Ophthalmic composition for treatment of dry eye disease

Abstract

To provide compositions for treating patients meeting certain criteria for dry eye disease, as well as for treating patients for which certain symptoms of dry eye disease is particularly prevalent.SOLUTION: The invention provides ophthalmic compositions comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in the topical treatment of dry eye disease. The invention further provides kits comprising such compositions for the same use.SELECTED DRAWING: None

Description

[Background technology]

[0001] Keratoconjunctivitis sicca, also known as dry eye disease or dysfunctional tear syndrome, is understood today as a multifunctional disorder of the tear film and ocular surface, resulting in discomfort, visual disturbance, and even ocular surface damage caused by tear film instability. Estimates of the prevalence of dry eye vary considerably depending on the criteria used to define the disease, but in the United States, as many as 3.2 million women and 1.7 million men aged 50 years or older are estimated to have dry eye, with a predicted 40% increase in the number of affected patients by 2030.

[0002] The pharmacological treatment of choice for dry eye disease is cyclosporine, which is available as an approved drug, at least in the United States, in the form of an ophthalmic (o / w) emulsion (Restasis®). This product has been shown to increase tear production in patients whose tear production is presumably suppressed by ocular inflammation associated with keratoconjunctivitis sicca.

[0003] WO 2011 / 073134 A1 discloses a pharmaceutical composition in the form of a solution comprising cyclosporine and a semifluorinated alkane as a liquid vehicle that can be administered to the eye of a patient, such as for the treatment of keratoconjunctivitis sicca, e.g. a composition comprising cyclosporine in the semifluorinated alkane 1-(perfluorobutyl)pentane (F4H5) in the presence of ethanol as a co-solvent.

[0004] Gehlsen et al. (Investigative Ophthalmology & Visual Science June 2015, Vol. 56, 319) describes a study testing the use of CsA in (F4H5) for topical therapy in a mouse model of experimental dry eye disease. Gehlsen et al. describe that in this study, mice with induced experimental dry eye disease were administered topical therapy three times per day (5 μL / eye). Gehlsen et al., however, do not disclose any treatment or dosing regimen for the treatment of dry eye disease in human subjects.

[0005] WO 2018 / 115097 describes a dosing regimen for the treatment of patients with dry eye disease based on an ophthalmic composition comprising about 0.05-0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane. However, the document does not disclose targeted treatment of specific symptoms associated with dry eye disease and their frequency of occurrence. The method of treatment also does not disclose a composition for use in the treatment of patients fulfilling a set of specific dry eye disease signs and symptoms.

[0006] Therefore, there remains a need for means and methods for treating patients who meet certain criteria for dry eye disease, and for treating patients in whom certain symptoms of dry eye disease are particularly prevalent.Therefore, the object of the present invention is to provide a composition for effective use in addressing these particular aspects.Further objects of the present invention will become apparent based on the following description, examples and claims of the present invention. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2011 / 073134 A1 [Patent Document 2] International Publication No. 2018 / 115097 [Non-patent literature]

[0008] (Non-patent document 1) Gehlsen et al. (Investigative Ophthalmology&Visual Science June 2015,Vol.56,319) Summary of the Invention

[0009] In a first aspect, the invention relates to an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a method of treating keratoconjunctivitis sicca (dry eye disease), the method comprising topically administering the composition to the eye of a patient, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 45 or greater. In another embodiment, the patient has an Total Ocular Surface Disease Index (OSDI) score of 55 or greater. In a second aspect, the present invention relates to an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a) a method for treating and / or ameliorating symptoms associated with keratoconjunctivitis sicca (dry eye), said symptoms being dryness and blurred vision, and / or b) a method for treating and / or ameliorating dry eye symptoms and the perception of the frequency of dryness. [Brief description of the drawings]

[0010] [Figure 1] Total Ocular Surface Disease Index (OSDI) - Change from baseline in total OSDI score (mean) at 2, 4, 8, and 12 weeks of treatment (twice daily) with vehicle (F4H5; N=90) and CyclASol 0.1% ophthalmic solution (clear ophthalmic solution of cyclosporine A in 1-(perfluorobutyl)pentane, 1.0% w / w ethanol; N=79) in subjects with a baseline total OSDI of 45 or greater. [Diagram 2]Total Ocular Surface Disease Index (OSDI) - Change from baseline in total OSDI score (mean) at 2, 4, 8, and 12 weeks of treatment (twice daily) with vehicle (F4H5; N=55) and CyclASol 0.1% ophthalmic solution (clear ophthalmic solution of cyclosporine A in 1-(perfluorobutyl)pentane, 1.0% w / w ethanol; N=41) in subjects with a baseline total OSDI of 55 or greater. [Diagram 3] Improvement in VAS symptoms. Mean change from baseline (Visit 1) in VAS scores after 4 weeks in study subjects receiving vehicle (F4H5; N=165) and CyclASol 0.1% ophthalmic solution (N=160; a clear ophthalmic solution of cyclosporine A in 1-(perfluorobutyl)pentane, containing 1.0% w / w ethanol) twice daily for blurred vision, awareness of dry eye symptoms, frequency of dryness, severity of dryness, and combined frequency and severity of dryness. [Figure 4] Total Ocular Surface Disease Index (OSDI) - Shows the change from baseline in total OSDI score (mean) at 2, 4, 8, and 12 weeks of treatment (twice daily) with vehicle (F4H5; N=166) and CyclASol 0.1% ophthalmic solution (clear ophthalmic solution of cyclosporine A in 1-(perfluorobutyl)pentane, 1.0% w / w ethanol; N=162) for the entire subject population. [Diagram 5] Total Corneal Fluorescein Staining (NEI Scale) - Change from baseline in total corneal fluorescein staining (mean) at 2, 4, 8, and 12 weeks of treatment (twice daily) with vehicle (F4H5; N=165) and CyclASol 0.1% ophthalmic solution (clear ophthalmic solution of cyclosporine A in 1-(perfluorobutyl)pentane, 1.0% w / w ethanol; N=160) for the entire subject population. Error bars indicate standard error of the mean (SEM). [Figure 6]Total Corneal Fluorescein Staining Responder Analysis (≥3 Grade Improvement) After 4 Weeks of Treatment. Comparing the percentage of subjects treated with CyclAsol 0.1% and vehicle, respectively, with an improvement of ≥3 grades in total corneal fluorescein staining (tCFS). [Figure 7] Central Corneal Fluorescein Staining (NEI Scale) Responder Analysis (≥1 Grade Improvement) After 4 Weeks of Treatment. Comparing the percentage of subjects treated with CyclAsol 0.1% and vehicle, respectively, with central corneal fluorescein staining (cCFS) improving by ≥1 grade. [Figure 8] Conjunctival Lissamine Green Staining Responder Analysis (≥2 grade improvement) after 12 weeks of treatment. Comparing the proportion of subjects treated with CyclAsol 0.1% and vehicle, respectively, with ≥2 grade improvement in conjunctival Lissamine Green staining. [Figure 9] Conjunctival Lissamine Green Staining (change from baseline on the Oxford Scale) - Change from baseline in conjunctival Lissamine Green staining values ​​(mean) for the entire subject population at 4 and 12 weeks of treatment (twice daily) with vehicle (F4H5) and CyclASol 0.1% ophthalmic solution (clear ophthalmic solution of cyclosporine A in 1-(perfluorobutyl)pentane, 1.0% w / w ethanol). Error bars indicate standard error of the mean (SEM). [Figure 10] Critical letter size for International Reading Speed ​​Texts (IResT) - a) in number of words read per minute for all patients (N=322) at baseline; b) tCFS non-responders after 4 weeks (N=172); c) tCFS responders after 4 weeks (N=150), where tCFS responders are subjects who achieve a reduction in tCFS score of ≥3 units (NEI) after 4 weeks. [Figure 11]Critical letter size for International Reading Speed ​​Texts (IResT) - Words read per minute for CyclASol patients at baseline (N=157), CyclASol tCFS non-responders after 4 weeks (N=74), and CyclASol tCFS responders after 4 weeks (N=83), respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In a first aspect, the present invention relates to an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a method of treating keratoconjunctivitis sicca (dry eye disease), the method comprising the step of topically administering the composition to the eye of a patient, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 45 or greater.

[0012] Dry eye disease (abbreviated DED, also known as keratoconjunctivitis sicca, tear dysfunction syndrome, or dry eye disease syndrome) is a complex disorder that causes symptoms of discomfort, visual disturbance, tear film instability, and may result in ocular surface damage. Dry eye disease may be accompanied by increased tear film osmolarity and ocular surface inflammation. Patients with keratoconjunctivitis sicca may experience either tear hyperosmolarity, tear film instability, or abnormalities in the lipid layer composition of the tear film, or a combination of these.

[0013] Today, two main categories of keratoconjunctivitis sicca or dry eye disease (DED) are distinguished: hypolacrimal DED and evaporative DED. Within the class of hypolacrimal DED, two main subtypes may be distinguished: Sjögren's syndrome and non-Sjögren's syndrome.

[0014] Patients with Sjögren's syndrome suffer from an autoimmune disease in which the lacrimal gland is infiltrated by activated T cells, which leads to dry eye disease as well as dry mouth conditions. Sjögren's syndrome may be a primary disease or may result from other autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. Non-Sjögren's patients suffering from hypolacrimal DED usually have lacrimal gland dysfunction, lacrimal duct obstruction, or reduced reflex secretion.

[0015] The second major class, evaporative dry eye disease, is also somewhat heterogeneous and can develop as a result of a variety of underlying causes, the primary causes being meibomian gland disease or dysfunction, impaired eyelid opening, blink disorders (e.g., Parkinson's disease), or ocular surface disorders (e.g., allergic conjunctivitis).

[0016] Symptoms of dry eye disease include, but are not limited to, any one or combination of dry, stinging, rough, or gritty eyes, foreign body sensation, pain or stinging, stinging or burning, itching, increased blinking, eye fatigue, photophobia, blurred vision, redness, mucus discharge, contact lens intolerance, and excessive reflex tearing. It is understood that not all patients suffering from dry eye disease will exhibit all of these symptoms at the same time.

[0017] A subject suffering from dry eye disease may experience individual or collective symptoms such as blurred vision or difficulty in seeing, which may be reflected by blurred vision, pain, irritation, or adverse effects on the subject's performance in functional tasks in which visual ability and visual acuity may be essential, which may contribute to visual impairment. Dry eye disease may also lead to or contribute to damage to the corneal surface, for example damage to the central cornea.

[0018] As understood herein, the term "dry eye disease" may refer individually to any one or combination of subtypes or categories, or to the underlying causes described herein, and may address any symptom or aspect, or pathophysiological consequence of dry eye disease.

[0019] The severity of a subject's or patient's dry eye disease can be classified and scored using one or more or a combination of standard tests based on the evaluation of dry eye disease symptoms. For example, the severity of dry eye disease can be determined using a test based on the patient's perception of their ocular symptoms and the evaluation of their impact on vision, based on a questionnaire such as the Ocular Surface Disease Index (OSDI) questionnaire, a 12-item questionnaire that focuses on symptoms of ocular irritation associated with dry eye disease in the week prior to the evaluation, and the impact on the patient's daily activities and lifestyle.

[0020] The OSDI test is scored using a scale of 0-4 for each question. For example, as part of the test, patients may be asked about problems with blurred vision in the last week and asked to indicate, if applicable, 0 for none, 1 for some of the time, 2 for half the time, 3 for most of the time, or 4 for all of the time. The questionnaire scores are summed and rated on a scale of 0-100, with higher scores indicating greater extent / severity and impact of dry eye disease. In the context of the present invention, the defined composition has been found to be particularly effective in treating dry eye disease, particularly in patients with a total OSDI score of 45 or more at baseline, or a total OSDI score of 55 or more, prior to the start of treatment with the composition.

[0021] The visual analog scale (VAS) of dry eye symptoms is a questionnaire-style test in which subjects are asked to rate their ocular symptoms (both eyes simultaneously) by placing a vertical mark on a horizontal line to indicate their level of discomfort on a scale of 0 to 100% for dryness, stickiness, burning / stinging, foreign body sensation, itching, blurred vision, sensitivity to light, and pain, where 0 corresponds to "no discomfort" and 100% corresponds to "maximum discomfort." The VAS test also assesses the frequency of occurrence of dryness experienced by the subject, and the percentage of time the subject is aware that they are experiencing dry eye symptoms (0 corresponds to "never" and 100% corresponds to "all the time"). VAS tests can be performed at various time points to assess the efficacy and patient response regarding the impact of treatment on these symptoms of dry eye disease.

[0022] The patient's eye symptoms of dry eye disease can also be evaluated and determined using any combination of objective clinical measurements, such as Schirmer type 1 test, corneal and conjunctival fluorescein staining, and / or Lissamine green staining, tear film breakup time (TFBUT, or TBUT) as a measure of tear quality, etc. The efficacy of treatment can also be evaluated by comparison of measurements of each or a combination of these clinical measurements obtained at various time points during a given treatment period, and in combination or conjunction with any of the symptom assessments described above.

[0023] In one embodiment of the present invention described herein, the subject or patient has a total OSDI score of 45 or greater, preferably 55 or greater, prior to treatment with a composition defined herein, and in at least one eye, or both eyes, any one or combination of the following: i. Total corneal fluorescein staining score by NEI grading ≥10 (i.e., sum of scores for inferior, superior, central, nasal, and temporal corneal regions ≥10); ii. Total Lissamine Green conjunctival score (temporal and nasal areas combined) according to the Oxford Scale ≥2; iii. Schirmer I scores between 1mm and 10mm, or any combination thereof.

[0024] Cyclosporine is a pharmacological treatment option for dry eye disease and is available by prescription in the United States, for example, in the form of a 0.05% ophthalmic (o / w) emulsion (Restasis®). This product has been shown to increase tear production in patients whose tear production is presumably suppressed by ocular inflammation associated with keratoconjunctivitis sicca. Restasis® is administered twice daily in each eye, approximately 12 hours apart. Restasis® is packaged in single vials (Prescribing Information, Restasis®).

[0025] Cyclosporine (synonyms include cyclosporine A, CsA, or cyclosporine) has the empirical formula C 62 H 111 N 11 O 12 Cyclosporine is a cyclic nonribosomal peptide containing 11 amino acids and a molecular weight of 1202.61. It is an immunosuppressant widely used in post-allergenic organ transplantation to reduce the activity of the patient's immune system, thereby reducing the risk of organ rejection. Cyclosporine is usually provided as a colorless or white powder. Cyclosporine is thought to bind to the cytosolic protein cyclophilin (immunophilin) ​​of immunocompetent lymphocytes, especially T lymphocytes. This complex of cyclosporine and cyclophilin inhibits calcineurin, which is responsible for activating the transcription of interleukin-2 under normal circumstances. It also inhibits lymphokine production and interleukin release, thereby reducing the function of effector T cells.

[0026] The ophthalmic composition according to the invention uses the compound 1-(perfluorobutyl)pentane as a liquid vehicle for cyclosporine. 1-(perfluorobutyl)pentane is a semifluorinated alkane with the chemical formula F(CF2)4(CH2)5H. It is an inert, water-insoluble liquid with a density of 1.284 g / cm at 25°C. 3, and the refractive index is 1.3204 at 20°C. Alternative nomenclature for this compound includes F4H5, where F represents a linear perfluorinated alkane segment containing 4 carbon atoms and H represents a linear non-fluorinated alkane hydrocarbon segment of 5 carbon atoms. Preferably, 1-(perfluorobutyl)pentane is substantially free of water.

[0027] In one embodiment, an ophthalmic composition for any one of the uses according to the invention may comprise or consist of at least about 97% (w / w) or more preferably at least about 98% (w / w), or at least about 99% (w / w) 1-(perfluorobutyl)pentane based on the total weight of the ophthalmic composition (final dosage form) in addition to cyclosporine characterized in any one of the preferred concentrations of the invention. In another embodiment, a pharmaceutical composition for any one of the uses according to the invention may consist of about 95.0 to about 99.99% (w / w), or about 96.0 to about 99.99% (w / w), or about 98.0 to 99.99% (w / w), or about 99.999 to about 99.9999% (w / w) 1-(perfluorobutyl)pentane based on the total weight of the final composition in addition to cyclosporine in an amount or concentration defined herein.

[0028] In another embodiment, the ophthalmic composition for any one of the uses described herein for the present invention may optionally further comprise 2-(perfluorobutyl)pentane. In addition to 1-(perfluorobutyl)pentane, the composition may optionally comprise a small amount of 2-(perfluorobutyl)pentane up to 2% (w / w), or up to 1% (w / w), or up to 0.5% (w / w).

[0029] The concentration of cyclosporine in the ophthalmic composition for any one of the uses according to the invention is 0.1% (w / v) of the composition.

[0030] Unless otherwise specified, the term "% (w / v)" refers to the amount of a component of a composition as a weight percent of the total volume of the composition (where "w" refers to weight and "v" refers to volume). For example, 0.1% (w / v) would correspond to 1.0 mg of a component in 1 mL of a composition. Unless otherwise specified, the term "% (w / w)" or % by weight refers to the amount of a component of a composition as a weight percent of the total weight of the composition (where "w" refers to weight).

[0031] The term "about" as used herein includes the exact value defined with reference to or in relation to a parameter such as, for example, the concentration of cyclosporine dissolved in the composition, or the volume characteristic of a single dose or drop of the composition applied, as well as any value that is within the degree of variability typically observed in measuring or determining these parameters using standard techniques and equipment known in the art.

[0032] The ophthalmic compositions defined herein may be used for the treatment of human subjects having dry eye disease, as well as related conditions, or the signs and symptoms associated therewith.

[0033] In a first aspect, the present invention provides the following:

[0034] 1.1 An ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a method for treating keratoconjunctivitis sicca (dry eye disease), the method comprising the step of topically administering the composition to the eye of a patient having a Total Ocular Surface Disease Index (OSDI) score of 45 or greater.

[0035] 1.2 The composition for use according to 1.1, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 55 or greater.

[0036] 1.3 An ophthalmic composition for use according to any one of the preceding clauses, wherein the composition comprises up to about 1.0% (w / w) ethanol.

[0037] 1.4 An ophthalmic composition for use according to any one of the preceding clauses, wherein the composition consists of 0.1% (w / v) cyclosporine, 1-(perfluorobutyl)pentane (F4H5) and up to 1.0% (w / w) ethanol.

[0038] 1.5 A composition for use according to any of the preceding clauses, wherein the ophthalmic composition is administered to the corneal and / or conjunctival surfaces in the form of droplets.

[0039] 1.6 The composition for use according to any of the preceding clauses, wherein the composition is administered as a single drop having a volume of about 8-11 μL, preferably about 8-10 μL.

[0040] 1.7 The composition for use according to any of the preceding clauses, wherein the composition is administered in a dose of one drop of about 8-10 μL volume per eye once daily.

[0041] 1.8 An ophthalmic composition for use according to any one of the preceding clauses, wherein the composition is administered as one drop having a volume of about 10 μl.

[0042] 1.9 An ophthalmic composition for use according to any one of the preceding clauses, wherein the composition is administered twice per day per eye.

[0043] 1.10 The composition for use according to any of the preceding clauses, wherein the composition is administered in a dose of one drop per eye, twice daily, with a volume of approximately 16-20 μL.

[0044] 1.11 The composition for use according to any one of the preceding clauses, wherein the dry eye disease is aqueous-deficient dry eye disease.

[0045] 1.12 The composition for use according to any of the preceding claims, wherein the dry eye disease is evaporative dry eye disease.

[0046] 1.13 A composition for use according to any of the preceding clauses, wherein the patient is unresponsive or responds poorly to treatment with an aqueous eye drop composition (e.g., aqueous cyclosporine emulsion eye drops).

[0047] 1.14 The composition for use according to any of the preceding clauses, wherein the time interval between topical administration of the composition to the eye or ocular surface of the first and second doses is at least 4 hours, or at least 6 hours, or at least 12 hours.

[0048] 1.15 The composition for use according to any of the preceding clauses, wherein the treatment period is at least 2 weeks, or at least 4 weeks, or at least 6 weeks, or at least 8 weeks, or at least 12 weeks.

[0049] 1.16 The composition for use according to any of the preceding clauses, wherein the patient is a human patient.

[0050] 1.17 The composition for use according to any of the preceding clauses, wherein the patient is a female patient.

[0051] 1.18 The composition for use according to any of the preceding clauses, wherein the patient is a male patient.

[0052] 1.19 The composition for use according to any of the preceding clauses, wherein the patient is 20-80 years old at the time of treatment, for example 20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or 30-70 years old, or 40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80 years old, or 50-70 years old.

[0053] 1.20 The composition for use according to any of the preceding clauses, wherein the patient is suffering from a co-morbid condition such as conjunctivitis, styes, chalazions, blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratitis, or ocular allergy, or any combination thereof.

[0054] 1.21 A composition for use according to any of the preceding clauses, wherein the patient is suffering from keratoconjunctivitis sicca caused by treatment of a co-morbid condition, e.g., treatment with one or more of isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, anticholinergics, oral contraceptives, antihistamines, antinasal congestion drugs, beta-adrenergic antagonists, phenothiazines, atropine, opiates (e.g., morphine), optionally with concurrent or prior such treatment, further optionally with such treatment being systemic (e.g., oral or parenteral).

[0055] 1.22 The composition for use according to any of the preceding clauses, wherein the patient is suffering from keratoconjunctivitis sicca caused by an ocular surgical intervention, such as corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally with the simultaneous or prior presence of such surgery.

[0056] 1.23 The composition for use according to any of the preceding clauses, wherein the patient is concurrently receiving treatment with another topical ophthalmic medication, such as an antibiotic, an antifungal, a corticosteroid, another immunosuppressant, a sympathomimetic, an anesthetic, an antihistamine, or any combination thereof.

[0057] 1.24 A composition for use according to any of the preceding clauses, wherein the patient is a contact lens wearer.

[0058] 1.25 A composition for use according to any of the preceding clauses, wherein the patient has not responded or has responded inadequately to previous treatments for keratoconjunctivitis sicca (dry eye disease).

[0059] 1.26. A composition for use according to 1.25, wherein the previous treatment comprises one or more of the following therapeutic methods: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporine), topical corticosteroid administration, or topical aqueous artificial tears administration.

[0060] 1.27 The composition for any of the uses described in the preceding paragraphs, wherein the patient has at least one eye with a total corneal fluorescein staining score of at least 10 or greater.

[0061] 1.28 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with any one or combination of criteria (e.g., signs of dry eye disease) selected from the group consisting of: i. Total Lissamine Green conjunctival score (temporal and nasal areas combined) according to the Oxford Scale ≥ 2; ii. Total corneal fluorescein staining (NEI scale) (i.e., sum of inferior, superior, central, nasal and temporal regions) ≥ 10; iii. Unanesthetized Schirmer test score is 1mm-10mm.

[0062] 1.29 The composition for use according to paragraph 1.28, wherein the patient has at least one eye (i.e., the same eye) that meets criteria (i), (ii), and (iii).

[0063] 1.30 The composition for use according to any one of the preceding clauses, wherein the patient has at least one or both eyes with any one or combination of the following: i. Central corneal fluorescein staining (NEI scale) score ≥ 2; ii. Inferior corneal fluorescein staining (NEI scale) score ≥ 2; iii. Total corneal fluorescein staining (NEI scale) score ≥ 11.

[0064] 1.31 The composition for use according to any of the preceding clauses, wherein the patient has a history of keratoconjunctivitis sicca (dry eye disease) in one or both eyes for at least 6 months.

[0065] 1.32 The composition for use according to any of the preceding clauses, wherein the composition is effective in alleviating one or more signs and / or symptoms of keratoconjunctivitis sicca (dry eye disease), preferably the one or more signs and / or symptoms are selected from ocular surface damage.

[0066] 1.33 The composition for use according to any of the preceding clauses, wherein the composition is effective to reduce one or more signs and / or symptoms of keratoconjunctivitis sicca (dry eye disease) within 2 weeks, 4 weeks, or 8 weeks after the first administration of the composition / start of treatment.

[0067] 1.34 A composition for use according to any of the preceding clauses, wherein the composition is effective in reducing ocular surface damage.

[0068] 1.35 The composition for use according to 1.32-1.34, wherein the ocular surface damage is selected from the group consisting of: i. Surface damage to the entire corneal area; ii. Superficial damage in the central corneal region; iii. Superficial damage in the nasal corneal region; iv. Superficial damage in the temporal corneal region; v. Surface damage in the lower corneal region; and vi. Combinations thereof.

[0069] 1.36 The composition for use according to 1.35, wherein the ocular surface damage is selected from ocular surface damage in the central corneal region and ocular surface damage in the inferior corneal region.

[0070] 1.37 A composition for use according to 1.32 to 1.36, wherein the reduction in ocular surface damage is determined by corneal fluorescein staining (NEI scale).

[0071] 1.38 The composition for use according to 1.37, wherein the corneal fluorescein staining method is selected from the group consisting of: iv. Total corneal fluorescein staining; v. Central corneal fluorescein staining; vi. Nasal corneal fluorescein staining; vii.Temporal fluorescein staining; viii. Inferior corneal fluorescein staining; and ix. Any combination thereof.

[0072] 1.39 A composition for use according to 1.32-1.38, wherein the treatment is effective to reduce the total corneal fluorescein staining score (sum of inferior, superior, central, nasal, and temporal staining scores; NEI scale) by at least 2 whole points or at least 3 points, optionally within a treatment period of at least 8 weeks, or at least 12 weeks.

[0073] 1.40 The composition for use according to any of the preceding clauses, which is effective for treating one or more ocular symptoms of keratoconjunctivitis sicca (dry eye disease) selected from: (x) dryness, (xi) stickiness, (xii) burning / stinging, (xiii) foreign body sensation, (xiv) itching, (xv) blurred vision, (xvi) sensitivity to light, (xvii) pain, and (xviii) any combination thereof.

[0074] 1.41 A composition for use according to any of the preceding clauses, which is effective in reducing (xix) the frequency of dryness, (xx) the perception of dry eye symptoms, and (xxi) the severity of dryness, and (xxi) any combination thereof.

[0075] 1.42 The composition for use according to item 1.41, wherein the composition is effective to reduce the severity of dryness or the frequency of dryness, or a combination thereof.

[0076] 1.43 A composition for use according to any of the preceding clauses, wherein the method of treatment comprises reducing ocular surface damage, for example ocular surface damage of the cornea, or ocular surface damage selected from: i. surface damage of the entire corneal region; ii. surface damage of the central corneal region; iii. surface damage of the nasal corneal region; iv. surface damage of the temporal corneal region; v. surface damage of the inferior corneal region; and vi. combinations thereof.

[0077] 1.44 The composition for use according to paragraph 1.43, wherein the ocular surface damage is selected from ocular surface damage in the central corneal region and ocular surface damage in the inferior corneal region.

[0078] 1.45 The composition for use according to paragraphs 1.43 to 1.44, wherein the reduction in ocular surface damage is determined by corneal fluorescein staining (NEI scale).

[0079] 1.46 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with any one or combination of criteria selected from the group consisting of: -total corneal fluorescein staining value in the range of 10 to 15, preferably 10 to 13 (NEI scale); -Central corneal fluorescein staining value in the range of 1 to 3 (NEI scale), preferably 2 to 3 (NEI scale); - A total Lissamine Green conjunctival staining score ranging from 2 to 6, preferably 3 to 5; - Unanesthetized Schirmer test score ranging from 2 to 8 mm.

[0080] 1.47 A composition for use according to any of the preceding clauses, wherein the patient does not suffer from meibomian gland dysfunction and / or blepharitis.

[0081] 1.48 The composition for use according to any of the preceding clauses, wherein the patient has an unanesthetized Schirmer test score in the range of 3-7 mm, preferably in the range of 4-6 mm, more preferably about 5 mm.

[0082] 1.49 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with a total corneal fluorescein staining score of at least 11 (NEI scale) or greater.

[0083] 1.50 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with a central corneal fluorescein staining score in the range of 1 to 3 (NEI scale).

[0084] 1.51 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with a total Lissamine Green conjunctival staining score in the range of 2 to 6.

[0085] 1.52 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with an unanesthetized Schirmer test score in the range of 4-6 mm.

[0086] 1.53 A composition for use according to any of the preceding clauses, having a central corneal fluorescein staining value of about 3 (NEI scale).

[0087] 1.54 A composition for use according to any of the preceding claims, having a Lissamine Green conjunctival staining score in the range of 3 to 5.

[0088] 1.55 A composition for use according to any of the preceding clauses, having an unanesthetized Schirmer test score of about 5 mm.

[0089] 1.56 An ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a method of treating keratoconjunctivitis sicca (dry eye disease), the method comprising the step of topically administering the composition to the eye, wherein the patient has at least one eye with a total corneal fluorescein staining score of at least 11 (NEI scale) or greater.

[0090] 1.57 An ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a method of treating keratoconjunctivitis sicca (dry eye disease), the method comprising the step of topically administering the composition to the eye, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 45 or greater, the patient having at least one eye with a total corneal fluorescein staining score of at least 11 or greater (NEI scale).

[0091] 1.58 An ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a method for treating keratoconjunctivitis sicca (dry eye disease), the method comprising the step of topically administering the composition to the eye of a patient, the patient having a Total Ocular Surface Disease Index (OSDI) score of 45 or greater, the patient: Total corneal fluorescein staining score of 11 or more (NEI scale) An ophthalmic composition having at least one eye having a central corneal fluorescein staining value (NEI scale) in the range of 1 to 3.

[0092] 1.59 An ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a method for treating keratoconjunctivitis sicca (dry eye disease), the method comprising the step of topically administering the composition to the eye of a patient, the patient having a Total Ocular Surface Disease Index (OSDI) score of 45 or greater, the patient: Total corneal fluorescein staining score of 11 or more (NEI scale) Central corneal fluorescein staining score (NEI scale) is in the range of 1 to 3, An ophthalmic composition having at least one eye having a total Lissamine green conjunctival staining score in the range of 2 to 6.

[0093] 1.60 An ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a method of treating keratoconjunctivitis sicca (dry eye disease), the method comprising the step of topically administering the composition to the eye of a patient, the patient having a Total Ocular Surface Disease Index (OSDI) score of 45 or greater, the patient: Total corneal fluorescein staining score of 11 or more (NEI scale) Central corneal fluorescein staining score (NEI scale) is in the range of 1 to 3, Total Lissamine green conjunctival staining score ranged from 2 to 6; An ophthalmic composition having at least one eye having an unanesthetized Schirmer test score in the range of 4-6 mm.

[0094] 1.61 A composition for use according to any one of paragraphs 1.58 to 1.60, wherein the central corneal fluorescein staining value is about 3 (NEI scale).

[0095] 1.62 The composition for use according to any one of paragraphs 1.59 to 1.61, wherein the Lissamine Green conjunctival staining score is in the range of 3 to 5.

[0096] 1.63 The composition for use according to any one of paragraphs 1.60 to 1.62, wherein the unanesthetized Schirmer test score is about 5 mm.

[0097] 1.64 The composition for use according to any one of paragraphs 1.57 to 1.63, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 55 or greater.

[0098] 1.65 The composition for use according to any one of paragraphs 1.49 to 1.64, wherein the patient has a total corneal fluorescein staining score, a central corneal fluorescein staining score, a Lissamine green conjunctival staining score, and / or an unanesthetized Schirmer test score in both eyes of the specified values.

[0099] In a second aspect, the disclosure may relate to a method of treatment as described below.

[0100] 2.1 A method for treating keratoconjunctivitis sicca (dry eye disease) comprising topically administering to the eye of a patient an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 45 or greater.

[0101] 2.2 The patient has a Total Ocular Surface Disease Index (OSDI) score of 55 or greater, Method 2.1.

[0102] 2.3 Any of the preceding methods, wherein the composition comprises up to about 1.0% (w / w) ethanol.

[0103] 2.4 Any of the preceding methods, wherein the composition consists of about 0.1% (w / v) cyclosporine, F4H5 and up to about 1.0% (w / w) ethanol.

[0104] 2.5 Any of the preceding methods, wherein the ophthalmic composition is administered to the corneal and / or conjunctival surfaces in the form of droplets.

[0105] 2.6 Any of the preceding methods, wherein the composition is administered as a single drop having a volume of about 8-11 μL, preferably about 8-10 μL.

[0106] 2.7 Any of the preceding methods, wherein the composition is administered in a dose of one drop per eye, once daily, with a volume of 8-10 μL.

[0107] 2.8 Any of the preceding methods, wherein the composition is administered as a single drop having a volume of about 10 μl.

[0108] 2.9 Any of the preceding methods, wherein the composition is administered twice daily to each eye.

[0109] 2.10 Any of the preceding methods, wherein the composition is administered in a dose of one drop per eye, twice daily, with a volume of 16-20 μL.

[0110] 2.11 Any of the preceding methods, wherein the dry eye disease is aqueous-deficient dry eye disease.

[0111] 2.12 Any of the preceding methods, wherein the dry eye disease is evaporative dry eye disease.

[0112] 2.13 Any of the preceding methods, wherein the patient is unresponsive or responds poorly to treatment with an aqueous eye drop composition (e.g., aqueous cyclosporine emulsion eye drops).

[0113] 2.14 Any of the preceding methods, wherein the time interval between the topical administration of the composition to the eye or ocular surface of the first and second doses is at least 4 hours, or at least 6 hours, or at least 12 hours.

[0114] 2.15 Any of the preceding methods, wherein the treatment period is at least 2 weeks, or at least 4 weeks, or at least 6 weeks, or at least 8 weeks, or at least 12 weeks.

[0115] 2.16 Any of the preceding methods, wherein the patient is a human patient.

[0116] 2.17 Any of the preceding methods, wherein the patient is a female patient.

[0117] 2.18 Any of the preceding methods, wherein the patient is a male patient.

[0118] 2.19 Any of the preceding methods, wherein the patient is between 20 and 80 years of age at the time of treatment, e.g., 20-50 years, or 20-70 years, or 30-80 years, or 30-50 years, or 30-70 years, or 40-80 years, or 40-60 years, or 40-70 years, or 50-80 years, or 50-70 years.

[0119] 2.20 Any of the preceding methods, wherein the patient is suffering from a co-morbid condition, e.g., conjunctivitis, styes, chalazions, blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratitis, or ocular allergy, or any combination thereof.

[0120] 2.21 Any of the foregoing methods, wherein the patient is suffering from keratoconjunctivitis sicca caused by treatment for a comorbid condition, e.g., treatment with one or more of isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, anticholinergics, oral contraceptives, antihistamines, antinasal congestion drugs, beta-adrenergic antagonists, phenothiazines, atropine, opiates (e.g., morphine), optionally with concurrent or prior such treatment, and further optionally with such treatment being systemic (e.g., oral or parenteral).

[0121] 2.22 Any of the preceding methods, wherein the patient suffers from keratoconjunctivitis sicca caused by ocular surgical intervention, e.g. corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally with concurrent or prior such surgery.

[0122] 2.23 Any of the preceding methods, wherein the patient is concurrently receiving treatment with another topical ophthalmic medication, e.g., an antibiotic, an antifungal, a corticosteroid, another immunosuppressant, a sympathomimetic, an anesthetic, an antihistamine, or any combination thereof.

[0123] 2.24 Any of the preceding methods wherein the patient is a contact lens wearer.

[0124] 2.25 Any of the preceding methods in which the patient has not responded or has responded inadequately to previous treatment for keratoconjunctivitis sicca (dry eye disease).

[0125] 2.26 The method of 2.25, wherein the prior treatment comprises one or more of the following therapeutic methods: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporine), topical corticosteroid administration, or topical aqueous artificial tears administration.

[0126] 2.27 Any of the preceding methods, wherein the patient has at least one eye with a total corneal fluorescein staining score of at least 10.

[0127] 2.28 Any of the preceding methods, wherein the patient has at least one eye with any one or combination of criteria (e.g., signs of dry eye disease) selected from the group consisting of: i. Total Lissamine Green conjunctival score (temporal and nasal areas combined) according to the Oxford Scale ≥ 2; ii. Total corneal fluorescein staining (NEI scale) (i.e., sum of inferior, superior, central, nasal and temporal regions) ≥ 10; iii. Unanesthetized Schirmer test score is 1mm-10mm.

[0128] 2.29 Method 2.28, wherein the patient has at least one eye (i.e., the same eye) that meets criteria (i), (ii), and (iii).

[0129] 2.30 Any of the preceding methods, wherein the patient has at least one or both eyes with any one or combination of the following: i. Central corneal fluorescein staining (NEI scale) score ≥ 2; ii. Inferior corneal fluorescein staining (NEI scale) score ≥ 2; iii. Total corneal fluorescein staining (NEI scale) score ≥ 11.

[0130] 2.31 Any of the preceding methods, wherein the patient has a history of keratoconjunctivitis sicca (dry eye disease) in one or both eyes for at least 6 months.

[0131] 2.32 Any of the preceding methods, wherein the composition is effective to alleviate one or more signs and / or symptoms of keratoconjunctivitis sicca (dry eye disease), preferably the one or more signs and / or symptoms are selected from ocular surface damage.

[0132] 2.33 Any of the preceding methods, wherein the composition is effective to reduce one or more signs and / or symptoms of keratoconjunctivitis sicca (dry eye disease) within 2 weeks, 4 weeks, or 8 weeks after the first administration of the composition / initiation of treatment.

[0133] 2.34 Any of the preceding methods, wherein the composition is effective to reduce ocular surface damage.

[0134] 2.35 Methods 2.32-2.34 in which the ocular surface injury is selected from the group consisting of: i. Surface damage to the entire corneal area; ii. Superficial damage in the central corneal region; iii. Superficial damage in the nasal corneal region; iv. Superficial damage in the temporal corneal region; v. Surface damage in the lower corneal region; and vi. Combinations thereof.

[0135] 2.36 Method 2.35, wherein the ocular surface injury is selected from a central corneal region ocular surface injury and an inferior corneal region ocular surface injury.

[0136] 2.37 Reduction of ocular surface damage is determined by corneal fluorescein staining (NEI scale), Methods 2.32-2.36.

[0137] 2.38 Method 2.37, wherein the corneal fluorescein staining method is selected from the group consisting of: iv. Total corneal fluorescein staining; v. Central corneal fluorescein staining; vi. Nasal corneal fluorescein staining; vii.Temporal fluorescein staining; viii. Inferior corneal fluorescein staining; and ix. Any combination thereof.

[0138] 2.39 Treatment is effective to reduce the total corneal fluorescein staining score (sum of inferior, superior, central, nasal, and temporal staining scores; NEI scale) by at least 2 whole points or at least 3 points within a treatment period of at least 8 weeks, or at least 12 weeks, optionally, Methods 2.32-2.38.

[0139] 2.40 Any of the preceding methods, which is effective to treat one or more ocular symptoms of keratoconjunctivitis sicca (dry eye disease) selected from: (x) dryness, (xi) stickiness, (xii) burning / stinging, (xiii) foreign body sensation, (xiv) itching, (xv) blurred vision, (xvi) sensitivity to light, (xvii) pain, (xviii) and any combination thereof.

[0140] 2.41 Any of the preceding methods which are effective in reducing (xix) the frequency of dryness, (xx) symptom awareness, and (xxi) the severity of dryness, and (xxi) any combination thereof.

[0141] 2.42 Methods 2.40-2.41, wherein the composition is effective to reduce the severity of dryness or the frequency of dryness, or a combination thereof.

[0142] 2.43 Any of the preceding methods, wherein the method of treatment includes reducing ocular surface damage, e.g., ocular surface damage of the cornea, or ocular surface damage selected from: i. surface damage of the entire corneal region; ii. surface damage of the central corneal region; iii. surface damage of the nasal corneal region; iv. surface damage of the temporal corneal region; v. surface damage of the inferior corneal region; and vi. combinations thereof.

[0143] 2.44 Method 2.43, wherein the ocular surface injury is selected from a central corneal region ocular surface injury and an inferior corneal region ocular surface injury.

[0144] 2.45 Ocular surface damage is determined by corneal fluorescein staining (NEI scale), Methods 2.43-2.44.

[0145] 2.46 Any of the preceding methods, wherein the patient has at least one eye with any one or combination of criteria selected from the group consisting of: -total corneal fluorescein staining value in the range of 10 to 15, preferably 10 to 13 (NEI scale); -Central corneal fluorescein staining value in the range of 1 to 3 (NEI scale), preferably 2 to 3 (NEI scale); - A total Lissamine Green conjunctival staining score ranging from 2 to 6, preferably 3 to 5; - Unanesthetized Schirmer test score in the range of 2-8 mm.

[0146] 2.47 Any of the preceding methods, wherein the patient is free of blepharitis and / or meibomian gland dysfunction.

[0147] 2.48 Any of the preceding methods, wherein the patient has an unanesthetized Schirmer test score in the range of 3-7 mm, preferably in the range of 4-6 mm, and more preferably about 5 mm.

[0148] 2.49 Any of the preceding methods, wherein the patient has at least one eye with a total corneal fluorescein staining score of at least 11 (NEI scale) or greater.

[0149] 2.50 Any of the preceding methods, wherein the patient has at least one eye with central corneal fluorescein staining value in the range of 1 to 3 (NEI scale).

[0150] 2.51 Any of the preceding methods, wherein the patient has at least one eye with a total Lissamine Green conjunctival staining score in the range of 2 to 6.

[0151] 2.52 Any of the preceding methods, wherein the patient has at least one eye with an unanesthetized Schirmer test score in the range of 4-6 mm.

[0152] 2.53 Any of the preceding methods, in which the central corneal fluorescein staining value is about 3 (NEI scale).

[0153] 2.54 Any of the preceding methods, in which the Lissamine green conjunctival staining score is in the range of 3 to 5.

[0154] 2.55 Any of the preceding methods in which the unanesthetized Schirmer test score is approximately 5 mm.

[0155] 2.56 A method of treating keratoconjunctivitis sicca (dry eye disease) comprising topically administering to an eye of a patient an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane, wherein the patient has at least one eye with a total corneal fluorescein staining score of at least 11 or greater (NEI scale).

[0156] 2.57 A method of treating keratoconjunctivitis sicca (dry eye disease) comprising topically administering to an eye of a patient an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane, wherein the patient has at least one eye with a Total Ocular Surface Disease Index (OSDI) score of 45 or greater and a Total Corneal Fluorescein Stain score of 11 or greater (NEI scale).

[0157] 2.58 A method of treating keratoconjunctivitis sicca (dry eye disease) comprising topically administering to the eye of a patient an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 45 or greater, and the patient: Total corneal fluorescein staining score of 11 or more (NEI scale) An ophthalmic composition having at least one eye having a central corneal fluorescein staining value (NEI scale) in the range of 1 to 3.

[0158] 2.59 A method of treating keratoconjunctivitis sicca (dry eye disease) comprising topically administering to the eye of a patient an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 45 or greater, and the patient: Total corneal fluorescein staining score of 11 or more (NEI scale) Central corneal fluorescein staining score (NEI scale) is in the range of 1 to 3, An ophthalmic composition having at least one eye having a total Lissamine green conjunctival staining score in the range of 2 to 6.

[0159] 2.60 A method of treating keratoconjunctivitis sicca (dry eye disease) comprising topically administering to the eye of a patient an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 45 or greater, and the patient: Total corneal fluorescein staining score of 11 or more (NEI scale) Central corneal fluorescein staining score (NEI scale) is in the range of 1 to 3, Total Lissamine green conjunctival staining score ranged from 2 to 6; An ophthalmic composition having at least one eye having an unanesthetized Schirmer test score in the range of 4-6 mm.

[0160] 2.61 Central corneal fluorescein staining value is approximately 3 (NEI scale), method 2.58 to 2.60.

[0161] 2.62 Methods with Lissamine green conjunctival staining scores in the range of 3-5 2.59-2.61.

[0162] 2.63 Unanesthetized Schirmer test score is approximately 5 mm, method 2.60-2.62.

[0163] 2.64 Patients have a Total Ocular Surface Disease Index (OSDI) score of 55 or greater, methods 2.57 to 2.63.

[0164] 2.65 Patients have the specified values ​​of total corneal fluorescein stain score, central corneal fluorescein stain score, Lissamine green conjunctival stain score, and / or unanesthetized Schirmer test score in both eyes, Methods 2.49-2.64.

[0165] In a third aspect, the present invention provides the following:

[0166] 3.1 Ophthalmic composition containing 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in: a) A method of treating and / or ameliorating symptoms associated with keratoconjunctivitis sicca (dry eye), the symptoms being dryness (severity of dryness) and blurred vision; and / or b) A method of treating and / or ameliorating the awareness and frequency of dry eye symptoms, preferably wherein the dry eye symptoms are selected from dryness, stickiness, burning / stinging, foreign body sensation, itching, blurred vision, sensitivity to light, and pain in the patient's eyes.

[0167] 3.2 A composition for use according to 3.1, wherein the composition is administered topically to the eye of a patient.

[0168] 3.3 A composition for use according to 3.1 or 3.2, wherein dryness (severity of dryness), blurred vision, frequency of dryness, and perception of dry eye symptoms are determined on a visual analog scale (VAS) on a scale of 0% to 100%, where in the case of frequency of dryness and perception of dry eye symptoms, the scale of 0% to 100% is the percentage of time that the patient experiences dryness and dry eye symptoms, and in the case of dryness and blurred vision, the scale of 0% to 100% is the percentage level of discomfort experienced by the patient.

[0169] 3.4 A composition for use according to any one of the preceding clauses, wherein the composition comprises up to about 1.0% (w / w) ethanol.

[0170] 3.5 A composition for use according to any one of the preceding clauses, wherein the composition consists of about 0.1% (w / v) cyclosporine, 1-perfluorobutylpentane (F4H5) and up to about 1.0% (w / w) ethanol.

[0171] 3.6 Composition for use according to any of the preceding clauses, wherein the ophthalmic composition is administered to the corneal and / or conjunctival surfaces in the form of droplets.

[0172] 3.7 The composition for use according to any of the preceding clauses, wherein the composition is administered as a single drop having a volume of about 8-11 μL, preferably about 8-10 μL.

[0173] 3.8 The composition for use according to any of the preceding clauses, wherein the composition is administered in a dose of one drop per eye with a volume of about 8-10 μL.

[0174] 3.9 A composition for use according to any one of the preceding claims, wherein the composition is administered as a drop having a volume of about 10 μl.

[0175] 3.10 An ophthalmic composition for use according to any one of the preceding clauses, wherein the composition is administered twice per day per eye.

[0176] 3.11 The composition for use according to any of the preceding clauses, wherein the composition is administered in a dose of one drop per eye, twice daily, with a volume of about 16-20 μL.

[0177] 3.12 The composition for use according to any one of the preceding clauses, wherein the dry eye disease is aqueous-deficient dry eye disease.

[0178] 3.13 The composition for use according to any of the preceding clauses, wherein the dry eye disease is evaporative dry eye disease.

[0179] 3.14 A composition for use according to any of the preceding clauses, wherein the patient is unresponsive or responds poorly to treatment with the aqueous eye drop composition.

[0180] 3.15 The composition for use according to any of the preceding clauses, wherein the time interval between topical administration of the composition to the eye or ocular surface of the first and second doses is at least 4 hours, or at least 6 hours, or at least 12 hours.

[0181] 3.16 The composition for use according to any of the preceding clauses, wherein the treatment period is at least 2 weeks, or at least 4 weeks, or at least 6 weeks, or at least 8 weeks, or at least 12 weeks.

[0182] 3.17 The composition for use according to any of the preceding clauses, wherein the patient is a human patient.

[0183] 3.18 The composition for use according to any of the preceding clauses, wherein the patient is a female patient.

[0184] 3.19 The composition for use according to any of the preceding clauses, wherein the patient is a male patient.

[0185] 3.20 The composition for use according to any of the preceding clauses, wherein the patient is 20-80 years old at the time of treatment, for example 20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or 30-70 years old, or 40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80 years old, or 50-70 years old.

[0186] 3.21 The composition for use according to any of the preceding clauses, wherein the patient is suffering from a co-morbid condition such as conjunctivitis, styes, chalazions, blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratitis, or ocular allergy, or any combination thereof.

[0187] 3.22 A composition for use according to any of the preceding clauses, wherein the patient is suffering from keratoconjunctivitis sicca caused by treatment of a co-morbid condition, e.g., treatment with one or more of isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, anticholinergics, oral contraceptives, antihistamines, antinasal congestion drugs, beta adrenergic antagonists, phenothiazines, atropine, opiates (e.g., morphine), optionally with concurrent or prior such treatment, further optionally with such treatment being systemic (e.g., oral or parenteral).

[0188] 3.23 The composition for use according to any of the preceding clauses, wherein the patient is suffering from keratoconjunctivitis sicca caused by an ocular surgical intervention, such as corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally with the simultaneous or prior presence of such surgery.

[0189] 3.24 The composition for use according to any of the preceding clauses, wherein the patient is concurrently receiving treatment with another topical ophthalmic medication, such as an antibiotic, an antifungal, a corticosteroid, another immunosuppressant, a sympathomimetic, an anesthetic, an antihistamine, or any combination thereof.

[0190] 3.25 A composition for use according to any of the preceding clauses, wherein the patient is a contact lens wearer.

[0191] 3.26 A composition for use according to any of the preceding clauses, wherein the patient has not responded or has responded inadequately to previous treatments for keratoconjunctivitis sicca (dry eye disease).

[0192] 3.27 Composition for use in 3.26, wherein the prior treatment comprises one or more of the following therapeutic methods: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporine), topical corticosteroid administration, or topical aqueous artificial tears administration.

[0193] 3.28 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with any one or combination of criteria (e.g., signs of dry eye disease) selected from the group consisting of: i. Total Lissamine Green conjunctival score (temporal and nasal areas combined) according to the Oxford Scale ≥ 2; ii. Total corneal fluorescein staining (NEI scale) (i.e., the sum of the inferior, superior, central, nasal and temporal regions) ≥ 10; and iii. Unanesthetized Schirmer test score of 1mm-10mm; and / or Patients have a total ocular surface disease index (OSDI) score of 20 or greater.

[0194] 3.29 The composition for use according to any of the preceding clauses, wherein the patient has a Total Ocular Surface Disease Index score (OSDI) of 45 or greater.

[0195] 3.30 The composition for use according to any of the preceding clauses, wherein the patient has a Total Ocular Surface Disease Index score (OSDI) of 55 or greater.

[0196] 3.31 The composition for use according to paragraphs 3.28 to 3.30, wherein the patient has at least one eye (i.e., the same eye) that meets all of criteria (i), (ii), and (iii).

[0197] 3.32 The composition for use according to any of the preceding clauses, wherein the patient has a history of keratoconjunctivitis sicca (dry eye disease) in one or both eyes for at least 6 months.

[0198] 3.33 The composition for use according to any of the preceding clauses, wherein the composition is effective to reduce the signs and / or symptoms of keratoconjunctivitis sicca (dry eye disease), preferably wherein the one or more signs and / or symptoms are selected from ocular surface damage.

[0199] 3.34 The composition for use according to any of the preceding clauses, wherein the composition is effective to reduce one or more signs and / or symptoms of keratoconjunctivitis sicca (dry eye disease) within 2 weeks, or within 4 weeks, or within 8 weeks after the first administration of the composition.

[0200] 3.35 A composition for use according to any of the preceding clauses, wherein the composition is effective in reducing ocular surface damage.

[0201] 3.36 The composition for use according to 3.35, wherein the ocular surface injury is selected from the group consisting of: i. Surface damage to the entire corneal area; ii. Superficial damage in the central corneal region; iii. Superficial damage in the nasal corneal region; iv. Superficial damage in the temporal corneal region; v. Surface damage in the lower corneal region; and vi. Combinations thereof.

[0202] 3.37 The composition for use according to paragraph 3.36, wherein the ocular surface damage is selected from ocular surface damage in the central corneal region and ocular surface damage in the inferior corneal region.

[0203] 3.38 The composition for use according to paragraphs 3.35 to 3.37, wherein the reduction in ocular surface damage is determined by corneal fluorescein staining (NEI scale).

[0204] 3.39 The composition for use according to paragraph 3.38, wherein the corneal fluorescein staining method is selected from the group consisting of: iv. Total corneal fluorescein staining; v. Central corneal fluorescein staining; vi. Nasal corneal fluorescein staining; vii.Temporal fluorescein staining; viii. Inferior corneal fluorescein staining; and ix. Any combination thereof.

[0205] 3.40 The composition for use according to any of the preceding clauses, wherein the composition is effective in reducing the frequency of dryness and / or perception of dry eye symptoms and / or the severity of dryness, and any combination thereof.

[0206] 3.41 The composition for use according to paragraph 3.40, wherein the composition is effective to reduce the frequency of dry eye and / or awareness of dry eye symptoms and / or severity of dry eye, or any combination thereof, within 2 weeks of initiating treatment, or within 4 weeks of initiating treatment.

[0207] 3.42 The composition for use according to paragraph 3.40 or 3.41, wherein the composition is effective to reduce the frequency of dryness and / or the severity of dryness by at least 25%, preferably at least 30%, after 2 weeks, or after 4 weeks, or after 8 weeks, or after 12 weeks of treatment.

[0208] 3.43 The composition for use according to paragraphs 3.40 to 3.42, wherein the composition is effective to reduce the severity and / or frequency of dryness by at least 25% in at least 20% of patients receiving treatment after 2 weeks of treatment, or in at least 30% of patients receiving treatment after 4 weeks of treatment, or in at least 35% of patients receiving treatment after 8 weeks of treatment.

[0209] 3.44 A composition for use according to paragraphs 3.40 to 3.43, wherein the effectiveness of the composition for use is determined by a visual analogue scale (VAS) test on a scale of 0 to 100%, wherein the frequency of dryness and awareness of dry eye symptoms is measured as the percentage of time that the patient experiences said symptom(s) on a scale of 0 to 100%, and the severity of dryness is measured as the percentage level of discomfort experienced by the patient on a scale of 0 to 100%.

[0210] 3.45 A composition for use according to any of the preceding clauses, wherein the method of treatment comprises reducing ocular surface damage, for example ocular surface damage of the cornea, or ocular surface damage selected from: i. surface damage of the entire corneal region; ii. surface damage of the central corneal region; iii. surface damage of the nasal corneal region; iv. surface damage of the temporal corneal region; v. surface damage of the inferior corneal region; and vi. combinations thereof.

[0211] 3.46 The composition for use according to paragraph 3.45, wherein the ocular surface damage is selected from ocular surface damage in the central corneal region and ocular surface damage in the inferior corneal region.

[0212] 3.47 A composition for use according to paragraphs 3.45 to 3.46, wherein the reduction in ocular surface damage is determined by corneal fluorescein staining (NEI scale).

[0213] 3.48 The composition for use according to any of the preceding items, wherein the patient has at least one eye with any one or combination of criteria selected from the group consisting of: -total corneal fluorescein staining value in the range of 10 to 15, preferably 10 to 13 (NEI scale); -Central corneal fluorescein staining value in the range of 1 to 3 (NEI scale), preferably 2 to 3 (NEI scale); - A total Lissamine Green conjunctival staining score ranging from 2 to 6, preferably 3 to 5; -Unanesthetized Schirmer test score in the range of 2-8 mm; - Total OSDI score in the range of 25 to 64, preferably 30 to 64.

[0214] 3.49 The composition for use according to any of the preceding clauses, wherein the patient has an unanesthetized Schirmer test score in the range of 3 to 7 mm, preferably in the range of 4 to 6 mm, more preferably about 5 mm.

[0215] 3.50 A composition for use according to any of the preceding clauses, wherein the composition is effective to reduce a patient's total corneal fluorescein staining score (sum of inferior, superior, central, nasal, and temporal staining scores; NEI scale) by at least 3 grades after 4 weeks of treatment, preferably in at least 50% of treated patients.

[0216] 3.51 The composition for use according to any of the preceding clauses, wherein the composition is effective to reduce a patient's central corneal fluorescein staining score by at least one grade after 4 weeks of treatment, preferably in at least 50% of patients receiving the treatment.

[0217] 3.52 The composition for use according to any of the preceding clauses, wherein the composition is effective to reduce the conjunctival Lissamine Green staining (Oxford Scale) of a patient by at least 2 grades after 4 weeks or 12 weeks of treatment, preferably in at least 30% of patients receiving treatment after 4 weeks of treatment, or preferably in 50% of patients after 12 weeks of treatment.

[0218] 3.53 A composition for use according to any of the preceding clauses, wherein the patient does not suffer from meibomian gland dysfunction and / or blepharitis.

[0219] 3.54 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with a total corneal fluorescein staining score of at least 11 (NEI scale) or greater.

[0220] 3.55 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with a central corneal fluorescein staining score in the range of 1 to 3 (NEI scale).

[0221] 3.56 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with a total Lissamine Green conjunctival staining score in the range of 2 to 6.

[0222] 3.57 The composition for use according to any of the preceding clauses, wherein the patient has at least one eye with an unanesthetized Schirmer test score in the range of 4-6 mm.

[0223] 3.58 A composition for use according to any of the preceding clauses, having a central corneal fluorescein staining value of about 3 (NEI scale).

[0224] 3.59 A composition for use according to any of the preceding claims, having a Lissamine Green conjunctival staining score in the range of 3 to 5.

[0225] 3.60 A composition for use according to any of the preceding clauses, having an unanesthetized Schirmer test score of about 5 mm.

[0226] 3.61 An ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in: a) A method of treating and / or ameliorating symptoms associated with keratoconjunctivitis sicca (dry eye), the symptoms being dryness (severity of dryness) and blurred vision; and / or b) a method of treating and / or ameliorating the awareness and frequency of dry eye symptoms, preferably wherein the dry eye symptoms are selected from dryness, stickiness, burning / stinging, foreign body sensation, itching, blurred vision, sensitivity to light, and pain in the patient's eyes; Here, the composition is administered topically to the eye of a patient, and the patient has at least one eye with a total corneal fluorescein staining score (NEI scale) of at least 11 or greater.

[0227] 3.62 The composition for use according to paragraph 3.61, wherein the patient has at least one eye with a central corneal fluorescein staining score in the range of 1 to 3 (NEI scale).

[0228] 3.63 The composition for use according to paragraphs 3.61-3.62, wherein the patient has at least one eye with a total Lissamine Green conjunctival staining score in the range of 2-6.

[0229] 3.64 The composition for use according to any one of paragraphs 3.61 to 3.63, wherein the patient has at least one eye with an unanesthetized Schirmer test score in the range of 4 to 6 mm.

[0230] 3.65 A composition for use according to any one of paragraphs 3.62 to 3.64, wherein the central corneal fluorescein staining value is about 3 (NEI scale).

[0231] 3.66 The composition for use according to any one of paragraphs 3.63 to 3.65, wherein the Lissamine Green conjunctival staining score is in the range of 3 to 5.

[0232] 3.67 The composition for use according to any one of paragraphs 3.64 to 3.66, wherein the unanesthetized Schirmer test score is about 5 mm.

[0233] 3.68 The composition for use according to any one of paragraphs 3.61 to 3.67, wherein the patient has a Total Ocular Surface Disease Index score (OSDI) of 45 or greater.

[0234] 3.69 The composition for use according to any one of paragraphs 3.61 to 3.68, wherein the patient has a Total Ocular Surface Disease Index score (OSDI) of 55 or greater.

[0235] 3.70 The composition for use according to any one of paragraphs 3.54 to 3.69, wherein the patient has a total corneal fluorescein staining score, a central corneal fluorescein staining score, a Lissamine green conjunctival staining score, and / or an unanesthetized Schirmer test score in both eyes of the specified values.

[0236] In a fourth aspect, the present invention provides a method comprising:

[0237] 4.1 A method for treating and / or ameliorating symptoms associated with keratoconjunctivitis sicca (dry eye), the symptoms being dryness (severity of dryness) and blurred vision, the method comprising administering to the eye of a patient an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane.

[0238] 4.2 Preferably, the symptoms of dry eye are selected from dryness, stickiness, burning / stinging, foreign body sensation, itching, and the method comprises administering to the patient's eye an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane.

[0239] 4.3 Method 4.1 or 4.2, wherein the composition is administered topically to the patient's eye.

[0240] 4.4 Dryness (severity of dryness), blurred vision, frequency of dryness, and perception of dry eye symptoms will be determined on a visual analog scale (VAS) on a scale of 0% to 100%, where for frequency of dryness and perception of dry eye symptoms, the scale of 0% to 100% is the percentage of time the patient experiences dryness and dry eye symptoms, and for dryness and blurred vision, the scale of 0% to 100% is the percentage level of discomfort experienced by the patient, Methods 4.1 to 4.3.

[0241] 4.5 Any of the preceding methods, wherein the composition comprises up to about 1.0% (w / w) ethanol.

[0242] 4.6 Any of the preceding methods, wherein the composition consists of about 0.1% (w / v) cyclosporine, 1-(perfluorobutyl)pentane (F4H5), and up to about 1.0% (w / w) ethanol.

[0243] 4.7 Any of the preceding methods, wherein the ophthalmic composition is administered to the corneal and / or conjunctival surfaces in the form of droplets.

[0244] 4.8 Any of the preceding methods, wherein the composition is administered as a single drop having a volume of about 8-11 μL, preferably about 8-10 μL.

[0245] 4.9 Any of the preceding methods, wherein the composition is administered in a dose of one drop per eye having a volume of about 8-10 μL.

[0246] 4.10 Any of the preceding methods, wherein the composition is administered as a drop having a volume of about 10 μl.

[0247] 4.11 Any of the preceding methods, wherein the composition is administered twice daily to each eye.

[0248] 4.12 Any of the preceding methods, wherein the composition is administered in a dose of one drop per eye, twice daily, with a volume of 16-20 μL.

[0249] 4.13 Any of the preceding methods, wherein the dry eye disease is aqueous-deficient dry eye disease.

[0250] 4.14 Any of the preceding methods, wherein the dry eye disease is evaporative dry eye disease.

[0251] 4.15 Any of the preceding methods, wherein the patient is unresponsive or responds poorly to treatment with the aqueous ophthalmic composition.

[0252] 4.16 Any of the preceding methods, wherein the time interval between the topical administration of the composition to the eye or ocular surface of the first and second doses is at least 4 hours, or at least 6 hours, or at least 12 hours.

[0253] 4.17 Any of the preceding methods, wherein the treatment period is at least 2 weeks, or at least 4 weeks, or at least 6 weeks, or at least 8 weeks, or at least 12 weeks.

[0254] 4.18 Any of the preceding methods, wherein the patient is a human patient.

[0255] 4.19 Any of the preceding methods, wherein the patient is a female patient.

[0256] 4.20 Any of the preceding methods, wherein the patient is a male patient.

[0257] 4.21 Any of the preceding methods, wherein the patient is between 20 and 80 years of age at the time of treatment, e.g., 20-50 years, or 20-70 years, or 30-80 years, or 30-50 years, or 30-70 years, or 40-80 years, or 40-60 years, or 40-70 years, or 50-80 years, or 50-70 years.

[0258] 4.22 Any of the preceding methods, wherein the patient is suffering from a co-morbid condition, e.g., conjunctivitis, styes, chalazions, blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratitis, or ocular allergy, or any combination thereof.

[0259] 4.23 Any of the foregoing methods, wherein the patient is suffering from keratoconjunctivitis sicca caused by treatment for a comorbid condition, e.g., treatment with one or more of isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, anticholinergics, oral contraceptives, antihistamines, antinasal congestion drugs, beta-adrenergic antagonists, phenothiazines, atropine, opiates (e.g., morphine), optionally with concurrent or prior such treatment, and further optionally with such treatment being systemic (e.g., oral or parenteral).

[0260] 4.24 Any of the preceding methods, wherein the patient suffers from keratoconjunctivitis sicca caused by ocular surgical intervention, e.g., corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally with concurrent or prior such surgery.

[0261] 4.25 Any of the preceding methods, wherein the patient is concurrently receiving treatment with another topical ophthalmic medication, e.g., an antibiotic, an antifungal, a corticosteroid, another immunosuppressant, a sympathomimetic, an anesthetic, an antihistamine, or any combination thereof.

[0262] 4.26 Any of the preceding methods wherein the patient is a contact lens wearer.

[0263] 4.27 Any of the preceding methods in which the patient has not responded or has responded inadequately to previous treatment for keratoconjunctivitis sicca (dry eye disease).

[0264] 4.28 Method 4.27, wherein the prior treatment comprises one or more of the following therapeutic methods: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporine), topical corticosteroid administration, or topical aqueous artificial tears administration.

[0265] 4.29 Any of the preceding methods, wherein the patient has at least one eye with any one or combination of criteria (e.g., signs of dry eye disease) selected from the group consisting of: i. Total Lissamine Green conjunctival score (temporal and nasal areas combined) according to the Oxford Scale ≥ 2; ii. Total corneal fluorescein staining (NEI scale) (i.e., the sum of the inferior, superior, central, nasal and temporal regions) ≥ 10; and iii. Unanesthetized Schirmer test score of 1mm-10mm; and / or Patients have a total ocular surface disease index (OSDI) score of 20 or greater.

[0266] 4.30 Any of the preceding methods, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 45 or greater.

[0267] 4.31 Any of the preceding methods, wherein the patient has a Total Ocular Surface Disease Index (OSDI) score of 55 or greater.

[0268] 4.32 Methods 4.29 through 4.31 in which the patient has at least one eye (i.e., the same eye) that meets all of criteria (i), (ii), and (iii).

[0269] 4.33 Any of the preceding methods where the patient has a history of keratoconjunctivitis sicca (dry eye disease) in one or both eyes for at least 6 months.

[0270] 4.34 Any of the preceding methods, wherein the composition is effective to alleviate one or more signs and / or symptoms of keratoconjunctivitis sicca (dry eye disease), preferably wherein the signs and / or symptoms are selected from ocular surface damage.

[0271] 4.35 Any of the preceding methods, wherein the composition is effective to reduce one or more signs and / or symptoms of keratoconjunctivitis sicca (dry eye disease) within 2 weeks, or within 4 weeks, or within 8 weeks after the initial administration of the composition.

[0272] 4.36 Any of the preceding methods, wherein the composition is effective to reduce ocular surface damage.

[0273] 4.37 Method 4.36, wherein the ocular surface injury is selected from the group consisting of: i. Surface damage to the entire corneal area; ii. Superficial damage in the central corneal region; iii. Superficial damage in the nasal corneal region; iv. Superficial damage in the temporal corneal region; v. Surface damage in the lower corneal region; and vi. Combinations thereof.

[0274] 4.38. Method 4.37, wherein the ocular surface injury is selected from a central corneal region ocular surface injury and an inferior corneal region ocular surface injury.

[0275] 4.39 Reduction of ocular surface damage is determined by corneal fluorescein staining (NEI scale), Methods 4.36-4.38.

[0276] 4.40 Method 4.39, in which the corneal fluorescein staining method is selected from the group consisting of: iv. Total corneal fluorescein staining; v. Central corneal fluorescein staining; vi. Nasal corneal fluorescein staining; vii.Temporal fluorescein staining; viii. Inferior corneal fluorescein staining; and ix. Any combination thereof.

[0277] 4.41 Any of the preceding methods, wherein the composition is effective in reducing the frequency of dryness and / or perception of dry eye symptoms and / or the severity of dryness, and any combination thereof.

[0278] 4.42 Method 4.41, wherein the composition is effective to reduce dry eye frequency and / or perception of dry eye symptoms and / or dry eye severity, or any combination thereof, within 2 weeks of initiating treatment, or within 4 weeks of initiating treatment.

[0279] 4.43 Method 4.41 or 4.42, wherein the composition is effective to reduce the frequency of dryness and / or the severity of dryness by at least 25% after 2 weeks, or after 4 weeks, or after 8 weeks, or after 12 weeks of treatment.

[0280] 4.44 Methods 4.41-3.43, wherein the composition is effective to reduce the severity of dryness and / or the frequency of dryness by at least 25% in greater than 20% of patients being treated after 2 weeks of treatment, or in greater than 30% of patients being treated after 4 weeks of treatment, or in greater than 35% of patients being treated after 8 weeks of treatment.

[0281] 4.45 Methods 4.41-4.44, wherein the efficacy of the composition for use is determined by visual analog scale (VAS) testing on a scale of 0-100%, wherein the frequency of dryness and awareness of dry eye symptoms is measured as the percentage of time the patient experiences the symptom(s) on a scale of 0-100%, and the severity of dryness is measured as the percentage level of discomfort experienced by the patient on a scale of 0-100%.

[0282] 4.46 Any of the preceding methods, wherein the method of treatment includes reducing ocular surface damage, e.g., ocular surface damage of the cornea, or ocular surface damage selected from: i. surface damage of the entire corneal region; ii. surface damage of the central corneal region; iii. surface damage of the nasal corneal region; iv. surface damage of the temporal corneal region; v. surface damage of the inferior corneal region; and vi. combinations thereof.

[0283] 4.47 Method 4.46, wherein the ocular surface injury is selected from a central corneal region ocular surface injury and an inferior corneal region ocular surface injury.

[0284] 4.48 Ocular surface damage is determined by corneal fluorescein staining (NEI scale), Methods 4.46-4.47.

[0285] 4.49 Any of the preceding methods, wherein the patient has at least one eye with any one or combination of criteria selected from the group consisting of: -total corneal fluorescein staining value in the range of 10 to 15, preferably 10 to 13 (NEI scale); -Central corneal fluorescein staining value in the range of 1 to 3 (NEI scale), preferably 2 to 3 (NEI scale); - A total Lissamine Green conjunctival staining score ranging from 2 to 6, preferably 3 to 5; -Unanesthetized Schirmer test score in the range of 2-8 mm; - Total OSDI score in the range of 25 to 64, preferably 30 to 64.

[0286] 4.50 Any of the preceding methods, wherein the patient is free of blepharitis and / or meibomian gland dysfunction.

[0287] 4.51 Any of the preceding methods, wherein the patient has an unanesthetized Schirmer test score in the range of 3-7 mm, preferably in the range of 4-6 mm, and more preferably about 5 mm.

[0288] 4.52 Any of the preceding methods, wherein the method is effective to reduce a patient's total corneal fluorescein staining score (sum of inferior, superior, central, nasal, and temporal staining scores; NEI scale) by at least 3 grades after 4 weeks of treatment, preferably in at least 50% of treated patients.

[0289] 4.53 Any of the preceding methods, wherein the method is effective to reduce the patient's central corneal fluorescein staining score by at least one grade after 4 weeks of treatment, preferably in at least 50% of the patients receiving the treatment.

[0290] 4.54 Any of the preceding methods, wherein the method is effective to reduce the patient's conjunctival Lissamine Green staining (Oxford Scale) by at least 2 grades after 4 weeks or 12 weeks of treatment, preferably in at least 30% of patients receiving the treatment after 4 weeks of treatment, or preferably in 50% of patients after 12 weeks of treatment.

[0291] 4.55 Any of the preceding methods, wherein the patient has at least one eye with a total corneal fluorescein staining score of at least 11 (NEI scale) or greater.

[0292] 4.56 Any of the preceding methods, wherein the patient has at least one eye with a central corneal fluorescein staining value in the range of 1 to 3 (NEI scale).

[0293] 4.57 Any of the preceding methods, wherein the patient has at least one eye with a total Lissamine Green conjunctival staining score in the range of 2 to 6.

[0294] 4.58 Any of the preceding methods, wherein the patient has at least one eye with an unanesthetized Schirmer test score in the range of 4-6 mm.

[0295] 4.59 Any of the preceding methods in which the central corneal fluorescein staining value is about 3 (NEI scale).

[0296] 4.60 Any of the preceding methods, with a Lissamine green conjunctival staining score in the range of 3-5.

[0297] 4.61 Any of the preceding methods in which the unanesthetized Schirmer test score is approximately 5 mm.

[0298] 4.62 A method for treating and / or ameliorating symptoms associated with keratoconjunctivitis sicca (dry eye), wherein the symptoms are dryness (severity of dryness) and blurred vision, the method comprising administering to an eye of a patient an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane, and wherein the patient has at least one eye with a total corneal fluorescein staining score (NEI scale) of at least 11 or greater.

[0299] 4.63 Preferably, the dry eye symptoms are selected from dryness, stickiness, burning / stinging, foreign body sensation, itching, and the method comprises administering to an eye of a patient an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane, and the patient has at least one eye with a total corneal fluorescein staining score of 11 or greater (NEI scale), and / or method 4.62 and / or a method of treating and / or ameliorating the awareness of dry eye symptoms and frequency of dryness.

[0300] 4.64 Methods 4.62-4.63, in which the patient has at least one eye with central corneal fluorescein staining value in the range of 1-3 (NEI scale).

[0301] 4.65 Methods 4.62 to 4.64, where the patient has at least one eye with a total Lissamine Green conjunctival staining score in the range of 2 to 6.

[0302] 4.66 Patient has at least one eye with an unanesthetized Schirmer test score in the range of 4-6 mm, Methods 4.62-4.65

[0303] 4.67 Central corneal fluorescein staining value is approximately 3 (NEI scale), method 4.64 to 4.66.

[0304] 4.68 Lissamine green conjunctival staining score in the range of 3-5, method 4.65-4.67.

[0305] 4.69 Unanesthetized Schirmer test score is approximately 5 mm, method 4.66 to 4.68.

[0306] 4.70 Patients have a total ocular surface disease index score (OSDI) of 45 or more, method 4.62 to 4.69.

[0307] 4.71 Patients have a total ocular surface disease index score (OSDI) of 55 or greater, methods 4.62 to 4.70.

[0308] 4.72 Patients have the specified values ​​of total corneal fluorescein stain score, central corneal fluorescein stain score, Lissamine green conjunctival stain score, and / or unanesthetized Schirmer test score in both eyes, Methods 4.55 to 4.71.

[0309] In another aspect, the present invention provides a method.

[0310] 5.1 A method for predicting improvement in visual function in a subject suffering from dry eye disease (keratoconjunctivitis sicca) and characterized by a baseline total corneal fluorescein staining score in the range of 10-15 (NEI scale), wherein a reduction in the total corneal fluorescein staining score (NEI scale) of 3 units or more indicates improvement in visual function.

[0311] 5.2 The method of Section 5.1, wherein the improvement in visual function includes an improvement in words read per minute on the International Reading Speed ​​Text (IReST).

[0312] 5.3 The method of claim 5.1 or 5.2, wherein the improvement in visual function includes improvement in blurred vision, reading, driving at night, working on a computer, working with an automated teller machine, reading at low contrast, and reading at low text size.

[0313] 5.4 The method of any of the preceding clauses, wherein the subject is receiving a treatment effective to reduce ocular surface damage.

[0314] 5.5 The method according to paragraph 5.4, wherein the treatment is selected from a) an ophthalmic composition comprising cyclosporine at a concentration of 0.05 to 0.1% (w / v), or b) an ophthalmic composition comprising lifitegrast.

[0315] 5.6 The method of any of the preceding clauses, wherein the treatment is a composition comprising 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutyl-pentane and up to about 1% (w / w) ethanol.

[0316] 5.7 The method of paragraph 5.6, wherein the composition is administered in a dose of one drop having a volume of about 8-12 μL per eye.

[0317] 5.8 The method of paragraph 5.7, wherein the composition is administered as one drop having a volume of about 10-12 μl per eye.

[0318] 5.9 The method of any of paragraphs 5.6-5.8, wherein the composition is administered twice daily to each eye.

[0319] 5.10 Any of the preceding methods, wherein the subject has at least one eye with a total corneal fluorescein staining score of at least 11 (NEI scale) or greater.

[0320] 5.11 Any of the preceding methods, wherein the subject has at least one eye with a central corneal fluorescein staining value in the range of 1 to 3 (NEI scale).

[0321] 5.12 Any of the preceding methods, wherein the subject has at least one eye with a total Lissamine Green conjunctival staining score in the range of 2-6.

[0322] 5.13 Any of the preceding methods, wherein the subject has at least one eye with an unanesthetized Schirmer test score in the range of 4-6 mm.

[0323] 5.14 Any of the preceding methods, wherein the central corneal fluorescein staining value is about 3 (NEI scale).

[0324] 5.15 Any of the preceding methods, with a Lissamine green conjunctival staining score in the range of 3-5.

[0325] 5.16 Any of the preceding methods, wherein the unanesthetized Schirmer test score is about 5 mm.

[0326] 5.17 A method for predicting improvement in visual function in a subject suffering from dry eye disease (keratoconjunctivitis sicca) and characterized by a baseline total corneal fluorescein staining score of at least 11 (NEI scale), wherein a reduction in the corneal fluorescein staining score (NEI scale) of 3 or more units indicates improvement in visual function.

[0327] 5.18 Method 5.17, where the subject has at least one eye with a central corneal fluorescein staining value in the range of 1 to 3 (NEI scale).

[0328] 5.19 Method 5.17 or 5.18, wherein the subject has at least one eye with a total Lissamine Green conjunctival staining score in the range of 2 to 6.

[0329] 5.20 Methods 5.17-5.19, wherein the subject has at least one eye with an unanesthetized Schirmer test score in the range of 4-6 mm.

[0330] 5.21 Methods 5.18 to 5.20, where the central corneal fluorescein staining value is approximately 3 (NEI scale).

[0331] 5.22 Methods 5.19-5.21 with Lissamine green conjunctival staining scores in the range of 3-5.

[0332] 5.23 Methods 5.20 to 5.22, where the unanesthetized Schirmer test score is approximately 5 mm.

[0333] 5.24 Methods 5.17-5.23, wherein the subject has a Total Ocular Surface Disease Index score (OSDI) of 45 or greater.

[0334] 5.25 Methods 5.17-5.24, wherein the subject has a Total Ocular Surface Disease Index score (OSDI) of 55 or greater.

[0335] 5.26 Patient has the specified values ​​of total corneal fluorescein stain score, central corneal fluorescein stain score, Lissamine green conjunctival stain score, and / or unanesthetized Schirmer test score in both eyes, Methods 5.10-5.25.

[0336] In a further aspect, the invention provides an ophthalmic composition for use in a method of increasing tear production in a subject, the composition comprising 0.1% w / v cyclosporine dissolved in 1-(perfluorobutyl)pentane. The method may include topically administering the composition to the subject's eye, e.g., to the surface of the eye (e.g., the corneal and / or conjunctival surface). The composition may be administered in the form of a single drop (i.e., one drop) per dose. Preferably, the drop volume for the administered dose is about 8-10 μL. In one embodiment of this aspect, the composition may be administered twice daily per eye of the subject. The composition according to this aspect may comprise about 0.1% w / v cyclosporine dissolved in 1-(perfluorobutyl)pentane and optionally up to about 1.0% w / w ethanol. In another embodiment according to this aspect, the composition for use in the method of increasing tear production in a subject may be a solution consisting of about 0.1% w / v cyclosporine dissolved in 1-(perfluorobutyl)pentane and about 1.0% w / w ethanol. In yet another embodiment according to this aspect, the composition is a solution of about 0.1% w / v cyclosporine dissolved in 1-(perfluorobutyl)pentane.

[0337] The ophthalmic composition for use according to any one of this aspect and its above-mentioned embodiments can be used in a method for increasing tear production in a subject whose tear production is suppressed or is assumed to be suppressed due to the eye inflammation associated with keratoconjunctivitis sicca.The suppression of tear production in a subject due to the eye inflammation associated with keratoconjunctivitis sicca, etc., can be determined in the subject based on, for example, any one or combination of the methods described herein for assaying the signs and symptoms of dry eye disease, such as Schirmer type I test or corneal fluorescein staining, or patient questionnaires.

[0338] In another aspect, the present invention provides an ophthalmic composition for use in a method of treating xerophthalmia, the composition comprising 0.1% w / v cyclosporine dissolved in 1-(perfluorobutyl)pentane. Preferably, the method of treatment increases tear production in the subject. The method according to this aspect may comprise topically administering the composition to the subject's eye, e.g., to the ocular surface (e.g., the cornea and / or conjunctiva). The composition may be administered in the form of a single drop per dose, and in one embodiment, the amount of drops administered is about 8-10 μL. The composition may be administered twice daily (bid) to each eye of the subject. In one embodiment, the composition according to this aspect may comprise about 0.1% w / v cyclosporine dissolved in 1-(perfluorobutyl)pentane and optionally up to about 1.0% w / w ethanol.

[0339] In another embodiment according to this aspect, the composition for use in the method of treating xerophthalmia is optionally a solution of about 0.1% w / v cyclosporine dissolved in 1-(perfluorobutyl)pentane and about 1.0% w / w ethanol, where the method increases tear production in the subject. In an alternative embodiment according to this aspect, the composition is a solution of 0.1% w / v cyclosporine dissolved in 1-(perfluorobutyl)pentane.

[0340] Damage to the cornea and associated tissues is prevalent in patients with dry eye disease, especially those with moderate to severe or severe dry eye disease. The tear film, which comprises lipid, aqueous and mucin layers, normally provides a protective barrier to the corneal tissue and corneal epithelium and has a moistening function, i.e., prevents drying / dehydration. The tear film acts as a conduit for the removal of potential pathogens, debris and waste products, along with the supply of oxygen and nutrients to the corneal epithelial cells. In patients with dry eye disease, the tear film is usually unstable or disrupted (e.g., as a result of reduced water secretion or increased evaporation of the tear film, or reduced secretion of mucin or lipids), which may result in the corneal tissue, and conjunctiva, becoming less protected, fragile and / or more susceptible to damage and deterioration.

[0341] For example, the severity of ocular surface damage, which may be characterized by punctate destruction of the corneal epithelium or surface destruction of the bulbar conjunctiva, can be assessed by, for example, corneal and conjunctival staining measurements as described herein, i.e., fluorescein staining (NEI scale) and Lissamine green staining (Oxford scale), which highlight and stain dead or damaged cells in the cornea and conjunctiva. In particular, central corneal fluorescein staining (NEI scale), which assays the central corneal region (compared to the peripheral corneal region, including the lower, upper, nasal, and temporal regions of the cornea), reflects ocular surface damage that affects visual dysfunction.

[0342] As used herein, the terms "corneal staining" or "total corneal staining" refer to staining observed in all areas of the cornea, i.e., the sum of the inferior, superior, central, temporal, and nasal areas of the cornea, optionally in conjunction with reference to fluorescein or a dye suitable or adapted for staining the cornea. A term such as "central corneal staining" (i.e., beginning with a particular corneal region) specifically refers to staining observed only in a particular anatomical region, optionally in conjunction with a dye used for staining, such as fluorescein.

[0343] As used herein, the term "conjunctival staining" or "total conjunctival staining", optionally with reference to fluorescein or a dye suitable or adapted for staining the cornea, refers to the staining observed in total for all areas of the conjunctiva, i.e., the temporal and nasal areas of the conjunctiva. When the term is used to designate a particular conjunctival area (e.g., nasal conjunctival staining), it is understood to refer specifically to the staining observed in that area, optionally with reference to the dye used for staining, such as Lissamine Green.

[0344] In one embodiment, the ophthalmic composition for any one of the uses according to the present invention may be used to treat and reduce the symptoms of dry eye disease, in particular to treat or reduce ocular surface damage, such as corneal and / or conjunctival damage, in a subject suffering from dry eye. In one embodiment, the subject being treated may have corneal ocular surface damage and may have a total corneal fluorescein staining score of at least 10 (≧10), which is the sum of the scores obtained for the inferior, superior, central, nasal, and temporal regions of the cornea based on the NEI grading scale of 0 to 3. In another embodiment, the subject may have a total corneal fluorescein staining score of at least 11 or more before the start of treatment, and optionally the subject has a total OSDI score of 45 or more, or 55 or more.

[0345] In another embodiment, the ophthalmic composition for any one of the uses according to the present invention may be used to reduce ocular surface damage, such as corneal and / or conjunctival damage, in a subject suffering from dry eye disease. In one embodiment, the subject may have a central corneal fluorescein staining score of at least 2 or more (≧2) based on the NEI grading scale of 0 to 3. In another embodiment, the subject may further have a total Lissamine green conjunctival staining score (temporal and nasal regions combined) of at least 2 or more (i.e., ≧2) based on the Oxford scale.

[0346] In one embodiment, the present invention relates to an ophthalmic composition for use in treating, i.e., reducing, ocular surface damage in a subject suffering from dry eye disease, the subject having a total OSDI score of 45 or greater, the composition comprising about 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane and optionally up to about 1.0% (w / w) ethanol, the composition being administered topically, one drop per eye, twice daily, in a drop volume of about 8-10 μL. In another particular embodiment, such use may be, for example, for treating, reducing ocular surface damage, particularly in the central corneal region and / or the subcorneal region.

[0347] In a further embodiment, the ophthalmic composition may be used for the effective treatment of patients with dry eye disease accompanied by signs of corneal ocular surface damage (e.g., a corneal staining score (NEI scale) of at least 11) where the composition is administered twice daily. The composition may be administered topically as one drop per dose per eye, the drop having a volume of about 10 μL.

[0348] In another embodiment, the present disclosure relates to an ophthalmic composition comprising 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a) a method of treating and / or ameliorating symptoms associated with keratoconjunctivitis sicca (dry eye disease), wherein the symptoms are dryness and blurred vision, and / or b) a method of treating and / or ameliorating the perception of the frequency of dryness and symptoms of dry eye disease.

[0349] Optionally, the method of treatment according to this embodiment comprises topically administering one drop of the composition per eye twice daily, further optionally in a drop volume of about 8-10 μL.In yet another embodiment, the composition may consist of 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane and optionally up to 1.0% (w / w) ethanol.

[0350] As used herein, the term "severity of dryness" may be used interchangeably with the term "ocular" "dryness," which refers to the symptomatic ocular dryness that may be experienced by patients with keratoconjunctivitis sicca (dry eye disease).

[0351] The composition for use defined above has been found to be surprisingly effective in treating, i.e., to reduce the severity of dry eye symptoms, particularly selected from dryness and blurred vision.As mentioned above, dryness refers to the feeling of dryness in the eyes, and is the first question in the VAS questionnaire, as described below.Blurred vision may refer to some degree of visual impairment, for example, objects / letters may appear unclear or unclear or partially unclear to subjects with blurred vision.These symptoms may contribute to overall visual impairment or difficulty, and may adversely affect the visual function and performance of subjects in functional tasks where visual acuity may be essential.Therefore, the positive, especially early impact in terms of relieving and alleviating these symptoms of subjects may be particularly beneficial in terms of improving the quality of vision and providing relief, especially in subjects who frequently experience very high levels of discomfort from these symptoms.

[0352] In addition to reducing the severity of dryness and blurred vision, the compositions according to the present invention have also been found to be effective in reducing the frequency of the overall degree of dryness.Reducing the frequency with which a subject experiences dry eye and / or reducing the subject's overall awareness of dry eye symptoms is also beneficial in terms of improving overall vision quality, allowing a subject to perform activities that may previously have been severely restricted due to frequent irritation or distraction from the constant awareness or occurrence of dry eye symptoms.

[0353] Improvement in these symptoms can be determined based on and by administration of a visual analog scale (VAS) dry eye test, in which the patient is rated for discomfort on a 0-100% level scale as well as the percentage of time the ocular symptom is noticed or experienced (i.e., frequent) on a 0-100% scale during a course of treatment.

[0354] In one embodiment, the composition for any of the uses of the present invention is effective in improving the severity and / or frequency of dryness (e.g., dry eyes) experienced by the patient or subject as described herein by reducing by at least 25%. In another embodiment, the composition is effective in reducing the severity and frequency of dryness by at least 25% within 2 weeks of starting treatment. In another embodiment, the composition is effective in reducing the severity and frequency of dryness by at least 25% within 2 weeks of starting treatment in at least 25% of the subjects receiving the treatment. In a further embodiment, the treatment is effective in reducing the severity and / or frequency of dryness by at least 25% from the start, i.e., within 4 weeks of starting treatment, in at least 30% of the subjects receiving the treatment. The reduction can be determined by comparing the VAS score of each or combination of the above symptoms with the initial baseline score obtained before treatment.

[0355] In a further embodiment, a method of treating keratoconjunctivitis sicca (dry eye disease) may comprise topical administration of a composition according to the invention to one or both eyes of a patient and treating or ameliorating the frequency of dryness and / or perception of symptoms associated with dry eye (e.g., symptoms selected from dryness, stickiness, burning / stinging, foreign body sensation, itching, blurred vision, sensitivity to light, and pain), wherein the treatment generally comprises an effective reduction of at least 25% in the frequency of dryness or perception of dry eye symptoms within 2 weeks or within 4 weeks of initiating treatment.

[0356] Optionally, the ophthalmic compositions and dosages thereof described herein can be used to treat patients or subjects who are unresponsive or inadequately responsive to treatment with aqueous artificial tears.

[0357] Artificial tears, also known as lubricating eye drops or tear substitutes, are used to relieve and treat the symptoms of dry eye disease and are usually available over the counter (OTC). These are usually aqueous compositions in solution form, but also in the form of gels or ointments that function by adding moisture to the eye, and usually may contain lubricants (e.g., liquid polyols such as hydroxypropylmethylcellulose (HPMC), carbomethylcellulose (CMC), polyvinyl alcohol, propylene glycol, polyethylene glycol, etc.) and may also contain additives that promote healing (e.g., hypromellose acid) or that mimic the electrolyte composition of the natural tear film, or that promote the retention of the composition of the ocular surface (e.g., gelling agents such as carbomer).

[0358] In one embodiment, the ophthalmic composition for any one use according to the present invention may be used to treat a patient in which symptoms of dry eye disease and associated conditions persist after a period of treatment with aqueous artificial tears alone of at least 2 weeks, or at least 1 month, or at least about 6 months.

[0359] The dose of the composition for any one of the uses according to the present invention and described in any of the embodiments herein is topically administered to the eye of the subject in the form of a single drop (i.e., one drop).The drop can be administered to the surface of the eye, preferably any surface area or tissue of the eye that is accessible to topical administration or injection, such as the cornea or conjunctiva.A drop of the composition can be instilled directly on the surface of the eye, such as the corneal surface of the eye, or in the space, i.e., the pouch or pocket, that is formed by gently pulling down the lower eyelid of the eye.

[0360] As used herein, the term "ocular administration" or "per eye" refers to administration of a given dose, e.g., a single dose, of an ophthalmic composition according to the present invention to an individual eye of a subject. However, the treatment of dry eye disease and dry eye disease-related conditions described herein is not limited to the treatment of one eye in a subject, but should be understood to also include treatments that include administration of a composition according to the present invention to each, i.e., both eyes of a subject affected by a dry eye condition.

[0361] In one embodiment of the present invention, the ophthalmic composition for any of the uses described herein is administered at a dose of one drop per eye, twice a day.Therefore, a patient who is receiving treatment for both eyes according to such a dosing regimen will receive a total of two drops for each eye on each day of a given treatment period.

[0362] When the ophthalmic composition is administered to each eye one or more times per day, for example, twice per day per eye, in further embodiments, the time interval between topical administration of the composition to the eye or ocular surface of the first and second doses can be at least 4 hours, or at least 6 hours, or at least 12 hours.

[0363] In further embodiments, the ophthalmic composition for any use of the invention is administered for a treatment period of at least one month (4 weeks), or even at least three months (12 weeks). In another embodiment, the ophthalmic composition for any use of the invention may be administered continuously for as long as symptoms and indicators of dry eye disease persist.

[0364] In other embodiments, the ophthalmic composition for any one use according to the present invention may contain up to about 1.0% (w / w) ethanol.

[0365] As used herein, the term "up to about" or "up to" used in the context of a parameter, such as in relation to the amount of ethanol in the compositions of the present invention, refers to any value of the parameter greater than zero and up to, including, the defined parameter. For example, an amount of "up to about 1.0% (w / w) ethanol" should be understood to include any value greater than zero, 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, in the range up to the value of 1.0% (w / w), taking into account any degree of variation normally observed in measuring or determining this parameter using standard techniques and equipment known in the relevant field.

[0366] In one embodiment of the present invention, the compositions for therapeutic use described herein may consist essentially of about 0.1% (w / v) cyclosporine in ethanol dissolved in 1-(perfluorobutyl)pentane and optionally about 1.0% (w / w) ethanol.

[0367] In another embodiment, the compositions described herein are essentially free of ethanol, and the composition consists essentially of cyclosporine dissolved in 1-(perfluorobutyl)pentane in an amount described in any of the embodiments described herein.

[0368] The absence of an organic co-solvent such as ethanol may provide an advantage of a simpler two-component formulation compared to a three-component formulation that further includes a co-solvent such as ethanol. The inclusion of even one additional composition component may add complexity with respect to factors such as cost, manufacturing, handling, packaging, and even patient compliance.

[0369] In a preferred embodiment of the invention, the composition for any of the uses described herein may preferably comprise or consist of: about 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane and about 0.5% (w / w) ethanol, or about 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane and about 1.0% (w / w) ethanol, or Approximately 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane.

[0370] The composition for any use of the invention is preferably provided as a clear solution in which cyclosporine is completely dissolved in a solution of 1-(perfluorobutyl)pentane (at room temperature, i.e., 15-25° C.). When ethanol is included, the composition is also provided as a clear solution of cyclosporine in a solution of 1-(perfluorobutyl)pentane and ethanol. In one embodiment, the composition is provided in a sterile form.

[0371] In another embodiment, the ophthalmic composition for any one of the uses according to the present invention is substantially free of water and / or substantially free of preservatives. As understood herein, the term "substantially free" or "essentially free" with respect to a component of a composition refers to the presence of no more than trace amounts of that component, where the component provides no technical contribution to the composition when present in trace amounts.

[0372] Preferably, the ophthalmic composition for any one of the uses according to the present invention is substantially free of water, substantially free of preservatives, and effective to inhibit microbial growth.

[0373] In another embodiment, the ophthalmic composition for any one of the uses according to the present invention is characterized by a remarkable wetting and spreading behavior that allows it to spread quickly and effectively on an ocular surface, such as the corneal and / or conjunctival surface, such that a drop (drop) of the ophthalmic composition for any one of the uses according to the present invention when administered to the ocular surface results in a rapid spreading of the composition to the corneal and / or conjunctival surface.

[0374] Preferably, the ophthalmic composition for any one of the uses according to the invention forms small droplets (drops) in the range of about 8-10 μl, for example about 10 μL, when administered from a drop dispenser.

[0375] In another preferred embodiment, the ophthalmic composition for any one of the uses according to the invention features about 10 μg of cyclosporine administered in a single dose per eye, or an equivalently smaller amount of cyclosporine administered in a single dose per eye, such as about 8-10 μg of cyclosporine administered in a single dose per eye.

[0376] As used herein, the term "consists" and related terms "consisting" or "consist" should be understood to mean that there are no other features other than those preceded by the term. In the context of the ophthalmic compositions described herein, if other ingredients or components are present in the composition other than those preceded by such terms, it is present only in minor or residual amounts that do not provide technical advantage or relevance for purposes of the present invention, and may be further understood, for example, by the terms "essentially" or "substantially" used in conjunction with these terms (e.g., "essentially consisting of").

[0377] Also provided in the context of the present invention is the use of an ophthalmic composition according to any one of the above embodiments in the manufacture or preparation of a medicament or medicament for the treatment of a subject in need thereof in connection with any one of the preferred dry eye disease conditions described herein. Also provided in the context of the present invention is a method of treating a subject diagnosed with and / or suffering from said dry eye disease conditions described herein, which may comprise local administration, such as by local injection directly into the eye, of any one of the defined compositions, preferably at any one of the doses or amounts described, and / or for any one of the time periods defined for the treatment method.

[0378] Moreover, for therapeutic use, the subject treatment methods and compositions are preferably targeted to human subjects or patients diagnosed with and / or suffering from dry eye disease.

[0379] In yet another aspect, the present invention also provides a kit comprising an ophthalmic composition for any one of the uses according to the present invention and any of the above embodiments. In one embodiment, the kit comprises a container for holding the ophthalmic composition and a drop dispenser adapted to administer the composition in a volume of about 8-10 μL, or about 10 μl per drop. The kit may also further comprise instructions for use, e.g., in the form of a leaflet, packaging, or other readable means, indicating use according to any one of the uses or methods described herein.

[0380] As understood herein, a drop dispenser can be a dispenser or applicator means that can be attached, secured, or connected to a container for holding an ophthalmic composition. Preferably, the drop dispenser is adapted to dispense a single dose in the form of a single droplet of the composition. More preferably, the drop dispenser is adapted to dispense a single dose of about 8-10 μl volume, or is adapted to dispense a single dose of about 10 μl volume.

[0381] Containers for holding ophthalmic compositions as understood herein are preferably of a capacity capable of holding a single dose, but more preferably are of a capacity capable of holding multiple or plurality doses of the composition.

[0382] The following examples serve to illustrate the invention, but they should not be understood as limiting its scope. EXAMPLES

[0383] Example 1 Study setup A Phase 2b / 3, multicenter, randomized, double-blind (vehicle) controlled clinical trial to evaluate the efficacy and safety of topical CyclASol® for the treatment of signs and symptoms of dry eye disease. The study is listed on clinicaltrials.gov under number NCT03292809.

[0384] Subjects eligible for randomization received one of the following treatments, administered bilaterally BID for approximately 85 days (Visit 1 to Visit 5): 1) CyclASol 0.1% eye drops (cyclosporine A 0.1% solution) 2) Vehicle eye drops (F4H5)

[0385] CyclASol 0.1% eye drop is a clear eye drop solution of cyclosporine A dissolved in 1-(perfluorobutyl)pentane. 1-(perfluorobutyl)pentane, commonly abbreviated as F4H5, is used as the vehicle. The only other ingredient in the formulation is ethanol 1.0% (w / w) as a cosolvent. The dosage, or volume of one drop, of CyclASol is approximately 8-10 μL.

[0386] A 14-day pre-study observation period was used for subject selection prior to randomization, during which all subjects received Systane® Balance to be administered bilaterally BID.

[0387] The study included six visits over a period of approximately 14 weeks. Visit 0, day −14 ± 2 days, screening; Visit 1, Day 1, Baseline / Randomization; visit 2, day 15 ± 1 day, and 2-week follow-up; visit 3, day 29 ± 2 days, and 4-week follow-up; Visit 4, day 57 ± 2 days, and 8-week follow-up; and Visit 5, day 85 ± 2 days, 12-week follow-up and end of study.

[0388] Study population Patients included in the study had to meet the following criteria: (a) you are 18 years of age or older; (b) provide written informed consent; (c) have subjects report a history of dry eye disease in both eyes for at least 180 days prior to Visit 0; (d) currently using over-the-counter (OTC) eye drops and / or artificial tears for dry eye symptoms at visit 0 (within 30 days of visit 0); (e) a total OSDI® score of ≥20 at Visit 0 and Visit 1; (f) a total corneal fluorescein staining score of 10 or more (i.e., the sum of the inferior, superior, central, nasal, and temporal regions) according to the NEI scale at visit 0 and visit 1; (g) A total Lissamine Green Oxford Scale conjunctival score (temporal and nasal areas combined) of 2 or greater at Visit 0 and Visit 1. (h) have an unanesthetized Schirmer test score between 1 mm and 10 mm, including visit 0 and visit 1; (i) At least one eye, which is the same eye, meets inclusion criteria f, g, and h; and (j) be able and willing to participate in all study evaluations and visits as directed.

[0389] Each subject must not have the following: a. At Visit 0, have clinically significant slit-lamp findings that require defined medical treatment and / or that, in the investigator's opinion, may interfere with study parameters, including trauma, Stevens-Johnson syndrome, and advanced epithelial basement membrane disease; b. Have active blepharitis, meibomian gland dysfunction (MGD), or eyelid margin inflammation requiring treatment with topical or systemic antibiotics, or topical steroids, or other prescribed medical procedures or hypochlorous acid wipes within the past 30 days prior to Visit 0, or will require such treatment during the study. Other treatments, such as lid scrubs, lid wipes, and warm compresses, must have been stable within the past 30 days prior to Visit 0, and the subject must be willing to continue those treatments throughout the study; c. Have abnormal eyelid anatomy (e.g., incomplete eyelid closure, entropion, or ectropion) or abnormal blinking; d. Dry eye disease secondary to scarring due to, for example, irradiation, alkali burns, cicatricial pemphigoid, or conjunctival goblet cell destruction (i.e., destruction of conjunctival goblet cells due to vitamin A deficiency); e. Ocular or periocular malignancy; f. Corneal epithelial defects or >50% confluent corneal staining in 2 or more of 5 corneal areas; g. History of herpetic keratitis; h. Active ocular allergy or ocular allergy that may become active during the study period; i. Diagnosed with an ongoing eye or systemic infection (bacterial, viral, or fungal) including fever or being treated with antibiotics at Visit 0 or Visit 1; j. wore contact lenses within 90 days prior to Visit 0 or planned to wear contact lenses during the study; k. Use of eye drops, gels, or scrubs within 2 hours prior to Visit 0 or Visit 1; l. Use of topical cyclosporine A (CsA) or lifitegrast within 60 days prior to visit 0; m. Participation in a previous CyclASol study (patients assigned to the Restasis treatment group were eligible to participate in the study); n. Having undergone intraocular or ocular laser surgery within 180 days prior to visit 0 or scheduled eye or eyelid surgery during the study period; o. Are pregnant, breastfeeding, or planning to become pregnant; p. Unwillingness to submit a urine pregnancy test at Visit 0 and Visit 5 (or early discontinuation visit) if of childbearing potential. Not of childbearing potential is defined as a woman who has undergone permanent sterilization (i.e., has undergone hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is postmenopausal (i.e., has not had menses for 12 consecutive months); q. Be a woman of childbearing potential who is not using an acceptable method of contraception. Acceptable methods of contraception include hormonal contraception (oral contraceptives, implantable contraceptives, injectable contraceptives, or transdermal contraceptives), contraceptive devices (i.e., spermicides combined with a barrier such as a diaphragm or condom), intrauterine devices (IUDs), or partner sterilization. For women who are not sexually active, abstinence may be considered an appropriate method of contraception, but if the subject becomes sexually active during the study, the subject must agree to use appropriate contraception as defined above for the remainder of the study; r. Having uncontrolled systemic disease; s. Known allergy or sensitivity to the investigational product or its components: cyclosporine A (CsA) or semifluorinated alkanes (SFAs); t. Having active ocular or periocular rosacea or pterygium; u. Currently enrolled in an investigational drug or device study or using an investigational drug or device within 60 days prior to Visit 0; v. Use of topical antiglaucoma medication within 90 days prior to visit 0; w. Use of topical ocular or facial steroids, or serum tears, or oral doxycycline, or oral tetracycline within 30 days prior to visit 0; x. Use of systemic steroids (including dermatological steroids with high potency or broad therapeutic window) or immunomodulators in a non-stable regimen within 90 days prior to Visit 0, or expected use in a non-stable regimen during the study period; y. Have used oral medications known to cause dry eyes (e.g., antihistamines or antidepressants) in an unstable regimen within 30 days prior to Visit 0 or anticipate unstable use of oral dry eye medications during the study; z. Have corrected visual acuity of logMAR+0.7 or better as assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale in either eye at Visit 0 or Visit 1; aa.There is a condition or circumstance that the investigator feels may place the subject at significant risk, confound the study results, or seriously interfere with the subject's participation in the study (e.g., language barrier); bb. Received or had a punctal plug removed within 90 days prior to Visit 0, or is anticipated to have a punctal plug implanted or removed during the study.

[0390] The complete analysis set of patients was 162 in the CyclAsol 0.1% treatment group and 166 in the vehicle treatment group, respectively.

[0391] At baseline, the CyclAsol 01.% patient group had the following characteristics: mean total corneal fluorescein staining NEI scale (SD) 11.5 (1.26); mean central corneal fluorescein staining NEI scale (SD) 2 (0.51); mean conjunctival staining (1.70) 4.1; mean total OSDI (SD) 46.9 (16.73); VAS dryness (SD) 68.5 (21.6); mean Schirmer test score 5.2 (2.83).

[0392] At baseline, patients in the vehicle group had the following characteristics: mean total corneal fluorescein staining NEI scale (SD) 11.5 (1.25); mean central corneal fluorescein staining NEI scale (SD) 2 (0.52); mean conjunctival staining 4.3 (1.66); mean total OSDI (SD) 47.1 (16.41); VAS dryness (SD) 69.9 (20.5); mean Schirmer test score 5.1 (2.64).

[0393] Instructions for use Subjects were instructed to apply one drop of treatment 1) or 2) to each lower eyelid twice daily (morning and evening before bedtime).

[0394] Evaluation criteria At each visit during the treatment period, each subject was evaluated for treatment efficacy using tests including subject symptom assessment questionnaires such as the Ocular Surface Disease Index questionnaire (OSDI, see Schiffman RMet al 2000;118:615-621) and visual analog scale (VAS), along with corneal fluorescein staining (NEI grading); conjunctival staining (Lissamine, Oxford grading).

[0395] The following efficacy measures were obtained during the study:

[0396] Primary efficacy measure The following primary endpoints were tested in sequence using hierarchical fixed-sequence testing: 1. Change from baseline in total corneal fluorescein staining (NEI scale) on day 29. 2. Change from baseline in Ocular Surface Disease Index (OSDI) at Day 29.

[0397] Key secondary efficacy measures: - Total corneal fluorescein staining (NEI scale) and change from baseline to each post-baseline visit (except day 29) measured - Ocular Surface Disease Index (OSDI) and change from baseline to each post-baseline visit measured (excluding Day 29) - Primary / worst symptom rating Reading disability scores and changes from baseline to each post-baseline visit - Unanesthetized Schirmer test and change from baseline to each post-baseline visit measured - Central and inferior corneal staining (NEI scale) and change from baseline to each post-baseline visit measured

[0398] Secondary Efficacy Measures: Reading assessment and change measured from baseline to each post-baseline visit - Corneal fluorescein staining of other small areas (NEI scale) and change from baseline to each post-baseline visit measured - Ocular Surface Disease Index (OSDI) subtotal score and change from baseline to each post-baseline visit measured Conjunctival Lissamine Green staining by area and total (Oxford scale) and change from baseline to each post-baseline visit measured - Tear film break-up time (TFBUT) and change from baseline to each post-baseline visit - Change from baseline to each post-baseline visit on visual analog scale (VAS) and perception of symptoms of dryness, burning / stinging, stickiness, foreign body sensation, itching, blurred vision, sensitivity to light, pain, and dry eye, and perception of frequency of dryness - InflammaDry® Study (MMP-9) and change from baseline to each post-baseline visit measured - Symptoms recorded in the subject's diary up to each post-baseline visit measured

[0399] Corneal staining For corneal staining (Sook Chun Y et al., Am J Ophthalmol. 2014 May;157(5):1097-102), 5 μl of a preservative-free 2% solution of sodium fluorescein was instilled into the conjunctival sac of the inferior conjunctiva of each eye. To achieve maximum fluorescence, fluorescein staining is assessed only approximately 3-5 minutes after instillation. A Wratten #12 yellow filter was used to enhance the ability to grade fluorescein staining.

[0400] Staining was graded with the NEI grading scale (National Eye Institute grading system) with only the cornea graded. Corneal fluorescein staining scores were obtained for each of the inferior, superior, central, temporal, and nasal regions of the cornea based on a scale of 0 to 3, with a score of 0 meaning that no staining was observed. The term "total corneal fluorescein staining score" refers to the sum of the scores from the inferior, superior, central, temporal, and nasal regions of the cornea.

[0401] Conjunctival Lissamine Green Staining Conjunctival Lissamine Green staining (Bron AJ et al, Cornea. 2003;22:640-650) was performed by dropping 10 μl of Lissamine Green solution into the conjunctival sac of the subject's lower conjunctiva. After waiting approximately 30 seconds, staining was assessed. Subjects were instructed to blink several times to disperse the Lissamine Green. Staining was graded with the Oxford grading scale. Here, Lissamine staining is represented by dashed dots on a series of panels (A-E). Staining ranges from 0-5 in each panel and 0-10 across the exposed interpalpebral conjunctiva. Both nasal and temporal regions were graded separately. A score of 0 means no staining. A total conjunctival Lissamine Green staining score was obtained by referring to the sum of the scores from both the temporal and nasal regions of the conjunctiva.

[0402] Ocular Surface Disease Index (OSDI) The Ocular Surface Disease Index (OSDI) (see Schiffman RM, et al., Arch Ophthalmol. 2000;118:615-621) is a survey tool used to assess symptoms of ocular irritation in dry eye disease and how they affect vision and related functions. It is a 12-item questionnaire that assesses the patient's dry eye symptoms over the past week and their impact on vision-related functions. The questionnaire has three subscales: ocular symptoms, vision-related functions, and environmental triggers. Patients rate their response on a scale of 0 to 4, with 0 corresponding to "never" and 4 corresponding to "always." A final score ranging from 0 to 100 is calculated.

[0403] The questions assess the dry eye symptoms experienced by the patient within the past week, including sensitivity to light, grittiness, eye pain or stinging, blurred vision, and reduced visual acuity; vision-related features in terms of problems with reading, driving at night, working on a computer or bank cash machine, watching television, as well as in terms of environmental factors or triggers (i.e., discomfort in windy conditions, low humidity, and air-conditioned places). Alongside all questions, a subtotal is obtained for the total number of questions answered. The OSDI index is assessed based on a scale of 0 to 100, with higher scores representing greater impairment. The OSDI index is calculated for the total number of questions answered by multiplying the sum of the scores by a factor of 25.

[0404] Visual Analogue Scale (VAS) Subjects were asked to rate their ocular symptoms due to dry eyes (both eyes simultaneously) in a 10-item questionnaire, and to indicate their level of discomfort by placing a vertical mark on a horizontal line starting with a value of 0% corresponding to no discomfort and ending with a value of 100% corresponding to maximum discomfort. Subjects were asked about each of the following: dryness (corresponding to the first question on the VAS questionnaire, also referred to as severity of dryness in the text and graphs), stickiness (question 2), burning / stinging (question 3), foreign body sensation (question 4), itching (question 5), blurred vision (question 6), sensitivity to light (question 7), and pain (question 8). Subjects were also asked about their perception of dry eye symptoms (question 9) and frequency of dryness (question 10) in terms of percentage of time. In these two questions, a value of 0% corresponds to "never" and a value of 100% corresponds to "always." The scale rating line is 100mm (10cm) in length and is graded every 10mm (recommended 10%, 20% etc.).

[0405] To determine the effectiveness of treatment, values ​​presented by patients at each visit can be compared to baseline values ​​at Visit 1 on Day 1.

[0406] Schirmer test I (without anesthesia) Schirmer Test Method I is performed as follows: Do not blot prior to testing. Using a sterile Tear Flo Schirmer test strip, bend the strip to fit the notch in the strip. Instruct the subject to look up. Place the Schirmer strip on the lower lid margin of each eye so that the strip fits snugly. Instruct the subject to close their eyes. After 5 minutes have elapsed, the Schirmer strip is removed. The length of the wetted area (mm) is recorded for each eye.

[0407] Tear film breakup time (TFBUT) The examiner instilled 5 μL of a 2% preservative-free solution of sodium fluorescein into the conjunctival sac of the lower conjunctiva of each eye. Subjects were instructed to blink several times to thoroughly mix the fluorescein with the tear film. To achieve maximum fluorescence, the examiner should wait approximately 30 seconds after instillation before assessing the TFBUT.

[0408] With the aid of a slit lamp, the examiner monitored the integrity of the tear film and recorded the time it took for the micelles to form from the time the eye was opened. The TFBUT was measured in seconds using a stopwatch and a digital image recording system for the right eye, followed by the left eye. A Wratten #12 yellow filter was used to enhance the ability to grade the TFBUT.

[0409] For each eye, two measurements were taken and averaged, unless the two measurements were more than 2 seconds apart and less than 10 seconds apart (in which case a third measurement was taken and the closest two of the three were averaged). All values ​​were recorded in the source document.

[0410] Research results Treatment with CyclAsol in patients with dry eye disease was observed to be particularly effective in those with a total OSDI score of 45 or greater (≥45) obtained at the first visit (Figure 1). Significant changes from baseline in total OSDI were observed during treatment. Notably, compared to vehicle, CyclAsol also had a significant effect in the patient group with a total OSDI of 55 or greater at baseline (Figure 2).

[0411] It was also observed that, compared with the study patient population, the mean change from baseline in total OSDI over the course of 12 weeks of treatment with Cyclasol was generally significant in patients with an OSDI of 45 or greater or 55 or greater.

[0412] We also found that compared to vehicle, the overall awareness and frequency of dry eye disease symptoms, assessed using a visual analog scale (VAS) test of dry eye symptoms, was already significantly reduced after just 4 weeks of treatment with CyclASol compared to baseline visit scores (Figure 3).

[0413] Regarding the severity of dryness, corresponding to the question related to the symptom "dryness" in the VAS questionnaire, it was also observed that the mean change from baseline was already significant at the 4th week of treatment in terms of the reduction in the level of dryness severity. The baseline values ​​of the VAS severity of dryness were 68.5 and 69.9 for CyclAsol 0.1% and vehicle, respectively.

[0414] Similarly, a reduction in the severity of blurred vision, as assessed as part of the VAS (visual analog scale) test, was observed. At the primary endpoint visit, a statistically significant (p=0.02-0.03) improvement in symptoms was demonstrated for the symptoms shown in Figure 3.

[0415] It was also found that the proportion of patients in the study who had at least a 25% or greater improvement (compared to baseline visit values) in terms of the reduction in severity of dryness as determined by VAS testing was higher with CyclASol at all visits compared to vehicle. The proportion of patients with a 25% or greater response rate from treatment with CyclASol in terms of the reduction in severity of dryness was already about 26% at the second week of treatment. It was observed that at 4, 8, and 12 weeks, the proportion of patients with a 25% or greater response rate, i.e., an improvement of 25% or greater, in terms of the reduction in severity of dryness was 33%, 37%, and 39%, respectively. Similarly, it was observed that the responder rate for the reduction in the frequency of dryness experienced by patients was also higher with CyclASol treatment compared to vehicle in terms of patients with a 25% or greater improvement (compared to baseline visit values) as determined by VAS testing. The proportion of patients with a 25% or greater response rate from treatment with CyclASol in terms of the reduction in frequency of dryness was already about 24% at the second week of treatment. The percentage of patients with a response rate of 25% or greater for reduction in frequency of dryness at 4, 8, and 12 weeks was observed to be 34%, 42%, and 37%, respectively.

[0416] As shown in Figures 5 and 6, the primary endpoint of the study at 4 weeks demonstrated high statistical and clinical significance. Onset of effect on total corneal fluorescein staining was as early as 2 weeks and sustained throughout the study period (Figure 5). Mean baseline values ​​of tCFS for CyclAsol 0.1% and vehicle were 11.5 in both groups. As shown in Figure 6, more than 50% of all patients responded to CyclAsol 0.1% with an improvement of ≥3 grades in total corneal fluorescein staining after 4 weeks of treatment.

[0417] The area of ​​the cornea that benefited most from CyclAsol 0.1% treatment was the central area, the area most critical to visual function. As shown in Figure 7, after 4 weeks of treatment, 58.6% of CyclAsol 0.1%-treated subjects had an improvement in central corneal fluorescein staining of ≥1 grade.

[0418] A high responder rate was also obtained in the conjunctiva. Figure 8 shows that after 12 weeks of treatment, 50.3% of CyclAsol 0.1%-treated patients had at least a 2-grade improvement in conjunctival Lissamine Green staining score, a sign related to ocular health. Figure 9 shows the change from baseline in conjunctival Lissamine Green staining in the two patient populations. The baseline values ​​for the CyclAsol 0.1% and vehicle groups are 4.1 and 4.3, respectively.

Claims

1. 1. An ophthalmic composition for use in a method for increasing tear production in a subject, the ophthalmic composition comprising 0.1% (w / v) cyclosporine and up to 1.0% (w / w) ethanol dissolved in 1-(perfluorobutyl)pentane, the method comprising topically administering the composition to the patient's eyes twice daily as one drop having a volume of about 8-10 μl per eye.

2. 1. An ophthalmic composition for use in a method for treating xerophthalmia in a subject, said ophthalmic composition comprising 0.1% (w / v) cyclosporine and up to 1.0% (w / w) ethanol dissolved in 1-(perfluorobutyl)pentane, said method comprising the step of topically administering said composition to the patient's eyes twice daily as one drop having a volume of about 8-10 μl per eye.

3. 1. An ophthalmic composition for use in a method for treating ocular surface damage in a subject suffering from dry eye disease (keratoconjunctivitis sicca), said ophthalmic composition comprising 0.1% (w / v) cyclosporine and up to 1.0% (w / w) ethanol dissolved in 1-(perfluorobutyl)pentane, said method comprising topically administering said composition to the patient's eyes twice daily as one drop having a volume of about 8-10 μl per eye, wherein said subject has a Total Ocular Surface Disease Index (OSDI) score of 45 or greater.

4. The ophthalmic composition of claim 1 , wherein the suppression of tear production in the subject is caused by ocular inflammation associated with keratoconjunctivitis sicca.

5. The ophthalmic composition of claim 2 , wherein the method for treating dry eye increases tear production in the subject.

6. The ophthalmic composition of any one of claims 1 to 5, wherein the composition is administered topically to the ocular surface.

7. 7. The ophthalmic composition of any one of claims 1 to 6, wherein the composition consists of 0.1% (w / v) cyclosporine, 1-(perfluorobutyl)pentane, and about 1.0% (w / w) ethanol.

8. The ophthalmic composition of claims 1 to 6, wherein the composition consists of 0.1% (w / v) cyclosporine dissolved in 1-(perfluorobutyl)pentane.

9. The ophthalmic composition of any one of claims 1 to 8, wherein the subject is unresponsive or responds poorly to treatment with topical aqueous artificial tears.

10. 10. The ophthalmic composition of any one of claims 1 to 9, wherein the cyclosporine administered in a single dose per eye is about 8 to 10 μg.

11. The composition of claim 3 , wherein the treatment is for reducing ocular surface damage to the central corneal region and / or the inferior corneal region.

12. 4. The composition of claim 3, wherein the composition is administered in one drop having a volume of 10 μl per dose and per eye.

13. The patient, i. Central corneal fluorescein staining (NEI scale) score ≥ 2; ii. Lower corneal fluorescein staining (NEI scale) score ≥ 2; iii. Total corneal fluorescein staining (NEI scale) score ≥ 11 The composition of claim 3, wherein the patient has at least one or both eyes with any one or combination of:

14. The patient, total corneal fluorescein staining values ​​ranging from −10 to 15 (NEI scale); central corneal fluorescein staining values ​​ranging from −2 to 3 (NEI scale); Total Lissamine Green conjunctival staining score ranging from −3 to 5; - unanesthetized Schirmer test scores ranging from 2 to 8 mm; The composition of claim 12, wherein the patient has at least one eye with any one or combination of criteria selected from the group consisting of:

15. The composition of claim 3, wherein the patient has an unanesthetized Schirmer test score in at least one eye in the range of 3 to 7 mm.

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