阅读说明：本技术 用于治疗眼表损伤和干燥症状的眼用组合物 (Ophthalmic compositions for treating ocular surface damage and dryness ) 是由 M·贝尔 D·维伦 S·克罗斯 T·施吕特 于 2019-09-20 设计创作，主要内容包括：本公开文本提供了使用包含1-全氟己基辛烷的眼用组合物的治疗方法,所述眼用组合物可用于治疗角膜的眼表损伤和/或干燥症状。(The present disclosure provides methods of treatment using ophthalmic compositions comprising 1-perfluorohexyloctane that are useful for treating ocular surface damage and/or dry symptoms of the cornea.)

1. An ophthalmic composition for treating severity of dryness in a patient suffering from dry eye disease associated with meibomian gland dysfunction, wherein the composition consists essentially of 1-perfluorohexyloctane, and wherein the composition is topically applied to the eye of the patient in a single drop of about 10-12 μ Ι, up to 4 times daily.

2. An ophthalmic composition for treating ocular surface damage of the central corneal region in a patient suffering from dry eye disease associated with meibomian gland dysfunction, wherein the composition consists essentially of 1-perfluorohexyloctane, and wherein the composition is topically applied to the eye of the patient in a single drop of about 10-12 μ Ι, up to 4 times daily.

3. An ophthalmic composition for treating ocular surface damage of the central corneal region and treating severity of dryness in a patient suffering from dry eye disease associated with meibomian gland dysfunction, wherein the composition consists essentially of 1-perfluorohexyloctane, and wherein the composition is topically applied to the eye of the patient in a single drop of about 10-12 μ Ι, up to 4 times daily.

4. The composition for use according to any preceding claim, wherein the composition is administered to the eye of a patient in a single drop of about 11 μ l.

5. The composition for use according to any preceding claim, wherein the composition is administered to the eye of the patient four times a day.

6. The composition for use according to any preceding claim, wherein the patient to be treated is highly symptomatic with significant involvement of meibomian gland dysfunction.

7. The composition for use according to any preceding claim, wherein the patient to be treated is characterized by one or more criteria selected from the group consisting of:

i. tear film break up time (TBUT) is between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2, and

an MGD score between 4.0 and 11.2,

schirmer i test equal to or greater than 5 mm.

8. The composition for use according to any preceding claim, wherein the patient to be treated is characterized by one or more criteria selected from the group consisting of:

i. tear film break up time (TBUT) is less than 3 seconds,

an Ocular Surface Disease Index (OSDI) of above 57,

total corneal fluorescein staining (NEI scale) between 5 and 9,

mgd score equal to or higher than 7,

schirmer i test equal to or greater than 10 mm.

9. The composition for use according to any preceding claim, wherein the composition is further effective in treating (reducing) ocular surface damage of the whole cornea area and/or the nasal side cornea area and/or the temporal side cornea area and/or the inferior cornea area.

10. The composition for use according to any preceding claim, wherein the composition is further effective in treating (reducing) the frequency of dryness and/or awareness of dryness and/or burning/stinging and/or itching and/or feelings of stickiness and/or blurred vision and/or feelings of foreign body and/or overall Ocular Surface Disease Index (OSDI) score.

11. The composition for the use according to any one of the preceding claims, wherein the patient does not have aqueous-deficient dry eye disease and/or wherein the patient has evaporative keratoconjunctivitis sicca (dry eye disease) associated with meibomian gland dysfunction.

12. The composition for use according to any one of the preceding claims, wherein the patient does not respond to treatment with artificial tears.

13. The composition for use according to any one of the preceding claims, wherein the patient is a female.

14. The composition for use according to any one of the preceding claims, wherein ocular surface damage of the corneal region is determined by grading the central corneal region via fluorescein staining of the cornea.

15. The composition for the use according to any one of the preceding claims, wherein dryness severity, burning/stinging, itching sensation, sticky sensation, blurred vision and/or foreign body sensation is determined by an eye dryness score on a Visual Analog Scale (VAS) of 0% to 100% indicating the level of discomfort of the patient, and wherein the reduction in dryness frequency and/or dryness awareness is determined by an eye dryness score on a Visual Analog Scale (VAS) of 0% to 100% indicating the percentage of time the patient experiences the dryness symptoms, and wherein the total Ocular Surface Disease Index (OSDI) score is determined on the scale of 1 to 100, wherein a higher score indicates greater disability of the patient.

Technical Field

The present disclosure relates to the field of ophthalmic compositions comprising 1-perfluorohexyloctane, which are useful for treating ocular surface damage and/or dry symptoms of the cornea.

Background

Keratoconjunctivitis sicca (also known as Dry Eye Disease (DED) or tear dysfunction syndrome) is a multifunctional disorder of the tear film and ocular surface that results in discomfort, visual impairment, and even often ocular surface damage. Its prevalence varies widely from region to region and is estimated to range from about 7.4% in the united states to about 33% in japan (j.l. gayton, Clinical Ophthalmology 2009:3, 405-412). According to another estimate, approximately 320 million women and 105 million men in the united states alone have keratoconjunctivitis sicca. If cases with mild symptoms are also considered, the United states may have as many as 2000 million affected people.

Dry Eye Disease (DED) today falls into two main categories, namely water-deficient DED and evaporative DED. These conditions are not necessarily mutually exclusive.

Evaporative DED is heterogeneous to some extent and can develop for a variety of different root causes. Causes associated with increased tear film evaporation loss include meibomian gland disease or dysfunction, eyelid aperture disorders, blink disorders (as in parkinson's disease), or ocular surface disorders (as in allergic conjunctivitis). In particular, meibomian gland disease and dysfunction are commonly associated with evaporative dry eye disease. For example, meibomian gland dysfunction (also abbreviated MGD) can result in alterations in the quantitative or qualitative secretion of the lipid components required for the tear film. Meibum may also have an altered composition, be enriched in certain components, and/or be deficient in other components compared to normal meibum. This may result in altered physical properties such as abnormal viscosity or abnormal solubility. This in turn can lead to failure to form a stable and continuous tear film, with consequent evaporation losses and high osmotic pressure. Meibomian gland dysfunction may be generally characterized by obstruction and blockage of the gland due to hyperkeratosis of the gland and increased viscosity of the meibum. The dysfunction may be caused by a primary blepharal margin related disease or a secondary disease caused by a systemic disorder (such as rosacea or seborrheic dermatitis).

The primary approach to non-pharmacological DED therapy is the use of artificial tears for tear replacement. Most of the available products are designed as lubricants. In addition, they can act as carriers for nutrients and electrolytes (importantly potassium and bicarbonate), and some products attempt to modify physical parameters, such as increasing the osmotic pressure in certain forms of DED.

Preservatives that may be used in ophthalmic formulations are potentially damaging to the eye, particularly the ocular surface, and should be avoided in the case of dry eye. This is particularly relevant for patients with moderate to severe dry eye symptoms, patients who may need frequent use to alleviate the symptoms, and patients who need multiple antiseptic topical medications.

WO 2011/073134 discloses an ophthalmic topical pharmaceutical composition for the treatment of keratoconjunctivitis sicca comprising an immunosuppressant macrolide, such as cyclosporin a, and a semifluorinated alkane. The semifluorinated alkanes in the disclosed compositions act as suitable liquid vehicles for the delivery of therapeutic agents to the eye and, in particular, have a high capacity to dissolve poorly soluble compounds such as cyclosporine. However, in this effect, semifluorinated alkanes are only taught as pharmaceutically inactive solvents for active therapeutic agents.

US 7,001,607 discloses a polyanhron (polyanhron) gel tear substitute comprising at least one water-soluble fluorinated surfactant, water and a non-polar component, wherein the non-polar component may be a fluorocarbon or silicone oil. The gel composition is specifically administered into the conjunctival sac to form a gel reservoir, and due to the blinking action, the gel composition spreads over the cornea of the eye only in the form of a liquid film on the cornea. Thus, such compositions are not useful for patients with dry eye symptoms caused by eyelid/blink disorders (e.g., as a result of parkinson's disease).

US 2015-0224064a1 discloses compositions of semifluorinated alkanes for the treatment of dry eye and symptoms and conditions associated therewith. The disclosed invention relates generally to compositions comprising a mixture of at least two different semifluorinated alkanes. These compositions can be administered to the eye or ocular tissue, for example, in patients with keratoconjunctivitis sicca and/or meibomian gland dysfunction. The publication does not disclose or suggest any method that provides for the enrichment of semifluorinated alkanes in ocular tissue or the delay of ocular release of semifluorinated alkanes.

It is therefore an object of the present disclosure to provide a composition for use in an improved and more efficient method of treating keratoconjunctivitis sicca and/or meibomian gland dysfunction associated with meibomian gland dysfunction.

Disclosure of Invention

In a first aspect, the present disclosure provides a method of treating (reducing) ocular surface damage in one or more corneal regions, wherein the one or more corneal regions are selected from the group consisting of a full corneal region, a central corneal region, a nasal corneal region, a temporal corneal region, a lower corneal region, and combinations thereof.

In a second aspect, the present disclosure provides a method of treating (reducing) one or more dryness symptoms selected from dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

In a third aspect, the present disclosure provides a method of treating (reducing) ocular surface damage in one or more corneal regions and treating (reducing) one or more dryness symptoms, wherein the one or more corneal regions are selected from the group consisting of full corneal region, central corneal region, nasal corneal region, temporal corneal region, inferior corneal region, and combinations thereof, and wherein the one or more dryness symptoms are selected from the group consisting of dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

In a fourth aspect, the present disclosure provides a method of treating ocular surface nerve sensation or one or more symptoms associated therewith.

In a fifth aspect, the present disclosure provides a composition for use in a method according to the first aspect of the present disclosure.

In a sixth aspect, the present disclosure provides a composition for use in a method according to the second aspect of the present disclosure.

In a seventh aspect, the present disclosure provides a composition for use in a method according to the third aspect of the present disclosure.

In an eighth aspect, the present disclosure provides a composition for use in a method according to the fourth aspect of the present disclosure.

Drawings

FIG. 1 shows a schematic view of a(ocular surface damage): improvement in ocular surface damage of (a) the whole cornea region, (b) the central cornea region, (c) the nasal side cornea region, (d) the lower cornea region, (e) the temporal side cornea region, and (f) the upper cornea region as determined by fluorescein staining (detailed information on corneal fluorescein staining and grading according to the NEI scale, see experimental section). The changes from baseline (visit 1, day 1) for visit (2 weeks), visit 3(4 weeks), and visit 4(8 weeks) are depicted, with the treatment group representing an ophthalmic composition consisting essentially of NOV03 (1-perfluorohexyloctane;solid line) of 4 treatments per day (QID), and placebo represents saline solution (0.9% sodium chloride solution; QID + BID; dashed line).

FIG. 2(symptom-Visual Analog Scale (VAS)): improvement in dryness symptoms determined by eye dryness scores on a Visual Analog Scale (VAS) including (a) "dryness severity" (problem 1 "dry" corresponding to 10 VAS questionnaires), (b) "frequency of drying", (c) "consciousness to dryness", (d) "burning/stinging", (e) "itching", (f) "sticky", (g) "blurred vision", (h) "foreign body sensation", (i) "photosensitivity", (j) "pain" (detailed information on Visual Analog Scale (VAS) questionnaires, see experimental section). Changes from baseline (visit 1, day 1) for visit (2 weeks), visit 3(4 weeks) and visit 4(8 weeks) are depicted, with the treatment group representing 4 treatments per day (QID) with NOV03 (ophthalmic composition consisting essentially of 1-perfluorohexyloctane; solid line) and the placebo representing saline solution (0.9% sodium chloride solution; QID + BID; dashed line).

FIG. 3(symptom-total Ocular Surface Disease Index (OSDI)): improvement in dry symptoms as determined by Ocular Surface Disease Index (OSDI) scores, including total OSDI scores (for detailed information on Visual Analog Scale (VAS) questionnaire, see experimental section). Changes from baseline (visit 1, day 1) for visit (2 weeks), visit 3(4 weeks) and visit 4(8 weeks) are depicted, with the treatment group representing 4 treatments per day (QID) with NOV03 (ophthalmic composition consisting essentially of 1-perfluorohexyloctane; solid line) and the placebo representing saline solution (0.9% sodium chloride solution; QID + BID; dashed line).

FIG. 4(symptom-total Ocular Surface Disease Index (OSDI)): improvement of individual dryness symptoms as determined by an Ocular Surface Disease Index (OSDI) score, the individual dryness symptoms including (a) "photosensitivity to light", (b) "gritty eye feel", (c) "painful or sore eye", (d) "blurred vision", (e) "low vision", (f) "reading problem", (g) "night driving problem", (h) "work problem with computer or banking machine (ATM)", (i) "watch tv problem", (j) "uncomfortable in case of strong wind", (k) "in low humidity area", (k) "area with low humidity")Discomfort "and (l)" discomfort in an air-conditioned area "(for detailed information on Visual Analog Scale (VAS) questionnaire, see experimental section). Changes from baseline (visit 1, day 1) for visit (2 weeks), visit 3(4 weeks) and visit 4(8 weeks) are depicted, with the treatment group representing 4 treatments per day (QID) with NOV03 (ophthalmic composition consisting essentially of 1-perfluorohexyloctane; solid line) and the placebo representing saline solution (0.9% sodium chloride solution; QID + BID; dashed line).

FIG. 5(patients who particularly benefited from NOV 03-treatment (QID)): an improvement in dryness symptoms as determined by an eye dryness score on a Visual Analog Scale (VAS) in a patient subpopulation characterized by an MGD score of ≧ 7, the dryness symptoms comprising: (a) "severity of drying" (corresponding to question 1 "dry" of 10 VAS questionnaires) and (b) "frequency of drying". Improvement of corneal ocular surface damage determined by fluorescein staining and grading of whole corneal zones in the following patient subpopulations: (c) in a patient subpopulation characterized by an MGD score ≧ 7, (d) in a patient subpopulation characterized by a TFBUT ≦ 3. (for details on Visual Analogue Scale (VAS) questionnaire, MGD score, TFBUT, fluorescein staining, see experimental part). Changes from baseline (visit 1, day 1) for visit (2 weeks), visit 3(4 weeks) and visit 4(8 weeks) are depicted, with the treatment group representing 4 treatments per day (QID) with NOV03 (ophthalmic composition consisting essentially of 1-perfluorohexyloctane; solid line) and the placebo representing saline solution (0.9% sodium chloride solution; QID + BID; dashed line).

FIG. 6(patients who particularly benefited from NOV 03-treatment (QID)): improvement of symptom "dryness severity" determined by eye dryness score on Visual Analog Scale (VAS) in a patient subpopulation characterized by a Schirmer I test equal to or greater than 10mm after 8 weeks of treatment compared to the general patient population. Changes from baseline for NOV 03-treatment (QID) and control saline solution (0.9% sodium chloride solution; QID + BID) are depicted. A subgroup of patients with Schirmer I scores greater than 10mm are considered to have normal tear production but dry eye associated with meibomian gland dysfunction.

Detailed Description

In a first aspect, embodiments of the present disclosure provide a method (method 1) of treating (reducing) ocular surface damage of one or more corneal regions, wherein the one or more corneal regions are selected from the group consisting of a full corneal region, a central corneal region, a nasal corneal region, a temporal corneal region, a lower corneal region, and combinations thereof, and wherein the method comprises the steps of: about 10-12 μ l of a single drop of a composition consisting essentially of (or consisting of) 1-perfluorohexyloctane and optionally up to about 3 wt.% of 2-perfluorohexyloctane is administered to the eye of a patient in need thereof up to 4 times daily. Further embodiments of the disclosure provide the following:

1.1 Process 1 wherein the composition consists essentially of 1-perfluorohexyloctane and optionally up to about 1 weight percent 2-perfluorohexyloctane.

1.2 Process 1 or 1.1 wherein the composition consists essentially of 1-perfluorohexyloctane.

1.3 method 1 or any one of 1.1 to 1.2, wherein the composition is administered to the eye of the patient in a single drop of 10-11 μ Ι, preferably in a single drop of about 11 μ Ι.

1.4 methods 1 to 1.3, wherein the composition is administered to the eye of the patient four times per day.

1.5 method 1 or any one of 1.1 to 1.4, wherein the method is effective to treat (reduce) ocular surface damage of the whole and/or central and/or nasal and/or temporal and/or inferior corneal regions.

1.6 method 1 or any one of 1.1-1.5, wherein said method is effective within 2, 4 or 8 weeks after the first administration of said composition to the eye of the patient.

1.7 method 1 or any one of 1.1 to 1.6, wherein the patient has keratoconjunctivitis sicca (dry eye disease) and/or keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or evaporative keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or meibomian gland dysfunction.

1.8 method 1 or any one of 1.1 to 1.7, wherein the ocular surface damage does not result from cataract surgery.

1.9 method 1 or any one of 1.1 to 1.8, wherein the ocular surface damage is determined by grading one or more corneal regions selected from the group consisting of: a full corneal zone, a central corneal zone, a nasal lateral corneal zone, a temporal lateral corneal zone, and combinations thereof.

1.10 method 1.9 wherein the grading is performed according to the National Eye Institute scale.

1.11 method 1 or any one of 1.1 to 1.10, wherein the method is effective to treat (reduce) the following ocular surface damage:

i. the total corneal region and the central corneal region

Full and lower corneal regions

Total and nasal corneal regions

Total and temporal corneal zones

v. central and lower corneal regions

Central and nasal corneal regions

Central and temporal corneal zones

The inferior and lateral corneal regions, or

The inferior and temporal corneal regions.

1.12 method 1 or any one of 1.1 to 1.11, wherein the patient to be treated is characterized by:

i. tear film break up time (TBUT) is between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2, and

mgd score between 4.0 and 11.2.

1.13 method 1 or any one of 1.1 to 1.12, wherein the patient to be treated is characterized by one or more criteria selected from the group consisting of:

i. tear film break up time (TBUT) is less than 3 seconds,

an Ocular Surface Disease Index (OSDI) of above 57,

total corneal fluorescein staining (NEI scale) between 5 and 9,

mgd score equal to or higher than 7.

1.14 method 1 or any one of 1.1 to 1.13, wherein said method is effective to treat (reduce)

i. Ocular surface damage in the whole corneal region in patients characterized by tear film disruption times (TBUT) below 3s,

ocular surface damage of the whole corneal region in a patient characterized by an MGD score equal to or higher than 7,

ocular surface damage of the central corneal region in a patient characterized by a tear film disruption time (TBUT) of less than 3s,

ocular surface damage of the central corneal region in a patient characterized by an MGD score equal to or higher than 7.

1.15 method 1 or any one of 1.1 to 1.14, wherein the patient is female.

1.16 method 1 or any one of 1.1 to 1.14, wherein the patient is male.

1.17 method 1 or any one of 1.1 to 1.16, wherein the patient is at the age of 20-80 years, 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 at the time of treatment.

1.18 method 1 or any one of 1.1 to 1.17, wherein the patient has a co-disease such as conjunctivitis, hordeolum, chalazion, blepharitis, blepharoectomy, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

1.19 method 1 or any one of 1.1-1.18, wherein the patient has keratoconjunctivitis sicca resulting from a co-morbid treatment, for example treatment with any one or more of: isotretinoin, a sedative, a diuretic, a tricyclic antidepressant, an antihypertensive, an anticholinergic, an oral contraceptive, an antihistamine, a nasal decongestant, a beta-adrenergic antagonist, a phenothiazine, an atropine opioid (e.g., morphine), optionally wherein any such treatment is simultaneous or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

1.20 method 1 or any one of 1.1 to 1.19, wherein the patient has keratoconjunctivitis sicca resulting from an ocular surgical intervention, such as corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ocular surgery is simultaneous or prior.

1.21 method 1 or any one of 1.1 to 1.20, wherein said patient is concomitantly receiving treatment with another topical ophthalmic drug, such as an antibiotic, antifungal, corticosteroid, immunosuppressive agent, sympathomimetic agent, anesthetic, antihistamine or any combination thereof.

1.22 method 1 or any one of 1.1 to 1.21, wherein the patient is a contact lens wearer.

1.23 method 1 or any one of 1.1 to 1.22, wherein the patient is non-responsive or insufficiently responsive to prior treatment for keratoconjunctivitis sicca (dry eye disease).

1.24 method 1.23, wherein the prior treatment comprises one or more of the following treatments: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporin), topical corticosteroid administration, or topical aqueous artificial tear administration.

1.25 method 1 or any one of 1.1 to 1.24, wherein the method is effective

i. Reducing ocular surface damage in the whole corneal region by at least 3 orders and/or

Reducing ocular surface damage of the central corneal region by at least grade 1

As determined by grading the corneal zone via fluorescein staining of the cornea according to the american national eye research scale.

1.26 method 1.25, wherein the method is effective within 2 weeks, preferably within 4 weeks, more preferably within 8 weeks of treatment.

In another aspect, the present disclosure provides a composition consisting essentially of 1-perfluorohexyloctane and optionally up to about 3 weight percent 2-perfluorohexyloctane for use in method 1 or any subsequent embodiment thereof (i.e., methods 1.1 to 1.24).

In yet another aspect, the present disclosure provides the use of a composition as defined in method 1 and its subsequent embodiments (methods 1.1 to 1.24) in the preparation or manufacture of a topically administered ophthalmic drug or medicament.

As understood herein, the phrases "consisting essentially of … … (or orientational constellations of)" and "consisting of … … (orientational of or orientating of)" are considered interchangeable and mean that there are no additional components in a composition or dosage form other than those listed, except for negligible amounts of material-inherent impurities (if present) that do not provide any technical contribution or function to the disclosed composition or dosage form. In contrast, as used herein, the term "comprising" is to be interpreted in an open-ended sense, wherein features other than those prefaced by the term, such as composition components, may be present.

As used herein, the terms "about," "substantially," "essentially," and the like in relation to an attribute or value, such as a dosage amount or concentration, include the exact attribute or value, and any attribute or value generally recognized as falling within the normal range or accepted variability associated with the art and the method of measuring or determining the attribute or value.

In a second aspect, the present disclosure provides a method (method 2) of treating (reducing) one or more dryness symptoms selected from dryness severity, frequency of dryness, awareness of dryness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof, wherein the method comprises the steps of: about 10-12 μ l of a single drop of a composition consisting of (or consisting essentially of) 1-perfluorohexyloctane and optionally up to about 3 weight percent 2-perfluorohexyloctane is administered to the eye of a patient in need thereof up to 4 times per day. Further embodiments of the disclosure provide the following:

2.1 Process 2 wherein the composition consists essentially of 1-perfluorohexyloctane and optionally up to about 1 weight percent 2-perfluorohexyloctane.

2.2 method 2 or 2.1 wherein the composition consists essentially of 1-perfluorohexyloctane.

2.3 method 2 or any one of 2.1 to 2.2, wherein the composition is administered to the eye of the patient in a single drop of 10-11 μ Ι, preferably in a single drop of about 11 μ Ι.

2.4 method 2 or any one of 2.1 to 2.3, wherein the composition is administered to the eye of the patient four times daily.

2.5 method 2 or any one of 2.1 to 2.4, wherein the method is effective to treat (reduce) one or more symptoms of dryness selected from the group consisting of severity of dryness, frequency of dryness, awareness of dryness, burning/stinging, itching, feelings of stickiness, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

2.6 method 2 or any one of 2.1 to 2.5, wherein the method is effective within 2, 4 or 8 weeks after the first administration of the composition to the eye of the patient.

2.7 method 2 or any one of 2.1 to 2.6, wherein the patient has keratoconjunctivitis sicca (dry eye disease) and/or keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or evaporative keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or meibomian gland dysfunction.

2.8 method 2 or any one of 2.1 to 2.7, wherein the ocular surface damage does not result from cataract surgery.

2.9 method 2 or any one of 2.1 to 2.8, wherein the reduction in severity of dryness and/or blurred vision and/or light sensitivity is determined by an eye dryness score on a Visual Analog Scale (VAS) of 0% to 100% indicating the level of discomfort of the patient.

2.10 method 2 or any one of 2.1 to 2.9, wherein the reduction in drying frequency and/or drying awareness is determined by an eye dryness score on a Visual Analog Scale (VAS) of 0% to 100% indicating the percentage of time the patient experienced the drying symptom.

2.11 method 2 or any one of 2.1 to 2.10, wherein the total Ocular Surface Disease Index (OSDI) score is determined on the scale of 1 to 100, wherein a higher score indicates greater disability in the patient.

2.12 method 2 or any one of 2.1 to 2.11, wherein the patient to be treated is characterized by:

i. tear film break up time (TBUT) is between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2, and

mgd score between 4.0 and 11.2;

or wherein the patient to be treated is characterized by one or more or all of the following criteria:

i. tear film break up time (TBUT) is between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2,

mgd score between 4.0 and 11.2; and

schirmer I test equal to or greater than 5 mm; or greater than 5 mm; or greater than 6, 7, 8 or 9 mm.

2.13 method 2 or any one of 2.1 to 2.12, wherein the patient to be treated is characterized by one or more criteria selected from the group consisting of:

i. tear film break up time (TBUT) is less than 3 seconds,

an Ocular Surface Disease Index (OSDI) of above 57,

total corneal fluorescein staining (NEI scale) between 5 and 9,

mgd score equal to or higher than 7,

schirmer I test equal to or greater than 10 mm; or greater than 10 mm; or 15mm or more; or equal to or greater than 20 mm.

2.14 method 2 or any one of 2.1 to 2.13, wherein said method is effective to treat (reduce)

i. Is characterized by a severity of dryness in patients with an MGD score equal to or higher than 7,

drying frequency in patients characterized by an MGD score higher than 7.

2.15 method 2 or any one of 2.1 to 2.14, wherein the patient is female.

2.16 method 2 or any one of 2.1 to 2.14, wherein the patient is male.

2.17 method 2 or any one of 2.1 to 2.16, wherein the patient is at age 20-80 years, 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 at the time of treatment.

2.18 method 2 or any one of 2.1 to 2.17, wherein the patient has a co-disease such as conjunctivitis, hordeolum, chalazion, blepharitis, blepharoectomy, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

2.19 method 2 or any one of 2.1 to 2.18, wherein the patient has keratoconjunctivitis sicca, the keratoconjunctivitis sicca resulting from a co-morbid treatment, for example treatment with any one or more of: isotretinoin, a sedative, a diuretic, a tricyclic antidepressant, an antihypertensive, an anticholinergic, an oral contraceptive, an antihistamine, a nasal decongestant, a beta-adrenergic antagonist, a phenothiazine, an atropine opioid (e.g., morphine), optionally wherein any such treatment is simultaneous or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

2.20 method 2 or any one of 2.1 to 2.19, wherein the patient has keratoconjunctivitis sicca resulting from an ocular surgical intervention, such as corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ocular surgery is simultaneous or prior.

2.21 method 2 or any one of 2.1 to 2.20, wherein the patient is concomitantly receiving treatment with another topical ophthalmic drug, e.g., an antibiotic, antifungal, corticosteroid, immunosuppressive agent, sympathomimetic agent, anesthetic, antihistamine, or any combination thereof.

2.22 method 2 or any one of 2.1 to 2.21, wherein the patient is a contact lens wearer.

2.23 method 2 or any one of 2.1 to 2.22, wherein the patient is non-responsive or insufficiently responsive to prior treatment for keratoconjunctivitis sicca (dry eye disease).

2.24 method 2.23, wherein the prior treatment comprises one or more of the following treatments: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporin), topical corticosteroid administration, or topical aqueous artificial tear administration.

In one embodiment of method 2 or any subsequent embodiment thereof (i.e., methods 2.1-2.24), there is provided a method for treating the severity of dryness (symptoms) in a patient suffering from dry eye associated with meibomian gland dysfunction, wherein the method comprises the steps of: administering to an eye of a patient in need thereof, up to 4 times per day, a single drop of about 10-12 μ l of a composition consisting of (or consisting essentially of) 1-perfluorohexyloctane and optionally up to about 3 weight percent 2-perfluorohexyloctane, and wherein the patient is characterized by a Schirmer I test equal to or greater than 10 mm.

In another aspect, the present disclosure provides a composition consisting essentially of 1-perfluorohexyloctane and optionally up to about 3 weight percent 2-perfluorohexyloctane for use in method 2 or any subsequent embodiment thereof (i.e., methods 2.1 to 2.24).

In yet another aspect, the present disclosure provides the use of a composition as defined in method 2 and its subsequent embodiments (methods 2.1 to 2.24) in the preparation or manufacture of a topically administered ophthalmic drug or medicament.

In a third aspect, the present disclosure provides a method (method 3) of treating (reducing) ocular surface damage in one or more corneal regions and treating (reducing) one or more dryness symptoms, wherein the one or more corneal regions are selected from the group consisting of total corneal region, central corneal region, lateral nasal corneal region, lateral temporal corneal region, inferior corneal region, and combinations thereof, and wherein the one or more dryness symptoms are selected from the group consisting of dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof, and wherein the method comprises the steps of: about 10-12 μ l of a single drop of a composition consisting of (or consisting essentially of) 1-perfluorohexyloctane and optionally up to about 3 weight percent 2-perfluorohexyloctane is administered to the eye of a patient in need thereof up to 4 times per day. Further embodiments of the disclosure provide the following:

3.1 Process 3 wherein the composition consists essentially of 1-perfluorohexyloctane and optionally up to about 1 weight percent 2-perfluorohexyloctane.

3.2 method 3 or 3.1 wherein the composition consists essentially of 1-perfluorohexyloctane.

3.3 method 3 or any one of 3.1 to 3.2, wherein the composition is administered to the eye of the patient in a single drop of 10-11 μ Ι, preferably in a single drop of about 11 μ Ι.

3.4 method 3 or any one of 3.1 to 3.3, wherein the composition is administered to the eye of the patient four times daily.

3.5 method 3 or any one of 3.1 to 3.4, wherein the method is effective to treat (reduce) ocular surface damage of one or more corneal regions and is effective to treat (reduce) one or more dryness symptoms, wherein the one or more corneal regions are selected from the group consisting of total corneal region, central corneal region, lateral nasal corneal region, lateral temporal corneal region, inferior corneal region, and combinations thereof, and wherein the one or more dryness symptoms are selected from the group consisting of dryness severity, frequency of dryness, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

3.6 method 3 or any one of 3.1 to 3.5, wherein the method is effective within 2, 4 or 8 weeks after the first administration of the composition to the eye of the patient.

3.7 method 3 or any one of 3.1 to 3.6, wherein the patient has keratoconjunctivitis sicca (dry eye disease) and/or keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or evaporative keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or meibomian gland dysfunction.

3.8 method 3 or any one of 3.1 to 3.7, wherein the ocular surface damage does not result from cataract surgery.

3.9 method 3 or any one of 3.1 to 3.8, wherein the reduction in severity of dryness and/or blurred vision and/or light sensitivity is determined by an eye dryness score on a Visual Analog Scale (VAS) of 0% to 100% indicating the level of discomfort of the patient.

3.10 method 3 or any one of 3.1 to 3.9, wherein the reduction in drying frequency and/or drying consciousness is determined by an eye dryness score on a Visual Analog Scale (VAS) of 0% to 100% indicating the percentage of time that the drying symptom is experienced.

3.11 method 3 or any one of 3.1 to 3.10, wherein the total Ocular Surface Disease Index (OSDI) score is determined on the scale of 1 to 100, wherein a higher score indicates greater disability in the patient.

3.12 method 3 or any one of 3.1 to 3.11, wherein the patient to be treated is characterized by:

i. tear film break up time (TBUT) is between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2, and

mgd score between 4.0 and 11.2;

or wherein the patient to be treated is characterized by one or more or all of the following criteria:

i. tear film break up time (TBUT) is between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2,

mgd score between 4.0 and 11.2; and

schirmer I test equal to or greater than 5 mm; or greater than 5 mm; or greater than 6, 7, 8 or 9 mm.

3.13 method 3 or any one of 3.1 to 3.12, wherein the patient to be treated is characterized by being selected from

One or more of the following criteria:

i. tear film break up time (TBUT) is less than 3 seconds,

an Ocular Surface Disease Index (OSDI) of above 57,

total corneal fluorescein staining (NEI scale) between 5 and 9,

mgd score equal to or higher than 7,

schirmer I test equal to or greater than 10 mm; greater than 10 mm; equal to or greater than 15 mm; or equal to or greater than 20 mm.

3.14 method 3 or any one of 3.1 to 3.13, wherein said method is effective to simultaneously treat (reduce) ocular damage and said dryness symptoms in one or more corneal regions, preferably within 2, 4 or 8 weeks after first administering said composition to the eye of a patient in need thereof.

3.15 method 3 or any one of 3.1 to 3.14, wherein the method is effective to treat (reduce) ocular surface damage in the whole corneal area, and is effective to treat (reduce) one or more dryness symptoms selected from dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

3.16 method 3 or any one of 3.1 to 3.14, wherein the method is effective to treat (reduce) ocular surface damage of the central corneal region, and is effective to treat (reduce) one or more dryness symptoms selected from dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

3.17 method 3 or any one of 3.1 to 3.14, wherein the method is effective to treat (reduce) ocular surface damage in the underlying corneal region, and is effective to treat (reduce) one or more dryness symptoms selected from dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

3.18 method 3 or any one of 3.1 to 3.14, wherein the method is effective to treat (reduce) ocular surface damage in the lateral corneal regions of the nose, and is effective to treat (reduce) one or more dryness symptoms selected from dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

3.19 method 3 or any one of 3.1 to 3.14, wherein the method is effective to treat (reduce) ocular surface damage in the temporal lateral cornea region, and is effective to treat (reduce) one or more dry symptoms selected from the group consisting of dryness severity, frequency of dryness, dry consciousness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

3.20 method 3 or any one of 3.1 to 3.14, wherein the method is effective to treat (reduce) ocular surface damage in both the full and central corneal regions, and is effective to treat (reduce) one or more dry symptoms selected from the group consisting of dryness severity, frequency of dryness, dry consciousness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

3.21 method 3 or any one of 3.1 to 3.14, wherein the method is effective to treat (reduce) ocular surface damage of the central and inferior corneal regions, and is effective to treat (reduce) one or more dryness symptoms selected from dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, slimy sensation, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

3.22 method 3 or any one of 3.1 to 3.21, wherein the patient is female.

3.23 method 3 or any one of 3.1 to 3.21, wherein the patient is male.

3.24 method 3 or any one of 3.1 to 3.23, wherein the patient is at age 20-80 years, 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 at the time of treatment.

3.25 method 3 or any one of 3.1 to 3.24, wherein the ocular surface damage is determined by grading one or more corneal regions selected from the group consisting of: a full corneal zone, a central corneal zone, a nasal lateral corneal zone, a temporal lateral corneal zone, and combinations thereof.

3.26 method 3 or any one of 3.1 to 3.25, wherein the patient has a co-disease such as conjunctivitis, hordeolum, chalazion, blepharitis, blepharoectomy, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

3.27 method 3 or any one of 3.1 to 3.26, wherein the patient has keratoconjunctivitis sicca, the keratoconjunctivitis sicca resulting from a co-morbid treatment, for example treatment with any one or more of: isotretinoin, a sedative, a diuretic, a tricyclic antidepressant, an antihypertensive, an anticholinergic, an oral contraceptive, an antihistamine, a nasal decongestant, a beta-adrenergic antagonist, a phenothiazine, an atropine opioid (e.g., morphine), optionally wherein any such treatment is simultaneous or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

3.28 method 3 or any one of 3.1 to 3.27, wherein the patient has keratoconjunctivitis sicca resulting from an ocular surgical intervention, such as corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ocular surgery is simultaneous or prior.

3.29 method 3 or any one of 3.1 to 3.28, wherein said patient is concurrently receiving treatment with another topical ophthalmic drug, such as an antibiotic, antifungal, corticosteroid, immunosuppressive agent, sympathomimetic, anesthetic, antihistamine, or any combination thereof.

3.30 method 3 or any one of 3.1 to 3.29, wherein the patient is a contact lens wearer.

3.31 method 3 or any one of 3.1 to 3.30, wherein the patient is non-responsive or inadequately responsive to prior treatment for keratoconjunctivitis sicca (dry eye disease).

3.32 method 3.31, wherein the prior treatment comprises one or more of the following treatments: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporin), topical corticosteroid administration, or topical aqueous artificial tear administration.

3.33 method 3 or 3.1 to 3.32, wherein the method is effective

i. Reducing ocular surface damage in the whole corneal region by at least 3 orders and/or

Reducing ocular surface damage of the central corneal region by at least grade 1

As determined by grading the corneal zone via fluorescein staining of the cornea according to the american national eye research scale.

3.34 method 3.33, wherein the method is effective within 2 weeks, preferably within 4 weeks, more preferably within 8 weeks of treatment.

In one embodiment of method 3 or any subsequent example thereof (i.e., methods 3.1 through 3.34), there is provided a method for treating (reducing) ocular surface damage of one or more corneal regions and treating (or reducing) symptoms of dryness severity in a patient having dry eye associated with meibomian gland dysfunction, wherein the method comprises the steps of: administering to an eye of a patient in need thereof, up to 4 times per day, a single drop of about 10-12 μ l of a composition consisting of (or consisting essentially of) 1-perfluorohexyloctane and optionally up to about 3 weight percent 2-perfluorohexyloctane, and wherein the patient is characterized by a Schirmer I test equal to or greater than 10 mm.

In another aspect, the present disclosure provides a composition consisting essentially of 1-perfluorohexyloctane and optionally up to about 3 weight percent 2-perfluorohexyloctane for use in method 3 or any subsequent embodiment thereof (i.e., methods 3.1 to 3.23).

In yet another aspect, the present disclosure provides the use of a composition as defined in method 3 and its subsequent embodiments (methods 3.1 to 3.23) in the preparation or manufacture of a topically administered ophthalmic drug or medicament.

In a fourth aspect, the present disclosure provides a method (method 4) of treating ocular surface neurosensory sensation or one or more symptoms associated therewith, wherein the method comprises the steps of: about 10-12 μ l of a single drop of a composition consisting of (or consisting essentially of) 1-perfluorohexyloctane, optionally containing up to about 1% by weight of 2-perfluorohexyloctane, is administered to the eye of a patient in need thereof up to 4 times per day. Further embodiments of the disclosure provide the following:

4.1 Process 4 wherein the composition consists essentially of 1-perfluorohexyloctane and optionally up to about 1 weight percent 2-perfluorohexyloctane.

4.2 Process 4 or 4.1 wherein the composition consists essentially of 1-perfluorohexyloctane.

4.3 method 4 or any one of 4.1 to 4.2, wherein the composition is administered to the eye of the patient in a single drop of 10-11 μ Ι, preferably in a single drop of about 11 μ Ι.

4.4 method 4 or any one of 4.1 to 4.3, wherein the composition is administered to the eye of the patient four times daily.

4.5 method 4 or any one of 4.1 to 4.4, wherein the method is effective to treat ocular surface nerve sensation or one or more symptoms associated therewith.

4.6 method 4 or any one of 4.1 to 4.5, wherein the method is effective in protecting ocular surface nerves.

4.7 method 4 or any one of 4.1 to 4.6, wherein the composition is effective to treat (reduce) pathological signaling of the ocular surface nerve.

4.8 method 4 or any one of 4.1 to 4.7, wherein the method is effective within 2, 4 or 8 weeks after the first administration of the composition to the eye of the patient.

4.9 method 4 or any one of 4.1 to 4.8, wherein the patient has keratoconjunctivitis sicca (dry eye disease) and/or keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or evaporative keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or meibomian gland dysfunction.

4.10 method 4 or any one of 4.1 to 4.9, wherein the ocular surface damage does not result from cataract surgery.

4.11 method 4 or any one of 4.1 to 4.9, wherein the ocular surface damage is from cataract surgery.

4.12 method 4 or any one of 4.1 to 4.11, wherein the ocular surface nerves are selected from nerves at the corneal and/or conjunctival surface.

4.13 method 4 or any one of 4.1 to 4.12, wherein the one or more symptoms associated with ocular surface nerve sensation is selected from the group consisting of ocular sensation of grit, ocular photosensitivity (photophobia), ocular pain, or soreness.

4.14 method 4 or any one of 4.1 to 4.13, wherein the patient is characterized by

i. One or more symptoms selected from the group consisting of gritty sensation in the eye, photosensitivity of the eye to light (photophobia) and/or pain or soreness in the eye, and

total corneal fluorescein staining (NEI scale) between 5 and 9.

4.15 method 4 or any one of 4.1 to 4.14, wherein the patient is female.

4.16 method 4 or any one of 4.1 to 4.14, wherein the patient is male.

4.17 method 4 or any one of 4.1 to 4.16, wherein the patient is at age 20-80 years, 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 at the time of treatment.

4.18 method 4 or any one of 4.1 to 4.17, wherein the patient has a co-disease such as conjunctivitis, hordeolum, chalazion, blepharitis, blepharoectomy, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

4.19 method 4 or any one of 4.1 to 4.18, wherein the patient has keratoconjunctivitis sicca, the keratoconjunctivitis sicca resulting from a co-morbid treatment, for example treatment with any one or more of: isotretinoin, a sedative, a diuretic, a tricyclic antidepressant, an antihypertensive, an anticholinergic, an oral contraceptive, an antihistamine, a nasal decongestant, a beta-adrenergic antagonist, a phenothiazine, an atropine opioid (e.g., morphine), optionally wherein any such treatment is simultaneous or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

4.20 method 4 or any one of 4.1 to 4.19, wherein the patient has keratoconjunctivitis sicca resulting from an ocular surgical intervention, such as corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ocular surgery is simultaneous or prior.

4.21 method 4 or any one of 4.1 to 4.20, wherein said patient is concurrently receiving treatment with another topical ophthalmic drug, such as an antibiotic, antifungal, corticosteroid, immunosuppressive agent, sympathomimetic agent, anesthetic, antihistamine, or any combination thereof.

4.22 method 4 or any one of 4.1 to 4.21, wherein the patient is a contact lens wearer.

4.23 method 4 or any one of 4.1 to 4.22, wherein the patient is non-responsive or inadequately responsive to prior treatment for keratoconjunctivitis sicca (dry eye disease).

4.24 method 4.23, wherein the prior treatment comprises one or more of the following treatments: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporin), topical corticosteroid administration, or topical aqueous artificial tear administration.

In another aspect, the present disclosure provides a composition consisting essentially of 1-perfluorohexyloctane and optionally up to about 3 weight percent 2-perfluorohexyloctane for use in process 4 or any subsequent embodiment thereof (i.e., processes 4.1 through 4.15).

In yet another aspect, the present disclosure provides the use of a composition as defined in method 4 and its subsequent embodiments (methods 4.1 to 4.15) in the preparation or manufacture of a topically administered ophthalmic drug or medicament.

In a fifth aspect, related to the first aspect, the present disclosure provides a composition for use in treating ocular surface damage of one or more corneal zones (composition 1 for use), wherein the one or more corneal zones are selected from the group consisting of a pan-cornea zone, a central cornea zone, a nasal cornea zone, a temporal cornea zone, a lower cornea zone, and combinations thereof, and wherein the composition consists essentially of (or consists of) 1-perfluorohexyloctane, and optionally up to about 3 wt.% 2-perfluorohexyloctane, and wherein the composition is administered to an eye of a patient in need thereof in single drops of about 10-12 μ Ι up to 4 times per day. Further embodiments of the disclosure provide the following:

5.1 composition 1 for use, wherein the composition consists essentially of 1-perfluorohexyloctane and optionally up to about 1 weight percent 2-perfluorohexyloctane.

5.2 composition 1 or 5.1 for use, wherein the composition consists essentially of 1-perfluorohexyloctane.

5.3 composition 1 or any one of 5.1 to 5.2 for use, wherein the composition is administered to the eye of the patient in a single drop of 10-11 μ Ι, preferably in a single drop of about 11 μ Ι.

5.4 any of composition 1 or 5.1 to 5.3 for use, wherein the composition is administered to the eye of the patient four times daily.

5.5 composition for use 1 or any one of 5.1 to 5.4, wherein the composition for use is effective in treating (reducing) ocular surface damage of the whole and/or central and/or nasal and/or temporal and/or inferior corneal regions.

5.6 composition for use 1 or any one of 5.1 to 5.5, wherein the composition for use is effective within 2, 4 or 8 weeks after first administering the composition to the eye of the patient.

5.7 composition 1 or any one of 5.1 to 5.6 for use, wherein the patient has keratoconjunctivitis sicca (dry eye disease) and/or keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or evaporative keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or meibomian gland dysfunction.

5.8 composition 1 or any one of 5.1 to 5.7 for use, wherein the ocular surface damage does not result from cataract surgery.

5.9 composition 1 or any one of 5.1 to 5.8 for use, wherein the ocular surface damage is determined by grading one or more corneal regions selected from the group consisting of: a full corneal zone, a central corneal zone, a nasal lateral corneal zone, a temporal lateral corneal zone, and combinations thereof.

5.10 composition for use 5.9, wherein the grading is according to the national eye research institute scale.

5.11 composition for use 1 or any one of 5.1 to 5.10, wherein the composition for use is effective to treat (reduce) the following ocular surface damage:

i. the total corneal region and the central corneal region

Full and lower corneal regions

Total and nasal corneal regions

Total and temporal corneal zones

v. central and lower corneal regions

Central and nasal corneal regions

Central and temporal corneal zones

The inferior and lateral corneal regions, or

The inferior and temporal corneal regions.

5.12 any of composition 1 or 5.1 to 5.11 for use, wherein the patient to be treated is characterized by:

i. tear film break up time (TBUT) is between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2, and

mgd score between 4.0 and 11.2.

5.13 composition for use 1 or any one of 5.1 to 5.12, wherein the patient to be treated is characterized by one or more criteria selected from the group consisting of:

i. tear film break up time (TBUT) is less than 3 seconds,

an Ocular Surface Disease Index (OSDI) of above 57,

total corneal fluorescein staining (NEI scale) between 5 and 9,

mgd score equal to or higher than 7.

5.14 composition for use 1 or any one of 5.1 to 5.13, wherein the composition for use is effective in treating (reducing)

i. Ocular surface damage in the whole corneal region in patients characterized by tear film disruption times (TBUT) below 3s,

ocular surface damage of the whole corneal region in a patient characterized by an MGD score equal to or higher than 7,

ocular surface damage of the central corneal region in a patient characterized by a tear film disruption time (TBUT) of less than 3s,

ocular surface damage of the central corneal region in a patient characterized by an MGD score equal to or higher than 7.

5.15 composition for use 1 or any one of 5.1 to 5.14, wherein the patient is a female.

5.16 any of composition 1 or 5.1 to 5.14 for use, wherein the patient is male.

5.17 composition for use 1 or any one of 5.1 to 5.16, wherein the patient is at the age of 20-80 years, 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 at the time of treatment.

5.18 composition 1 or any of 5.1 to 5.17 for use, wherein the patient has a co-disease such as conjunctivitis, hordeolum, chalazion, blepharitis, blepharoedema, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

5.19 composition 1 or any one of 5.1 to 5.18 for use, wherein the patient has keratoconjunctivitis sicca, the keratoconjunctivitis sicca resulting from a co-morbid treatment, for example with any one or more of: isotretinoin, a sedative, a diuretic, a tricyclic antidepressant, an antihypertensive, an anticholinergic, an oral contraceptive, an antihistamine, a nasal decongestant, a beta-adrenergic antagonist, a phenothiazine, an atropine opioid (e.g., morphine), optionally wherein any such treatment is simultaneous or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

5.20 composition 1 or any of 5.1 to 5.19 for use, wherein the patient has keratoconjunctivitis sicca resulting from an ocular surgical intervention, such as corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ocular surgery is simultaneous or prior.

5.21 any one of composition 1 or 5.1 to 5.20 for use, wherein the patient is concurrently receiving treatment with another topical ophthalmic drug, such as an antibiotic, antifungal, corticosteroid, immunosuppressive agent, sympathomimetic, anesthetic, antihistamine, or any combination thereof.

5.22 composition for use 1 or any one of 5.1 to 5.21, wherein the patient is a contact lens wearer.

5.23 composition 1 or any one of 5.1 to 5.22 for use, wherein the patient is non-responsive or insufficiently responsive to prior treatment for keratoconjunctivitis sicca (dry eye disease).

5.24 composition for use 5.23, wherein the prior treatment comprises one or more of the following methods of treatment: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporin), topical corticosteroid administration, or topical aqueous artificial tear administration.

5.25 composition for use or any of 5.1 to 5.24, wherein the composition is effective

i. Reducing ocular surface damage in the whole corneal region by at least 3 orders and/or

Reducing ocular surface damage of the central corneal region by at least grade 1

As determined by grading the corneal zone via fluorescein staining of the cornea according to the american national eye research scale.

5.26 composition for use 5.25, wherein the composition is effective within 2 weeks, preferably within 4 weeks, more preferably within 8 weeks of treatment.

In a sixth aspect, related to the second aspect, the present disclosure provides a composition (composition 2 for use) for use in treating one or more dryness symptoms selected from dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, stickiness, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof, and wherein the composition consists essentially of (or consists of) 1-perfluorohexyloctane and optionally up to about 3% by weight of 2-perfluorohexyloctane, and wherein the composition is administered to the eye of a patient in need thereof in a single drop of about 10-12 μ Ι up to 4 times per day. Further embodiments of the disclosure provide the following:

6.1 composition 2 for use, wherein the composition consists essentially of 1-perfluorohexyloctane and optionally up to about 1 weight percent 2-perfluorohexyloctane.

6.2 composition 2 or 6.1 for use, wherein the composition consists essentially of 1-perfluorohexyloctane.

6.3 composition 2 or any one of 6.1 to 6.2 for use, wherein the composition is administered to the eye of the patient in a single drop of 10-11 μ Ι, preferably in a single drop of about 11 μ Ι.

6.4 any of composition 2 or 6.1 to 6.3 for use, wherein the composition is administered to the eye of the patient four times daily.

6.5 any of composition 2 or 6.1 to 6.4 for use, wherein the composition for use is effective to treat (reduce) one or more dry symptoms selected from the group consisting of dryness severity, frequency of drying, dry consciousness, burning/stinging, itching, sticky feeling, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

6.6 composition for use 2 or any one of 6.1 to 6.5, wherein the composition for use is effective within 2, 4 or 8 weeks after first administration of the composition to the eye of the patient.

6.7 composition 2 or any one of 6.1 to 6.6 for use, wherein the patient has keratoconjunctivitis sicca (dry eye disease) and/or keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or evaporative keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or meibomian gland dysfunction.

6.8 composition 2 or any one of 6.1 to 6.7 for use, wherein the ocular surface damage does not result from cataract surgery.

6.9 composition 2 or any one of 6.1 to 6.8 for use, wherein the reduction in severity of dryness and/or blurred vision and/or light sensitivity is determined by an eye dryness score on a Visual Analog Scale (VAS) of 0% to 100% indicating a level of discomfort for the patient.

6.10 composition 2 or any of 6.1 to 6.9 for use, wherein the reduction in drying frequency and/or drying awareness is determined by an eye dryness score on a Visual Analog Scale (VAS) of 0% to 100% indicating the percentage of time that the drying symptom is experienced.

6.11 composition for use 2 or any one of 6.1 to 6.10, wherein the total Ocular Surface Disease Index (OSDI) score is determined on the scale of 1 to 100, wherein a higher score indicates a greater disability of the patient.

6.12 any one of composition 2 or 6.1 to 6.11 for use, wherein the patient to be treated is characterized by:

i. tear film break up time (TBUT) is between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2, and

mgd score between 4.0 and 11.2;

or wherein the patient to be treated is characterized by one or more or all of the following criteria:

tear film break up time (TBUT) between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2,

mgd score between 4.0 and 11.2; and

schirmer I test equal to or greater than 5 mm; or greater than 5 mm; or greater than 6, 7, 8 or 9 mm.

6.13 composition for use 2 or any one of 6.1 to 6.12, wherein the patient to be treated is characterized by one or more criteria selected from the group consisting of:

i. tear film break up time (TBUT) is less than 3 seconds,

an Ocular Surface Disease Index (OSDI) of above 57,

total corneal fluorescein staining (NEI scale) between 5 and 9,

mgd score equal to or higher than 7,

schirmer I test equal to or greater than 10 mm; greater than 10 mm; equal to or greater than 15 mm; or equal to or greater than 20 mm.

6.14 composition for use 2 or any one of 6.1 to 6.13, wherein the composition for use is effective in treating (reducing)

i. Is characterized by a severity of dryness in patients with an MGD score equal to or higher than 7,

drying frequency in patients characterized by an MGD score higher than 7.

6.15 composition for use 2 or any one of 6.1 to 6.14, wherein the patient is a female.

6.16 any one of composition 2 or 6.1 to 6.14 for use, wherein the patient is male.

6.17 composition for use 2 or any one of 6.1 to 6.16, wherein the patient is at the age of 20-80 years, 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 at the time of treatment.

6.18 composition 2 or any one of 6.1 to 6.17 for use, wherein the patient has a co-disease such as conjunctivitis, hordeolum, chalazion, blepharitis, blepharoedema, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

6.19 composition 2 or any one of 6.1 to 6.18 for use, wherein the patient has keratoconjunctivitis sicca, the keratoconjunctivitis sicca resulting from a co-morbid treatment, for example with any one or more of: isotretinoin, a sedative, a diuretic, a tricyclic antidepressant, an antihypertensive, an anticholinergic, an oral contraceptive, an antihistamine, a nasal decongestant, a beta-adrenergic antagonist, a phenothiazine, an atropine opioid (e.g., morphine), optionally wherein any such treatment is simultaneous or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

6.20 composition 2 or any one of 6.1 to 6.19 for use, wherein the patient has keratoconjunctivitis sicca resulting from an ocular surgical intervention, such as corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ocular surgery is simultaneous or prior.

6.21 any of composition 2 or 6.1 to 6.20 for use, wherein the patient is concurrently receiving treatment with another topical ophthalmic drug, such as an antibiotic, antifungal, corticosteroid, immunosuppressive agent, sympathomimetic, anesthetic, antihistamine, or any combination thereof.

6.22 composition for use 2 or any one of 6.1 to 6.21, wherein the patient is a contact lens wearer.

6.23 composition 2 or any one of 6.1 to 6.22 for use, wherein the patient is non-responsive or insufficiently responsive to prior treatment for keratoconjunctivitis sicca (dry eye disease).

6.24 composition for use 6.23, wherein the prior treatment comprises one or more of the following methods of treatment: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporin), topical corticosteroid administration, or topical aqueous artificial tear administration.

In one embodiment of composition 2 for use or any of its subsequent embodiments (i.e., composition 6.1-6.24 for use), there is provided a composition for use in treating (a symptom of) dryness severity, wherein the composition consists essentially of (or consists of) 1-perfluorohexyloctane and optionally up to about 3% by weight of 2-perfluorohexyloctane, and wherein the composition is administered to the eye of a patient in need thereof in a single drop of about 10-12 μ Ι up to 4 times per day, and wherein the patient is characterized by a Schirmer I test equal to or greater than 10 mm.

In a seventh aspect, related to the third aspect, the present disclosure further provides a composition for treating ocular surface damage of one or more corneal regions and for treating one or more dryness symptoms (composition 3 for use), wherein the one or more corneal regions are selected from the group consisting of total corneal region, central corneal region, nasal corneal region, temporal corneal region, inferior corneal region, and combinations thereof, and wherein the one or more dryness symptoms are selected from the group consisting of dryness severity, drying frequency, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof, and wherein the composition consists essentially of (or consists of) 1-perfluorohexyloctane and optionally up to about 3 wt% 2-perfluorohexyloctane, and wherein the composition is administered to an eye of a patient in need thereof in a single drop of about 10 to 12 μ Ι, up to 4 times per day. Further embodiments of the disclosure provide the following:

7.1 composition 3 for use, wherein the composition consists essentially of 1-perfluorohexyloctane and optionally up to about 1 weight percent 2-perfluorohexyloctane.

7.2 composition 3 or 7.1 for use, wherein the composition consists essentially of 1-perfluorohexyloctane.

7.3 composition 3 or any one of 7.1 to 7.2 for use, wherein the composition is administered to the eye of the patient in a single drop of 10-11 μ Ι, preferably in a single drop of about 11 μ Ι.

7.4 any of composition 3 or 7.1 to 7.3 for use, wherein the composition is administered to the eye of the patient four times daily.

7.5 any one of composition 3 or 7.1 to 7.4 for use, wherein the composition for use is effective to treat ocular surface damage of one or more corneal regions, and wherein the composition for use is effective to treat one or more dryness symptoms, wherein the one or more corneal regions are selected from the group consisting of full corneal region, central corneal region, nasal lateral corneal region, temporal lateral corneal region, inferior corneal region, and combinations thereof, and wherein the one or more dryness symptoms are selected from the group consisting of dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, sticky sensation, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

7.6 any one of composition 3 or 7.1 to 7.5 for use, wherein the composition for use is effective within 2, 4 or 8 weeks after first administering the composition to the eye of the patient.

7.7 composition for use 3 or any one of claims 7.1 to 7.6, wherein the patient has keratoconjunctivitis sicca (dry eye disease) and/or keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or evaporative keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or meibomian gland dysfunction.

7.8 any one of composition 3 or 7.1 to 7.7 for use, wherein the ocular surface damage does not result from cataract surgery.

7.9 composition 3 or any of 7.1 to 7.8 for use, wherein the reduction in severity of dryness and/or blurred vision and/or light sensitivity is determined by an eye dryness score on a Visual Analog Scale (VAS) of 0% to 100% indicating a level of discomfort for the patient.

7.10 any of composition 3 or 7.1 to 7.8 for use, wherein the reduction in drying frequency and/or drying awareness is determined by an eye dryness score on a Visual Analog Scale (VAS) of 0% to 100% indicating the percentage of time the patient experienced the drying symptom.

7.11 any one of composition 3 or 7.1 to 7.10 for use, wherein the total Ocular Surface Disease Index (OSDI) score is determined on the scale of 1 to 100, wherein a higher score indicates greater disability in the patient.

7.12 any one of composition 3 or 7.1 to 7.11 for use, wherein the patient to be treated is characterized by:

i. tear film break up time (TBUT) is between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2, and

mgd score between 4.0 and 11.2;

or wherein the patient to be treated is characterized by one or more or all of the following criteria:

i. tear film break up time (TBUT) is between 2.1 and 3.9 seconds,

an Ocular Surface Disease Index (OSDI) of between 38 and 72,

total corneal fluorescein staining (NEI scale) between 4.8 and 9.2,

mgd score between 4.0 and 11.2; and

schirmer I test equal to or greater than 5 mm; or greater than 5 mm; or greater than 6, 7, 8 or 9 mm.

7.13 any one of composition 3 or 7.1 to 7.12 for use, wherein the patient to be treated is characterized by one or more criteria selected from the group consisting of:

i. tear film break up time (TBUT) is less than 3 seconds,

an Ocular Surface Disease Index (OSDI) of above 57,

total corneal fluorescein staining (NEI scale) between 5 and 9,

mgd score equal to or higher than 7,

schirmer I test equal to or greater than 10 mm; equal to or greater than 15 mm; equal to or greater than 20 mm.

7.14 any one of composition 3 or 7.1 to 7.13 for use, wherein the composition for use is effective to simultaneously treat (reduce) ocular surface damage in one or more corneal regions and to treat (reduce) one or more symptoms of dryness, preferably within 2, 4 or 8 weeks after first administering the composition to an eye of a patient in need thereof.

7.15 any one of composition 3 or 7.1 to 7.14 for use, wherein the composition for use is effective to treat (reduce) ocular surface damage in the whole corneal region, and is effective to treat (reduce) one or more dry symptoms selected from the group consisting of dryness severity, frequency of dryness, dry consciousness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

7.16 any one of composition 3 or 7.1 to 7.14 for use, wherein the composition for use is effective to treat (reduce) ocular surface damage in the central corneal region, and is effective to treat (reduce) one or more dry symptoms selected from the group consisting of dryness severity, frequency of dryness, dry consciousness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

7.17 any of composition 3 or 7.1 to 7.14 for use, wherein the composition for use is effective to treat (reduce) ocular surface damage in the underlying corneal region, and is effective to treat (reduce) one or more dry symptoms selected from the group consisting of dryness severity, frequency of dryness, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

7.18 any one of composition 3 or 7.1 to 7.14 for use, wherein the composition for use is effective to treat (reduce) ocular surface damage in the lateral corneal regions of the nose, and is effective to treat (reduce) one or more dry symptoms selected from the group consisting of dryness severity, frequency of dryness, dry consciousness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

7.19 any one of composition 3 or 7.1 to 7.14 for use, wherein the composition for use is effective to treat (reduce) ocular surface damage in the temporal corneal region, and is effective to treat (reduce) one or more dryness symptoms selected from dryness severity, dryness frequency, dryness awareness, burning/stinging, itching, sliminess, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

7.20 any one of composition 3 or 7.1 to 7.14 for use, wherein the composition for use is effective to treat (reduce) ocular surface damage in the full and central corneal regions, and is effective to treat (reduce) one or more dry symptoms selected from the group consisting of dryness severity, frequency of dryness, dry consciousness, burning/stinging, itching, sticky feeling, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

7.21 any one of composition 3 or 7.1 to 7.14 for use, wherein the composition for use is effective to treat (reduce) ocular surface damage of the central and inferior corneal regions, and is effective to treat (reduce) one or more dry symptoms selected from the group consisting of dryness severity, frequency of dryness, dry consciousness, burning/stinging, itching, sticky feeling, blurred vision, foreign body sensation, total Ocular Surface Disease Index (OSDI) score, and combinations thereof.

7.22 any one of composition 3 or 7.1 to 7.21 for use, wherein the patient is a female.

7.23 any one of composition 3 or 7.1 to 7.21 for use, wherein the patient is male.

7.24 composition for use 3 or any one of 7.1 to 7.23, wherein the patient is at the age of 20-80 years, 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 at the time of treatment.

7.25 any of composition 3 or 7.1 to 7.24 for use, wherein the patient has a co-disease such as conjunctivitis, hordeolum, chalazion, blepharitis, blepharoedema, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

7.26 any one of composition 3 or 7.1 to 7.25 for use, wherein the patient has keratoconjunctivitis sicca, which is caused by a comorbid treatment, for example with any one or more of: isotretinoin, a sedative, a diuretic, a tricyclic antidepressant, an antihypertensive, an anticholinergic, an oral contraceptive, an antihistamine, a nasal decongestant, a beta-adrenergic antagonist, a phenothiazine, an atropine opioid (e.g., morphine), optionally wherein any such treatment is simultaneous or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

7.27 any of composition 3 or 7.1 to 7.26 for use, wherein the patient has keratoconjunctivitis sicca resulting from an ocular surgical intervention, such as corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ocular surgery is simultaneous or prior.

7.28 any one of composition 3 or 7.1 to 7.27 for use, wherein the patient is concurrently receiving treatment with another topical ophthalmic drug, such as an antibiotic, antifungal, corticosteroid, immunosuppressive agent, sympathomimetic, anesthetic, antihistamine, or any combination thereof.

7.29 any one of composition 3 or 7.1 to 7.28 for use, wherein the patient is a contact lens wearer.

7.30 any one of composition 3 or 7.1 to 7.29 for use, wherein the patient is non-responsive or insufficiently responsive to prior treatment for keratoconjunctivitis sicca (dry eye disease).

7.31 composition for use 7.30, wherein the prior treatment comprises one or more of the following methods of treatment: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporin), topical corticosteroid administration, or topical aqueous artificial tear administration.

7.32 any of compositions 3 or 7.1 to 7.31 for use, wherein the method is effective

i. Reducing ocular surface damage in the whole corneal region by at least 3 orders and/or

Reducing ocular surface damage of the central corneal region by at least grade 1

As determined by grading the corneal zone via fluorescein staining of the cornea according to the american national eye research scale.

7.33 composition for use 7.32, wherein the composition is effective within 2 weeks, preferably within 4 weeks, more preferably within 8 weeks of treatment.

In one embodiment of composition 3 for use or any of its subsequent embodiments (i.e., compositions 7.1 to 7.33 for use), there is provided a composition for use in treating (reducing) ocular surface damage of one or more corneal regions and for treating (reducing the symptoms of) the severity of dryness, wherein the composition consists essentially of (or consists of) 1-perfluorohexyloctane and optionally up to about 3% by weight of 2-perfluorohexyloctane, and wherein the composition is administered to the eye of a patient in need thereof in a single drop of about 10-12 μ Ι up to 4 times per day, and wherein the patient is characterized by a Schirmer I test of equal to or greater than 10 mm.

In an eighth aspect, in relation to the fourth aspect, the present disclosure further provides a composition for use in treating (reducing) ocular surface nerve sensation or one or more symptoms associated therewith (composition 4 for use), wherein the method comprises the steps of: about 10-12 μ l of a single drop of a composition consisting of (or consisting essentially of) 1-perfluorohexyloctane, optionally containing up to about 1% by weight of 2-perfluorohexyloctane, is administered to the eye of a patient in need thereof up to 4 times per day. Further embodiments of the disclosure provide the following:

8.1 composition 4 for use, wherein the composition consists essentially of 1-perfluorohexyloctane and optionally up to about 1 weight percent 2-perfluorohexyloctane.

8.2 composition 4 or 8.1 for use, wherein the composition consists essentially of 1-perfluorohexyloctane.

8.3 composition for use 4 or any one of 8.1 to 8.2, wherein the composition is administered to the eye of the patient in a single drop of 10-11 μ Ι, preferably in a single drop of about 11 μ Ι.

8.4 composition for use 4 or any one of 8.1 to 8.3, wherein the composition is administered to the eye of the patient four times daily.

8.5 composition for use 4 or any one of 8.1 to 8.4, wherein the composition for use is effective to treat ocular surface nerve sensation or one or more symptoms associated therewith.

8.6 composition for use 4 or any one of 8.1 to 8.5, wherein the composition for use is effective in protecting ocular surface nerves.

8.7 composition for use 4 or any one of 8.1 to 8.6, wherein the composition for use is effective in treating (reducing) pathological signaling of the ocular surface nerve.

8.8 composition for use 4 or any one of 8.1 to 8.7, wherein the composition for use is effective within 2, 4 or 8 weeks after the composition is first administered to the eye of a patient.

8.9 composition for use 4 or any one of 8.1 to 8.8, wherein the patient has keratoconjunctivitis sicca (dry eye disease) and/or keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or evaporative keratoconjunctivitis sicca associated with meibomian gland dysfunction (dry eye disease) and/or meibomian gland dysfunction.

8.10 composition for use 4 or any one of 8.1 to 8.9, wherein the ocular surface damage does not result from cataract surgery.

8.11 composition for use 4 or any one of 8.1 to 8.9, wherein the ocular surface damage is from cataract surgery.

8.12 composition for use 4 or any one of 8.1 to 8.11, wherein the ocular surface nerves are selected from nerves at the cornea and/or conjunctival surface.

8.13 composition for use 4 or any one of 8.1 to 8.12, wherein the one or more symptoms associated with ocular surface nerve sensation is selected from the group consisting of gritty eye sensation, photosensitivity of the eye (photophobia), ocular pain or soreness.

8.14 any one of composition 4 or 8.1 to 8.13 for use, wherein the patient is characterized by one or more symptoms selected from the group consisting of:

i. the eye feels gritty, the eye is sensitive to light (photophobia) and/or one or more symptoms of ocular pain or soreness, an

Total corneal fluorescein staining (NEI scale) between 5 and 9.

8.15 composition for use 4 or any one of 8.1 to 8.14, wherein the patient is a female.

8.16 any of composition 4 or 8.1 to 8.14 for use, wherein the patient is male.

8.17 composition for use 4 or any of 8.1 to 8.16, wherein the patient is at the age of 20-80 years, 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 at the time of treatment.

8.18 composition for use 4 or any one of 8.1 to 8.17, wherein the patient has a co-disease such as conjunctivitis, hordeolum, chalazion, blepharitis, blepharoedema, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

8.19 composition 4 or any of 8.1 to 8.18 for use, wherein the patient has keratoconjunctivitis sicca, the keratoconjunctivitis sicca resulting from a co-morbid treatment, for example with any one or more of: isotretinoin, a sedative, a diuretic, a tricyclic antidepressant, an antihypertensive, an anticholinergic, an oral contraceptive, an antihistamine, a nasal decongestant, a beta-adrenergic antagonist, a phenothiazine, an atropine opioid (e.g., morphine), optionally wherein any such treatment is simultaneous or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

8.20 any of composition 4 or 8.1 to 8.19 for use, wherein the patient has keratoconjunctivitis sicca resulting from an ocular surgical intervention, such as corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ocular surgery is simultaneous or prior.

8.21 any one of composition 4 or 8.1 to 8.20 for use, wherein the patient is concurrently receiving treatment with another topical ophthalmic drug, such as an antibiotic, antifungal, corticosteroid, immunosuppressive agent, sympathomimetic, anesthetic, antihistamine, or any combination thereof.

8.22 composition for use 4 or any one of 8.1 to 8.21, wherein the patient is a contact lens wearer.

8.23 composition for use 4 or any one of 8.1 to 8.22, wherein the patient is non-responsive or insufficiently responsive to prior treatment for keratoconjunctivitis sicca (dry eye disease).

8.24 composition for use 8.23, wherein the prior treatment comprises one or more of the following methods of treatment: topical aqueous immunosuppressant administration (e.g., topical aqueous cyclosporin), topical corticosteroid administration, or topical aqueous artificial tear administration.

Keratoconjunctivitis sicca is a complex, multifaceted disease or condition as described above. It is also known as dry eye syndrome, Dry Eye Disease (DED), or tear dysfunction syndrome. The water-deficient DED, evaporative DED, is within the scope of keratoconjunctivitis sicca and forms a particular subtype thereof. SkygrenSyndromes, lacrimal gland insufficiency, meibomian gland disease, meibomian gland dysfunction and other disorders fall within the scope of keratoconjunctivitis sicca, and are a direct or indirect cause thereof.

Meibomian gland disease encompasses a wide range of meibomian gland disorders, including neoplasia and congenital disorders. Meibomian gland dysfunction, on the other hand, is understood to be an abnormality of the meibomian glands, which is usually characterized by obstruction of the glandular vessels and/or by changes (qualitative and/or quantitative) in the secretion of the glands. Generally, a disorder or disease state that causes or results in abnormal, decreased, or increased delivery of lipids to the tear film can cause keratoconjunctivitis sicca and its associated symptoms.

Symptoms of keratoconjunctivitis sicca include dry eyes, itching, gritty feel, or sandy feel; a foreign body sensation; pain or soreness; stinging or burning; itching; (ii) increased blinking; eye fatigue; photophobia; blurred vision; redness; discharging mucus; contact lens intolerance; excessive reflex tearing. In addition to the symptoms of keratoconjunctivitis sicca as described, patients with meibomian gland dysfunction may experience symptoms including itching, redness, swelling, pain or soreness, discharge accumulation or crusting, particularly at the eyelid margin. It is understood that not all patients with keratoconjunctivitis sicca exhibit all symptoms simultaneously. Thus, there is currently no unified set of criteria for diagnosing the disease. It is also understood that the patient may have one or more subtypes of keratoconjunctivitis sicca, or one or more conditions or disease pathways that cause keratoconjunctivitis sicca. It is important to note, however, that any aspect, symptom, or pathophysiological consequence of dry eye can be addressed within the scope of the present invention.

Preferably, the patient to be treated with the methods and/or compositions used according to the present disclosure is a human patient.

According to a preferred embodiment, the patient to be treated with the methods and/or compositions used according to the present disclosure suffers from evaporative dry eye disease associated with meibomian gland dysfunction (keratoconjunctivitis sicca).

Semifluorinated alkanes are linear or branched alkanes in which some of the hydrogen atoms have been replaced by fluorine. The semifluorinated alkanes (SFA) used in the present disclosure are composed of at least one non-fluorinated hydrocarbon segment and at least one perfluorinated hydrocarbon segment, and are of the general formula F (CF)₂)_n(CH₂)_mH, the method is described. Another nomenclature that may be used herein is to refer to the above SFA having two segments as RFRH, where RF indicates a perfluorinated hydrocarbon segment and RH indicates a non-fluorinated segment. Alternatively, the compound may be referred to as FnHm, where F means a perfluorinated hydrocarbon segment, H means a non-fluorinated segment, and n and m are the number of carbon atoms of the respective segment. For example, F6H8 was used for 1-perfluorohexyloctane. Furthermore, this nomenclature is generally used for compounds having linear segments. Accordingly, unless otherwise indicated, it should be assumed that F3H3 means 1-perfluoropropylpropane, rather than 2-perfluoropropylpropane, 1-perfluoroisopropylpropane or 2-perfluoroisopropylpropane.

In some embodiments, the composition comprising a semifluorinated alkane as defined in the context of the present disclosure is free of active ingredient or is a drug-free composition, i.e. free of any pharmaceutically active drug useful in ophthalmic therapy. In particular embodiments, the composition is free of or excludes a therapeutically effective amount of any active ingredient or pharmaceutically active drug substance, e.g., useful for ophthalmic treatment. As used herein, active ingredient refers to any type of pharmaceutically active compound or derivative that can be used for the prevention, diagnosis, stabilization, treatment, or management in general of a disorder or disease. A therapeutically effective amount refers to a dose, concentration, or intensity that is useful for producing a desired pharmacological effect. As used herein, a composition according to the present disclosure that is "free of active ingredient" or "free of drug substance" or "free of any pharmaceutically active drug substance that is useful for ophthalmic treatment" or a similar variant thereof is a composition that comprises at least one or more semifluorinated alkanes, but does not include any other pharmaceutically active ingredient or drug substance that is useful, or active, for example, for ophthalmic treatment.

In certain jurisdictions, 1-perfluorohexyloctane may be considered an active pharmaceutical ingredient. Thus, a composition according to the present disclosure that is "free of active ingredient" or "free of drug substance" or "free of any pharmaceutically active drug substance that may be used in ophthalmic treatment" or a similar variant thereof is a composition comprising at least 1-perfluorohexyloctane and optionally 2-perfluorohexyloctane, but does not comprise any other pharmaceutically active ingredient or drug substance that may be used in ophthalmic treatment or that is active in ophthalmic treatment, for example. In other words, the composition according to the present disclosure does not comprise any active pharmaceutical ingredient other than 1-perfluorohexyloctane and optionally 2-perfluorohexyloctane.

SFAs of the present disclosure are 1-perfluorohexyloctane (F6H8) and optionally 2-perfluorohexyloctane, and in particular embodiments, SFAs are 1-perfluorohexyloctane (F (CF)₂)₆(CH₂)₈H；F6H8)。

In some embodiments, the composition may further comprise a second SFA, i.e., 2-perfluorohexyloctane (F (CF)₂)₆(CH(CH3))(CH₂)₆H)。

Liquid SFAs are chemically and physiologically inert, colorless and stable. They typically have a density in the range of 1.1 to 1.7g/cm³(e.g., density of F6H8 is 1.35g/cm³) And its surface tension can be as low as 19 mN/m. F (CF)₂)_n(CH₂)_mSFAs of the H type are insoluble in water but some areAmphiphilicity, whose increase in lipophilicity is associated with an increase in the size of the non-fluorinated segment.

Liquid SFAs of RFRH type are commercially used for unrolling and reapplication of the retina, as a vitreous humor replacement for long-term tamponade (h.meinert et al, European Journal of opthalmology, volume 10 (3), page 189-. They have also been used experimentally as blood substitutes (H.Meiinert et al, Biomaterials, Art specialty Cells, and Immobilisation Biotechnology, Vol.21 (5), pp.583-95, 1993). These applications have established SFA as a physiologically well tolerated compound.

As shown in preclinical testing, the eyes are well-tolerated for SFA. In contrast, organic or non-aqueous solvents (possibly excluding oily compounds) are often very irritating or even severely damaging when topically applied to the eye.

Furthermore, SFAs exhibit refractive indices in the range of 1.29 to 1.35, which are better compatible with the goal of minimal visual impact, and therefore cause little blur, compared to oily carriers or vehicles in topically applied ophthalmic compositions.

The SFA compositions of the present disclosure have several useful functional effects when applied to the eye. The semifluorinated alkanes are well mixed and/or dissolved with non-polar and lipophilic substances. It is suggested that SFAs (e.g., F (CF)) as defined in the context of this disclosure₂)₆(CH₂)₈H (F6H8) and F (CF)₂)₆(CH(CH₃))(CH₂)₆H (2-perfluorohexyloctane)) may be particularly useful for dissolving meibum lipids and removing abnormal and obstructive meibum found in obstructed meibomian ducts.

Meibum is a lipid secretion from the meibomian ducts and is usually secreted in the form of a clear fluid containing a complex mixture of polar and non-polar lipids (such as cholesterol and wax esters, acyl glycerides, free fatty acids and phospholipids). In its dysfunctional state, meibum-producing glands can extrude secretions with altered composition of those lipidsThe secretions exhibit increased viscosity and may also contain particulate cellular material. Such secretions can block the ducts of the glands and may not be effective in forming a functionally stable and continuous lipid layer of the tear film, resulting in lipid tear film deficiencies and disorders and symptoms of keratoconjunctivitis sicca. Comprising the formula F (CF) as defined in the context of the present disclosure₂)_n(CH₂)_mThe semi-fluorinated ophthalmic composition of H is effective to dissolve meibum, and in particular to dissolve abnormal (e.g., sticky) meibum that occludes the meibomian glands and/or meibomian gland ducts.

Additionally, the ophthalmic compositions of the present disclosure may also serve as a replacement, substitute, or supplement to the tear film lipid layer. The SFA compositions of the present disclosure may have a lubricating as well as protective effect for patients with dry eye symptoms. SFA compositions are believed to be capable of forming a protective film on the corneal surface and preventing aqueous evaporative loss of the tear film.

In one embodiment, an ophthalmic SFA composition as defined in the present disclosure may serve as a replacement, substitute, or supplement to the tear film lipid layer, e.g., as a lubricant and/or to form a protective film, and also effectively dissolve meibum, and in particular, abnormal (e.g., sticky) meibum that blocks the meibomian glands and/or meibomian gland ducts.

In addition, SFAs exhibit significant wetting and spreading behavior, whereby they can be quickly and efficiently spread over the corneal surface and conjunctiva. This pronounced wetting and spreading behavior causes the SFA to quickly and completely disperse from the administered eye drops, further allowing the SFA to enter the meibomian ducts on the upper and/or lower eyelids. SFAs, due to their high solvency power, can penetrate the meibomian gland embolism that is prevalent in Meibomian Gland Dysfunction (MGD) or disease, thereby allowing the embolism to be dissolved and removed, restoring proper meibomian gland function.

Wetting refers to the ability of a liquid to establish and maintain contact with a solid surface by intermolecular interactions when two molecules are brought together. The balance between adhesion and cohesion determines the degree of wetting. The higher the adhesion force compared to the cohesion, the more droplets will spread across the surface of the solid material. In contrast, very high cohesion within the liquid will cause the droplets to form spheres, thereby avoiding contact with the surface. Similarly, spreading may also occur at the interface of two liquids in contact with each other.

A measure of wetting and spreading is the contact angle theta. The contact angle is the angle at which a liquid-vapor interface meets a solid-liquid or liquid-liquid interface. The tendency of the droplets to spread outward increases as the contact angle decreases. Thus, the contact angle provides an inverse measure of wettability.

A low contact angle of less than 90 ° indicates high wettability and/or spreading, while a higher contact angle indicates poor wettability and spreading. Perfect wetting and spreading resulted in a contact angle of 0 °, also reported as no measurable contact angle.

The enhanced spreading behavior and stable film properties of such SFA-containing ophthalmic compositions are particularly advantageous for treating dry eye disorders. A droplet applied to the ocular surface can cause the SFA mixture composition to rapidly spread and form a film on the corneal surface. A stable film that does not break immediately may provide a more durable lubricating effect on the ocular surface. Efficient spreading not only distributes the SFA more effectively on the ocular surface, but also to more distant ocular tissues, such as the meibomian or lacrimal glands.

One of the results is a significant reduction in the patient's reliance on blinking mechanisms (which may be ineffective or hindered by diseased states) for spreading the composition on the ocular surface. It is believed that the compositions of the present disclosure can therefore be applied to the ocular surface more efficiently than conventional formulations that are substantially water-based and have poor spreading behavior. Thus, less frequent applications to alleviate dry eye can be achieved using these compositions.

In particular, the compositions of the present disclosure as described in the embodiments above may be used to treat patients who are unresponsive to traditional physical methods of treating meibomian gland dysfunction or dry eye disease caused or exacerbated by meibomian gland dysfunction, such as physical or forced extrusion of meibum or meibum obstructions from the meibomian glands; applying heat, for example to the eyelid (thermotherapy); physical extrusion and heat therapy, eyelid scrub or intratubular probing of the meibomian gland orifice were performed simultaneously. Unresponsive to treatment may refer to the presence of a persistent disorder, progression, or recurrence of meibomian gland dysfunction and its associated symptoms in a patient despite a prescribed or recommended treatment period, e.g., using traditional methods of treatment. The use of the compositions and methods of treatment of the present invention according to the present disclosure may be used in place of, or as an alternative to, such conventional methods, which may often need to be performed at the physician's office and are inconvenient and/or intolerable due to pain during the application of these physical methods.

In another aspect, the compositions of the present disclosure may be used to treat such conditions as described in the embodiments above, where the patient is unresponsive to treatment with an aqueous ophthalmic eye drop composition. In particular, the compositions may be used to treat patients who have meibomian gland dysfunction and who are unresponsive to treatment with water-based ophthalmic eye drop compositions (e.g., emulsions) or aqueous solutions (such as tear supplements or tear substitutes), and who, despite the course of treatment of such compositions, may have a persistent disorder, progression, or recurrence of dry eye disease or MGD or symptoms thereof.

Another advantage of using an ophthalmic composition comprising an SFA is that the SFA is capable of forming very small droplets, for example droplets of a volume of about 10-12 μ l or 10-11 μ l or 11 μ l, when dispensed from a conventional dropper, such as a conventional ophthalmic dropper. Without being bound by theory, it is believed that the droplet size is a result of the unique characteristic interactions of the SFA in its density, viscosity and surface tension. Small drops or volumes of administration are considered to be very advantageous for topical administration into the eye because the capacity of the lacrimal sac to receive and retain fluid is very limited. In fact, it is quite common that the administration of conventional eye drop formulations based on water or oil immediately results in the expulsion of most of the administered drug as well as some tears. At the same time, there is a risk that some of the administered dose will be absorbed systemically through the nasolacrimal duct.

The present disclosure also provides a means of formulating a microbiologically stable non-aqueous ophthalmic composition. Aqueous ophthalmic compositions are susceptible to bacterial contamination. In contrast, SFA has bacteriostatic properties and does not support microbial growth. Thus, preservative-free ophthalmic compositions can be formulated that are better tolerated by many patients, particularly patients with keratoconjunctivitis sicca. Such compositions also do not promote bacterial infection of the eyelid margin in patients, for example, with meibomian gland obstruction or blockage.

Ocular tissue includes any ocular anatomical surface that is or may be (i.e., by non-surgical means) locally exposed. Optionally, the composition is administered as a single drop to the cornea or conjunctiva. Ocular tissues include, but are not limited to, the cornea, conjunctiva (bulbar and palpebral conjunctiva), lacrimal glands (including the lacrimal duct and lacrimal sac), meibomian glands, and sclera.

In some embodiments, the compositions of the present disclosure can be used to reduce or alleviate ocular symptoms associated with ophthalmic disorders or conditions, including keratoconjunctivitis sicca and meibomian gland dysfunction. For example, the compositions may be used in combination with medicaments comprising an active ingredient whose frequency of administration is generally limited by tolerability or safety considerations. The composition is useful for reducing or alleviating any dry, irritated or uncomfortable feeling of the eye not associated with disease. The composition can be used simultaneously or in combination with an ophthalmic composition (e.g., immunosuppressant eye drops) having a pharmaceutically active ingredient intended to cure or treat the underlying pathogenic pathway of ophthalmic diseases.

In some embodiments, the compositions of the present disclosure may be used as a cleaning solution for the eye or ocular tissue. The composition is used to clean or help remove or rinse away any accumulated debris or discharge, such as meibum secretions from the eyelids, eyelid margin, eyelashes, or eye seams. The SFA composition is able to spread more easily than aqueous formulations, and thus is able to reach areas where the eyelid anatomy is more difficult to access. In a particular embodiment, the composition for use as a cleaning solution is formulated for administration as a spray. This is useful for patients who are unwilling or unable to apply the composition via eye drops.

Optionally, the compositions of the present disclosure are highly stable, anhydrous, preservative-free.

All patents, publications, and other references mentioned herein are hereby incorporated by reference in their entirety.

Examples

Example 1: clinical study in the United states

A phase 2, multicenter, randomized, double-blind, saline-controlled study was conducted to evaluate the effect of 1-perfluorohexyloctane (NOV03) on signs and symptoms of Dry Eye Disease (DED) under two different dosing regimens. This study was conducted in 11 study cities in the united states. The study was reviewed and approved by the respective ethical committee and registered at www.clinicaltrials.gov (NCT 03333057).

The main objective of the study was to evaluate the effectiveness, safety and tolerability of an ophthalmic composition consisting essentially of 1-perfluorohexyloctane (NOV03) under two different dosing regimens (QID, BID) in subjects suffering from dry eye compared to physiological saline solution. A secondary objective was to compare the effect of an ophthalmic composition consisting essentially of 1-perfluorohexyloctane (NOV03) and a physiological saline solution on signs and symptoms of dry eye under two different dosage regimens and to evaluate the pharmacokinetics 57 days after administration.

And (3) inclusion standard:

the subject must:

a. the age is at least 18 years.

b. Written informed consent was provided.

c. At least 6 months prior to visit 0, subjects reported a history of dry eye disease in both eyes.

d. Tear Film Break Up Time (TFBUT) was ≦ 5 seconds for visit 0 and visit 1.

e. Total Ocular Surface Disease Index (OSDI) ≧ 25 at visit 0 and visit 1.

f. At visit 0 and visit 1, the Schirmer test I was ≧ 5 mm.

g. Meibomian Gland Dysfunction (MGD), defined as MGD score ≧ 3 at visit 0 and visit 1(5 central gland secretions on the lower eyelid will be evaluated, each will be scored 0-3; 0 ═ normal, 1 ═ viscous/yellow, whitish, granular, 2 ═ paste; 3 ═ none/occluded; total score range 0-15).

h. At visit 0 and visit 1, the total corneal fluorescein staining score was 4. ltoreq. X.ltoreq.11 (i.e., the sum of inferior, superior, central, nasal and temporal) according to the American national institute of ophthalmology (NEI) grading.

i. At visit 0 and visit 1, at least one eye (the same eye) meets all of the above criteria d, f, g, and h.

j. Indications can and are willing to be followed, including participation in all research assessments and visits.

Exclusion criteria: (section selection)

The subject must not have the following:

a. female who is pregnant, lactating or scheduled to become pregnant

b. If fertility is available, there is a reluctance to submit blood pregnancy tests (or early termination of visits) at screening and last visit, or to use acceptable means of birth control

c. In screening, clinically significant slit lamp findings or eyelid anatomical abnormalities

d. Malignant tumor of eye/eye periphery

e. History of herpetic keratitis

f. Active ocular allergies or ocular allergies expected to be active during the study

g. Persistent ocular or systemic infection

h. Contact lens wear within 1 month prior to screening or anticipated use during the study

i. Intraocular surgery or ocular laser surgery was performed within the first 6 months, or ocular and/or eyelid surgery was planned during the study

j. There is an uncontrolled systemic disease

k. Known allergies and/or sensitivities to study drug or saline composition

Within 2 months prior to screening, any local steroid therapy, local cyclosporine, leticistat (lifitegrast), serum tears, or local anti-glaucoma medication is used.

Subjects eligible for randomization received one of the following treatments administered bilaterally from visit 1 to visit 4:

after receiving training on how to use the treatments, patients were advised to administer 1 drop of the respective treatment in each of both eyes, 4 times daily or 2 times accordingly.

The drop volume of a single drop of NOV03 (ophthalmic composition consisting essentially of 1-perfluorohexyloctane; d ═ 1.35g/ml) relates to 10-12 μ l, converted to 13.5-16.2mg for a single dose per eye, or to 27-32.4mg daily (20-24 μ l) per eye for 2 treatments per day (BID), or correspondingly to 54-64.8mg daily (40-48 μ l) per eye for 4 treatments per day (QID).

The drop volume of a single drop of physiological saline (0.9% sodium chloride solution) relates to 35-40. mu.l, converted to a daily dose of 70-80. mu.l/eye for 2 treatments per day (BID), or correspondingly to a daily dose of 140-.

In the following, the treatment with NOV03 (ophthalmic composition consisting essentially of 1-perfluorohexyloctane) is also referred to as "treatment group", while the treatment with saline (0.9% sodium chloride solution) is also referred to as "placebo".

Visit schedule:

this study consisted of two phases: a 14 day screening period and a 57 day treatment period.

Screening (visit 0): subjects were asked to sign an informed consent form within 14 days prior to visit 1, before completing any study-related procedures. At the screening visit, vital signs will be assessed and subjects will provide blood for safety laboratory testing. They also received a series of tests to confirm the extent and severity of their symptoms and objective signs of dry eye. At least one eye must meet the following objective criteria: tear film break-up time of 5 seconds or less, Schirmer test of 5mm or more and is defined asMeibomian Gland Dysfunction (MGD) with an MGD score of 3 or more, inclusive.

Baseline visit day 1 (visit 1 st): on day 1 (visit 1), eligible subjects were evaluated for baseline signs and symptoms of dry eye. After randomization, the subject will provide a blood sample for PK at the selected site. Subjects were given a 14-day supply and self-administered a single drop of study drug in each eye in the clinic. Each subject was given a diary to record the doses they took. The investigator helped the subject know how to use the diary and when the remaining dose should be taken.

2 to 4 timesVisiting and watching: subjects returned to the clinic on days 15 ± 1 (visit 2), 29 ± 2 (visit 3) and 57 ± 2 (visit 4) to evaluate signs and symptoms of dry eye. During this period, subjects QID and BID were administered NOV03 or saline solution. The unused portion of the study drug should be returned to the clinic and a new study drug kit distributed. The diary is checked. At visit 4, vital signs were evaluated and a second blood draw was performed at the selected site for PK. Diaries were collected at the clinics during each visit. After all 4 visit assessments had been completed, subjects exited the study.

Patient and examination parameters

336 patients meeting inclusion/exclusion criteria were selected by the study site. The study population represents a highly symptomatic Dry Eye (DED) population with significant MGD involvement as evidenced by low TBUT (average TBUT about 3), high OSDI score (average OSDI about 55), high VAS dryness severity score (average VAS dryness severity score about 69), and high MGD score (average MGD score about 7.6) at baseline.

Parameters determined at baseline and follow-up visits included the OSDI questionnaire, the 10-item Visual Analog Scale (VAS) questionnaire, visual acuity (ETDRS), slit lamp biomicroscope, TFBUT, fluorescein-stained NEI grading, lissamine green-stained oxford scale, meibomian gland assessment (MGD score), and Schirmer test I (no anesthesia).

323 patients completed the study, with 110 patients in NOV03/QID, 105 patients in NOV03/BID, and 108 patients in the saline/QID + BID group. Statistical analysis was performed on the examination parameters to identify statistically significant differences between the treatment and placebo groups.

(a)Corneal fluorescein staining

For staining, 5 μ L of a 2% preservative-free fluorescein sodium solution was instilled into the subconjunctival fornix of each eye (fluorescein strips could be used, but only at visit 0). To achieve maximum fluorescence, fluorescein staining was evaluated after waiting about 2-3 minutes after dropping. The ability to grade fluorescein staining was enhanced using a Wratten #12 yellow filter. Staining was graded using the NEI (national institute of ophthalmology) grading scale. Only staining of the cornea was graded. Digital images of fluorescein staining can be taken for digital analysis.

The ocular surface damage rating for each eye based on the measured fluorescein uptake will be scored for each of the five corneal regions based on the NEI/Industry Workshop Scale (Industry Workshop Scale). In the NEI/industry seminar scale, the cornea of the right eye (often denoted as OD) and the cornea of the left eye (often denoted as OS) were each evaluated by illustrating as a substantially circular area divided into 5 areas comprising: a central circular area, denoted as the central cornea area (area 1), with the remaining circumferential area divided into four quadrants, representing the upper (area 2), lower (area 5) cornea areas as the upper and lower quadrants, respectively, and the nasal (area 4, located relatively close to the subject's nose) and temporal (area 3, located relatively close to the subject's temporal) cornea areas as the lateral quadrants.

Surface lesions were defined for each of five regions (central, superior, temporal, nasal and inferior) on each cornea using a standardized grading system of 0-3 according to the NEI grading scale. When no fluorescein staining is present, a rating of 0 will be assigned. Grades 1, 2 and 3 define an increasing density and extent of fluorescein staining observed, with a maximum total score of 15 for each eye.

(b)Ocular surface and disease index (OSD)I) Questionnaire

Ocular surface disease indexPerhaps the most commonly used investigative tool for assessing the severity of ocular surface disease in dry eye studies.Was created by the outcome Research Group (Outcomes Research Group) at Allergan Inc. with the aim of rapidly assessing the ocular irritation symptoms of dry eye and how they affect vision-related functions. The 12 questionnaires assessed dry eye symptoms and their effect on vision-related functions over the past week in the life of the patient. The questionnaire has 3 subscales: ocular symptoms, vision-related functions, and environmental cues. Patients rated their responses on a scale of 0 to 4, where 0 corresponds to "none at any time" and 4 corresponds to "all at time". A final score in the range of 0 to 100 was calculated.

These questions evaluated the following: dry eye symptoms experienced by patients over the past week: photosensitivity, gritty sensation, ocular pain or soreness, blurring and poor vision; vision-related functions in the past week with respect to the following questions: reading, driving at night, working on a computer or banking machine, watching television; and discomfort experienced during the following situations within the past week, in terms of environmental factors or causes: in windy conditions, in low humidity areas and in air conditioned areas.

Subtotal is obtained for all questions and the total number of questions answered. The OSDI index is evaluated on a scale of 0 to 100, where a higher score indicates greater disability. The OSDI index is calculated by multiplying the sum of the scores by a factor of 25 divided by the total number of questions answered. Higher scores indicate greater degree/severity and impact of dry eye.

(c)Visual Analog Scale (VAS); eye dryness score

The eye dryness score was determined based on 10 questionnaires provided to the subject, who was asked to assess ocular symptoms caused by eye dryness (binocular simultaneously) by: a vertical mark is placed on the horizontal line scale to indicate discomfort level (0% corresponds to "no dry" and 100% corresponds to "maximum dry"). The subjects were asked the severity of the following dry eye symptoms, representing dry symptoms corresponding to the first 8 questions in the VAS questionnaire below: dryness (corresponding to the first problem in the VAS questionnaire and also referred to herein and in the figures as "dryness severity"; where the terms "dryness" and "dryness severity" are used interchangeably herein as dry eye symptom designations), sticky feeling, burning/stinging, foreign body sensation, itching, blurred vision, photosensitivity, and pain.

Subjects will also be asked their awareness of their dry eye symptoms and their frequency of dry eye symptoms, questions 9-10 of the VAS questionnaire. The assessment of these problems is indicated by the subject by placing a vertical marker on the horizontal line scale to indicate the percentage of time or frequency of consciousness, where 0% corresponds to "never" and 100% corresponds to "all times".

All problematic scales evaluate line lengths of 100mm (10cm), with ratings provided every 10mm (10%, 20%, etc. are recommended).

(d)Tear Film Break Up Time (TFBUT)

For analysis, 5 μ L of a 2% preservative-free fluorescein sodium solution was instilled into the subconjunctival fornix of each eye (fluorescein strips could be used, but only at visit 0). To mix fluorescein well with the tear film, subjects were instructed to blink several times. To achieve maximum fluorescence, TFBUT was evaluated after waiting about 30 seconds after dropping.

The integrity of the tear film is monitored by means of a slit lamp, taking care of the time it takes for micelles to form starting from the time the eye is opened. TFBUT was measured in seconds for the right eye and subsequently the left eye using a stopwatch and digital image recording system. The ability to stage TFBUT was enhanced using a Wratten #12 yellow filter.

(e)Meibomian gland assessment (MGD score)

Meibomian Gland Dysfunction (MGD) is an obstruction or other abnormality of the meibomian glands, so they do not secrete sufficient oil into the tears. Then MGD is the main cause of dry eye syndrome because tear fluid evaporates too quickly.

For the analysis of meibum, meibomian gland evaluation bar (Korb)-a rod; tear Science, moryvale, usa) allows reproducible and standardized application of force (1.25g/mm 2). The MGE-bars were used according to the manufacturer's instructions.

For the analysis, the secretion of 5 central meibomian glands (meibum) on the lower eyelid was obtained by pressing the glands with a standard force of 1.25g/mm2 using an MGE-rod and evaluated. Expressed secretions (meibum) were scored on a scale of 0 to 3, where 0 is normal and 1 is viscous/yellow, whitish, grainy; 2, paste-like; no/clogging. Thus, the MGD score represents the sum of the scores of the 5 central meibomian glands, thus the total score ranges from 0-15.

Herein, an MGD score equal to or higher than 6 relates to at least 3 of the 5 central meibomian glands appearing as pasty (viscous) material or being obstructed after the meibum is expressed from said glands by a standard force of about 1.0-2.0g/mm2, preferably by a standard force of about 1.25g/mm 2.

Furthermore, an MGD score equal to or higher than 7 relates to at least 2 of the 5 central meibomian glands appearing as pasty (viscous) material and at least 1 central meibomian gland appearing occluded after the expression of meibum from the gland by a standard force of about 1.0-2.0g/mm2, preferably by a standard force of about 1.25g/mm 2.

(f)Schirmer I test

The Schirmer I test (also referred to herein as Schirmer test I) is a simple test to assess aqueous tear production. In this test, a strip of filter paper was placed on the lower eyelid margin without anaesthesia, after 5 minutes the strip was removed and the amount of wetting was measured in millimeters. It is generally believed that a Schirmer I test of 5mm or less within 5min is associated with abnormal tear production (insufficient tear production). In another aspect, individuals characterized by a Schirmer I test equal to or greater than 10mm are considered to have normal tear production.

Results NOV 03-treatment (QID)

Examination parameters were compared between 4 treatments per day (QID) and placebo (saline solution; 0.9% sodium chloride solution; QID + BID) for NOV03 (ophthalmic composition consisting essentially of 1-perfluorohexyloctane; treatment group).

The present study demonstrates a relevant and statistically significant improvement in both signs and symptoms in a population of highly symptomatic Dry Eye Disease (DED) with significant MGD involvement when the patient's eyes are treated 4 times daily with 10-12 μ Ι of a single drop of an ophthalmic composition consisting essentially of 1-perfluorohexyloctane.

The study reached the pre-specified primary efficacy endpoint for total corneal fluorescein staining, demonstrating that the QID dosing regimen reduced ocular surface damage in the whole corneal region at 8 weeks.

In addition, significant improvements were also observed for the reduction of ocular surface damage in the central, nasal and temporal corneal regions, as evidenced by the corresponding fluorescein staining determinations of the central, nasal, temporal and inferior corneal regions. Notably, it is important to reduce ocular surface damage in the central corneal region because the central corneal region is centered on the visual axis and thus the improvement in this respect is directly related to the visual acuity of the patient. The upper cornea region did not show such a significant improvement in ocular surface damage [ see fig. 1(a) to 1(f) ].

The therapeutic effect associated with signs started surprisingly early (2 weeks) and was significant throughout the visit (at 4 weeks, 8 weeks).

Furthermore, the study showed a highly statistically significant improvement in various symptoms as compared to the placebo group, as determined by the eye dryness score (including "awareness of dryness", "severity of dryness", "frequency of dryness", "burning/stinging", "itching", "sensation of stickiness", "blurred vision", "sensation of foreign body", "photosensitivity") on the Visual Analog Scale (VAS). VAS symptoms "pain" did show higher variability and did not improve at the 4 week time point. [ see FIGS. 2(a) -2 (j) ]

Furthermore, the therapeutic effect associated with VAS symptoms started surprisingly early (2 weeks) and was significant throughout the visit (at 4 weeks, 8 weeks).

Furthermore, this study showed that various symptoms had a highly statistically significant improvement compared to the placebo group, as determined by Ocular Surface Disease Index (OSDI) scores, including total OSDI scores [ see figure 3 ].

In addition, significant improvement was observed for individual symptoms identified by the Ocular Surface Disease Index (OSDI) questionnaire as follows: "photosensitivity", "gritty eyes", "painful or sore eyes", "blurred vision", "poor vision", "reading problems", "night driving problems", "problems watching tv", "uncomfortable in windy conditions", "uncomfortable in low humidity areas" and "uncomfortable in air conditioned areas". OSDI symptoms "work with computers or banking machines (ATMs)" do show higher data variability and do not improve at the 4 and 8 week time points. [ see FIGS. 4(a) -4 (l) ].

Furthermore, the therapeutic effect associated with OSDI symptoms started surprisingly early (2 weeks) and was significant throughout the visit (at 4 weeks, 8 weeks).

NOV 03-treatment (QID) was found to be beneficial for patients who were highly symptomatic (i.e., characterized by a high OSDI score) and exhibited significant MGD involvement (i.e., characterized by a low TBUT or high MGD score) and/or moderate corneal ocular surface damage (i.e., characterized by moderate total corneal fluorescein staining).

It was further found that the response to NOV 03-treatment (QID) with respect to the improvement of the corneal staining parameters started very early and resulted in a surprisingly high response rate. Herein, an improvement of grade 3 or more in total corneal staining was found in 32% of patients after 2 weeks of treatment and in 42% of patients after 8 weeks. Notably, the improvement in central corneal staining was found to be grade 1 or greater in 39% of patients after 2 weeks of treatment and 50% of patients after 8 weeks, which translates into a significant reduction in visual impairment from evaporative dry eye associated with meibomian gland dysfunction.

The present study revealed that NOV 03-treatment (QID) is beneficial to a patient population that is highly symptomatic (i.e., characterized by a high OSDI score, i.e., between 38 and 72) and exhibits significant MGD involvement (i.e., characterized by a low TBUT, i.e., between 2.1 and 3.9 seconds; or a high MGD score, i.e., between 4.0 and 11.2) and/or moderate corneal ocular surface damage (i.e., characterized by moderate total corneal fluorescein staining, i.e., between 4.8 and 9.2) [ see fig. 1-4 ].

Thus, patients benefit in particular from NOV 03-treatment (QID) when one or more criteria selected from the following are met at baseline (before starting therapy): tear film break up time (TBUT) equal to or lower than 3 and/or Ocular Surface Disease Index (OSDI) higher than 57 and/or total corneal fluorescein total staining (NEI scale) between 5 and 9 and/or MGD score equal to or higher than 7[ see figure 5] and/or Schirmer I test greater than or equal to 10 mm.

Surprisingly, it was also found that individuals suffering from dry eye associated with meibomian gland dysfunction (e.g. having an MGD score equal to above 7) but characterized by relatively normal tear production (as indicated by a Schirmer I test score of greater than or equal to 10 mm) benefit from treatment with NOV 03-treatment (QID) [ see figure 6 ]. As described above, the Schirmer I test assesses aqueous tear production, and a threshold of 10mm or greater is generally indicative of unimpaired or normal tear production. Unexpectedly, significant changes from baseline, i.e., improvements in dry eye symptoms with respect to treating/reducing the severity of dryness, were observed for patients with relatively normal tear production levels.