein the composition comprises at least 0.01% (w / w) or at least 0.1% (w / w) of 2-perfluorobutylpentane;

[0171] 3.12. Method 3 or any of 3.1-3.11, wherein the composition is free or substantially free of water, e.g., less than 2 wt.%, or less than 1 wt.%, or less than 0.5 wt.%, or less than 0.2 wt.%, or less than 0.1 wt.% of water by weight of the composition;

[0172] 3.13. Method 3 or any of 3.1-3.12, wherein the composition is free or substantially free of any preservative, e.g., less than 3 wt.%, or less than 2 wt.%, or less than 1 wt.%, or less than 0.5 wt.%, or less than 0.1 wt.% of preservative by weight of the composition, or wherein the composition is formulated to not include any preservative;

[0173] 3.14. Method 3 or any of 3.1-3.13, wherein the composition further comprises an alcoholic co-solvent;

[0174] 3.15. Method 3.14, wherein the alcoholic co-solvent is ethanol;

[0175] 3.16. Any of methods 3.14-3.15, wherein the composition comprises the alcoholic co-solvent in an amount of 0.01% to 5% (w / w), or 0.05% to 4% (w / w), or 0.1% to 3% (w / w), or 0.2% to 2% (w / w), or 0.5% to 2% (w / w), or 0.5% to 1.5% (w / w), or 0.8% to 1.2% (w / w), or about 1% (w / w), or about 1.0% (w / w);

[0176] 3.17. The method of 3 or any of 3.1-3.16, wherein the composition comprises about 0.05-0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane;

[0177] 3.18. The method of 3.17, wherein the composition comprises about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane;

[0178] 3.19. The method of 3.18, wherein the composition comprises or consists essentially of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane with about 1% (w / w) ethanol;

[0179] 3.20. The method of 3.19, wherein the composition comprises or consists essentially of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane with about 1% (w / w) ethanol and up to about 2% (w / w) or up to about 1% (w / w) 2-perfluorobutylpentane;

[0180] 3.21. The method of 3.20, wherein the composition consists of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane with about 1% (w / w) ethanol and up to about 2% (w / w) or up to about 0.5% (w / w) 2-perfluorobutylpentane;

[0181] 3.22. The method of 3 or any of 3.1-3.21, wherein the composition is administered four times per day;

[0182] 3.23. The method of 3 or any of 3.1-3.21, wherein the composition is administered three times per day;

[0183] 3.24. The method of 3 or any of 3.1-3.21, wherein the composition is administered twice per day;

[0184] 3.25. The method of 3 or any of 3.1-3.21, wherein the composition is administered once per day;

[0185] 3.26. The method of 3 or any of 3.1-3.25, wherein the amount of cyclosporine administered in a single dose per eye is about 8-12 µg, e.g., 9-11 µg, e.g., 9-10 µg, or about 9 µg, or about 10 µg cyclosporine;

[0186] 3.27. The method of 3 or any of 3.1-3.26, wherein the volume administered in a single dose per eye is about 8-12 µL, e.g., 9-11 µL, e.g., 9-10 µL, or about 9 µl or about 10 µL;

[0187] 3.28. Method 3 or any of 3.1-3.27, wherein the composition is administered to the patient for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days;

[0188] 3.29. Method 3 or any of 3.1-1.28, wherein the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) precedes the step of performing a biomicroscopy measurement;

[0189] 3.30. Method 3 or any of 3.1-3.29, wherein the last day of administration of the composition precedes the biomicroscopy measurement of the patient by, e.g., at least 1 day, or at least 2 days, or at least 3 days, or at least 5 days, or at least 7 days, or 1-7 days;

[0190] 3.31. Method 3 or any of 3.1-3.31, wherein the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) precedes the administration of the composition;

[0191] 3.32. Method 3 or any of 3.1-3.31, wherein administration of the composition continues after the biomicroscopy measurement, optionally until 1-3 days prior to ocular surgery of the patient;

[0192] 3.33. Method 3 or any of 3.1-3.32, wherein administration of the composition continues after the ocular surgery;

[0193] 3.34. Method 3 or any of 3.1-3.33, wherein the method further comprises topical ocular administration of a corticosteroid;

[0194] 3.35. Method 3 or any of 3.1-3.33, wherein the method does not further comprise topical ocular administration of a corticosteroid;

[0195] 3.36. Method 3 or any of 3.1-3.35, wherein the method does not further comprise topical ocular administration of a drug that blocks LFA-1 binding to ICAM-1 (e.g., lifitegrast);

[0196] 3.37. Method 3 or any of 3.1-3.36, wherein the composition is the only topical ophthalmic composition administered to the patient during the period of time in which the method is performed;

[0197] 3.38. Method 3 or any of 3.1-3.37, wherein the patient has not been previously diagnosed with a dry eye disease prior to evaluation for the ocular surgery;

[0198] 3.39. Method 3 or any of 3.1-3.37, wherein the patient was previously diagnosed with dry eye disease prior to being evaluated for the ocular procedure;

[0199] 3.40. Method 3 or any of 3.1-3.39, wherein the patient has an ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up);

[0200] 3.41. Method 3 or any of 3.1-3.40, wherein the patient is first identified as having an ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) at the time of evaluation for the ocular procedure or in preparation for the ocular procedure;

[0201] 3.42. Method 3 or any of 3.1-3.41, wherein the method further comprises the step of measuring or evaluating the extent of the ocular surface disease prior to administering the composition;

[0202] 3.43. Method 3 or any of 3.1-3.42, wherein the method comprises the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up), e.g., by total corneal fluorescein staining score and / or central corneal fluorescein staining score, after completion of administration of the composition (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), e.g., for purposes of comparison to pre-treatment conditions;

[0203] 3.44. Method 3.44, wherein the method further comprises the step of comparing the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) before and after administration of the composition (e.g., before and after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days) to determine whether the patient can undergo the biometric measurement and / or the ocular procedure;

[0204] 3.45. Method 3 or any of 3.1-3.44, wherein prior to initiating administration of the composition according to the method, the patient is characterized by an eye for which ocular surgery is anticipated to exhibit:

[0205] (a) a total corneal fluorescein staining score greater than or equal to 7 (e.g., greater than 8, 9, 10, 11, or 12), or greater than or equal to 10 (e.g., greater than 11, 12, or 13), such as 7-15, 7-13, 10-15, or 10-13;

[0206] (b) a central corneal fluorescein staining score equal to or greater than 1 (e.g., greater than 1 or greater than 2), such as 1-2 or 1-3 or 2-3; and / or

[0207] 3.46. The method of 3 or any of 3.1-3.45, wherein after treatment of the patient according to the method for a period of time (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), the eye of the patient for which eye surgery is contemplated is characterized by:

[0208] (a) a total corneal fluorescein staining score less than 7 (e.g., less than or equal to 1, 2, 3, 4, 5, or 6) or less than 10 (e.g., less than or equal to 3, 4, 5, 6, 7, 8, or 9); and / or a total corneal fluorescein staining score that has been reduced by at least 3 grades from a pre-treatment score; and / or

[0209] (b) a central corneal fluorescein staining score less than or equal to 1; and / or a central corneal fluorescein staining score that has been reduced by at least 1 grade from a pre-treatment score;

[0210] 3.47. The method of 3 or any of 3.1-3.45, wherein the method improves the total corneal fluorescein staining score of the eye of the patient for which eye surgery is contemplated by at least 3 grades prior to performing the biometry measurement and / or prior to performing the eye surgery.

[0211] 3.48. The method of 3 or any of 3.1-3.47, wherein the method improves the central corneal fluorescein staining score of the eye of the patient for which eye surgery is contemplated by at least 1 grade prior to performing the biometry measurement and / or prior to performing the eye surgery.

[0212] 3.49. The method of 3 or any of 3.1-3.48, wherein the biometry measurement is performed after the total corneal fluorescein staining score of the eye of the patient for which eye surgery is contemplated has been reduced by at least 3 grades.

[0213] 3.50. The method of 3 or any of 3.1-3.49, wherein the method further comprises the step of subjecting the patient to eye surgery after the total corneal fluorescein staining score of the eye of the patient for which eye surgery is contemplated has been reduced by at least 3 grades.

[0214] 3.51. The method of 3 or any of 3.1-3.50, wherein the method improves tear quality in the eye of the patient for which surgery is anticipated, e.g., as shown by improved tear film break-up time (TFBUT) and / or improved Schirmer's test score;

[0215] 3.52. The method of any of 3.46-3.51, wherein the patient achieves the level of improvement after less than 8 weeks of treatment, e.g., after 1 to 6 weeks of administration of the composition, or after 1 to 5 weeks of administration of the composition, or after 1 to 4 weeks of administration of the composition, or after 2 to 6 weeks of administration of the composition, or after 2 to 5 weeks of administration of the composition, or after 2 to 4 weeks of administration of the composition, or after 2 to 3 weeks of administration of the composition, or after less than 4 weeks of administration of the composition;

[0216] 3.53. The method of 3 or any of 3.1-3.52, wherein the patient is subjected to biomicroscopy after administration of the composition for a sufficient time to reduce the tCFS score of the eye for which eye surgery is anticipated by at least 3 grades;

[0217] 3.54. The method of 3 or any of 3.1-3.53, wherein the patient is administered the composition until the total corneal fluorescein staining score of the eye of the patient for which eye surgery is anticipated is reduced by at least 3 grades;

[0218] 3.55. The method of 3 or any of 3.1-3.54, wherein the patient has dry eye disease at the time of evaluation for or preparation for the eye surgery, optionally, wherein the patient has not been diagnosed with dry eye disease prior to the time of evaluation for or preparation for the eye surgery;

[0219] 3.56. The method of 3.55, wherein the patient has ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film breakage) caused by the dry eye disease;

[0220] 3.57. The method of 3 or any of 3.1-3.55, wherein the patient has ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film breakage) that is not caused by the dry eye disease;

[0221] 3.58. The method of 3.57, wherein the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film breakage) is caused by corneal abrasion, ocular chemical irritation, irritation due to contact lens wear (e.g., improper contact lens wear or sensitivity to contact lens care solutions), foreign body exposure, ultraviolet light damage, or ionizing radiation damage;

[0222] 3.59. The method of 3 or any of 3.1-3.58, wherein the patient does not have meibomian gland dysfunction;

[0223] 3.60. The method of 3 or any of 3.1-3.59, wherein the patient does not have blepharitis or uveitis;

[0224] 3.61. The method of 3 or any of 3.1-3.60, wherein the composition does not comprise latanoprost, tafluprost, bimatoprost, travoprost, unoprostone, tacrolimus, sirolimus, eprosartan, timolol, nebivolol, an antibacterial agent, an antifungal agent, an antiviral agent.

[0225] 3.62. The method of 3 or any of 3.1-3.61, wherein the administration of the composition improves the ocular surface for more accurate biometry measurements.

[0226] The present disclosure is also directed to embodiments described according to the following items:

[0227] 1. A method for preparing a patient for ocular surgery (e.g., cataract surgery), the method comprising topically administering to an eye (e.g., the eye undergoing ocular surgery) of the patient a composition comprising about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane optionally having about 1% (w / w) ethanol, twice daily.

[0228] 2. A method for treating corneal surface damage in a patient preparing for ocular surgery (e.g., cataract surgery), the method comprising topically administering to an eye of the patient a composition comprising about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane optionally having about 1% (w / w) ethanol, twice daily.

[0229] 3. The method of any of items 1-2, wherein the method further comprises the step of performing biometry measurements in preparation for the ocular surgery.

[0230] 4. A method for performing biometry measurements for ocular surgery (e.g., cataract surgery), the method comprising topically administering to an eye of the patient a composition comprising about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane optionally having about 1% (w / w) ethanol, twice daily prior to the biometry measurements.

[0231] 5. The method of any of items 1-4, wherein the composition comprises about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane having about 1% (w / w) ethanol and optionally up to about 1% (w / w) 2-perfluorobutylpentane.

[0232] 6. The method of any of items 1-5, wherein the composition consists of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane with about 1% (w / w) ethanol and optionally up to about 0.5% (w / w) 2-perfluorobutylpentane.

[0233] 7. The method of any of items 1-6, wherein the amount of cyclosporine administered in a single dose per eye is about 8-12 pg, for example 9-11 pg or about 10 pg of cyclosporine.

[0234] 8. The method of any of items 1-7, wherein the composition is administered to the patient for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days.

[0235] 9. The method of any of items 1-8, wherein the method further comprises the step of determining the extent of corneal surface damage in preparation for the ocular surgery.

[0236] 10. The method of item 9, wherein the extent of corneal surface damage is determined by a total corneal fluorescein staining score and / or a central corneal fluorescein staining score.

[0237] 11. The method of any of items 1-10, wherein prior to initiating administration of the composition according to the method, the patient is characterized in that the eye for which ocular surgery is anticipated exhibits:

[0238] (a) a total corneal fluorescein staining score greater than or equal to 7 (e.g., greater than 8, 9, 10, 11, or 12), such as 7-15, 7-13, 10-15, or 10-13;

[0239] (b) a central corneal fluorescein staining score equal to or greater than 1 (e.g., greater than 1, greater than 2), such as 1-2 or 1-3 or 2-3.

[0240] 12. The method of any of items 1-11, wherein after treatment of the patient with the composition according to the method for a period of time (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), the patient is characterized in that the eye for which ocular surgery is anticipated exhibits:

[0241] (a) a total corneal fluorescein staining score that has been reduced by at least 3 grades; and / or

[0242] (b) a central corneal fluorescein staining score that has been reduced by at least 1 grade.

[0243] 13. The method of any of items 1-12, wherein the method improves the total corneal fluorescein staining score of the patient's eye intended for the ocular surgery by at least 3 grades prior to performing the biometry measurement and / or prior to performing the ocular surgery.

[0244] 14. The method of any of items 1-13, wherein the method improves the central corneal fluorescein staining score of the patient's eye intended for the ocular surgery by at least 1 grade prior to performing the biometry measurement and / or prior to performing the ocular surgery.

[0245] 15. The method of items 1 to 14, wherein the step of determining the extent of the corneal surface damage is prior to administration of the composition.

[0246] 16. The method of items 1 to 15, wherein the patient is subjected to biometry without first achieving a reduction of at least 3 grades in the total corneal fluorescein staining score of the patient's eye intended for the ocular surgery.

[0247] 17. The method of items 1 to 16, wherein the composition is administered to the patient until the total corneal fluorescein staining score of the patient's eye intended for the ocular surgery achieves a reduction of at least 3 grades.

[0248] 18. The method of items 1 to 17, wherein the patient has a corneal surface damage not caused by a dry eye disease.

[0249] 19. The method of items 1 to 18, wherein the composition is continued to be administered after the ocular surgery.

[0250] In a fourth aspect, the present disclosure provides the use of a composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane optionally with an alcohol co-solvent for performing the method of any of method 1 and its subsequent items, method 2 and its subsequent items, or method 3 and its subsequent items.

[0251] In a fifth aspect, the present disclosure provides a pharmaceutical composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane optionally with an alcohol cosolvent; or a pharmaceutical composition as defined in any one or combination of the embodiments described herein, for use in a method according to any one of Method 1 and its subsequent items, Method 2 and its subsequent items, or Method 3 and its subsequent items. For example, the present disclosure provides a pharmaceutical composition for use in: (a) preparing a patient for an ocular surgery (e.g., cataract surgery), or (b) treating an ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) in a patient being prepared for an ocular surgery (e.g., cataract surgery), or (c) performing a biometry measurement in preparation for an ocular surgery (e.g., cataract surgery), wherein the composition comprises about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane optionally with an alcohol cosolvent, and is formulated for topical administration to the eye of the patient.

[0252] Another embodiment according to this aspect of the present disclosure relates to a composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane optionally with an alcohol cosolvent (e.g., ethanol), for use in:

[0253] a) a method of preparing a patient for an ocular surgery (e.g., cataract surgery); and / or

[0254] b) a method of treating an ocular surface disease (e.g., corneal surface injury, tear film deficiency, or tear film break-up) in a patient being prepared for an ocular surgery (e.g., cataract surgery); and / or

[0255] c) a method for performing a biometry measurement in preparation for an ocular surgery (e.g., cataract surgery), wherein the composition is topically administered to the eye of the patient prior to the biometry measurement;

[0256] wherein the composition is topically administered to the eye (e.g., the eye undergoing the ocular surgery (e.g., cataract surgery)) of the patient one to four times per day (e.g., twice per day).

[0257] Further embodiments relating to the composition for use in the methods and treatments of a), b), or c) provide:

[0258] 5.1. A composition for use according to any one of the preceding items, wherein the eye surgery is selected from the group consisting of cataract surgery, refractive surgery (including corneal abrasion, corneal transplantation, radial keratotomy and intraocular lens implantation), glaucoma surgery (including canaloplasty, laser trabeculoplasty, iridotomy, iridectomy, sclerectomy, trabeculectomy and viscoanastomosis), laser eye surgery (e.g. laser-assisted in situ keratomileusis or LASIK, and photorefractive keratectomy, also known as LASEK, laser-assisted sub-epithelial keratomileusis) and vitreoretinal surgery (e.g. vitrectomy, repair of retinal detachment);

[0259] 5.2. A composition for use according to item 5.1, wherein the eye surgery is cataract surgery or refractive surgery;

[0260] 5.3. A composition for use according to any one of the preceding items, or a composition according to item 5.2, wherein the eye surgery is cataract surgery or refractive surgery via intraocular lens implantation;

[0261] 5.4. A composition for use according to any one of the preceding items, or a composition according to any one of items 5.1-5.3, wherein the method further comprises the step of determining the extent of ocular surface disease (e.g. corneal surface damage, tear film deficiency and / or tear film break-up) in preparation for the eye surgery;

[0262] 5.5. A composition for use according to item 5.4, wherein determining the extent of ocular surface disease comprises the step of determining the extent of corneal surface damage, and / or tear film deficiency or break-up;

[0263] 5.6. A composition for use according to item 5.5, wherein the extent of corneal surface damage is determined by a total corneal fluorescein staining score and / or a central corneal fluorescein staining score, and / or wherein the extent of tear film deficiency or break-up is determined by tear film break-up time (TFBUT) or Schirmer’s test;

[0264] 5.7. A composition for use according to any one of the preceding items, or a composition according to any one of items 5.1-5.6, wherein the method further comprises the step of performing biometry measurements in preparation for the eye surgery;

[0265] 5.8. A composition for use according to item 5.7, wherein the biometry measurements comprise corneal curvature measurements and / or optical biometry, such as measuring the corneal curvature (e.g. corneal anterior curvature, corneal posterior curvature), the axial length, the anterior chamber depth, the lens thickness and / or the corneal power of the eye on which the eye surgery is to be performed;

[0266] 5.9. The composition for use or the composition of any one of items 5.1-5.8, wherein the semifluorinated alkane is 1-perfluorobutylpentane;

[0267] 5.10. The composition for use or the composition of any one of items 5.1-5.9, wherein the composition comprises 1-perfluorobutylpentane and 2- perfluorobutylpentane;

[0268] 5.11. The composition for use or the composition of any one of items 5.9-5.10, wherein the composition comprises 1-perfluorobutylpentane and 2- perfluorobutylpentane in a weight ratio of about 95 : 5, or about 96 : 4, or about 97 : 3, or about 98 : 2, or about 99 : 1, or about 99.5 : 0.5, or about 99.6 : 0.4, or about 99.7 : 0.3, or about 99.8 : 0.2, or about 99.9 : 0.1;

[0269] 5.12. The composition for use or the composition of any one of items 5.9-5.11, wherein the composition comprises at most 5% (w / w) of 2- perfluorobutylpentane, or at most 3% (w / w), or at most 2% (w / w), or at most 1% (w / w), or at most 0.5% (w / w), or at most 0.4% (w / w), or at most 0.3% (w / w), or at most 0.2% (w / w), or at most 0.1% (w / w) of 2- perfluorobutylpentane, optionally wherein the composition comprises at least 0.01% (w / w), or at least 0.1% (w / w), or at least 0.3% (w / w) of 2- perfluorobutylpentane;

[0270] 5.13. The composition for use or the composition of any one of items 5.1-5.12, wherein the composition is free or substantially free of water, for example less than 2 wt.%, or less than 1 wt.%, or less than 0.5 wt.%, or less than 0.2 wt.%, or less than 0.1 wt.% of water by weight of the composition;

[0271] 5.14. The composition for use or the composition of any one of items 5.1-5.13, wherein the composition is free or substantially free of any preservative, for example less than 3 wt.%, or less than 2 wt.%, or less than 1 wt.%, or less than 0.5 wt.%, or less than 0.1 wt.% of preservative by weight of the composition, or wherein the composition is formulated to not comprise any preservative;

[0272] 5.15. The composition for use or the composition of any one of items 5.1-5.14, wherein the composition further comprises an alcoholic co-solvent;

[0273] 5.16. The composition for use or the composition of item 5.15, wherein the alcoholic co-solvent is ethanol;

[0274] 5.17. The composition for use or the composition of any one of items 5.15-5.16, wherein the composition comprises the alcoholic co-solvent in an amount of 0.01% to 5% (w / w), or 0.05% to 4% (w / w), or 0.1% to 3% (w / w), or 0.2% to 2% (w / w), or 0.2% to 1.5% (w / w), or 0.2% to 1.0% (w / w), or 0.5% to 1.2% (w / w), or about 0.5% (w / w), or about 1.0% (w / w);

[0275] 5.18. The composition for use or the composition of any one of items 5.1-5.17, wherein the composition comprises about 0.05% - 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane;

[0276] 5.19. The composition for use or the composition of item 5.18, wherein the composition comprises about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane;

[0277] 5.20. The composition for use or the composition of item 5.19, wherein the composition comprises or consists essentially of about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane with about 1% (w / w) ethanol;

[0278] 5.21. The composition for use or the composition of item 5.20, wherein the composition comprises or consists essentially of about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane with about 1% (w / w) ethanol and up to about 1% (w / w) 2- perfluorobutylpentane;

[0279] 5.22. The composition for use or the composition of item 5.21, wherein the composition consists of about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane with about 1% (w / w) ethanol and up to about 0.5% (w / w) 2- perfluorobutylpentane;

[0280] 5.23. The composition for use or the composition of any one of items 5.1-5.22, wherein the composition is administered four times per day;

[0281] 5.24. The composition for use or the composition of any one of items 5.1-5.22, wherein the composition is administered three times per day;

[0282] 5.25. The composition for use or the composition of any one of items 5.1-5.22, wherein the composition is administered twice per day;

[0283] 5.26. The composition for use or the composition of any one of items 5.1-5.22, wherein the composition is administered once per day;

[0284] 5.27. The composition for use or the composition of any one of items 5.1-5.26, wherein the amount of cyclosporine administered in a single dose per eye is about 8-12 pg, e.g., 9-11 pg, e.g., 9-10 pg, or about 9 pg, or about 10 pg cyclosporine;

[0285] 5.28. The composition for use or the composition of any one of items 5.1-5.27, wherein the volume administered in a single dose per eye is about 8-12 pL, e.g., 9-11 pL, e.g., 9-10 pL, or about 9 pL or about 10 pL;

[0286] 5.29. The composition for use or the composition of any one of items 5.1-5.28, wherein the composition is administered to the patient for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days;

[0287] 5.30. The composition for use or the composition of any one of items 5.1-5.29, wherein the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) precedes the step of performing a biomicroscopy measurement;

[0288] 5.31. The composition for use or the composition of any one of items 5.1-5.30, wherein the last day of administration of the composition precedes the biomicroscopy measurement of the patient by, e.g., at least 1 day, or at least 2 days, or at least 3 days, or at least 5 days, or at least 7 days, or 1-7 days;

[0289] 5.32. The composition for use or the composition of any one of items 5.1-5.31, wherein the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) precedes administration of the composition;

[0290] 5.33. The composition for use or the composition of any one of items 5.1-5.32, wherein administration of the composition continues after the biomterics measurement, optionally until 1-3 days prior to the ocular surgery in the patient;

[0291] 5.34. The composition for use or the composition of any one of items 5.1-5.33, wherein administration of the composition continues after the ocular surgery;

[0292] 5.35. The composition for use or the composition of any one of items 5.1-5.34, wherein the method further comprises topical ocular administration of a corticosteroid;

[0293] 5.36. The composition for use or the composition of any one of items 5.1-5.34, wherein the method does not further comprise topical ocular administration of a corticosteroid;

[0294] 5.37. The composition for use or the composition of any one of items 5.1-5.36, wherein the method does not further comprise topical ocular administration of a drug that blocks LFA-1 binding to ICAM-1 (e.g., lifitegrast);

[0295] 5.38. The composition for use or the composition of any one of items 5.1-5.37, wherein the composition is the only topical ophthalmic composition administered to the patient during the period of time in which the method or treatment is performed;

[0296] 5.39. The composition for use or the composition of any one of items 5.1-5.38, wherein the patient has not been previously diagnosed with dry eye disease prior to evaluation for the ocular surgery;

[0297] 5.40. The composition for use or the composition of any one of items 5.1-5.38, wherein the patient has been previously diagnosed with dry eye disease prior to evaluation for the ocular surgery;

[0298] 5.41. The composition for use or the composition of any one of items 5.1-5.40, wherein the patient has ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film breakup);

[0299] 5.42. The composition for use or the composition of any one of items 5.1-5.41, wherein the patient is first identified as having an ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) when being evaluated for the ocular procedure or in preparation for the ocular procedure;

[0300] 5.43. The composition for use or the composition of any one of items 5.1-5.41, wherein the method further comprises the step of measuring or evaluating the extent of the ocular surface disease prior to administering the composition;

[0301] 5.44. The composition for use or the composition of any one of items 5.1-5.43, wherein the method further comprises the step of determining the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up), e.g., by total corneal fluorescein staining score and / or central corneal fluorescein staining score, after completion of the administration of the composition (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), e.g., for the purpose of comparison to pre-treatment conditions;

[0302] 5.45. The composition for use or the composition of item 5.44, wherein the method further comprises the step of comparing the extent of the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) before and after administration of the composition (e.g., before and after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), to determine whether the patient can undergo the biometrical measurement and / or the ocular procedure;

[0303] 5.46. The composition for use or the composition of any one of items 5.1-5.45, wherein the method further comprises the step of subjecting the patient to an ocular procedure after determining that the ocular surface disease (e.g., corneal surface injury, tear film deficiency, and / or tear film break-up) has been reduced to a level that is safe and suitable for biometrical measurement and / or performance of the ocular procedure;

[0304] 5.47. The composition for use or the composition of any one of items 5.1-5.46, wherein prior to initiating administration of the composition according to the method, the patient is characterized by an eye for which an ocular procedure is anticipated to exhibit:

[0305] (a) total corneal fluorescein staining score greater than or equal to 7 (e.g., greater than 8, 9, 10, 11, or 12), or greater than or equal to 10 (e.g., greater than 10, 11, 12, or 13), such as 7-15, 7-13, 10-15, or 10-13; and / or

[0306] (b) central corneal fluorescein staining score equal to or greater than 1 (e.g., greater than 1, greater than 2), such as 1-2 or 1-3 or 2-3;

[0307] 5.48. The composition for use or the composition of any of items 5.1-5.47, wherein after treatment of the patient with the composition according to the method for a period of time (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), the patient is characterized in that the eye for which eye surgery is contemplated exhibits:

[0308] (a) total corneal fluorescein staining score less than 7 (e.g., less than or equal to 1, 2, 3, 4, 5, or 6) or less than 10 (e.g., less than or equal to 3, 4, 5, 6, 7, 8, or 9); and / or total corneal fluorescein staining score has been reduced by at least 3 grades from the pre-treatment score; and / or

[0309] (b) central corneal fluorescein staining score less than or equal to 1; and / or central corneal fluorescein staining score has been reduced by at least 1 grade from the pre-treatment score;

[0310] 5.49. The composition for use or the composition of any of items 5.1-5.48, wherein the method improves the total corneal fluorescein staining score of the patient’s eye for which eye surgery is contemplated by at least 3 grades prior to performing the biometry measurements and / or prior to performing the eye surgery;

[0311] 5.50. The composition for use or the composition of any of items 5.1-5.49, wherein the method improves the central corneal fluorescein staining score of the patient’s eye for which eye surgery is contemplated by at least 1 grade prior to performing the biometry measurements and / or prior to performing the eye surgery;

[0312] 5.51. The composition for use or the composition of any of items 5.1-5.50, wherein the method further comprises the step of subjecting the patient to biometry measurements after the total corneal fluorescein staining score of the patient’s eye for which eye surgery is contemplated has been reduced by at least 3 grades;

[0313] 5.52. The composition for use or the composition of any one of items 5.1-5.51, wherein the method further comprises the step of subjecting the patient to an ocular surgery after the total corneal fluorescein staining score of the eye for which ocular surgery is contemplated in the patient is reduced by at least 3 grades;

[0314] 5.53. The composition for use or the composition of any one of items 5.1-5.52, wherein the method improves tear quality in the eye for which surgery is contemplated in the patient, e.g., as shown by an improved tear film break-up time (TFBUT) and / or an improved Schirmer’s test score;

[0315] 5.54. The composition for use or the composition of any one of items 5.48-5.53, wherein the patient achieves the level of improvement after less than 8 weeks of treatment, e.g., after 1 to 6 weeks of administration of the composition, or after 1 to 5 weeks of administration of the composition, or after 1 to 4 weeks of administration of the composition, or after 2 to 6 weeks of administration of the composition, or after 2 to 5 weeks of administration of the composition, or after 2 to 4 weeks of administration of the composition, or after 2 to 3 weeks of administration of the composition, or after less than 4 weeks of administration of the composition;

[0316] 5.55. The composition for use or the composition of any one of items 5.1-5.54, wherein the patient is subjected to biometry after administration of the composition for a sufficient time to reduce the tCFS score of the eye for which ocular surgery is contemplated by at least 3 grades;

[0317] 5.56. The composition for use or the composition of any one of items 5.1-5.55, wherein the patient is administered the composition until the total corneal fluorescein staining score of the eye for which ocular surgery is contemplated in the patient is reduced by at least 3 grades;

[0318] 5.57. The composition for use or the composition of any one of items 5.1-5.56, wherein the patient has dry eye disease at the time of evaluation for or preparation for the ocular surgery (e.g., cataract surgery), optionally, wherein the patient has not been diagnosed with dry eye disease prior to the evaluation for or preparation for the ocular surgery (e.g., cataract surgery);

[0319] 5.58. The composition for use or the composition of item 5.57, wherein the patient has ocular surface disease (e.g., corneal surface damage, tear film deficiency, and / or tear film breakage) caused by the dry eye disease;

[0320] 5.59. The composition for use or the composition of any one of items 5.1-5.57, wherein the patient has an ocular surface disease (e.g., corneal surface damage, tear film deficiency, and / or tear film break-up) that is not caused by the dry eye disease;

[0321] 5.60. The composition for use or the composition of item 5.59, wherein the ocular surface disease (e.g., corneal surface damage, tear film deficiency, and / or tear film break-up) is caused by corneal abrasion, ocular chemical irritation, irritation due to contact lens wear (e.g., improper contact lens wear or sensitivity to contact lens care solutions), foreign body exposure, ultraviolet light damage, or ionizing radiation damage;

[0322] 5.61. The composition for use or the composition of any one of items 5.1-5.60, wherein the patient does not have meibomian gland dysfunction;

[0323] 5.62. The composition for use or the composition of any one of items 5.1-5.61, wherein the patient does not have blepharitis or uveitis;

[0324] 5.63. The composition for use or the composition of any one of items 5.1-5.62, wherein the composition does not comprise latanoprost, tafluprost, bimatoprost, travoprost, unoprostone, tacrolimus, sirolimus, eprosartan, timolol, nebivolol, an antibacterial agent, an antifungal agent, an antiviral agent.

[0325] 5.64. The composition for use or the composition of any one of items 5.1-5.63, wherein the administration of the composition improves the ocular surface for more accurate biometry measurements.

[0326] Further embodiments according to this aspect of the present disclosure provide:

[0327] 1.1. A composition comprising about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane optionally having about 1% (w / w) ethanol, for use in a method of preparing a patient for an ocular procedure (e.g., cataract surgery), the method comprising topically administering the composition to an eye (e.g., the eye undergoing the ocular procedure) of the patient twice per day.

[0328] 1.2. A composition comprising about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane optionally having about 1% (w / w) ethanol, for use in a method of treating a corneal surface injury in a patient in preparation for an ocular surgery (e.g., cataract surgery), the method comprising topically administering the composition to the eye of the patient twice a day.

[0329] 1.3. The composition for use of any of items 1.1-1.2, wherein the method further comprises the step of performing a biometry measurement in preparation for the ocular surgery.

[0330] 1.4. A composition comprising about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane optionally having about 1% (w / w) ethanol, for use in a method of performing a biometry measurement in preparation for an ocular surgery (e.g., cataract surgery), the method comprising topically administering the composition to the eye of the patient twice a day prior to the biometry measurement.

[0331] 1.5. The composition for use of any of items 1.1-1.4, wherein the composition comprises about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane having about 1% (w / w) ethanol and optionally up to about 1% (w / w) 2- perfluorobutylpentane.

[0332] 1.6. The composition for use of any of items 1.1-1.5, wherein the composition consists of about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane having about 1% (w / w) ethanol and optionally up to about 0.5% (w / w) 2- perfluorobutylpentane.

[0333] 1.7. The composition for use of any of items 1.1-1.6, wherein the amount of cyclosporine administered in a single dose per eye is about 8-12 µg, e.g., 9-11 µg or about 10 µg cyclosporine.

[0334] 1.8. The composition for use of any of items 1.1-1.7, wherein the composition is administered to the patient for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days.

[0335] 1.9. The composition for use of any of items 1.1-1.8, wherein the method further comprises the step of determining the extent of the corneal surface injury in preparation for the ocular surgery.

[0336] 1.10. The composition for use of any of items 1.9, wherein the extent of corneal surface damage is determined by a total corneal fluorescein staining score and / or a central corneal fluorescein staining score.

[0337] 1.11. The composition for use of any of items 1.1-1.10, wherein prior to initiating administration of the composition according to the method, the patient is characterized by an eye for which ocular surgery is contemplated that exhibits:

[0338] (a) a total corneal fluorescein staining score greater than or equal to 7 (e.g., greater than 8, 9, 10, 11, or 12), such as 7-15, 7-13, 10-15, or 10-13;

[0339] (b) a central corneal fluorescein staining score equal to or greater than 1 (e.g., greater than 1, greater than 2), such as 1-2 or 1-3 or 2-3.

[0340] 1.12. The composition for use of any of items 1.1-1.11, wherein after treatment of the patient with the composition according to the method for a period of time (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), the patient is characterized by an eye for which ocular surgery is contemplated that exhibits:

[0341] (a) a total corneal fluorescein staining score that has been reduced by at least 3 grades; and / or

[0342] (b) a central corneal fluorescein staining score that has been reduced by at least 1 grade.

[0343] 1.13. The composition for use of any of items 1.1-1.12, wherein the method improves the total corneal fluorescein staining score of the patient’s eye for which ocular surgery is contemplated by at least 3 grades prior to performing the biometry measurements and / or prior to performing the ocular surgery.

[0344] 1.14. The composition for use of any of items 1.1-1.13, wherein the method improves the central corneal fluorescein staining score of the patient’s eye for which ocular surgery is contemplated by at least 1 grade prior to performing the biometry measurements and / or prior to performing the ocular surgery.

[0345] 1.15. The composition for use of any of items 1.1-1.14, wherein the step of determining the extent of corneal surface damage is prior to administration of the composition.

[0346] 1.16. The composition for use of any one of items 1.1 to 1.15, wherein a total corneal fluorescein staining score of the eye for which ocular surgery is anticipated in the patient is reduced by at least 3 grades, the patient is subjected to biomicroscopy.

[0347] 1.17. The composition for use of any one of items 1.1 to 1.16, wherein the composition is administered to the patient until a total corneal fluorescein staining score of the eye for which ocular surgery is anticipated in the patient is reduced by at least 3 grades.

[0348] 1.18. The composition for use of any one of items 1.1 to 1.17, wherein the patient has a corneal surface damage not caused by dry eye disease.

[0349] 1.19. The composition for use of any one of items 1.1 to 1.18, wherein the composition is continued to be administered after the ocular surgery.

[0350] In another embodiment, the present disclosure provides a pharmaceutical composition comprising about 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane optionally having about 1% (w / w) ethanol and further optionally up to about 1% (w / w) 2-perfluorobutylpentane for use in: (a) preparing a patient for cataract surgery (or a procedure involving intraocular lens implantation), or (b) treating ocular surface disease (such as corneal surface injury) in a patient being prepared for cataract surgery (or a procedure involving intraocular lens implantation), wherein the method comprises topically administering the composition to the patient’s eye at least twice a day, preferably in an amount of between 8 and 12 µL (or 9 to 11 µL or 10 µL) volume of the composition. In some embodiments, the composition is used to prepare a patient for cataract surgery, for example, to prepare the patient’s eye for biometry measurements prior to surgery, wherein the use comprises first evaluating the eye for corneal surface injury, for example, by corneal fluorescein staining as described herein, followed by administering the composition as described herein to the eye prior to any biometry measurements and / or surgery. The eye (which can be one or both eyes) of a patient who is scheduled for cataract or lens implantation surgery and can use the composition can be assessed as having corneal surface injury, for example, having a corneal fluorescein staining score as described in Method 1.47 or Method 2.47. The use of the composition includes administering the composition to the eye scheduled for surgery for a treatment period prior to determining biometry measurements of the eye and / or cataract surgery, optionally wherein the step of evaluating the corneal surface injury can be repeated, for example, at least once during the treatment period, and treatment can also continue until an improvement in total corneal fluorescein staining is observed; for example, a decrease in score of between 1 and 3 grades prior to the next biometry measurement step and / or eye surgery. Optionally, the use of the composition can continue after biometry measurements and until surgery, for example, until 1-3 days prior to the patient’s ocular surgery.

[0351] In a further aspect, the present disclosure provides a kit comprising a pharmaceutical composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in a semifluorinated alkane optionally having an alcohol cosolvent, formulated for topical administration to a patient’s eye; or a pharmaceutical composition as defined in any one or combination of embodiments described in the present disclosure, wherein the kit comprises a container for holding the composition and a droplet dispenser adapted for administering about 8-12 µL volume (or 9-11 µl, or 9-10 µl, or about 9 µl or about 10 µl) of the composition per drop, and instructions for administering the composition according to any one of Method 1 and its subsequent items, Method 2 and its subsequent items, or Method 3 and its subsequent items.

[0352] As used herein, "preparing for an ocular procedure" means any pre-operative preparation for an ocular procedure, such as cataract surgery, including any diagnostic tests performed to confirm that a patient is a suitable candidate for an ocular procedure or for preparing an intraocular lens. The preparation is typically performed after a decision has been made that an ocular procedure is necessary or desirable, typically by or under the direction of an eye care provider.

[0353] As used herein, "evaluation for an ocular procedure" means any diagnostic or evaluation steps taken prior to preparing for an ocular procedure, such as cataract surgery, including diagnostic tests to determine the presence of a correctable defect or a patient's potential need and suitability for an ocular procedure. The evaluation is typically performed by or under the direction of an ophthalmologist and is performed prior to a determination that cataract surgery is necessary or appropriate.

[0354] In preparing for an ocular procedure, especially one involving intraocular lens implantation, it is necessary to measure the length of the eye in what is called an A-scan, and it is necessary to measure the curvature of the cornea using a technique called keratometry. These measurements are critical to enable the surgeon to define the appropriate parameters for the ocular procedure, such as selecting the appropriate lens implant for the eye.

[0355] Keratometry (K) is the measurement of the curvature of the cornea; the curvature of the cornea determines the refractive power of the cornea. Differences in the refractive power of the cornea (relative meridians) result in astigmatism; thus, keratometry measures astigmatism. It can be obtained manually with a variety of instruments or via automated methods.

[0356] The measurement can be very complex, such as using a corneal topography, which measures the cornea across a wide number of points, or can be measured in more limited areas of the cornea, for example, using a manual keratometer or using an IOL Master (Carl Zeiss Meditec). The IOL Master also measures axial length of the eye and other ocular parameters, such as anterior chamber depth and white-to-white measurement, and includes the K reading.

[0357] Keratometry is a particularly critical measurement, as any error in the measurement will directly result in a decrease in the refractive outcome. Thus, if the K is inaccurate, the patient will have an unexpected refractive surprise post-operatively, and this refractive error outcome is very disappointing to both the physician and the patient. Correcting such errors often requires a second procedure, such as replacement of a new intraocular lens, piggybacking another intraocular lens, or a surface modification procedure.

[0358] Optometry is the process of measuring the corneal power and length of the eye. Inaccuracy in either of these measurements will also lead to unpredictable postoperative refractive errors. Optometry is the current standard in clinical practice for intraocular lens (IOL) power calculation. Optometry is a highly accurate non-invasive automated method for measuring anatomical features of the eye. Accurate measurements are essential to determine the correct power of the intraocular lens before implantation of the intraocular lens.

[0359] Optometry using partial coherence interferometry, also known as ophthalmometry, has become the gold standard in ocular biometry due to its high accuracy, ease of execution, non-invasiveness and patient comfort.

[0360] Four main components are determined in an optometry measurement:

[0361] (1) corneal curvature (keratometry),

[0362] (2) axial length (AL),

[0363] (3) anterior chamber depth (ACD), and

[0364] (4) optionally, lens thickness (LT).

[0365] These are the four key variables used to calculate the power of the intraocular lens.

[0366] The anterior surface of the cornea can be measured using a variety of techniques, including reflection-based methods such as keratometry and corneal topography, Scheimpflug imaging and anterior segment OCT. Each technique has its own advantages and disadvantages. Reflection-based methods can measure very accurately, but they have limitations when it comes to obtaining information about the posterior surface of the cornea and even ultrastructural information from the cornea. Scheimpflug measurements and anterior segment OCT, on the other hand, provide this information. The current measurement precision is a limitation of both techniques due to motion artifacts related to data collection.

[0367] In addition to a correct keratometry, an accurate AL measurement is also required. In commercially available instruments, optical coherence methods are used to determine the AL. In this case, three aspects influence the accuracy: (1) signal-to-noise ratio of the peak detection; (2) eye movement during the AL scan procedure; and (3) fluctuations in the refractive index of the ocular media. Signal-to-noise ratio and scan speed are often linked. Faster scans eliminate eye movement anomalies, but they can potentially reduce the signal, especially in dense cataracts.

[0368] The unknown effective refractive index of the lens is an unsolved challenge in currently available technology. To calculate the geometric AL from the optical coherence signal, most systems use an ultrasound equivalent. The accuracy of the AL measurement is compromised because the refractive index varies significantly from eye to eye depending on the cataract grade.

[0369] ACD and optionally LT have been established as preoperative features that can help accurately predict IOL position. Therefore, ocular biometry should be able to reliably and correctly quantify these features.

[0370] As used herein, “miswearing of contact lenses” includes overuse of contact lenses, insufficient cleaning of contact lenses, improper care of contact lenses, not following contact lens instructions (including lens replacement frequency, cleaning frequency, wear duration), wearing expired contact lenses, wearing contact lenses of an incorrect prescription (including outdated prescriptions), and wearing contact lenses of an improper prescription (e.g., wearing contact lenses that are not suitable).

[0371] The tear film, which has a lipid layer, a hydro-lipid layer, and a mucin layer, generally provides a protective barrier for the corneal tissue and the corneal epithelium, and it also has a wetting function to prevent the ocular tissue from drying or dehydrating. The tear film also acts as a conduit to provide oxygen and nutrients to the corneal epithelial cells and as a conduit to clear any potential pathogens, debris, and waste. In many patients preparing for ocular surgery, the tear film can be deficient, unstable, or disrupted, for example, due to decreased tear secretion or increased tear film evaporation, or decreased mucin or lipid secretion. As a result, the ocular surface, including the cornea, can become less protected and vulnerable and / or susceptible to injury and exacerbation.

[0372] The term “ocular surface disease (OSD)” relates to a disease or condition affecting and impairing the surface layer of the eye, such as affecting the cornea, the conjunctiva, and the glandular network, including the meibomian glands. Ocular surface disease can include diseases such as dry eye disease (the most common subtype of OSD), but also blepharitis, neurotrophic keratitis, ocular rosacea, and meibomian gland dysfunction. Ocular surface disease can include any combination of conditions selected from the group consisting of corneal surface damage, conjunctival surface damage, tear film deficiency, and / or tear film disruption.

[0373] The term “corneal surface damage” can include any combination of surface damage to the cornea, including the full corneal area, the central corneal area, the nasal corneal area, the temporal corneal area, and the inferior corneal area. The extent of corneal surface damage can be evaluated by examining the eye using a corneal staining technique (e.g., by staining with fluorescein), which preferentially stains dead and damaged cells of the cornea, thus showing corneal surface damage that would otherwise be difficult to observe.

[0374] As used herein, the term“corneal fluorescein staining score” or“corneal staining score” refers to a measurement of corneal staining according to the NEI (National Eye Institute) grading system. In this system, the cornea is divided into five sections (inferior, superior, central, nasal, and temporal regions of the cornea) and each section is assigned a value from 0 (no damage) to 3 (severe damage) for a maximum of 15 points. The measurement is made by staining the patient’s cornea with fluorescein staining. While the total corneal fluorescein staining score (tCFS; 0-15) considers all 5 corneal sections, the central corneal staining score (cCFS; 0-3) considers only the central corneal region. In some embodiments, the moderately to severely affected patients can have a total corneal fluorescein staining score of more than 10 or even 11 at the start of the treatment period. The central corneal region is more critical to patient outcome due to its importance in vision. In some embodiments, the moderately to severely affected patients can have a central corneal fluorescein staining score of more than 2 at the start of the treatment period.

[0375] Tear film quality can be evaluated using the Schirmer test type I and / or tear film break-up time (TFBUT or TBUT). In some embodiments, prior to the treatment period, the patient has a non-anesthetized Schirmer test score in the range of 2 to 8 mm or 4 to 6 mm.

[0376] As used herein, the term“treatment period” or any reference to the length of treatment refers to the period of time from the first day to the last day of administering the composition to the eye of the patient according to any of the methods described herein.

[0377] In some embodiments according to the present disclosure, the patient can have dry eye disease. This is a complex disease that results in symptoms of discomfort, visual disturbance, and tear film instability, and potentially produces damage to the ocular surface. It can be accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Patients with dry eye disease can experience any one or combination of tear hyperosmolarity, tear film instability, or abnormal composition of the tear film lipid layer.

[0378] Two major categories of dry eye disease (DED) are now distinguished, aqueous-deficient DED and evaporative DED. Within the aqueous-deficient form of DED, two major subtypes can be distinguished, Sjogren's and non-Sjogren's. Sjogren's syndrome can be a primary disease or can be caused by other autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. Non-Sjogren's patients with aqueous-deficient DED usually have lacrimal gland hypofunction, lacrimal duct obstruction, or inadequate reflex tearing. Within the second major category of evaporative DED, one of the main causes is meibomian gland disease or dysfunction, eyelid aperture disorders, disorders of blinking (as in Parkinson's disease), or ocular surface disorders (as in allergic conjunctivitis).

[0379] The ophthalmic compositions according to the present disclosure employ a semifluorinated alkane as a liquid vehicle for the cyclosporine, preferably the compound 1-(perfluorobutyl)pentane. 1-(perfluorobutyl)pentane is a semifluorinated alkane having the chemical formula F(CF2)4(CH2)5H. It is an inert, water-insoluble liquid with a density of 1.284 g / cm3at 25ºC 3 and a refractive index of 1.3204 at 20ºC. Alternative nomenclature for this compound includes F4H5, where F represents a linear perfluorinated alkane segment comprising 4 carbon atoms, and where H represents a linear and non-fluorinated alkane segment of 5 carbon atoms. Preferably, the 1-(perfluorobutyl)pentane is substantially free of water.

[0380] In one embodiment, the ophthalmic compositions for any of the uses or for use in any of the methods according to the present disclosure can comprise or consist of at least about 97% (w / w) or more preferably at least about 98% (w / w) or at least about 98.5% (w / w) or at least about 99% (w / w) of 1-(perfluorobutyl)pentane based on the total weight of the ophthalmic composition (final dosage form) in addition to the cyclosporine characterized in any of the preferred concentrations of the present disclosure. In another embodiment, the pharmaceutical compositions for any of the methods or uses according to the present disclosure can consist of from about 95.0% to about 99.99% (w / w) or from about 98.0% to about 99.99% (w / w) or from about 98.5% to 99.99% (w / w) or from about 99.00% to about 99.9999% (w / w) of 1-(perfluorobutyl)pentane based on the total weight of the final composition in addition to the cyclosporine in the amounts or concentrations as defined herein.

[0381] In another embodiment, the ophthalmic composition for any of the uses or in any of the methods in the present disclosure can optionally further comprise 2-(perfluorobutyl)pentane. In addition to 1-(perfluorobutyl)pentane, the composition can optionally comprise up to 2% (w / w), or up to 1% (w / w), or up to 0.5% (w / w) or up to 3% (w / w), or up to 0.2% (w / w) of a small amount of 2-(perfluorobutyl)pentane.

[0382] The concentration of cyclosporine in the ophthalmic composition for any of the methods or uses according to the present disclosure is 0.1% (w / v) of the composition.

[0383] Unless otherwise indicated, the term "% (w / v)" denotes the amount of a component in a composition as a weight percentage relative to the total volume of the composition (where "w" denotes weight and "v" denotes volume). For example, 0.1% (w / v) corresponds to 1.0 mg of the component in 1 mL of the composition. Unless otherwise indicated, the term "% (w / w)" or wt. % refers to the amount of a component of a composition as a percentage of weight relative to the total weight of the composition (where "w" denotes weight).

[0384] The term "about," as used herein and in reference to or in connection with a parameter such as, for example, the concentration of cyclosporine dissolved in a composition or the volume characterized in a single dose or applied drop of a composition, includes the recited exact value as well as any value falling within the degree of variation typically observed when measuring or determining such parameters using standard techniques and equipment known in the art of using.

[0385] The dose of the composition for any of the methods or uses according to the present disclosure and as described in any one of the embodiments herein is administered topically to the eye of a subject in the form of a single drop (i.e., one drop). The drop can be administered to the surface of the eye, preferably to any surface area or tissue of the eye to which topical administration or instillation is accessible, for example to the cornea. The single drop of the composition can be instilled directly onto the surface of the eye, such as the corneal surface of the eye, or alternatively into the space (i.e., the pocket or bag) formed by gently pulling down the lower eyelid of the eye.

[0386] The term "administered to the eye" or "per eye," as used herein, means administration of a given dose (e.g., a single dose) of the ophthalmic composition according to the present disclosure to a single eye of a subject.

[0387] In one embodiment of the present disclosure, the ophthalmic composition for any of the methods or uses described herein is administered in a single drop dose twice per day per eye. Thus, a patient treated with this dosing regimen for both eyes will receive a total of two drops per eye per day on each day of a given treatment period.

[0388] In another embodiment, where the ophthalmic composition is administered more than once per day to each eye, for example, twice per day to each eye, the time interval between the topical administration of the first dose and the second dose of the composition to the eye or ocular surface can be at least 4 hours, or at least 6 hours, or at least 12 hours.

[0389] As used herein, the term "up to about" or "up to" used in the context of a parameter (as presently in reference to the amount of ethanol in the composition) means any parameter value greater than zero and up to, and including, the parameter value defined. For example, an amount of "up to about 1.0% (w / w) ethanol" should be interpreted as including any value greater than zero up to and including a value of 1.0% (w / w) ethanol, and would include, for example, values such as 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.95%, 0.99% (w / w) ethanol, taking into account any variation expected by standard techniques and equipment used in measuring or determining this parameter in the relevant art.

[0390] The absence of an organic cosolvent such as ethanol can provide the advantage of a simple two-component formulation as compared to a three-component formulation that additionally comprises a cosolvent such as ethanol. Further inclusion of even one additional composition component can increase complexity of factors such as cost, manufacturing, handling, packaging, and patient compliance.

[0391] The compositions for any of the methods or uses of the present disclosure are preferably provided as a clear solution in which the cyclosporine is completely dissolved and in solution in 1-(perfluorobutyl)pentane (at room temperature conditions, i.e., between 15 °C to 25 °C). If ethanol is included, the composition is also provided as a clear solution of the cyclosporine and ethanol dissolved and in solution in 1-(perfluorobutyl)pentane. Further, if 2-(perfluorobutyl)pentane is included, the composition is also provided as a clear solution of the cyclosporine dissolved in a mixture of 1-(perfluorobutyl)-pentane, 2-(perfluorobutyl)-pentane, and ethanol. In one embodiment, the composition is provided in sterile form.

[0392] In another embodiment, the ophthalmic composition for any of the methods or uses according to the present disclosure is substantially free of water and / or substantially free of a preservative. As understood herein, the term "substantially free of" or alternatively "substantially free from" in reference to a composition ingredient means that the ingredient is not present in more than trace amounts, and if present in trace amounts, the ingredient does not contribute technically to the composition.

[0393] Preferably, the ophthalmic compositions for any of the methods or uses according to the present disclosure are substantially free of water, substantially free of preservatives, and effective to inhibit microbial growth.

[0394] In another embodiment, the ophthalmic compositions for any of the methods or uses according to the present disclosure are characterized by a pronounced wetting and spreading behavior by which they can rapidly and effectively spread over the surface of the eye, such as the corneal surface. Thus, the microdroplets (droplets) of the ophthalmic compositions for any of the methods or uses according to the present disclosure result in a rapid spreading of the composition over the corneal surface when applied to the surface of the eye.

[0395] Preferably, the ophthalmic compositions for any of the methods or uses according to the present disclosure form small microdroplets (droplets) ranging from about 8-10 µl, or 9-10 µl, or 9-11 µl (such as about 10 µL or about 9 µl) when applied from a droplet dispenser.

[0396] In another preferred embodiment, the ophthalmic compositions for any of the methods or uses according to the present disclosure are characterized by a relatively low amount of cyclosporine administered per eye in a single dose, such as about 10 µg cyclosporine per eye in a single dose, or about 8 to 10 µg or 9 to 10 µg cyclosporine per eye in a single dose.

[0397] As used herein, the term "consists" and related terms "consisting" or "consist" are understood to mean that in addition to those features recited at the beginning of such terms, there are no other features. In the context of the ophthalmic compositions as described herein, if there are any other ingredients or components in the composition in addition to those recited at the beginning of such terms, they are present only in trace or residual amounts to such an extent that they do not impart technical advantage or relevance to the objects of the present disclosure, as can be further understood by the term "substantially" or "essentially" used in conjunction with these terms (e.g., "substantially consists of").

[0398] The methods and compositions for the uses described herein preferably target a human subject or patient.

[0399] As described above, the present disclosure contemplates a kit comprising an ophthalmic composition as described herein, with a container for holding the ophthalmic composition and a droplet dispenser adapted for administering about 8 to 10 µL, or about 9 to 11 µl, or about 9 to 10 µl, or about 10 µl, or about volume of the composition per drop. The kit can further comprise instructions for use, e.g., in the form of a leaflet, package or other readable means, instructing use according to any of the uses or methods described herein.

[0400] As understood herein, the droplet dispenser can be a dispenser or applicator device that is mountable, fixed or connectable to a container for containing the ophthalmic composition. Preferably, the droplet dispenser is adapted to dispense a single dose of the composition in the form of a single drop. More preferably, the droplet dispenser is adapted to dispense a single dose of about 8 to 10 μΐ volume or 9 to 10 μΐ volume, or a single dose of about 10 μΐ volume or about 9 μΐ volume.

[0401] As understood herein, the container for containing the ophthalmic composition preferably has a volume that can contain a single dose, but more preferably has a volume that can contain multiple or a plurality of doses of the composition.

[0402] The following examples are intended to illustrate the present application and should not be construed as limiting the scope thereof.

[0403] Example

[0404] Test drug CyclASol ® is a clear ophthalmic solution of 0.1% (w / v) cyclosporine A dissolved in 1-perfluorobutylpentane (F4H5) with 1.0% (w / w) ethanol as a co-solvent. It has been investigated for use as a treatment for dry eye disease in several international clinical trials, including Phase I, II and III trials, with very promising results for the treatment of dry eye disease.

[0405] Example 1

[0406] In the recently completed ESSENCE 2 trial, CyclASol ® 0.1% ophthalmic solution for efficacy, safety and tolerability in the treatment of dry eye disease. The study was conducted as a randomized, double-blind trial. 834 participants were enrolled, of which 423 were assigned to the treatment group and 411 to the placebo group. The treatment group received daily treatment for a period of 29 days: CyclASol 0.1% twice daily, while the placebo group received vehicle (F4H5 with 0.1% (w / w) ethanol).

[0407] At the end of the initial 29-day study period, the primary endpoints were analyzed: total corneal fluorescein staining score (tCFS, NEI scale) and dryness score (visual analog scale, VAS). In addition, the secondary endpoints were analyzed: total conjunctival lissamine green staining score (tCLGS, Oxford scale), central corneal fluorescein staining score (cCFS, NEI scale) and blurring of vision score (VAS).

[0408] The key inclusion criteria were patients with dry eye disease for at least 6 months prior to enrollment and a VAS dryness score of at least 50, tCFS score of at least 10 (NEI scale), tCLGS of at least 2 (Oxford scale), and a non-anesthetized Schirmer's test score of 1 to 10 mm. The enrolled patient characteristics were as follows:

[0409]

[0410] At the Day 29 evaluation, the patients' characteristics improved as follows:

[0411]

[0412] These results demonstrate that treatment with CyclASol ® Statistically significant improvements in the primary and secondary endpoints in the table above were observed after 29 days of treatment with 0.1% ophthalmic solution. Importantly, at Day 29, the degree of corneal surface damage was effectively reduced, as evidenced by a decrease in tCFS of ≥ 3 grades in 72% of participants and a decrease in cCFS of ≥ 1 grade in 67% of participants.

[0413] Following the initial 29-day study period, a total of 12 months of open-label safety extension follow-up was conducted on a subset of 177 of the total of 202 patients (all patients were rolled over into a single treatment group). Surprisingly, at 6 months, the results for both tCFS and Schirmer's test continued to improve steadily in the treatment group. For example, at Day 39, the tCFS in the treatment group decreased by 39% from baseline, and at 6 months, it further decreased by 53% from baseline. Similarly, at Day 29, the Schirmer's test result increased by 45% from baseline, and at 6 months, it further increased by 70% from baseline.

[0414] In addition, the study results demonstrated that the safety profile was comparable between the treatment and placebo groups. Importantly, less than 10% of the treatment patients reported mild instillation site reactions, only 0.2% of the treatment patients reported moderate instillation site reactions (1 patient), and no patients reported severe instillation site reactions. These results were comparable to the placebo group and demonstrate that, unlike Restasis, patients tolerated CyclASol much better, thereby improving patient compliance.

[0415] Example 2

[0416] Damaged ocular surface can affect biometry and refractive outcomes after cataract surgery, leading to patient dissatisfaction. Analysis of pooled data from the ESSENCE-1 and ESSENCE-2 clinical trials evaluated the coexistence of cataract and dry eye disease (DED) and the efficacy of non-aqueous CyclASol eye drops (0.1% (w / v) cyclosporine dissolved in a vehicle comprising 1 - perfluorobutylpentane and 1 wt.% ethanol) in patients with DED with cataract.

[0417] Analysis was performed using data from the two prospective, randomized, double-masked, controlled phase III DED trials, ESSENCE-1 and ESSENCE-2 (NCT03292809 / NCT04523129). Both studies demonstrated significant improvement in ocular surface (e.g., at the 2-week timepoint).

[0418] Pooled data were stratified into 3 groups: patients without cataract, patients with cataract, and patients with intraocular lens. The key outcome measure was change from baseline in total corneal fluorescein staining (tCFS) (0-15) and central corneal fluorescein staining (cCFS) at day 15 and day 29. A responder analysis was also performed for tCFS (> 3-grade improvement) and cCFS (> 1 -grade improvement).

[0419] The analysis included 1162 patients with moderate to severe DED; 35% had coexisting cataract, 20% had intraocular lens, and 45% had no cataract. Demographics or baseline DED characteristics were comparable between groups, except for age and visual acuity. Patients with intraocular lens and patients with cataract had worse visual acuity and were older compared to patients without cataract.

[0420] In all three subgroups, CyclASol eye drops showed statistically significant reduction in tCFS scores compared to its vehicle at day 15 and day 29. In the cataract subgroup, 62% of patients treated with CyclASol eye drops were tCFS responders and 63% of patients were cCFS responders. Thus, the extent of corneal surface damage, an important indicator of ocular surface disease, was effectively improved in the cataract subgroup. Results for the cataract subgroup at day 29 are shown in the table below:

[0421]

[0422] In addition, in the cataract subgroup, at day 15, 56% of patients treated with CyclASol eye drops were tCFS responders and 59% of patients were cCFS responders. Thus, the extent of corneal surface damage, an important indicator of ocular surface disease, was effectively improved in the cataract subgroup in just 15 days of treatment. Results for the cataract subgroup at day 15 are shown in the table below:

[0423]

[0424] CyclASol eye drops demonstrated a rapid and clinically meaningful improvement in corneal staining in patients with DED and cataract, comparable to the overall population. The magnitude of effect and onset make this treatment an ideal candidate for preoperative ocular surface disease management in cataract patients.

Claims

1. A composition comprising about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane optionally with about 1% (w / w) ethanol, for use in a method of preparing a patient for an ocular procedure (e.g., cataract surgery), the method comprising topically administering the composition to the eye (e.g., the eye undergoing the ocular procedure) of the patient twice daily.

2. A composition comprising about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane optionally with about 1% (w / w) ethanol, for use in a method of treating a corneal surface injury in a patient preparing for an ocular procedure (e.g., cataract surgery), the method comprising topically administering the composition to the eye of the patient twice daily.

3. The composition for use according to any one of claims 1-2, wherein the method further comprises the step of performing biometry measurements in preparation for the ocular procedure.

4. A composition comprising about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane optionally with about 1% (w / w) ethanol, for use in a method of performing biometry measurements for an ocular procedure (e.g., cataract surgery), the method comprising topically administering the composition to the eye of the patient twice daily prior to the biometry measurements.

5. The composition for use according to any one of claims 1-4, wherein the composition comprises about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane with about 1% (w / w) ethanol and optionally up to about 1% (w / w) 2- perfluorobutylpentane.

6. The composition for use according to any one of claims 1-5, wherein the composition consists of about 0.1% (w / v) cyclosporine dissolved in 1- perfluorobutylpentane with about 1% (w / w) ethanol and optionally up to about 0.5% (w / w) 2- perfluorobutylpentane.

7. The composition for use according to any one of claims 1-6, wherein the amount of cyclosporine administered in a single dose per eye is about 8-12 µg, e.g., 9-11 µg or about 10 µg cyclosporine.

8. The composition for use according to any one of claims 1-7, wherein the composition is administered to the patient for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days.

9. The composition for use according to any one of claims 1-8, wherein the method further comprises the step of determining the extent of corneal surface injury in preparation for the ocular procedure.

10. The composition for use according to claim 9, wherein the extent of corneal surface injury is determined by total corneal fluorescein staining score and / or central corneal fluorescein staining score.

11. The composition for use according to any one of claims 1-10, wherein prior to initiating administration of the composition according to the method, the patient is characterized by an eye for which ocular surgery is contemplated that exhibits: (a) a total corneal fluorescein staining score of greater than or equal to 7 (e.g., greater than 8, 9, 10, 11, or 12), such as 7-15, 7-13, 10-15, or 10-13; (b) a central corneal fluorescein staining score of equal to or greater than 1 (e.g., greater than 1, greater than 2), such as 1-2 or 1-3 or 2-3.

12. The composition for use according to any one of claims 1-11, wherein after treatment of the patient with the composition according to the method for a period of time (e.g., after administration of the composition for a period of at least 7 days, or for at least 14 days, or for at least 21 days, or for at least 28 days, or for at least 35 days, or for at least 42 days), the patient is characterized by an eye for which ocular surgery is contemplated that exhibits: (a) a total corneal fluorescein staining score that has been reduced by at least 3 grades; and / or (b) a central corneal fluorescein staining score that has been reduced by at least 1 grade.

13. The composition for use according to any one of claims 1-12, wherein the method improves the total corneal fluorescein staining score of the patient’s eye for which ocular surgery is contemplated by at least 3 grades prior to performing the biomterics measurements and / or prior to performing the ocular surgery.

14. The composition for use according to any one of claims 1-13, wherein the method improves the central corneal fluorescein staining score of the patient’s eye for which ocular surgery is contemplated by at least 1 grade prior to performing the biomterics measurements and / or prior to performing the ocular surgery.

15. The composition for use according to any one of claims 1 to 14, wherein the step of determining the extent of corneal surface damage is prior to administration of the composition.

16. The composition for use according to any one of claims 1 to 15, wherein the patient is subjected to biomterics without first achieving a reduction of at least 3 grades in the total corneal fluorescein staining score of the patient’s eye for which ocular surgery is contemplated.

17. The composition for use according to any one of claims 1 to 16, wherein the patient is administered the composition until the total corneal fluorescein staining score of the patient’s eye for which ocular surgery is contemplated achieves a reduction of at least 3 grades.

18. The composition for use according to any one of claims 1 to 17, wherein the patient has a corneal surface damage that is not caused by a dry eye disease.

19. The composition for use according to any one of claims 1 to 18, wherein administration of the composition is continued after the ocular surgery.

Images