Ophthalmic compositions comprising F6H8

Abstract

The present disclosure provides a method of treating keratoconjunctivitis sicca and / or meibomian gland dysfunction using an ophthalmic composition comprising a semifluorinated alkane, the method providing enrichment of the ophthalmic tissue for a semifluorinated alkane, and optionally delayed release of semi-fluorinated alkanes from enriched ocular tissue to the surface of cornea and / or conjunctiva and / or to meibomian glands.

Description

[0001] This application is a divisional application of Chinese patent application No. 201880064649.6 (application date: October 3, 2018, invention name: ophthalmic composition containing F6H8). Technical Field

[0002] The present disclosure relates to the field of ophthalmic compositions comprising semifluorinated alkanes, which can be used to treat keratoconjunctivitis sicca and / or meibomian gland dysfunction and symptoms associated therewith, and the method can provide enrichment of semifluorinated alkanes in ocular tissues. In some embodiments, the present invention provides a method for delayed release of semifluorinated alkanes from enriched ocular tissues to the surface of the cornea and / or conjunctiva and / or to the meibomian glands. Background Art

[0003] 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 can cause discomfort, visual disturbances, and often even ocular surface damage. Its prevalence varies greatly from region to region, and is estimated to range from about 7.4% in the United States to about 33% in Japan (JLGayton, Clinical Ophthalmology 2009: 3, 405-412). According to another estimate, there are about 3.2 million women and 1.05 million men suffering from keratoconjunctivitis sicca in the United States alone. If mild cases are also considered, there may be as many as 20 million affected people in the United States.

[0004] The main physiological function of the tear film is to lubricate the ocular surface and inner eyelid. In addition, it provides the ocular surface with the nutrients it needs and provides the eye with a smooth and regular optical surface. In addition, the tear film protects the ocular surface from pathogens through multiple mechanisms, including mechanical removal of foreign particles and through the antimicrobial substances it contains. Therefore, the loss of dynamic stability of the structure, composition, volume and distribution of the tear film and the clearance of the tear film can lead to the occurrence of dry eye disease.

[0005] The tear film is a dynamic structure composed of mucus, aqueous and lipid components. The innermost layer of the film is the mucus layer or mucus component, which is bound to the ocular epithelium through the interaction of mucin molecules produced by conjunctival goblet cells and by stratified squamous cells of the conjunctiva and cornea. The lubricating effect of the tear film is essentially based on the mucus layer and its composition.

[0006] Located above the mucus layer is the aqueous layer produced by the main and accessory lacrimal glands. Its main function is to hydrate the mucus component and help transport nutrients, electrolytes, antimicrobial compounds and oxygen to the ocular surface. The aqueous component contains water, electrolytes, lysozyme, lactoferrin, immunoglobulins (especially IgA), retinol, hepatocyte growth factor and epidermal growth factor as its important components.

[0007] The outermost layer is a lipid layer, which covers the water layer. The lipid layer is formed by meibum (a complex mixture of polar and non-polar lipids, including wax and cholesterol esters, phospholipids, diglycerides and triglycerides and hydrocarbons) secreted by the meibomian glands located at the tarsal plate of the eyelid and to some extent by the meibomian glands that pass into the eyelash follicles. A lipid mixture with a low melting point and a fluid state maintained at the temperature of the tissue and cornea is secreted into the marginal reservoir of the upper and lower eyelid edges. It should be understood that the blinking action helps to promote the diffusion and mixing of lipids in the lipid layer. The main effect of the lipid layer is mainly to reduce the evaporation rate of the water layer by evaporation, but it also plays a role in enhancing the spread of the tear film, forming a barrier to prevent tear film contamination and providing a clear optical surface. It has been proposed that the tear film stability increase is related to the thicker tear film lipid layer. Compared with what is seen in healthy eyes, patients with keratoconjunctivitis sicca (dry eye), particularly patients with functionally impaired meibomian glands, show meibum with abnormal composition.

[0008] Keratoconjunctivitis sicca is a complex, multifunctional disorder involving several interacting pathophysiological mechanisms that are only beginning to be understood. (HD Perry, Am. J. Man. Care 13:3, S79-S87, 2008). Two well-recognized mechanisms are tear hyperosmolarity and tear film instability, which are mutually reinforcing. Hyperosmolar tears can be caused by excessive tear film evaporation or reduced aqueous humor flow. This triggers an inflammatory cascade and leads to the release of inflammatory mediators into the tears, which, along with a variety of pathophysiological effects, ultimately lead to tear film instability and further increase in tear film evaporation. Therefore, tear film instability may be a result of hyperosmolarity. Alternatively, tear film instability may occur through its own etiological pathways, for example, through abnormalities in lipid layer composition (such as from meibomian gland disease).

[0009] The inflammatory cycle is one of the key processes that maintains and potentially drives dry eye disease. Depending on the severity of the condition, patients often develop reversible squamous intermediate and punctate erosions of the ocular epithelium. Secondary diseases whose development can be triggered by dry eye disease include filamentary keratitis, microbial keratitis, corneal neovascularization, and ocular surface keratinization.

[0010] Two main categories of dry eye disease (DED) have been distinguished, aqueous DED and evaporative DED. These conditions are not necessarily mutually exclusive.

[0011] Within the category of the aqueous form of DED, two major subtypes are distinguished, namely Sjögren's and non-Sjögren's. Patients with Sjögren's syndrome suffer from an autoimmune disease in which the tear glands are invaded by activated T cells, which leads not only to keratoconjunctivitis sicca but also to xerostomia. Patients with the non-Sjögren's form of aqueous DED often have tear gland insufficiency, blocked tear ducts or insufficient reflex secretion.

[0012] The second major category, evaporative DED, is also heterogeneous in some respects and can develop due to a variety of underlying causes. Causes associated with increased evaporative loss of the tear film include meibomian gland disease or dysfunction, eyelid foramen disorders, blink disorders (such as in Parkinson's disease), or ocular surface disorders (such as in allergic conjunctivitis). In particular, meibomian gland disease and dysfunction are commonly associated with evaporative dry eye. For example, meibomian gland dysfunction (also abbreviated as MGD) can lead to changes in the quantitative or qualitative secretion of lipid components required for the tear film. Meibum can also have an altered composition, enrichment of certain components and / or lack of other components compared to normal meibum. This can lead to changes in physical properties, such as abnormal viscosity or abnormal solubility. In turn, this can lead to an inability to form a stable and continuous tear film, followed by evaporative loss and hyperosmolarity. Meibomian gland dysfunction is often characterized by glandular obstruction and blockage due to excessive keratinization of the glands and increased viscosity of the meibum. Dysfunction may result from primary eyelid-related disease or from secondary disease caused by systemic conditions such as rosacea or seborrheic dermatitis.

[0013] The management of dry eye disease relies on both non-pharmacological and pharmacological approaches, and the choice of treatment depends largely on the severity of the disease state (MALemp, Am. J. Man. Care 14:3, S88-S101, 2008).

[0014] Moderate to more severe forms of keratoconjunctivitis sicca require medical treatment. However, few currently available medical therapies have been shown to be effective and / or have been approved by regulatory agencies. In the United States, the main medical treatment for moderate to severe keratoconjunctivitis sicca is the use of ciclosporin (ciclosporin A, also known as cyclosporine A), which is an approved drug in the form of an ophthalmic emulsion (Liyanda). ), is used to increase “tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca” (Liyanda prescribing information).

[0015] When only mild symptoms are present, nonpharmacological approaches can be used first to treat dry eye disease and its symptoms and also as palliative measures to support pharmacological and medical interventions. Nonpharmacological approaches include avoidance of exacerbating factors, such as avoidance of dry air, wind and drafts, tobacco smoke, and changes in work habits; eyelid hygiene; tear supplementation; and physical tear retention with the aid of punctal plugs or therapeutic contact lenses. Traditional measures, such as warm compresses, eyelid massage, or forceful gland compression, are also often recommended for cases of dry eye disease that are exacerbated or caused by meibomian gland dysfunction.

[0016] The main purpose of non-drug DED treatment is to use artificial tears for tear replacement. Most of the available products are designed as lubricants. In addition, they can act as carriers of nutrients and electrolytes (importantly potassium and bicarbonate), and some products attempt to modify physical parameters, such as increasing osmotic pressure in certain forms of DED. The main functional components of artificial tear compositions are agents that increase or adjust viscosity to increase residence time on the ocular surface and also exhibit lubricant function. Common compounds used for this purpose include carboxymethylcellulose and its sodium salt (CMC, carboxymethylcellulose), polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC, hydroxypropyl methylcellulose), hyaluronic acid and its sodium salt and hydroxypropyl guar gum.

[0017] Some artificial tears include lipids as substitutes for lipid components, and their purpose is to imitate the lipid layer of natural tear film, to reduce the tear evaporation rate. For example, US 5,981,607 discloses a composition for alleviating the symptoms associated with dry eye-based emulsions, which have higher fatty acid glycerides, such as castor oil, corn oil or sunflower oil or light mineral oil. However, these types of lipids are physically and biochemically poorly correlated with natural lipid compositions. In addition, under physiological conditions, the exact fate (exact fate) of the emulsion mixed with tears is not fully predictable, particularly considering that the volume and content of the tear film of patients with dry eye disease vary.

[0018] One of the drawbacks of such formulations containing oils for ocular administration is that they inherently can have a negative impact on vision. Whether used as oily solutions or oil-in-water emulsions, their refractive index is significantly different from that of physiological tears, leading to visual disturbances and blurring.

[0019] Moreover, in contrast to single-phase systems, emulsions can be more complex and difficult to manufacture, especially in sterile form. Typically, emulsions cannot be easily sterilized by heat treatment without negatively affecting the physical properties of the emulsion. On the other hand, aseptic processing is complex and expensive and is accompanied by a higher risk of failure, i.e., microbial contamination. Oil-in-water emulsions are also more susceptible to microbial contamination during use.

[0020] Preservatives that may be used in ophthalmic preparations are potentially harmful to the eye, particularly to the ocular surface, and should be avoided in the setting of dry eye disease. This is particularly important for patients with moderate to severe dry eye symptoms who may require frequent use for symptom relief, and for patients who require multiple preservative-containing topical medications.

[0021] Some manufacturers have attempted to avoid the preservation problem by relying on single-dose containers developed for administering non-preserved formulations. However, these are less cost-effective and less convenient for patients to handle than conventional multi-dose bottles. In addition, ophthalmic formulations using "vanishing" preservatives (such as sodium chlorite or sodium perborate) that convert to non-toxic ions and water after instillation and contact with the tear film may still irritate patients, especially those with serious illnesses who may not have sufficient tear volume to effectively degrade the preservatives.

[0022] WO 2011 / 073134 discloses an ophthalmic topical pharmaceutical composition for treating keratoconjunctivitis sicca, comprising an immunosuppressant macrolide such as cyclosporin A and a semifluorinated alkane. The semifluorinated alkane in the disclosed composition is used as a suitable liquid vehicle for delivering therapeutic drugs to the eye, and in particular has a high ability to dissolve poorly soluble compounds such as cyclosporin. However, in this role, the use of the semifluorinated alkane as a pharmaceutically inert solvent for the active therapeutic agent is only taught.

[0023] US 7,001,607 discloses a multi-microbubble 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 composition is spread on the cornea of ​​the eye only in the form of a liquid film on the cornea. Thus, for patients with dry eye symptoms caused by eyelid / blink disorders (e.g., as a result of Parkinson's disease), this composition cannot be used.

[0024] US2015-0224064A1 discloses semifluorinated alkane compositions for treating dry eye and symptoms and conditions associated therewith. The disclosed invention is primarily directed to compositions comprising a mixture of at least two different semifluorinated alkanes. These compositions can be administered to the eye or ocular tissue in patients such as those suffering from keratoconjunctivitis sicca and / or meibomian gland dysfunction. The publication does not disclose or suggest methods for providing any semifluorinated alkane enrichment in ocular tissue or delayed ocular release of the semifluorinated alkane.

[0025] Therefore, it is an object of the present invention to provide a composition for use in an improved and more effective method for treating keratoconjunctivitis sicca and / or keratoconjunctivitis sicca caused by meibomian gland dysfunction and / or meibomian gland dysfunction. Summary of the invention

[0026] The present invention provides novel methods for providing delayed ocular release of semifluorinated alkanes, for example, from ocular tissues enriched with semifluorinated alkanes as a result of treatment with an ophthalmic composition comprising the semifluorinated alkanes, wherein the semifluorinated alkanes are selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 8 H. In some embodiments, the composition comprises a single semifluorinated alkane, and optionally does not contain any pharmaceutically active drug that can be used for ocular treatment. In some embodiments, the composition consists of a single semifluorinated alkane. In some embodiments, the method comprises administering the composition to the eye of a patient in need thereof in an amount and / or frequency sufficient to enrich the semifluorinated alkane in the ocular tissue. In some embodiments, the composition is administered less than 4 times a day, for example, 3 times a day, or 2 times a day or 1 time a day, or less than 1 time a day (e.g., every other day).

[0027] In another aspect, the present disclosure provides a method for providing delayed ocular release of a semifluorinated alkane, for example from an ocular tissue enriched with a semifluorinated alkane and enriching a semifluorinated alkane in an ocular tissue and an ophthalmic composition comprising a semifluorinated alkane for use in the method, the use comprising topically administering an ophthalmic composition comprising a semifluorinated alkane to an eye of a patient in need thereof, wherein the semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 )8 H and F (CF 2 ) 8 (CH 2 ) 8 H.

[0028] In another aspect, the present disclosure provides an ophthalmic composition comprising a semifluorinated alkane selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 8 H, for use in a method for treating keratoconjunctivitis sicca (dry eye) and / or treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or for treating a condition of the conjunctiva or cornea, wherein the method comprises the step of topically administering the composition to the eye of a patient in need thereof at a dosage of a single drop per eye twice a day. In some embodiments, the ophthalmic composition used is composed of the semifluorinated alkane 1-perfluorohexyl-octane (F6H8).

[0029] In a further aspect, the present disclosure provides a method for treating keratoconjunctivitis sicca (dry eye) and / or treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or for treating a condition of the conjunctiva or cornea, wherein the method comprises the step of topically administering to the eye of a patient in need thereof a single drop per eye twice daily of an ophthalmic composition comprising a semifluorinated alkane selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 )6 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 8 H. In some embodiments, the method comprises administering a composition consisting of the semifluorinated alkane 1-perfluorohexyl-octane (F6H8).

[0030] Further, the objects of the present invention will become clear from the following description, examples and patent claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 (a) to 1(d). Assessment of ocular surface damage (fluorescein corneal staining, NEI scale grading) - depicts the changes in ocular surface damage of the cornea from baseline (Visit 1, Day 1) at Visit 2 (Week 2), Visit 3 (Week 4), and Visit 4 (Week 8), where Verum represents twice daily treatment (BID) with NOV03 (an ophthalmic composition consisting essentially of 1-perfluorohexyloctane; solid line) and Placebo represents saline solution (0.9% sodium chloride solution; QID+BID; dashed line).

[0032] Figure 1 (a) Depicts the change from baseline in ocular surface damage of total corneal area measured by fluorescein staining.

[0033] Figure 1 (b) Depicts the change from baseline in ocular surface damage in the central corneal area as measured by fluorescein staining.

[0034] Figure 1 (c) Depicts the change from baseline in ocular surface damage in the nasal corneal area as measured by fluorescein staining.

[0035] Figure 1 (d) Depicts the change from baseline in ocular surface damage in the temporal corneal region as measured by fluorescein staining.

[0036] Figure 2 (a) to 2(e). Assessment of dryness symptoms determined by Eye Dryness Score on a visual analogue scale (VAS). Changes from baseline (Visit 1, Day 1) at Visit 2 (Week 2), Visit 3 (Week 4), and Visit 4 (Week 8) are depicted, where real drug represents twice daily treatment (BID) with NOV03 (an ophthalmic composition consisting essentially of 1-perfluorohexyloctane; solid line) and placebo represents saline solution (0.9% sodium chloride solution; QID+BID; dashed line).

[0037] Figure 2 (a) Describes the change from baseline in the VAS for “severity of dryness”.

[0038] Figure 2 (b) Describes the changes in the VAS parameter regarding “frequency of dryness” from baseline to follow-up.

[0039] Figure 2 (c) Describes the changes in VAS parameters regarding “dryness awareness” from baseline to follow-up.

[0040] Figure 2 (d) Describes the changes in VAS parameters regarding “blurred vision” from baseline to follow-up.

[0041] Figure 2 (e) Describes the changes in the VAS parameters for “light sensitivity” from baseline to follow-up.

[0042] Figure 3 .Total Ocular Surface Disease Index (OSDI) - describes the change from baseline (Visit 1, Day 1) in total OSDI scores for Visit 2 (2 weeks), Visit 3 (4 weeks), and Visit 4 (8 weeks), where real drug represents twice daily treatment (BID) with NOV03 (an ophthalmic composition consisting essentially of 1-perfluorohexyloctane; solid line) and placebo represents saline solution (0.9% sodium chloride solution; QID+BID; dashed line). Improvement in dryness symptoms was determined by the Ocular Surface Disease Index (OSDI) score (see Experimental Section for details on the OSDI questionnaire).

[0043] Figure 4 . Response assessment to NOV03-treatment (BID) based on the severity of dryness assessment using ocular dryness score on a visual analogue scale (VAS); depicted is a graph plotting the patient response to the dryness symptom "severity of dryness" shortly after starting treatment in subjects treated with NOV03 (an ophthalmic composition consisting essentially of 1-perfluorohexyloctane; real drug; solid line) compared to patients treated with saline ((0.9% sodium chloride solution; QID+BID; placebo; dotted line).

[0044] In this context, response to treatment was defined as an improvement of ≥ 25% in the dryness symptom "severity of dryness". The study showed that within 2 weeks of the start of treatment, 50% of patients in the NOV03-BID part had responded to treatment, compared to only 35% of patients treated with placebo. DETAILED DESCRIPTION

[0045] In a first aspect, the present disclosure provides a method for providing delayed ocular release of a semifluorinated alkane from an ocular tissue that has been enriched with the semifluorinated alkane, e.g., due to treatment with an ophthalmic composition comprising the semifluorinated alkane (Method 1), wherein the method comprises the steps of: (a) administering to an eye of a patient in need thereof an amount of an ophthalmic composition comprising the semifluorinated alkane, optionally wherein the amount is effective to enrich the ocular tissue with the semifluorinated alkane, and optionally, (b) delayed release of the semifluorinated alkane from the enriched ocular tissue; and wherein the semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 8 H. Further embodiments of the present disclosure are provided as follows:

[0046] 1.1 Method 1, wherein the semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H and F (CF 2 ) 6 (CH 2 ) 8 H.

[0047] 1.2 Method 1 or 1.1, wherein the semifluorinated alkane is F(CF 2 ) 6 (CH 2 ) 8 H.

[0048] 1.3 Any of methods 1 or 1.1 below, wherein the composition comprises the single semifluorinated alkane.

[0049] 1.4 Any of methods 1 or 1.1 below, wherein the composition does not contain any pharmaceutically active drug useful for ophthalmic treatment.

[0050] 1.5 Any of the methods 1 or 1.1 below, wherein the composition consists of a single semifluorinated alkane.

[0051] 1.6 Any of methods 1 or 1.1 to 1.2, wherein the composition comprises at least one other semifluorinated alkane.

[0052] 1.7 Method 1.6, wherein the other semifluorinated alkane has the formula F(CF 2 ) n (CH 2 ) m H, and wherein n is an integer from 4 to 8 and m is an integer from 5 to 10, and wherein the other semifluorinated alkane is different from the first semifluorinated alkane.

[0053] 1.8 Method 1.7, wherein the other semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H、F(CF 2 ) 6 (CH 2 ) 10 H、F(CF 2 ) 8 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 10 H.

[0054] 1.9 Method 1.6, 1.7 or 1.8 wherein the composition comprises two semifluorinated alkanes.

[0055] 1.10 Any of methods 1.6-1.9, wherein the composition does not contain any pharmaceutically active drug useful for ophthalmic treatment.

[0056] 1.11 Any of methods 1.6-1.10, wherein the composition consists of two semifluorinated alkanes.

[0057] 1.12 Any of Method 1 or 1.1 below, wherein the ophthalmic composition is administered to the surface of the cornea and / or conjunctiva in the form of droplets.

[0058] 1.13 Any of Method 1 or 1.1 below, wherein the patient suffers from keratoconjunctivitis sicca (dry eye disease), for example, the patient suffers from keratoconjunctivitis sicca (dry eye disease) caused by meibomian gland dysfunction.

[0059] 1.14 Method 1.13, wherein the dry eye disease is aqueous deficiency dry eye disease.

[0060] 1.15 Method 1.13 or 1.14 wherein the dry eye disease is evaporative dry eye disease.

[0061] 1.16 Any of Method 1 or 1.1 below, wherein the patient suffers from meibomian gland dysfunction.

[0062] 1.17 Method 1.16, wherein the patient is unresponsive to traditional physical methods of treating meibomian gland dysfunction (MGD) (e.g., methods discussed in Blackie et al., Review of Optometry, June 21, 2012, pp. 1-12, which reference is incorporated herein by reference in its entirety).

[0063] 1.18 Any of Method 1 or 1.1 below, wherein the patient is unresponsive to treatment with an aqueous ophthalmic eye drop composition.

[0064] 1.19 Any of Method 1 or 1.1 below, wherein the composition is administered at a dose of a single drop per eye less than 4 times a day, for example, 3 times a day, or 2 times a day, or once a day, or less than once a day (e.g., every other day).

[0065] 1.20 Method 1.19, wherein the volume of each drop is 9-13 μL, e.g., 9-12 μL, or 10-13 μL, or 10-12 μL, or 10-11 μL, or about 11 μL.

[0066] 1.21 Any of Method 1 or 1.1 below, wherein the composition is administered three times a day at a dose of a single drop per eye in a net volume of 30-33 μL.

[0067] 1.22 Any of Method 1 or 1.1 below, wherein the composition is administered twice daily at a dose of a single drop per eye in a net volume of 20-22 μL.

[0068] 1.23 Any of Method 1 or 1.1 below, wherein the composition is administered once daily in a net volume of 10-11 μL as a single drop per eye.

[0069] 1.24 Any of the methods 1 or 1.1 below, wherein the ocular tissue enriched with semifluorinated alkanes is the palpebral conjunctiva, cornea, meibomian glands, lacrimal glands and / or bulbar conjunctiva.

[0070] 1.25 Any of the methods 1 or 1.1 below, wherein the ocular tissue enriched in semifluorinated alkanes is, for example, the meibomian glands of the upper and / or lower eyelids.

[0071] 1.26 Any of Methods 1 or 1.1 below, wherein the semifluorinated alkane-enriched ocular tissue releases all or substantially all of the semifluorinated alkane within 24 hours, optionally within 8 hours, of the last dose of the composition, and the enriched tissue optionally releases at least 60% within 4 to 8 hours, or at least 80% within 8 hours of the last dose of the composition.

[0072] 1.27 Any of Methods 1 or 1.1 below, wherein, following sequential administration of the composition (e.g., at least 2 doses within 24 hours), the ocular tissue enriched with semifluorinated alkanes releases all or substantially all of the semifluorinated alkanes within 24 hours, optionally within 8 hours, of the last dose, and the enriched tissue optionally releases at least 50% within 4 to 8 hours, or at least 70% within 8 to 12 hours of the last dose of the composition.

[0073] 1.28 Any of methods 1 or 1.1 below, wherein the semifluorinated alkane-enriched ocular tissue comprises about 0.00001 to 0.5 wt % semifluorinated alkane, optionally 0.0001 to 0.05 wt %, for example, 0.0001 to 0.001 wt %, or 0.0004 to 0.0009 wt %, or 0.001 to 0.01 wt %, or 0.001 to 0.003 wt %, or 0.001 to 0.05%, or 0.005 to 0.03% semifluorinated alkane.

[0074] 1.29 Any of Methods 1 or 1.1 below, wherein the enriched ocular tissue is meibomian glands, and the meibomian glands comprise 0.0001 to 0.05 wt%, optionally 0.0005 to 0.05 wt%, or 0.001 to 0.03 wt% of a semifluorinated alkane.

[0075] 1.30 Any of Method 1 or 1.1 below, wherein the treatment is carried out for about at least 1 day, or at least 5 days, or at least 10 days, or at least 30 days, or at least 60 or at least 90 days.

[0076] 1.31 Method 1 or any of 1.1 below, wherein the method (a) increases tear film thickness, (b) increases lipid layer thickness, (c) replenishes tear film, (d) lubricates the ocular surface, (e) treats dry eye disease, (f) treats meibomian gland dysfunction, or (g) treats a condition of the conjunctiva or cornea in a patient with dry eye disease, or any combination thereof.

[0077] 1.32 Any of the following methods 1 or 1.1, wherein the method is effective to (a) increase the thickness of the tear film,

[0078] (b) increasing lipid layer thickness, (c) replenishing tear film, (d) lubricating the ocular surface, (e) treating dry eye disease, (f) treating meibomian gland dysfunction, or (g) treating a condition of the conjunctiva or cornea in a patient suffering from dry eye disease, or any combination thereof.

[0079] 1.33 Any of Method 1 or 1.1 below, wherein the patient is a human patient.

[0080] 1.34 Any of methods 1 or 1.1 below, wherein the patient is an animal patient, for example,

[0081] Mammals such as dogs, cats, rabbits and / or farm animals such as horses, pigs, cows or sheep. 1.35 Method 1.33, wherein the patient is a female patient.

[0082] 1.36 Method 1.33, wherein the patient is a male patient.

[0083] 1.37 Method 1.35 or 1.36, wherein the patient is 20 to 80 years old at the time of treatment,

[0084] For example, 20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or 30-70 years old,

[0085] or 40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80 years old, or 50-70 years old. In further embodiments of the first aspect, the disclosure further provides the following other embodiments: 1.38 Method 1, or any one of 1.1 to 1.37, wherein the composition consists of 1-(perfluorohexyl)octane (F6H8).

[0086] 1.39 Any of Method 1 or 1.1 to 1.37, wherein the composition consists of a mixture of F6H8 and 2-(perfluorohexyl)octane.

[0087] 1.40 Method 1.39, wherein the composition comprises up to about 3% by weight, or up to about 2% by weight.

[0088] wt %, or 2-(perfluorohexyl)octane in an amount up to about 1 wt %.

[0089] 1.41 Any of Method 1 or 1.1-1.40, wherein the composition is administered twice daily in a single drop dose of about 10-12 μl, or about 10-11 μl, or about 11 μl per eye of the patient. 1.42 Any of Method 1 or 1.1-1.41, wherein the patient is characterized by at least two

[0090] Items were selected from the following criteria:

[0091] i. Tear film break-up time (TFBUT) less than 5 seconds (e.g., less than 3.8 seconds),

[0092] ii. Overall Ocular Surface Disease Index (OSDI) higher than 25 (e.g., higher than 36),

[0093] iii. Total corneal fluorescein staining (NEI scale) of 4 to 11 (e.g., 5 to 9),

[0094] iv. Schirmer test I greater than 5 mm (e.g., equal to or greater than 10 mm, or equal to or greater than 15 mm), and

[0095] v. MGD score is higher than 3 (eg, higher than 4).

[0096] 1.43 Method 1.42, wherein at least one eye of the patient meets criteria (i), (iii), (iv)

[0097] and (v).

[0098] 1.44 Any of Method 1 or 1.1-1.43, wherein the patient has a history of keratoconjunctivitis sicca (dry eye) in one or both eyes for at least 6 months.

[0099] 1.45 Method 1 or any one of 1.1-1.44, wherein the composition is effective for simultaneously treating (reducing) keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or

[0100] Ocular damage and dryness symptoms in one or more corneal areas in patients with meibomian gland dysfunction.

[0101] 1.46 Method 1.45 wherein the composition is effective in reducing the eye damage and dryness symptoms within 2 weeks, within 4 weeks or within 8 weeks after the first administration of the composition.

[0102] 1.47 Methods 1.45 to 1.46, wherein the ocular surface damage to one or more corneal regions is selected from:

[0103] i. Ocular surface damage in the total corneal area;

[0104] ii. Ocular surface damage in the central corneal area;

[0105] iii. Ocular surface damage in the nasal corneal area;

[0106] iv. ocular surface damage in the temporal corneal region; and

[0107] v.A combination of these.

[0108] 1.48 Method 1.45 to 1.47, wherein the reduction in ocular surface damage is determined by corneal fluorescein staining (NEI scale).

[0109] 1.49 Method 1.48, wherein the ocular surface damage is determined by grading one or more corneal areas selected from the group consisting of: total corneal area, central corneal area, nasal corneal area, and temporal corneal area by corneal fluorescein staining.

[0110] 1.50 Any of Method 1 or 1.1-1.49 wherein the composition is effective in reducing one or more dryness symptoms associated with keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or meibomian gland dysfunction.

[0111] 1.51 Methods 1.45-1.50, wherein the one or more dryness symptoms are selected from:

[0112] i. Severity of dryness;

[0113] ii. Blurred vision;

[0114] iii. Light sensitivity;

[0115] iv. Frequency of drying;

[0116] v. Dryness awareness; and

[0117] vi. Any combination thereof.

[0118] 1.52 Method 1.51, wherein said symptoms (i) to (iii) are determined on a visual analog scale (VAS) of 0% to 100% representing the patient's level of discomfort, and wherein symptoms (iv) to (v) are determined on a visual analog scale (VAS) of 0% to 100% representing the percentage of time that the patient experiences said dryness symptoms.

[0119] 1.53 Method 1.45 to 1.51, wherein the one or more symptoms are graded using an overall ocular surface disease index (OSDI) score.

[0120] 1.54 Method 1.53, wherein the overall ocular surface disease index (OSDI) score is assessed on a scale of 1 to 100, with higher scores indicating greater disability in the patient.

[0121] In further embodiments of the first aspect, the present disclosure further provides the following additional embodiments: 1.55 Method 1 or any one of 1.1 to 1.54, wherein the composition consists of F6H8 (1-(perfluorohexyl)octane).

[0122] 1.56 Method 1.55 wherein the delayed ocular release is from an anterior segment tissue selected from the group consisting of:

[0123] Meibomian glands, conjunctiva (bulbar conjunctiva), conjunctiva (palpebral conjunctiva), cornea, sclera (anterior sclera), lacrimal glands (accessory lacrimal glands), lacrimal glands (main lacrimal glands), and tears (e.g., tear film).

[0124] 1.57 Method 1.56, wherein the method provides at least

[0125] A maximum concentration of 2000 ng of a semifluorinated alkane (eg, F6H8), optionally wherein said concentration is provided by a single drop dose of 40-60 mg of a semifluorinated alkane (eg, F6H8) administered once a day or twice a day.

[0126] 1.58 Method 1.56, wherein the method provides at least

[0127] A maximum concentration of 2270 ng of a semifluorinated alkane (eg, F6H8), optionally wherein said concentration is provided by a single drop dose of 40-60 mg of a semifluorinated alkane (eg, F6H8) administered once a day or twice a day.

[0128] 1.59 Method 1.57 or 1.58, wherein the concentration is provided by a single drop dose of about 50 mg (e.g., about 47 mg) of a semifluorinated alkane (e.g., F6H8) administered once a day or twice a day. 1.60 Any of Methods 1.57 to 1.59, wherein the anterior segment tissue of the eye at which the maximum concentration of the semifluorinated alkane (e.g., F6H8) is achieved is selected from the group consisting of meibomian glands, conjunctiva (bulbar conjunctiva), conjunctiva (palpebral conjunctiva), cornea, sclera (anterior sclera), and tears.

[0129] 1.61 Method 1.60, wherein 0.25 to 2 hours (e.g., 0.25 to 1 hour, or 0.25 to 0.5 hours) after administration of a single drop dose of the composition once daily or twice daily

[0130] The maximum concentration of the semifluorinated alkane (e.g., F6H8) is reached within 2 hours.

[0131] 1.62 Any of Methods 1.56 to 1.61, wherein the anterior segment tissue that reaches the maximum concentration of the semifluorinated alkane (e.g., F6H8) is selected from the lacrimal gland (accessory lacrimal gland) and the lacrimal gland (main lacrimal gland). 1.63 Method 1.62, wherein the maximum concentration of the semifluorinated alkane (e.g., F6H8) is reached within 3 to 5 hours (e.g., 4 hours) after administration of a single drop dose of the composition once a day or twice a day.

[0132] 1.64 Any of methods 1.56 to 1.63, wherein following administration of a single drop dose of the composition once daily or twice daily, the method provides a maximum concentration of a semifluorinated alkane (e.g., F6H8) of at least:

[0133] a. In the meibomian glands, 222,000 ng / g tissue;

[0134] b. In the conjunctiva (bulbar conjunctiva), 5450 ng / g tissue;

[0135] c. In the conjunctiva (palpebral conjunctiva), 14,000 ng / g tissue;

[0136] d. In the cornea, 8230 ng / g tissue;

[0137] e. In the sclera (anterior sclera), 2270 ng / g tissue;

[0138] f. In the lacrimal gland (accessory lacrimal gland), 4280 ng / g tissue;

[0139] g. In the lacrimal gland (main lacrimal gland), 4130 ng / g tissue; and / or

[0140] h.1300ng / g tears.

[0141] 1.65 Method 1.64, wherein the method provides a maximum concentration of a semifluorinated alkane (e.g., F6H8) of at least 5000 ng / g tear fluid, e.g., at least 10,000 ng / g, or at least 50,000 ng / g

[0142] ng / g, or at least 100,000ng / g, or at least 500,000ng / g, or at least 1,000,000

[0143] ng / g, or at least 2,000,000 ng / g, up to a maximum concentration of semifluorinated alkanes (e.g., F6H8) of about 2,330,000 ng / g of tear fluid.

[0144] In a second aspect, the present disclosure provides a method for increasing tear film thickness and / or increasing lipid layer thickness and / or replenishing tear film and / or lubricating the ocular surface (Method 2), wherein the method comprises the following steps: (a) administering to the eye of a patient in need thereof an amount of an ophthalmic composition comprising a semifluorinated alkane selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 )6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 8 H, optionally wherein the amount is effective to enrich the ocular tissue with the semifluorinated alkane, and optionally, (b) the semifluorinated alkane is delayed in release from the enriched ocular tissue. Further embodiments of the present disclosure provide as follows:

[0145] 2.1 Method 2, wherein the semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H and F (CF 2 ) 6 (CH 2 ) 8 H.

[0146] 2.2 Method 2 or 2.1, wherein the semifluorinated alkane is F(CF 2 ) 6 (CH 2 ) 8 H.

[0147] 2.3 Any of Method 2 or 2.1 below, wherein the composition comprises a single semifluorinated alkane.

[0148] 2.4 Any of methods 2 or 2.1 below, wherein the composition does not contain any pharmaceutically active drug useful for ophthalmic treatment.

[0149] 2.5 Any of the methods 2 or 2.1 below, wherein the composition consists of a single semifluorinated alkane.

[0150] 2.6 Any of Method 2 or 2.1 to 2.2, wherein the composition comprises at least one other semifluorinated alkane.

[0151] 2.7 Method 2.6, wherein the other semifluorinated alkane has the formula F(CF 2 ) n (CH 2 ) m H, and wherein n is an integer from 4 to 8 and m is an integer from 5 to 10, and wherein the other semifluorinated alkane is different from the first semifluorinated alkane.

[0152] 2.8 Method 2.7, wherein the other semifluorinated alkane is selected from F(CF 2 )4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H、F(CF 2 ) 6 (CH 2 ) 10 H、F(CF 2 ) 8 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 10 H.

[0153] 2.9 Method 2.6, 2.7 or 2.8 wherein the composition comprises two semifluorinated alkanes.

[0154] 2.10 Any of methods 2.6 to 2.9, wherein the composition does not contain any pharmaceutically active drug useful for ophthalmic treatment.

[0155] 2.11 Any of methods 2.6 to 2.10, wherein the composition consists of two semifluorinated alkanes.

[0156] 2.12 Any of Method 2 or 2.1 below, wherein the ophthalmic composition is administered to the surface of the cornea and / or conjunctiva in the form of droplets.

[0157] 2.13 Any of Method 2 or 2.1 below, wherein the patient has keratoconjunctivitis sicca (dry eye), optionally wherein the patient has keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0158] 2.14 Method 2.13, wherein the dry eye disease is aqueous deficiency dry eye disease.

[0159] 2.15 Method 2.13 or 2.14 wherein the dry eye disease is evaporative dry eye disease.

[0160] 2.16 Any of Method 2 or 2.1 below, wherein the patient suffers from meibomian gland dysfunction.

[0161] 2.17 Method 2.16, wherein the patient is unresponsive to traditional physical methods of treating meibomian gland dysfunction MGD (e.g., methods discussed in Blackie et al., Review of Optometry, June 21, 2012, pp. 1-12, which reference is incorporated herein by reference in its entirety).

[0162] 2.18 Any of Method 2 or 2.1 below, wherein the patient is unresponsive to treatment with an aqueous ophthalmic eye drop composition.

[0163] 2.19 Any of Method 2 or 2.1 below, wherein the composition is administered at a dose of a single drop per eye less than 4 times a day, for example, 3 times a day, or 2 times a day, or once a day, or less than once a day (e.g., every other day).

[0164] 2.20 Method 2.19, wherein the volume of each drop is 9-13 μL, for example, 9-12 μL, or 10-13 μL, or 10-12 μL, or 10-11 μL, or about 11 μL.

[0165] 2.21 Any of Method 2 or 2.1 below, wherein the composition is administered three times a day at a dose of a single drop per eye in a net volume of 30-33 μL.

[0166] 2.22 Any of Method 2 or 2.1 below, wherein the composition is administered twice daily at a dose of a single drop per eye in a net volume of 20-22 μL.

[0167] 2.23 Any of Method 2 or 2.1 below, wherein the composition is administered once daily in a net volume of 10-11 μL as a single drop per eye.

[0168] 2.24 Any of the following methods 2 or 2.1, wherein the ocular tissue enriched with semifluorinated alkanes is the palpebral conjunctiva, cornea, meibomian gland, lacrimal gland and / or bulbar conjunctiva.

[0169] 2.25 Any of Method 2 or 2.1 below, wherein the ocular tissue enriched in semifluorinated alkanes is, for example, the meibomian glands of the upper and / or lower eyelids.

[0170] 2.26 Any of Methods 2 or 2.1 below, wherein the semifluorinated alkane-enriched ocular tissue releases all or substantially all of the semifluorinated alkane within 24 hours, optionally within 8 hours, of the last dose of the composition, and the enriched tissue optionally releases at least 60% within 4 to 8 hours, or at least 80% within 8 hours of the last dose of the composition.

[0171] 2.27 Any of Methods 2 or 2.1 below, wherein, following sequential administration of the composition (e.g., at least 2 doses within 24 hours), the ocular tissue enriched with semifluorinated alkanes releases all or substantially all of the semifluorinated alkanes within 24 hours, optionally within 8 hours, of the last dose, and the enriched tissue optionally releases at least 50% within 4 to 8 hours, or at least 70% within 8 to 12 hours of the last dose of the composition.

[0172] 2.28 Any of methods 2 or 2.1 below, wherein the semifluorinated alkane-enriched ocular tissue comprises about 0.00001 to 0.5 wt % semifluorinated alkane, optionally 0.0001 to 0.05 wt %, for example, 0.0001 to 0.001 wt %, or 0.0004 to 0.0009 wt %, or 0.001 to 0.01 wt %, or 0.001 to 0.003 wt %, or 0.001 to 0.05%, or 0.005 to 0.03% semifluorinated alkane.

[0173] 2.29 Any of Methods 2 or 2.1 below, wherein the enriched ocular tissue is meibomian glands, and the meibomian glands comprise 0.0001 to 0.05 wt%, optionally 0.0005 to 0.05 wt%, or 0.001 to 0.03 wt% of the semifluorinated alkane.

[0174] 2.30 Any of the following methods 2 or 2.1, wherein the treatment is carried out for at least 1 day, or at least

[0175] 5 days, or at least 10 days, or at least 30 days, or at least 60 or at least 90 days (eg, consecutive days).

[0176] 2.31 Any of Method 2 or 2.1 below, wherein the patient is a human patient.

[0177] 2.32 Any of Method 2 or 2.1 below, wherein the patient is an animal patient, eg, a mammal such as a dog, cat, rabbit and / or a farm animal such as a horse, pig, cow or sheep.

[0178] 2.33 Method 2.31, wherein the patient is a female patient.

[0179] 2.34 Method 2.31, wherein the patient is a male patient.

[0180] 2.35 Method 2.33 or 2.34, wherein the patient is 20 to 80 years old at the time of treatment,

[0181] For example, 20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or 30-70 years old,

[0182] Or 40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80 years old, or 50-70 years old. In a further embodiment of the second aspect, the present disclosure further provides the following other embodiments:

[0183] 2.36 Any of Method 2 or 2.1 to 2.35 wherein the composition consists of 1-(perfluorohexyl)octane (F6H8).

[0184] 2.37 Any of Method 2 or 2.1 to 2.35 wherein the composition consists of a mixture of F6H8 and 2-(perfluorohexyl)octane.

[0185] 2.38 Method 2.37, wherein the composition comprises up to about 3% by weight, or up to about 2

[0186] wt %, or 2-(perfluorohexyl)octane in an amount up to about 1 wt %.

[0187] 2.39 Any of method 2 or 2.1-2.38, wherein the composition is in a volume of about 10-12 μl,

[0188] Or a single drop dose of about 10-11 μl or about 11 μl is administered twice a day to each eye of the patient.

[0189] 2.40 Any of Method 2 or 2.1-2.39, wherein the patient has highly symptomatic eye disease.

[0190] Disease, for example, characterized by meeting at least two criteria selected from the group consisting of:

[0191] i. Tear film break-up time (TFBUT) less than 5 seconds (e.g., less than 3.8 seconds),

[0192] ii. Overall Ocular Surface Disease Index (OSDI) above 25 (e.g., above 40),

[0193] iii. Total corneal fluorescein staining (NEI scale) of 4 to 11 (e.g., 5 to 9),

[0194] iv. Schirmer test I greater than 5 mm (e.g., equal to or greater than 10 mm, or equal to or greater than 15 mm), and

[0195] v. MGD score is higher than 3 (eg, higher than 4).

[0196] 2.41 Method 2.40, wherein at least one eye of the patient meets criteria (i), (iii), (iv), and (v).

[0197] 2.42 Any of Method 2 or 2.1-2.41 wherein the patient has a history of keratoconjunctivitis sicca (dry eye) in one or both eyes for at least 6 months.

[0198] 2.43 Any of Method 2 or 2.1-2.42 wherein the composition is effective to simultaneously treat (reduce) ocular damage and dryness symptoms in one or more corneal regions in a patient suffering from meibomian gland dysfunction and / or keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0199] 2.44 Method 2.43 wherein the composition is effective in reducing the ocular surface damage and dryness symptoms within 2 weeks, or within 4 weeks, or within 8 weeks after the first administration of the composition.

[0200] 2.45 Any of Method 2 or 2.1-2.44 wherein the composition is effective in reducing ocular damage and dryness symptoms in one or more corneal regions within 2 weeks, preferably within 4 weeks, more preferably or within 8 weeks after the first administration of the composition.

[0201] 2.46 Methods 2.43 to 2.45, wherein the ocular surface injury is selected from:

[0202] i. Ocular surface damage in the total corneal area;

[0203] ii. Ocular surface damage in the central corneal area;

[0204] iii. Ocular surface damage in the nasal corneal area;

[0205] iv. ocular surface damage in the temporal corneal region; and

[0206] v.A combination of these.

[0207] 2.47 Methods 2.43 to 2.46, wherein the reduction in ocular surface damage is determined by corneal fluorescein staining (NEI scale).

[0208] 2.48 Method 2.47, wherein the ocular surface damage is determined by grading one or more corneal areas selected from the group consisting of: total corneal area, central corneal area, nasal corneal area, and temporal corneal area by corneal fluorescein staining.

[0209] 2.49 Any of Method 2 or 2.1-2.48 wherein the composition is effective in reducing one or more dryness symptoms associated with keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or meibomian gland dysfunction.

[0210] 2.50 Methods 2.43-2.49, wherein the one or more dryness symptoms are selected from:

[0211] i. Severity of dryness;

[0212] ii. Blurred vision;

[0213] iii. Light sensitivity;

[0214] iv. Frequency of drying;

[0215] v. Dryness awareness; and

[0216] vi. Any combination thereof.

[0217] 2.51 Method 2.50, wherein the symptoms (i) to (iii) are present at a level between 0% and 10% representing the patient's level of discomfort.

[0218] 100% on a visual analogue scale (VAS), and wherein symptoms (iv) to (v) are determined on a visual analogue scale (VAS) from 0% to 100% representing the percentage of time the patient experiences said dryness symptom.

[0219] 2.52 Method 2.43 to 2.50, wherein the one or more dryness symptoms are graded using an overall ocular surface disease index (OSDI) score.

[0220] 2.53 Method 2.52, wherein the overall ocular surface disease index (OSDI) score is assessed on a scale of 1 to 100, with higher scores indicating greater disability in the patient.

[0221] In further embodiments of the second aspect, the present disclosure further provides the following other embodiments:

[0222] 2.54 Any of Method 2 or 2.1 to 2.53 wherein the composition consists of F6H8 (1-(perfluorohexyl)octane).

[0223] 2.55 Method 2.54 wherein the delayed ocular release is from an anterior segment tissue selected from the group consisting of:

[0224] Meibomian glands, conjunctiva (bulbar conjunctiva), conjunctiva (palpebral conjunctiva), cornea, sclera (anterior sclera), lacrimal glands (accessory lacrimal glands), lacrimal glands (main lacrimal glands), and tears (e.g., tear film).

[0225] 2.56 Method 2.55, wherein the method provides at least

[0226] A maximum concentration of 2000 ng of a semifluorinated alkane (eg, F6H8), optionally wherein said concentration is provided by a single drop dose of 40-60 mg of a semifluorinated alkane (eg, F6H8) administered once a day or twice a day.

[0227] 2.57 Method 2.55, wherein the method provides at least

[0228] A maximum concentration of 2270 ng of a semifluorinated alkane (eg, F6H8), optionally wherein said concentration is provided by a single drop dose of 40-60 mg of a semifluorinated alkane (eg, F6H8) administered once a day or twice a day.

[0229] 2.58 Method 2.56 or 2.57 wherein the concentration is provided by a single drop dose of about 50 mg (eg, about 47 mg) of a semifluorinated alkane (eg, F6H8) administered once daily or twice daily.

[0230] 2.59 Any of Methods 2.55 to 2.58, wherein the anterior segment tissue where the maximum concentration of the semifluorinated alkane (e.g., F6H8) is reached is selected from the group consisting of meibomian glands, conjunctiva (bulbar conjunctiva), conjunctiva (palpebral conjunctiva), cornea, sclera (anterior sclera), and tears.

[0231] 2.60 Method 2.59, wherein 0.25 to 2 hours (e.g., 0.25 to 1 hour, or 0.25 to 0.5 hours) after administration of a single drop dose of the composition once daily or twice daily

[0232] The maximum concentration of the semifluorinated alkane (e.g., F6H8) is reached within 2 hours.

[0233] 2.61 Any of Methods 2.55 to 2.60, wherein the anterior segment tissue of the eye that reaches the maximum concentration of the semifluorinated alkane (eg, F6H8) is selected from the lacrimal gland (accessory lacrimal gland) and the lacrimal gland (main lacrimal gland).

[0234] 2.62 Method 2.61 wherein the maximum concentration of the semifluorinated alkane (eg, F6H8) is achieved within 3 to 5 hours (eg, 4 hours) following administration of a single drop dose of the composition once daily or twice daily.

[0235] 2.63 Any of Methods 2.55 to 2.62, wherein following administration of a single drop dose of the composition once daily or twice daily, the method provides a maximum concentration of a semifluorinated alkane (e.g., F6H8) of at least:

[0236] a. In the meibomian glands, 222,000 ng / g tissue;

[0237] b. In the conjunctiva (bulbar conjunctiva), 5450 ng / g tissue;

[0238] c. In the conjunctiva (palpebral conjunctiva), 14,000 ng / g tissue;

[0239] d. In the cornea, 8230 ng / g tissue;

[0240] e. In the sclera (anterior sclera), 2270 ng / g tissue;

[0241] f. In the lacrimal gland (accessory lacrimal gland), 4280 ng / g tissue;

[0242] g. In the lacrimal gland (main lacrimal gland), 4130 ng / g tissue; and / or

[0243] h.1300ng / g tears.

[0244] 2.64 Method 2.63, wherein the method provides a maximum concentration of a semifluorinated alkane (e.g., F6H8) of at least 5000 ng / g tear fluid, e.g., at least 10,000 ng / g, or at least 50,000 ng / g

[0245] ng / g, or at least 100,000ng / g, or at least 500,000ng / g, or at least 1,000,000

[0246] ng / g, or at least 2,000,000 ng / g, up to a maximum concentration of semifluorinated alkanes (e.g., F6H8) of about 2,330,000 ng / g of tear fluid.

[0247] In a third aspect, the present disclosure provides a method for treating dry eye and / or treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or treating a condition of the conjunctiva or cornea (Method 3), wherein the method comprises the steps of: (a) administering to the eye of a patient in need thereof an amount of an ophthalmic composition comprising a semifluorinated alkane, optionally wherein the amount is effective to enrich the ocular tissue with the semifluorinated alkane, and optionally, (b) delaying the release of the semifluorinated alkane from the enriched ocular tissue, and wherein the semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 8 H. Further embodiments of the present disclosure are provided as follows:

[0248] 3.1 Method 3, wherein the semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H and F (CF 2 ) 6 (CH 2 ) 8 H.

[0249] 3.2 Any one of methods 3 or 3.1, wherein the semifluorinated alkane is F(CF 2 ) 6 (CH 2 ) 8 H.

[0250] 3.3 Any of Method 3 or 3.1 below, wherein the composition comprises a single semifluorinated alkane.

[0251] 3.4 Any of Method 3 or 3.1 below, wherein the composition does not contain any pharmaceutically active drug useful for ophthalmic treatment.

[0252] 3.5 Any of Method 3 or 3.1 below, wherein the composition consists of a single semifluorinated alkane.

[0253] 3.6 Any of Method 3 or 3.1 below, wherein the composition comprises at least one other semifluorinated alkane.

[0254] 3.7 Method 3.6, wherein the other semifluorinated alkane has the formula F(CF 2 ) n (CH 2 ) m H, and wherein n is an integer from 4 to 8 and m is an integer from 5 to 10, and wherein the other semifluorinated alkane is different from the first semifluorinated alkane.

[0255] 3.8 Method 3.7, wherein the other semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H、F(CF 2 ) 6(CH 2 ) 10 H、F(CF 2 ) 8 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 10 H.

[0256] 3.9 Method 3.6, 3.7 or 3.8 wherein the composition comprises two semifluorinated alkanes.

[0257] 3.10 Any of methods 3.6 to 3.9, wherein the composition does not contain any pharmaceutically active drug useful for ophthalmic treatment.

[0258] 3.11 Any of methods 3.6 to 3.10, wherein the composition consists of two semifluorinated alkanes.

[0259] 3.12 Any of Method 3 or 3.1 below, wherein the ophthalmic composition is administered to the surface of the cornea and / or conjunctiva in the form of drops.

[0260] 3.13 Any of Method 3 or 3.1 below, wherein the patient has keratoconjunctivitis sicca (dry eye), optionally wherein the patient has keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0261] 3.14 Method 3.13, wherein the dry eye disease is aqueous deficiency dry eye disease.

[0262] 3.15 Method 3.13 or 3.14 wherein the dry eye disease is evaporative dry eye disease.

[0263] 3.16 Any of Method 3 or 3.1 below, wherein the patient suffers from meibomian gland dysfunction.

[0264] 3.17 Method 3.16, wherein the patient is unresponsive to traditional physical methods of treating meibomian gland dysfunction (MGD) (e.g., methods discussed in Blackie et al., Review of Optometry, June 21, 2012, pp. 1-12, which reference is incorporated herein by reference in its entirety).

[0265] 3.18 Any of Method 3 or 3.1 below, wherein the patient is unresponsive to treatment with an aqueous ophthalmic eye drop composition.

[0266] 3.19 Any of Method 3 or 3.1 below, wherein the composition is administered at a dose of a single drop per eye less than 4 times a day, for example, 3 times a day, or 2 times a day, or once a day, or less than once a day (e.g., every other day).

[0267] 3.20 Method 3.19, wherein the volume of each drop is 9-13 μL, e.g., 9-12 μL, or 10-13 μL, or 10-12 μL, or 10-11 μL, or about 11 μL.

[0268] 3.21 Any of Method 3 or 3.1 below, wherein the composition is administered three times a day at a dose of a single drop per eye in a net volume of 30-33 μL.

[0269] 3.22 Any of Method 3 or 3.1 below, wherein the composition is administered twice daily at a dose of a single drop per eye in a net volume of 20-22 μL.

[0270] 3.23 Any of Method 3 or 3.1 below, wherein the composition is administered once daily in a net volume of 10-11 μL as a single drop per eye.

[0271] 3.24 Any of the following methods 3 or 3.1, wherein the ocular tissue enriched with semifluorinated alkanes is the palpebral conjunctiva, cornea, meibomian gland, lacrimal gland and / or bulbar conjunctiva.

[0272] 3.25 Any of Method 3 or 3.1 below, wherein the ocular tissue enriched in semifluorinated alkanes is, for example, meibomian glands of the upper and / or lower eyelids.

[0273] 3.26 Any of Methods 3 or 3.1 below, wherein the semifluorinated alkane-enriched ocular tissue releases all or substantially all of the semifluorinated alkane within 24 hours, optionally within 8 hours, of the last dose of the composition, and the enriched tissue optionally releases at least 60% within 4 to 8 hours, or at least 80% within 8 hours of the last dose of the composition.

[0274] 3.27 Any of Methods 3 or 3.1 below, wherein, following sequential administration of the composition (e.g., at least 2 doses within 24 hours), the ocular tissue enriched with semifluorinated alkanes releases all or substantially all of the semifluorinated alkanes within 24 hours, optionally within 8 hours, of the last dose, and the enriched tissue optionally releases at least 50% within 4 to 8 hours, or at least 70% within 8 to 12 hours of the last dose of the composition.

[0275] 3.28 Method 3 or 3.1 below, wherein the semifluorinated alkane-enriched ocular tissue comprises about 0.00001 to 0.5 wt. % semifluorinated alkane, optionally 0.0001 to 0.05

[0276] wt %, for example, 0.0001 to 0.001 wt %, or 0.0004 to 0.0009 wt %,

[0277] or 0.001 to 0.01 wt %, or 0.001 to 0.003 wt %, or 0.001 to 0.05%,

[0278] or 0.005 to 0.03% of a semifluorinated alkane.

[0279] 3.29 Any of Methods 3 or 3.1 below, wherein the enriched ocular tissue is meibomian glands, and the meibomian glands comprise 0.0001 to 0.05 wt%, optionally 0.0005 to 0.05 wt%, or 0.001 to 0.03 wt% of a semifluorinated alkane.

[0280] 3.30 Method 3 or 3.1 below, wherein the treatment is carried out for at least 1 day, or at least

[0281] 5 days, or at least 10 days, or at least 30 days, or at least 60 or at least 90 days, for example consecutive days.

[0282] 3.31 Any of Method 3 or 3.1 below, wherein the patient is a human patient.

[0283] 3.32 Any of Method 3 or 3.1 below, wherein the patient is an animal patient, eg, a mammal such as a dog, cat, rabbit, and / or a farm animal such as a horse, pig, cow, or sheep.

[0284] 3.33 Method 3.31, wherein the patient is a female patient.

[0285] 3.34 Method 3.31, wherein the patient is a male patient.

[0286] 3.35 Method 3.33 or 3.34, wherein the patient is 20 to 80 years old at the time of treatment,

[0287] For example, 20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or 30-70 years old,

[0288] or 40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80 years old, or 50-70 years old. In a further embodiment of the third aspect, the present disclosure further provides the following other embodiments: 3.36 Method 3 or any one of 3.1 to 3.35 wherein the composition is 1-(perfluorohexyl)

[0289] Octane (F6H8).

[0290] 3.37 Any of Method 3 or 3.1 to 3.35 wherein the composition consists of a mixture of F6H8 and 2-(perfluorohexyl)octane.

[0291] 3.38 Method 3.37, wherein the composition comprises up to about 3% by weight, or up to about 2% by weight.

[0292] wt %, or 2-(perfluorohexyl)octane in an amount up to about 1 wt %.

[0293] 3.39 Any of method 3 or 3.1-3.38, wherein the composition is in a volume of about 10-12 μl,

[0294] Or about 10-11 μl or about 11 μl of a single drop dose administered twice a day to each eye of the patient. 3.40 Method 3 or any of 3.1-3.39, wherein the patient has a highly symptomatic eye disease, for example, characterized by meeting at least two criteria selected from the following:

[0295] i. Tear film break-up time (TFBUT) less than 5 seconds (e.g., less than 3.8 seconds),

[0296] ii. Overall Ocular Surface Disease Index (OSDI) above 25 (e.g., above 40),

[0297] iii. Total corneal fluorescein staining (NEI scale) of 4 to 11 (e.g., 5 to 9),

[0298] iv. Schirmer test I greater than 5 mm (e.g., equal to or greater than 10 mm, or equal to or greater than 15 mm), and

[0299] v. MGD score is higher than 3 (eg, higher than 4).

[0300] 3.41 Method 3.40, wherein at least one eye of the patient meets criteria (i), (iii), (iv), and (v).

[0301] 3.42 Any of Method 3 or 3.1-3.41 wherein the patient has a history of keratoconjunctivitis sicca (dry eye) in one or both eyes for at least 6 months.

[0302] 3.43 Any of Method 3 or 3.1-3.42 wherein the composition is effective in reducing ocular surface damage and one or more symptoms of dryness in a patient suffering from meibomian gland dysfunction and / or keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0303] 3.44 Method 3.43, wherein the composition is administered within 2 weeks after the first administration of the composition,

[0304] The ocular surface damage and one or more dryness symptoms are effectively reduced within 4 weeks or within 8 weeks. 3.45 Method 3.44, wherein the ocular surface damage of one or more corneal regions is selected from:

[0305] i. Ocular surface damage in the total corneal area;

[0306] ii. Ocular surface damage in the central corneal area;

[0307] iii. Ocular surface damage in the nasal corneal area;

[0308] iv. ocular surface damage in the temporal corneal region; and

[0309] v.A combination of these.

[0310] 3.46 Method 3.43 to 3.45, wherein the reduction in ocular surface damage is determined by corneal fluorescein staining (NEI scale).

[0311] 3.47 Method 3.46 wherein the ocular surface damage is determined by grading one or more corneal areas selected from the group consisting of: total corneal area, central corneal area, nasal corneal area, and temporal corneal area by corneal fluorescein staining.

[0312] 3.48 Any of Method 3 or 3.1-3.47 wherein the composition is effective to reduce one or more dryness symptoms associated with keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or meibomian gland dysfunction.

[0313] 3.49 Methods 3.43 to 3.48, wherein the one or more dryness symptoms are selected from:

[0314] i. Severity of dryness;

[0315] ii. Blurred vision;

[0316] iii. Light sensitivity;

[0317] iv. Frequency of drying;

[0318] v. Dryness awareness; and

[0319] vi. Any combination thereof.

[0320] 3.50 Method 3.49, wherein the symptoms (i) to (iii) are present at a level between 0% and 10% representing the patient's discomfort level.

[0321] 100% on a visual analogue scale (VAS), and wherein symptoms (iv) to (v) are determined on a visual analogue scale (VAS) from 0% to 100% representing the percentage of time the patient experiences said dryness symptom.

[0322] 3.51 Method 3.57 wherein the one or more dryness symptoms are graded using the Overall Ocular Surface Disease Index (OSDI) score.

[0323] 3.52 Method 3.51 wherein the overall ocular surface disease index (OSDI) score is assessed on a scale of 1 to 100, with higher scores indicating greater disability in the patient.

[0324] In further embodiments of the third aspect, the present disclosure further provides the following additional embodiments: 3.53 Method 3 or any one of 3.1 to 3.52, wherein the composition consists of F6H8 (1-(perfluorohexyl)octane).

[0325] 3.54 Method 3.53 wherein the delayed ocular release is from an anterior segment tissue selected from the group consisting of:

[0326] Meibomian glands, conjunctiva (bulbar conjunctiva), conjunctiva (palpebral conjunctiva), cornea, sclera (anterior sclera), lacrimal glands (accessory lacrimal glands), lacrimal glands (main lacrimal glands), and tears (e.g., tear film).

[0327] 3.55 Method 3.54, wherein the method provides at least

[0328] A maximum concentration of 2000 ng of a semifluorinated alkane (eg, F6H8), optionally wherein said concentration is provided by a single drop dose of 40-60 mg of a semifluorinated alkane (eg, F6H8) administered once a day or twice a day.

[0329] 3.56 Method 3.54, wherein the method provides at least

[0330] 2270 ng of a semifluorinated alkane (e.g., F6H8), optionally wherein the concentration is achieved by once-daily or twice-daily administration of 40-60 mg of a semifluorinated alkane (e.g.,

[0331] F6H8) is provided as a single drop dose.

[0332] 3.57 Method 3.55 or 3.56, wherein the concentration is provided by a single drop dose of about 50 mg (e.g., about 47 mg) of a semifluorinated alkane (e.g., F6H8) administered once daily or twice daily. 3.58 Any of Methods 3.54 to 3.57, wherein the anterior segment tissue of the eye at which the maximum concentration of the semifluorinated alkane (e.g., F6H8) is achieved is selected from the group consisting of meibomian glands, conjunctiva (bulbar conjunctiva), conjunctiva (palpebral conjunctiva), cornea, sclera (anterior sclera), and tears.

[0333] 3.59 Method 3.58 wherein the maximum concentration of the semifluorinated alkane (eg, F6H8) is achieved within 0.25 to 2 hours (eg, 0.25 to 1 hour, or 0.25 to 0.5 hours) following administration of a single drop dose of the composition once daily or twice daily.

[0334] 3.60 Any of methods 3.54 to 3.57, wherein the anterior segment tissue that reaches the maximum concentration of the semifluorinated alkane (e.g., F6H8) is selected from the lacrimal gland (accessory lacrimal gland) and the lacrimal gland (main lacrimal gland). 3.61 Method 3.60, wherein the concentration of the semifluorinated alkane (e.g., F6H8) is reached within 3 to 5 hours (e.g., 4 hours) after administration of a single drop dose of the composition once a day or twice a day.

[0335] F6H8) maximum concentration.

[0336] 3.62 Any of methods 3.54 to 3.61, wherein following administration of a single drop dose of the composition once daily or twice daily, the method provides a maximum concentration of a semifluorinated alkane (e.g., F6H8) of at least:

[0337] a. In the meibomian glands, 222,000 ng / g tissue;

[0338] b. In the conjunctiva (bulbar conjunctiva), 5450 ng / g tissue;

[0339] c. In the conjunctiva (palpebral conjunctiva), 14,000 ng / g tissue;

[0340] d. In the cornea, 8230 ng / g tissue;

[0341] e. In the sclera (anterior sclera), 2270 ng / g tissue;

[0342] f. In the lacrimal gland (accessory lacrimal gland), 4280 ng / g tissue;

[0343] g. In the lacrimal gland (main lacrimal gland), 4130 ng / g tissue; and / or

[0344] h.1300ng / g tears.

[0345] 3.63 Method 3.62, wherein the method provides a maximum concentration of a semifluorinated alkane (e.g., F6H8) of at least 5000 ng / g tear fluid, e.g., at least 10,000 ng / g, or at least 50,000 ng / g

[0346] ng / g, or at least 100,000ng / g, or at least 500,000ng / g, or at least 1,000,000

[0347] ng / g, or at least 2,000,000 ng / g, up to a maximum concentration of semifluorinated alkanes (e.g., F6H8) of about 2,330,000 ng / g of tear fluid.

[0348] The present disclosure further provides an ophthalmic composition comprising a semifluorinated alkane for use in any one of methods 1 to 3 or any subsequent embodiments (i.e., methods 1.1 to 1.65, methods 2.1 to 2.64, and methods 3.1 to 3.63). In another aspect, the present disclosure also provides an ophthalmic composition comprising a semifluorinated alkane, i.e., an ophthalmic composition as defined in any one of methods 1 to 3 or any subsequent embodiments (i.e., methods 1.1 to 1.65, methods 2.1 to 2.64, and methods 3.1 to methods 3.63), for use in the production or preparation of a topical ophthalmic drug or medicament.

[0349] In a fourth aspect, the present disclosure provides an ophthalmic composition comprising a semifluorinated alkane for use in treating keratoconjunctivitis sicca (dry eye disease), and / or in a method for treating keratoconjunctivitis sicca (dry eye disease) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or for treating a condition of the conjunctiva or cornea (Method 4), wherein the semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 8 H, wherein the method comprises the step of topically administering the composition to the eye of a patient in need thereof at a dosage of a single drop per eye twice a day. Further embodiments of the present disclosure are provided as follows:

[0350] 4.1 Compositions for use in method 4, wherein the semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H and F (CF 2 ) 6 (CH 2 ) 8 H.

[0351] 4.2 The composition for use in any one of methods 4 or 4.1, wherein the semifluorinated alkane is F(CF 2 ) 6 (CH 2 ) 8 H.

[0352] 4.3 A composition for use in any of methods 4 or 4.1 below, wherein the composition comprises a single semifluorinated alkane.

[0353] 4.4 A composition for use in any of methods 4 or 4.1 below, wherein the composition does not contain any pharmaceutically active drug useful for ophthalmic treatment.

[0354] 4.5 A composition for use in any of methods 4 or 4.1 below, wherein the composition consists of a single semifluorinated alkane.

[0355] 4.6 A composition for use in method 4 or any one of 4.1 to 4.2, wherein the composition comprises at least one other semifluorinated alkane.

[0356] 4.7 Compositions for use in method 4.6, wherein the other semifluorinated alkane has the formula F(CF 2 ) n (CH 2 ) m H, and wherein n is an integer from 4 to 8 and m is an integer from 5 to 10, and wherein the other semifluorinated alkane is different from the first semifluorinated alkane.

[0357] 4.8 Compositions for use in method 4.7, wherein the other semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H、F(CF 2 ) 6 (CH 2 ) 10 H、F(CF 2 ) 8 (CH 2 ) 8 H and F (CF 2 )8 (CH 2 ) 10 H。

[0358] 4.9 A composition for use in Method 4.6, 4.7 or 4.8, wherein the composition comprises two semi-fluorinated alkanes.

[0359] 4.10 A composition for use in any one of Methods 4.6 to 4.9, wherein the composition does not contain any pharmaceutically active drug that can be used for ophthalmic treatment.

[0360] 4.11 A composition for use in any one of Methods 4.6 to 4.10, wherein the composition consists of two semi-fluorinated alkanes.

[0361] 4.12 A composition for use in any one of Method 4 or 4.1 or below, wherein the ophthalmic composition is administered to the surface of the cornea and / or conjunctiva in the form of droplets.

[0362] 4.13 A composition for use in any one of Method 4 or 4.1 or below, wherein the patient has keratoconjunctivitis sicca (dry eye), optionally wherein the patient has keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0363] 4.14 A composition for use in Method 4.13, wherein the dry eye is aqueous-deficient dry eye. 4.15 A composition for use in Method 4.13 or 4.14, wherein the dry eye is evaporative dry eye.

[0364] 4.16 A composition for use in any one of Method 4 or 4.1 or below, wherein the patient has meibomian gland dysfunction.

[0365] 4.17 A composition for use in Method 4.16, wherein the patient does not respond to conventional physical methods for treating meibomian gland dysfunction (e.g., the methods discussed in Blackie et al., Review of Optometry, June 21, 2012, pp. 1-12, which is incorporated herein by reference in its entirety).

[0366] 4.18 A composition for use in any one of Method 4 or 4.1 or below, wherein the patient does not respond to treatment with aqueous ophthalmic drop compositions.

[0367] 4.19 A composition for use in any one of Method 4 or 4.1 or below, wherein the volume of each drop is 9 - 13 μL, e.g., 9 - 12 μL, or 10 - 13 μL, or 10 - 12 μL, or 10 - 11 μL, or about 11 μL.

[0368] 4.20 A composition for use in any of Methods 4 or 4.1 below, wherein the composition is administered three times a day at a dose of a single drop per eye in a net volume of 30-33 μL.

[0369] 4.21 A composition for use in any of Method 4 or 4.1 below, wherein the composition is administered twice daily at a dose of a single drop per eye in a net volume of 20-22 μL.

[0370] 4.22 A composition for use in any of Methods 4 or 4.1 below, wherein the composition is administered once daily in a net volume of 10-11 μL as a single drop per eye.

[0371] 4.23 A composition for use in any of Methods 4 or 4.1 below, wherein the ocular tissue is enriched in semifluorinated alkanes, and wherein the release of the semifluorinated compound from the enriched ocular tissue is delayed.

[0372] 4.24 A composition for use in Method 4.23 wherein the enriched ocular tissue is selected from the group consisting of palpebral conjunctiva, cornea, meibomian glands, lacrimal glands, and / or bulbar conjunctiva.

[0373] 4.25 A composition for use in methods 4.23 to 4.24 wherein the ocular tissue is, for example, the meibomian glands of the upper and / or lower eyelid.

[0374] 4.26 A composition for use in methods 4.23 to 4.25 wherein the enriched tissue releases all or substantially all of the semifluorinated alkane within 24 hours, optionally within 8 hours, of the last dose of the composition, the enriched tissue optionally releasing at least 60% within 4 to 8 hours, or at least 80% within 8 hours of the last dose of the composition.

[0375] 4.27 A composition for use in methods 4.23 to 4.26 wherein following sequential administration of the compositions (e.g., 2 doses within 24 hours), the ocular tissue that has accumulated the semifluorinated alkane releases all or substantially all of the semifluorinated alkane within 24 hours, optionally within 8 hours, of the last dose, the enriched tissue optionally releasing at least 50% within 4 to 8 hours, or at least 70% within 8 to 12 hours of the last dose of the composition.

[0376] 4.28 A composition for use in any of methods 4 or 4.1 below, wherein the semifluorinated alkane-enriched ocular tissue comprises about 0.00001 to 0.5 wt % semifluorinated alkane, optionally 0.0001 to 0.05 wt %, for example, 0.0001 to 0.001 wt %, or 0.0004 to 0.0009 wt %, or 0.001 to 0.01 wt %, or 0.001 to 0.003 wt %, or 0.001 to 0.05%, or 0.005 to 0.03% semifluorinated alkane.

[0377] 4.29 A composition for use in any of Methods 4 or 4.1 below, wherein the enriched ocular tissue is meibomian glands, and the meibomian glands comprise 0.0001 to 0.05 wt%, optionally 0.0005 to 0.05 wt%, or 0.001 to 0.03 wt% of a semifluorinated alkane.

[0378] 4.30 A composition for use in any of methods 4 or 4.1 below, wherein the treatment is performed for at least about

[0379] 1 day, or at least 5 days, or at least 10 days, or at least 30 days, or at least 60 days, or at least

[0380] 90 days.

[0381] 4.31 A composition for use in any of Method 4 or 4.1 below, wherein the patient is a human patient.

[0382] 4.32 A composition for use in any of Methods 4 or 4.1 below wherein the patient is an animal patient, eg, a mammal such as a dog, cat, rabbit and / or a farm animal such as a horse, pig, cow or sheep.

[0383] 4.33 A composition for use in method 4.31 wherein the patient is a female patient.

[0384] 4.34 A composition for use in method 4.31 wherein the patient is a male patient.

[0385] 4.35 A composition for use in method 4.33 or 4.34 wherein the patient is 20-80 years old, e.g., 20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or 30-70 years old, or 40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80 years old, or 50-70 years old at the time of treatment.

[0386] In further embodiments of the fourth aspect, the present disclosure further provides the following additional embodiments: 4.36 A composition for use in any one of methods 4 or 4.1 to 4.35, wherein the composition consists of 1-(perfluorohexyl)octane (F6H8).

[0387] 4.37 A composition for use in Method 4 or any of 4.1 to 4.35 wherein the composition consists of a mixture of F6H8 and 2-(perfluorohexyl)octane.

[0388] 4.38 A composition for use in method 4.37 wherein the composition comprises 2-(perfluorohexyl)octane in an amount of up to about 3 weight percent, or up to about 2 weight percent, or up to about 1 weight percent.

[0389] 4.39 A composition for use in Method 4 or any of 4.1 to 4.35, or 4.36 to 4.38, wherein the composition is administered twice daily in a single drop dose of about 10-12 μl, or about 10-11 μl, or about 11 μl per eye of the patient.

[0390] 4.40 A composition for use in any of Method 4 or 4.1 to 4.39 wherein the composition is administered twice daily at a dose of a single drop per eye in a net volume of 20-24 μL.

[0391] 4.41 A composition for use in any of Method 4 or 4.1-4.40, wherein the patient's

[0392] Characterized by at least two criteria selected from the following:

[0393] i. Tear film break-up time (TFBUT) is 5 seconds or less (i.e. 0 to 5 seconds),

[0394] ii. Overall Ocular Surface Disease Index (OSDI) of 25 or higher (i.e. OSDI score of 25 to 100), iii. Total corneal fluorescein staining (NEI scale) of 4 to 11,

[0395] iv. Schirmer test I is 5 mm or greater (e.g., equal to, or greater than 10 mm, or equal to or greater than 15 mm), and

[0396] v. Meibomian gland dysfunction (MGD) score of 3 or higher (i.e., score of 3 to 15).

[0397] 4.42 A composition for use in method 4.41 wherein the patient is characterized by at least two criteria selected from:

[0398] i. Tear film break-up time (TFBUT) of 3.8 seconds or less (i.e., 0 to 3.8 seconds), or 2 to 3.8 seconds,

[0399] ii. Total Ocular Surface Disease Index (OSDI) of 36 or higher (i.e. 36 to 100), or 36 to 74, iii. Total corneal fluorescein staining (NEI scale) of 4.6 to 8.8, preferably 5 to 9;

[0400] iv. Schirmer test I is 5 mm or more, preferably 10 mm or more, and

[0401] v. Meibomian gland dysfunction (MGD) score of 3.6, or higher (eg, a score of 3.6 to 15), or a score of 3.6 to 11, preferably 4 to 15.

[0402] 4.43 A composition for use in method 4.41 or 4.42 wherein at least one eye of the patient meets all of criteria (i), (iii), (iv), and (v).

[0403] 4.44 A composition for use in Method 4 or any of 4.1-4.43 wherein the patient has a history of keratoconjunctivitis sicca (dry eye) in one or both eyes for at least 6 months.

[0404] 4.45 A composition for use in any of Method 4 or 4.1-4.44, wherein the composition is effective in reducing ocular surface damage and / or keratoconjunctivitis sicca (dry eye) in one or more corneal regions in a patient suffering from meibomian gland dysfunction and / or keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0405] or one or more symptoms of dryness.

[0406] 4.46 A composition for use in method 4.45 wherein the composition is effective in reducing the ocular surface damage and dryness symptoms within 2 weeks, or within 4 weeks, or within 8 weeks after the first administration of the composition.

[0407] 4.47 A composition for use in methods 4.45-4.46 wherein the ocular surface damage to one or more corneal regions is selected from the group consisting of ocular surface damage to the total corneal region, the central corneal region, the nasal corneal region, the temporal corneal region, and combinations thereof.

[0408] 4.48 A composition for use in methods 4.45 to 4.47 wherein the reduction in ocular surface damage is determined by corneal fluorescein staining (according to the NEI scale).

[0409] 4.49 A composition for use in methods 4.45 to 4.48 wherein the ocular surface damage is determined by grading one or more corneal areas selected from the group consisting of total corneal area, central corneal area, nasal corneal area, temporal corneal area, and combinations thereof by corneal fluorescein staining.

[0410] 4.50 A composition for use in Method 4 or any of 4.1-4.49 wherein the composition is effective in reducing one or more dryness symptoms in a patient suffering from meibomian gland dysfunction and / or keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0411] 4.51 A composition for use in methods 4.45 to 4.50 wherein the one or more symptoms of dryness are selected from:

[0412] i. Severity of dryness;

[0413] ii. Blurred vision;

[0414] iii. Light sensitivity;

[0415] iv. Frequency of drying;

[0416] v. Dryness awareness; and

[0417] vi. Any combination thereof.

[0418] 4.52 A composition for use in 4.51 wherein said symptoms (i) to (iii) are determined on a visual analog scale (VAS) of 0% to 100% representing the patient's level of discomfort, and wherein symptoms (iv) to (v) are determined on a visual analog scale (VAS) of 0% to 100% representing the percentage of time that the patient experiences said dryness symptom.

[0419] 4.53 A composition for use in methods 4.45 to 4.52 wherein the one or more symptoms of dryness are graded using the Overall Ocular Surface Disease Index (OSDI) score.

[0420] 4.54 A composition for use in method 4.53, wherein the total ocular surface disease index (OSDI) score is assessed on a scale of 1 to 100, with higher scores indicating greater disability in the patient. 4.55 A composition for use in methods 4.36 to 4.54, wherein the patient has a concomitant disease,

[0421] For example, conjunctivitis, hordeolum, chalazion, blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof. 4.56 A composition for use in Methods 4.36 to 4.55 wherein the patient has keratoconjunctivitis sicca caused by treatment of a concomitant disease, e.g., treatment with any one or more of the following: isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, anticholinergics, oral contraceptives, antihistamines, nasal vasoconstrictors, beta-adrenergic antagonists, phenothiazines, atropines, optionally wherein any such treatment is concurrent or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

[0422] 4.57 A composition for use in methods 4.36 to 4.56 wherein the patient has keratoconjunctivitis sicca resulting from an ocular surgical intervention, eg, corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ophthalmic surgery is concurrent or prior.

[0423] 4.58 A composition for use in methods 4.36 to 4.57 wherein the patient is concurrently being treated with another topical ophthalmic medication, e.g., an antibiotic, antifungal, corticosteroid, immunosuppressant, sympathomimetic, anesthetic, antihistamine, or any combination thereof.

[0424] 4.59 A composition for use in methods 4.36 to 4.58 wherein the patient is a contact lens wearer.

[0425] 4.60 Compositions for use in methods 4.36 to 4.59 wherein the patient has not responded or has responded inadequately to prior treatment for keratoconjunctivitis sicca (dry eye).

[0426] 4.61 A composition for use in method 4.60 wherein the prior treatment comprises one or more of the following treatment methods: topical aqueous immunosuppressant administration (eg, topical aqueous cyclosporine administration), topical corticosteroid administration, or topical aqueous artificial tears administration.

[0427] In a fifth aspect, related to the fourth aspect, the present disclosure further provides a method for treating keratoconjunctivitis sicca (dry eye) and / or treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or for treating a condition of the conjunctiva or cornea (Method 5), wherein the method comprises the step of topically administering to the eye of a patient in need thereof a single drop per eye twice daily of an ophthalmic composition comprising a semifluorinated alkane selected from F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 8 H. Further embodiments of the present disclosure are provided as follows:

[0428] 5.1 Method 5, wherein the semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H and F (CF 2 ) 6 (CH 2 ) 8 H.

[0429] 5.2 Any one of methods 5 or 5.1, wherein the semifluorinated alkane is F(CF 2 ) 6 (CH 2 ) 8 H.

[0430] 5.3 Any of Method 5 or 5.1 below, wherein the composition comprises a single semifluorinated alkane.

[0431] 5.4 Any of Method 5 or 5.1 below, wherein the composition does not contain any pharmaceutically active drug useful for ophthalmic treatment.

[0432] 5.5 Any of Method 5 or 5.1 below, wherein the composition consists of a single semifluorinated alkane.

[0433] 5.6 Any of Methods 5 or 5.1 to 4.2, wherein the composition comprises at least one other semifluorinated alkane.

[0434] 5.7 Method 5.6, wherein the other semifluorinated alkane has the formula F(CF 2 ) n (CH 2 ) m H, and wherein n is an integer from 4 to 8 and m is an integer from 5 to 10, and wherein the other semifluorinated alkane is different from the first semifluorinated alkane.

[0435] 5.8 Method 5.7, wherein the other semifluorinated alkane is selected from F(CF 2 ) 4 (CH 2 ) 5 H.

[0436] F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH2 ) 8 H、F(CF 2 ) 6 (CH 2 ) 10 H.

[0437] F(CF 2 ) 8 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 10 H.

[0438] 5.9 Method 5.6, 5.7 or 5.8, wherein the composition comprises two semifluorinated alkanes. 5.10 Methods 5.6 to 5.9, wherein the composition does not contain any pharmaceutically active drug useful for ophthalmic treatment.

[0439] 5.11 Methods 5.6 to 5.10 wherein the composition consists of two semifluorinated alkanes.

[0440] 5.12 Any of Method 5 or 5.1 below, wherein the ophthalmic composition is administered to the surface of the cornea and / or conjunctiva in the form of droplets.

[0441] 5.13 Any of Method 5 or 5.1 below, wherein the patient has keratoconjunctivitis sicca (dry eye), optionally wherein the patient has keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0442] 5.14 Method 5.13, wherein the dry eye disease is aqueous deficiency dry eye disease.

[0443] 5.15 Method 5.13 or 5.14 wherein the dry eye disease is evaporative dry eye disease.

[0444] 5.16 Any of Method 5 or 5.1 below, wherein the patient suffers from meibomian gland dysfunction.

[0445] 5.17 Method 5.16 wherein the patient is unresponsive to traditional physical methods of treating meibomian gland dysfunction (e.g., methods discussed in Blackie et al., Review of Optometry, June 21, 2012, pp. 1-12, which reference is incorporated herein by reference in its entirety).

[0446] 5.18 Any of Method 5 or 5.1 below, wherein the patient is unresponsive to treatment with an aqueous ophthalmic eye drop composition.

[0447] 5.19 Any of the following methods 5 or 5.1, wherein the volume of each drop is 9-13 μL, for example,

[0448] 9-12 μL, or 10-13 μL, or 10-12 μL, or 10-11 μL, or about 11 μL.

[0449] 5.20 Any of Method 5 or 5.1 below, wherein the composition is administered twice daily at a dose of a single drop per eye in a net volume of 20-22 μL.

[0450] 5.21 Any of Method 5 or 5.1 below, wherein the ocular tissue is enriched in semifluorinated alkanes, and wherein release of the semifluorinated compound from the enriched ocular tissue is delayed.

[0451] 5.22 Method 5.21 wherein the enriched ocular tissue is selected from the group consisting of palpebral conjunctiva, cornea, meibomian glands, lacrimal glands, and / or bulbar conjunctiva.

[0452] 5.23 Methods 5.21 to 5.22 wherein the ocular tissue is, for example, meibomian glands of the upper and / or lower eyelid.

[0453] 5.24 Methods .21 to 5.23, wherein the enriched tissue releases all or substantially all of the semifluorinated alkane within 24 hours, optionally within 8 hours, of the last dose of the composition, and the enriched tissue optionally releases at least 60% within 4 to 8 hours, or at least 80% within 8 hours of the last dose of the composition.

[0454] 5.25 Methods 5.21 to 5.24, wherein following sequential administration of the compositions (e.g., 2 doses within 24 hours), the ocular tissue that has accumulated the semifluorinated alkane releases all or substantially all of the semifluorinated alkane within 24 hours, optionally within 8 hours, of the last dose, and the enriched tissue optionally releases at least 50% within 4 to 8 hours, or at least 70% within 8 to 12 hours of the last dose of the composition.

[0455] 5.26 Any of methods 5 or 5.1 below, wherein the semifluorinated alkane-enriched ocular tissue comprises about 0.00001 to 0.5 wt % semifluorinated alkane, optionally 0.0001 to 0.05 wt %, for example, 0.0001 to 0.001 wt %, or 0.0004 to 0.0009 wt %, or 0.001 to 0.01 wt %, or 0.001 to 0.003 wt %, or 0.001 to 0.05%, or 0.005 to 0.03% semifluorinated alkane.

[0456] 5.27 Any of Methods 5 or 5.1 below wherein the enriched ocular tissue is meibomian glands, and the meibomian glands comprise 0.0001 to 0.05 wt%, optionally 0.0005 to 0.05 wt%, or 0.001 to 0.03 wt% semifluorinated alkane.

[0457] 5.28 Any of Method 5 or 5.1 below wherein the treatment is carried out for about at least 1 day, or at least 5 days, or at least 10 days, or at least 30 days, or at least 60 or at least 90 days.

[0458] 5.29 Any of Method 5 or 5.1 below, wherein the patient is a human patient.

[0459] 5.30 Any of Method 5 or 5.1 below, wherein the patient is an animal patient, eg, a mammal such as a dog, cat, rabbit, and / or a farm animal such as a horse, pig, cow, or sheep.

[0460] 5.31 Method 5.29, wherein the patient is a female patient.

[0461] 5.32 Method 5.29, wherein the patient is a male patient.

[0462] 5.33 Method 5.31 or 5.32, wherein the patient is 20 to 80 years old at the time of treatment,

[0463] For example, 20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or 30-70 years old,

[0464] or 40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80 years old, or 50-70 years old. In a further embodiment of the fifth aspect, the disclosure further provides the following other embodiments: 5.34 Method 5 or any one of 5.1 to 5.33, wherein the composition consists of 1-(perfluorohexyl)octane (F6H8).

[0465] 5.35 Any of Method 5 or 5.1 to 5.33 wherein the composition consists of a mixture of F6H8 and 2-(perfluorohexyl)octane.

[0466] 5.36 Method 5.35, wherein the composition comprises up to about 3% by weight, or up to about 2% by weight.

[0467] wt %, or 2-(perfluorohexyl)octane in an amount up to about 1 wt %.

[0468] 5.37 Method 5 or any of 5.1-5.36, wherein the composition is administered twice daily in a single drop dose of about 10-12 μl, or about 10-11 μl, or about 11 μl per eye of the patient. 5.38 Method 5 or any of 5.1-5.37, wherein the composition is administered twice daily in a single drop dose of 20-24 μl per eye.

[0469] 5.39 Any of Method 5 or 5.1-5.37, wherein the patient is characterized by at least two

[0470] Items were selected from the following criteria:

[0471] i. Tear film break-up time (TFBUT) is 5 seconds or less (i.e. 0 to 5 seconds),

[0472] ii. Overall Ocular Surface Disease Index (OSDI) of 25 or higher (i.e. OSDI score of 25 to 100),

[0473] iii. Total corneal fluorescein staining (NEI scale) of 4 to 11 (e.g., 5 to 9),

[0474] iv. Schirmer test I is greater than 5 mm (e.g., equal to or greater than 10 mm, or equal to or greater than 15 mm), and

[0475] v. MGD score of 3 or higher (i.e., score of 3 to 15, e.g., 4 or higher). 5.40 Any of Method 5 or 5.1 to 5.38, wherein the patient is characterized by at least

[0476] Two criteria selected from the following:

[0477] i. Tear film break-up time (TFBUT) of 3.8 seconds, or less (i.e., 0 to 3.8 seconds), or 2 to 3.8 seconds;

[0478] ii. Overall Ocular Surface Disease Index (OSDI) of 36 or higher (i.e. OSDI score of 36 to 100), or 36 to 74;

[0479] iii. Total corneal fluorescein staining (NEI scale) is 4 to 8.8, preferably 5 to 9;

[0480] iv. Schirmer test I greater than 5 mm (e.g., equal to or greater than 10 mm, or equal to or greater than 15 mm), and

[0481] v. MGD score of 3.6, or higher (e.g., score of 3.6 to 15), or score of 3.6 to 11, preferably 4 to 15.

[0482] 5.41 The method of 5.39 or 5.40, wherein at least one eye of the patient meets the criteria (i),

[0483] (iii), (iv), and (v), or wherein the patient

[0484] 5.42 The method of 5 or any one of 5.1 - 5.41, wherein the patient has a history of keratoconjunctivitis sicca (dry eye disease) in one or both eyes for at least 6 months.

[0485] 5.43 The method of 5 or any one of 5.1 to 5.42, wherein the composition effectively reduces ocular surface damage in one or more corneal regions and / or one or more dryness symptoms in a patient suffering from meibomian gland dysfunction and / or keratoconjunctivitis sicca (dry eye disease) caused by meibomian gland dysfunction.

[0486] 5.44 The method of 5.43, wherein the composition effectively reduces the symptoms of ocular surface damage and dryness within 2 weeks, 4 weeks, or 8 weeks after the first administration of the composition.

[0487] 5.45 The method of 5.43 to 5.44, wherein the ocular surface damage in one or more corneal regions is selected from the total corneal region, central corneal region, nasal corneal region, temporal corneal region, and combinations thereof.

[0488] 5.46 The method of 5.43 to 5.45, wherein the reduction of ocular surface damage is determined by corneal fluorescein staining (according to the NEI scale).

[0489] 5.47 The method of 5.43 to 5.46, wherein the ocular surface damage is determined by grading one or more corneal regions by corneal fluorescein staining, and the corneal regions are selected from the total corneal region, central corneal region, nasal corneal region, temporal corneal region, and combinations thereof.

[0490] 5.48 The method of 5 or any one of 5.1 - 5.47, wherein the composition effectively reduces one or more dryness symptoms in a patient suffering from meibomian gland dysfunction and / or keratoconjunctivitis sicca (dry eye disease) caused by meibomian gland dysfunction.

[0491] 5.49 The method of 5.43 to 5.48, wherein the one or more ocular symptoms are selected from:

[0492] i. The severity of dryness;

[0493] ii. Blurred vision;

[0494] iii. Light sensitivity;

[0495] iv. The frequency of dryness;

[0496] v. Dryness awareness; and

[0497] vi. Any combination thereof.

[0498] 5.50 Method 5.49, wherein said symptoms (i) to (iii) are determined on a visual analog scale (VAS) of 0% to 100% representing the patient's level of discomfort, and wherein symptoms (iv) to (v) are determined on a visual analog scale (VAS) of 0% to 100% representing the percentage of time that the patient experiences said dryness symptom.

[0499] 5.51 Methods 5.43 to 5.49 wherein the one or more dryness symptoms are graded using the Overall Ocular Surface Disease Index (OSDI) score.

[0500] 5.52 Method 5.50, wherein the overall ocular surface disease index (OSDI) score is assessed on a scale of 1 to 100, with higher scores indicating greater disability in the patient.

[0501] 5.53 Methods 5.34 to 5.52 wherein the patient suffers from a concomitant disease, e.g., conjunctivitis, hordeolum, chalazion, blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

[0502] 5.54 A composition for use in methods 5.34 to 5.53 wherein the patient has keratoconjunctivitis sicca resulting from treatment of a concomitant disease, e.g., treatment with any one or more of the following: isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, anticholinergics, oral contraceptives, antihistamines, nasal vasoconstrictors, beta-adrenergic antagonists, phenothiazines, atropines, optionally wherein any such treatment is concurrent or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

[0503] 5.55 A composition for use in methods 5.34 to 5.54 wherein the patient has keratoconjunctivitis sicca resulting from an ocular surgical intervention, eg, corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ophthalmic surgery is concurrent or prior.

[0504] 5.56 A composition for use in methods 5.34 to 5.55 wherein the patient is concurrently being treated with another topical ophthalmic medication, e.g., an antibiotic, an antifungal, a corticosteroid, an immunosuppressant, a sympathomimetic, an anesthetic, an antihistamine, or any combination thereof.

[0505] 5.57 A composition for use in methods 5.34 to 5.56 wherein the patient is a contact lens wearer.

[0506] 5.58 A composition for use in methods 5.34 to 5.57 wherein the patient has not responded or has responded inadequately to prior treatment for keratoconjunctivitis sicca (dry eye).

[0507] 5.59 A composition for use in method 5.58 wherein the prior treatment comprises one or more of the following treatment methods: topical aqueous immunosuppressant administration (eg, topical aqueous cyclosporine administration), topical corticosteroid administration, or topical aqueous artificial tears administration.

[0508] In a sixth aspect, the present disclosure also provides:

[0509] 6.1 An ophthalmic composition composed of 1-perfluorohexyl-octane (F6H8), which is used in a method for treating keratoconjunctivitis sicca (dry eye disease) and / or treating keratoconjunctivitis sicca (dry eye disease) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or treating conditions of the conjunctiva or cornea, wherein the method comprises the step of topically administering the composition to the eyes of a patient in need thereof in a single drop twice a day, at a dose of about 10-12 μL per eye.

[0510] 6.2 1-perfluorohexyl-octane (F6H8) and optionally up to 3 wt %, or up to about 1

[0511] An ophthalmic composition composed of 2-perfluorohexyl-octane of % by weight, which is used in a method for treating keratoconjunctivitis sicca (dry eye disease) and / or treating keratoconjunctivitis sicca (dry eye disease) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or treating conditions of the conjunctiva or cornea, wherein the method comprises the step of topically administering the composition to the eyes of a patient in need thereof in a single drop twice a day, at a dose of about 10-12 μL per eye.

[0512] 6.3 An ophthalmic composition composed of 1-perfluorohexyl-octane (F6H8) for use in a method for treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating a condition of the conjunctiva or cornea, wherein the method comprises applying to the eye of a patient a single drop of about

[0513] The step of topically administering the composition at a dose of 10-12 μL per eye twice a day.

[0514] 6.4 A composition for use in 6.1, 6.2 or 6.3, wherein the composition is administered to the patient's eye as a single drop of 10-11 μL, preferably as a single drop of about 11 μL.

[0515] 6.5 A composition for use in 6.1, 6.2 or 6.3, wherein the composition is administered twice daily as a single drop per eye in a net volume of 20-24 μL.

[0516] 6.6 A composition for use in 6.4, wherein the composition is administered as a single drop per eye,

[0517] A net volume of 20-22 μL or about 22 μL is administered twice daily.

[0518] 6.7 Compositions for use in 6.1 to 6.6, wherein the second dose is administered at least 1 hour after the first dose, or wherein the second dose is administered at least 2 hours after the first dose, or wherein the second dose is administered at least 3 hours after the first dose, or wherein the second dose is administered at least 4 hours after the first dose.

[0519] 6.8 A composition for use in 6.1 to 6.7 wherein the time interval between administration of the first and second doses is no more than about 8 hours or no more than 12 hours.

[0520] 6.9 A composition for use in 6.1 to 6.8 wherein the patient has a history of keratoconjunctivitis sicca (dry eye) or keratoconjunctivitis sicca caused by meibomian gland dysfunction, or meibomian gland dysfunction in one or both eyes for at least 6 months prior to treatment.

[0521] 6.10 A composition for use in 6.1 to 6.9 wherein the method of treatment comprises administering the composition over a period of at least 2 weeks, at least 4 weeks, or at least 8 weeks.

[0522] 6.11 A composition for use in 6.1 to 6.10, wherein the patient meets at least two criteria selected from:

[0523] i. Tear film break-up time (TFBUT) of 3.8 seconds or less (e.g., 0 to 3.8 seconds), ii. Overall ocular surface disease index (OSDI) of 36 or more (e.g., 36 to 100),

[0524] iii. Total corneal fluorescein staining (NEI scale) of 5 to 9;

[0525] iv. Schirmer test I is 10 mm or greater,

[0526] v. Meibomian gland dysfunction (MGD) score of 4 or higher (e.g., score of 4 to 15), and

[0527] vi. VAS dryness severity score is above 50, such as 50 to 100.

[0528] 6.12 A composition for use in 6.1 to 6.11 wherein the patient meets at least two criteria selected from:

[0529] i. Tear film break-up time (TFBUT) is 2 to 3.8 seconds,

[0530] ii. Overall Ocular Surface Disease Index (OSDI) of 36 to 74,

[0531] iii. Total corneal fluorescein staining (NEI scale) of 5 to 9,

[0532] iv. Schirmer test I is 10 mm or greater,

[0533] v. Meibomian gland dysfunction (MGD) score of 4 to 11; and

[0534] vi. VAS dryness severity score ranged from 50 to 90.

[0535] 6.13 A composition for use in 6.11 or 6.12 wherein the patient meets all of the criteria (ie, signs of dry eye) (i), (iii), (iv), and (v) in at least one eye.

[0536] 6.14 A composition for use in 6.11 or 6.12 wherein the patient meets all of criteria (i) to (vi).

[0537] 6.15 A composition for use in 6.11 or 6.12 wherein the patient is characterized by at least one criterion selected from (i), (iii), (iv) and (v) (i.e., associated with signs of dry eye disease) and at least one criterion selected from (ii) and (vi) (i.e., associated with symptoms of dry eye disease).

[0538] 6.16 A composition for use in 6.1 to 6.10 wherein the patient meets at least two criteria selected from:

[0539] i. Tear film breakup time (TFBUT) of 3.8 seconds or less (e.g., 0 to 3.8 seconds), ii. Total corneal fluorescein staining (NEI scale) of 5 to 9;

[0540] iii. Meibomian gland dysfunction (MGD) score of 4 or higher (e.g., score of 4 to 15)

[0541] iv. an overall ocular surface disease index (OSDI) of 36 or higher (e.g., 36 to 100),

[0542] v. VAS dryness severity score is above 50, such as 50 to 100.

[0543] 6.17 A composition for use in 6.1 to 6.10 or 6.16 wherein the patient meets at least two criteria selected from:

[0544] i. Tear film break-up time (TFBUT) is 2 to 3.8 seconds,

[0545] ii. Total corneal fluorescein staining (NEI scale) of 5 to 9;

[0546] iii. Meibomian gland dysfunction (MGD) score of 4 to 11, and

[0547] iv. Overall Ocular Surface Disease Index (OSDI) of 36 to 74)

[0548] v.VAS dryness severity score ranges from 50 to 90.

[0549] 6.18 A composition for use in 6.16 or 6.17 wherein the patient meets all of the criteria (ie, signs of dry eye) of (i), (ii), and (iii) in at least one eye.

[0550] 6.19 A composition for use in 6.16 or 6.17 wherein the patient meets all of criteria (i) to (v).

[0551] 6.20 Compositions for use in 6.16 or 6.17 wherein the patient is characterized by at least one criterion selected from (i), (ii) and (iii) (i.e., associated with signs of dry eye disease) and at least one criterion selected from (iv) and (v) (i.e., associated with symptoms of dry eye disease).

[0552] 6.21 A composition for use in 6.1 to 6.20 wherein the overall ocular surface disease index (OSDI) score is assessed on a scale of 1 to 100, with higher scores indicating greater disability in the patient.

[0553] 6.22 A composition for use in 6.1 to 6.21 wherein the patient has a condition of the cornea characterized by ocular surface damage to one or more zones of the cornea, e.g., the total corneal zone and / or the central corneal zone and / or the nasal corneal zone and / or the temporal corneal zone.

[0554] 6.23 Compositions for use in 6.1 to 6.22 wherein the treatment comprises reducing ocular surface damage in one or more regions of the cornea, for example, the total corneal area and / or the central corneal area and / or the nasal corneal area and / or the temporal corneal area.

[0555] 6.24 A composition for use in 6.23 wherein the patient has a condition of the cornea characterized by ocular surface damage, and wherein the method of treatment comprises treating or reducing the ocular surface damage of:

[0556] i. Total corneal area and central corneal area;

[0557] ii. Total corneal area and nasal corneal area

[0558] iii. Total corneal area and temporal corneal area

[0559] iv. Central corneal area and nasal corneal area

[0560] v. Central corneal region and temporal corneal region

[0561] 6.25 A composition for 6.1 to 6.24, wherein the method comprises treating or reducing ocular surface damage in one or more corneal regions and / or treating or reducing one or more dryness symptoms in a patient suffering from meibomian gland dysfunction and / or keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0562] 6.26 A composition for 6.25, wherein the method comprises treating or reducing ocular surface damage in one or more corneal regions and treating or reducing one or more dryness symptoms in a patient suffering from keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0563] 6.27 A composition for 6.26, wherein the ocular surface damage in one or more corneal regions is selected from (a) the total corneal region, (b) the central corneal region, (c) the nasal corneal region, (d) the temporal corneal region, and (e) any combination thereof.

[0564] 6.28 A composition for 6.22 to 6.27, wherein the ocular surface damage and / or its reduction is determined by corneal fluorescein staining, optionally wherein grading of the one or more corneal regions by fluorescein staining is performed using the (National Eye Institute) NEI scale.

[0565] 6.29 A composition for 6.25 to 6.28, wherein the one or more dryness symptoms are selected from (a) severity of dryness, (b) blurred vision, (c) light sensitivity, (d) frequency of dryness;

[0566] (e) dryness awareness, and (d) any combination thereof.

[0567] 6.30 A composition for 6.29, wherein symptoms (a) to (c) are determined on a visual analogue scale (VAS) of 0% to 100% representing the level of discomfort of the patient, and wherein symptoms (d) and (e) are determined on a visual analogue scale (VAS) of 0% to 100% representing the percentage of time the patient experiences the dryness symptoms.

[0568] 6.31 A composition for 6.11 to 6.30, wherein the dryness symptoms and / or their reduction are graded using the Ocular Surface Disease Index (OSDI) score.

[0569] 6.32 A composition for 6.31, wherein the Ocular Surface Disease Index (OSDI) score is evaluated on a scale of 1 to 100, with a higher score indicating greater disability of the patient.

[0570] 6.33 A composition for use in 6.1 to 6.32, wherein the composition is effective in reducing the severity of dryness symptoms within 2 weeks of initiation of treatment.

[0571] 6.34 The composition for use in 6.33 wherein the patient's dryness symptoms are reduced in severity by at least 25%.

[0572] 6.35 A composition for use in 6.1 to 6.34 wherein the patient has keratoconjunctivitis sicca (dry eye) selected from evaporative dry eye, or wherein the patient has keratoconjunctivitis sicca (dry eye) selected from evaporative dry eye caused by meibomian gland dysfunction.

[0573] 6.36 A composition for use in 6.1 to 6.35 wherein the patient does not suffer from aqueous dry eye or aqueous deficient dry eye.

[0574] 6.37 Compositions for use in 6.1 to 6.36 wherein the treatment is carried out for about at least 1 day, or at least 5 days, or at least 10 days, or at least 30 days, or at least 60 or at least 90 days.

[0575] 6.38 A composition for use in 6.1 to 6.37 wherein the patient is a human patient.

[0576] 6.39 The composition for use in 6.38 wherein the patient is a female patient.

[0577] 6.40 A composition for use in 6.38 wherein the patient is a male patient.

[0578] 6.41 A composition for use in 6.39 or 6.40 wherein the patient is 20-80 years old, e.g., 20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or 30-70 years old, or 40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80 years old, or 50-70 years old at the time of treatment.

[0579] 6.42 A composition for use in 6.1 to 6.41 wherein the patient has a concomitant disease, e.g., conjunctivitis, hordeolum, chalazion, blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

[0580] 6.43 A composition for use in 6.1 to 6.42 wherein the patient has keratoconjunctivitis sicca resulting from treatment of a concomitant disease, e.g., treatment with any one or more of the following: isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, anticholinergics, oral contraceptives, antihistamines, nasal vasoconstrictors, beta-adrenergic antagonists, phenothiazines, atropines, optionally wherein any such treatment is concurrent or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

[0581] 6.44 A composition for use in 6.1 to 6.43 wherein the patient suffers from keratoconjunctivitis sicca resulting from an ocular surgical intervention, eg, corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ophthalmic surgery is concurrent or prior.

[0582] 6.45 A composition for use in 6.1 to 6.44 wherein the patient is concurrently being treated with another topical ophthalmic medication, e.g., an antibiotic, an antifungal, a corticosteroid, an immunosuppressant, a sympathomimetic, an anesthetic, an antihistamine, or any combination thereof.

[0583] 6.46 A composition for use in 6.1 to 6.45 wherein the patient is a contact lens wearer.

[0584] 6.47 A composition for use in 6.1 to 6.46 wherein the patient has not responded or has responded inadequately to prior treatment for keratoconjunctivitis sicca (dry eye).

[0585] 6.48 A composition for use in 6.47 wherein the prior treatment comprises one or more of the following treatment methods: topical aqueous immunosuppressant administration (eg, topical aqueous cyclosporine administration), topical corticosteroid administration, or topical aqueous artificial tears administration.

[0586] The composition used in the present invention can be provided to the patient in the form of a kit. In a further and related aspect of the sixth aspect, the present disclosure also provides the use of a kit, or a kit for:

[0587] 6.49 A kit comprising:

[0588] a. an ophthalmic composition consisting essentially of 1-perfluorohexyl octane, or a composition as defined in any of the compositions of 6.1 or 6.2, and

[0589] b. a container for containing the composition,

[0590] For use in a method of treating keratoconjunctivitis sicca (dry eye), and / or treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or treating a condition of the conjunctiva or cornea.

[0591] 6.50 A kit for use in 6.49, for use in any one of the methods described in 6.1 to 6.48.

[0592] 6.51 A kit for use in 6.49 for use in a method of treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating a condition of the cornea.

[0593] 6.52 A kit for use in 6.49 to 6.51, wherein the container is suitable for containing at least

[0594] 600-720 μl of said composition.

[0595] 6.53 A kit for use in 6.49 to 6.52 wherein the container is suitable for containing an amount of the composition to support twice daily treatment for at least 30 days.

[0596] 6.54 A kit for use in 6.49 to 6.53, wherein the kit further comprises a droplet dispenser suitable for dispensing droplets having a volume of 10-12 μl, droplets having a volume of 10 to 11 μl, or droplets having a volume of about 11 μl.

[0597] 6.55 A kit for use in 6.49 to 6.54, wherein the kit further comprises instructions for use, and wherein the instructions for use are in a readable or tangible form, preferably printed form (for example, provided in the form of a brochure or insert of a container label) or in any machine or computer readable form (for example, a machine readable label, such as a barcode or QR code) indicating daily administration of the composition twice a day according to any of the methods described in 6.1 to 6.48, or optionally according to any of the aforementioned methods 4 or 4.1 to 4.61 or methods 5 or 5.1 to 5.59.

[0598] The present disclosure also further provides a seventh aspect, related to the sixth aspect, regarding a method of treatment according to the following embodiments:

[0599] 7.1 A method for treating keratoconjunctivitis sicca (dry eye) and / or treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or treating a condition of the conjunctiva or cornea, wherein the method comprises topically administering to the eye of a patient in need thereof a single drop of about 10-12 μL per eye twice daily.

[0600] The invention relates to a process for preparing an ophthalmic composition composed of 1-perfluorohexyl-octane (F6H8).

[0601] 7.2 A method for treating keratoconjunctivitis sicca (dry eye) and / or treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or treating a condition of the conjunctiva or cornea, wherein the method comprises the step of topically administering to the eyes of a patient in need thereof an ophthalmic composition consisting of 1-perfluorohexyl-octane (F6H8) and optionally up to 3 wt % or up to about 1 wt % of 2-perfluorohexyl-octane at a single drop of about 10-12 μL per eye twice a day.

[0602] 7.3 A method for treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating a condition of the conjunctiva or cornea, wherein the method comprises the step of topically administering to the eye of a patient in need thereof a single drop of about 10-12 μL per eye twice a day of an ophthalmic composition consisting of 1-perfluorohexyl-octane (F6H8).

[0603] 7.4 The method according to 7.1, 7.2 or 7.3, wherein the composition is administered to the patient's eye as a single drop of 10-11 μL, preferably as a single drop of about 11 μL.

[0604] 7.5 The method according to 7.1, 7.2 or 7.3, wherein the composition is administered twice daily at a dose of a single drop per eye in a net volume of 20-24 μL.

[0605] 7.6 The method of 7.4, wherein the composition is administered as a single drop per eye, twice daily in a net volume of 20-22 μL or about 22 μL.

[0606] 7.7 The method of 7.1 to 7.6, wherein the second dose is administered at least 1 hour after the first dose, or wherein the second dose is administered at least 2 hours after the first dose, or wherein the second dose is administered at least 3 hours after the first dose, or wherein the second dose is administered at least 4 hours after the first dose.

[0607] 7.8 The method of 7.1 to 7.7, wherein the time interval between administration of the first and second doses is no more than about 8 hours or no more than 12 hours.

[0608] 7.9 The method of 7.1 to 7.8, wherein the patient has a history of keratoconjunctivitis sicca (dry eye), or keratoconjunctivitis sicca caused by meibomian gland dysfunction, or meibomian gland dysfunction in one or both eyes for at least 6 months prior to treatment.

[0609] 7.10 The method of 7.1 to 7.9, wherein the method comprises administering the composition over a period of at least 2 weeks, at least 4 weeks, or at least 8 weeks.

[0610] 7.11 The method of 7.1 to 7.10, wherein the patient meets at least two criteria selected from the group consisting of:

[0611] i. Tear film break-up time (TFBUT) of 3.8 seconds or less (e.g., 0 to 3.8 seconds), ii. Overall ocular surface disease index (OSDI) of 36 or more (e.g., 36 to 100),

[0612] iii. Total corneal fluorescein staining (NEI scale) of 5 to 9;

[0613] iv. Schirmer test I is 10 mm or greater,

[0614] v. Meibomian gland dysfunction (MGD) score of 4 or higher (e.g., score of 4 to 15), and

[0615] vi. VAS dryness severity score is above 50, such as 50 to 100.

[0616] 7.12 The method of 7.1 to 7.11, wherein the patient meets at least two criteria selected from the group consisting of:

[0617] i. Tear film break-up time (TFBUT) is 2 to 3.8 seconds,

[0618] ii. Overall Ocular Surface Disease Index (OSDI) of 36 to 74,

[0619] iii. Total corneal fluorescein staining (NEI scale) of 5 to 9,

[0620] iv. Schirmer test I is 10 mm or greater,

[0621] v. Meibomian gland dysfunction (MGD) score of 4 to 11; and

[0622] vi. VAS dryness severity score ranged from 50 to 90.

[0623] 7.13 The method of 7.11 or 7.12, wherein the patient meets all of the criteria (i), (iii), (iv) and (v) (i.e., signs of dry eye disease) in at least one eye.

[0624] 7.14 The method of 7.11 or 7.12, wherein the patient meets all of criteria (i) to (vi).

[0625] 7.15 A method according to 7.11 or 7.12, wherein the patient is characterized by at least one criterion selected from (i), (iii), (iv) and (v) (i.e., associated with signs of dry eye disease) and at least one criterion selected from (ii) and (vi) (i.e., associated with symptoms of dry eye disease).

[0626] 7.16 The method of 7.1 to 7.10, wherein the patient meets at least two criteria selected from the group consisting of:

[0627] i. Tear film break-up time (TFBUT) of 3.8 seconds or less (e.g., 0 to 3.8 seconds), ii. Overall ocular surface disease index (OSDI) of 36 or more (e.g., 36 to 100),

[0628] iii. Total corneal fluorescein staining (NEI scale) of 5 to 9;

[0629] iv. Meibomian gland dysfunction (MGD) score of 4 or higher (e.g., score of 4 to 15)

[0630] v. VAS dryness severity score is above 50, such as 50 to 100.

[0631] 7.17 The method of 7.1 to 7.10 or 7.16, wherein the patient meets at least two criteria selected from:

[0632] i. Tear film break-up time (TFBUT) is 2 to 3.8 seconds,

[0633] ii. Overall ocular surface disease index (OSDI) of 36 to 74),

[0634] iii. Total corneal fluorescein staining (NEI scale) of 5 to 9;

[0635] iv. Meibomian gland dysfunction (MGD) score of 4 to 11, and

[0636] v.VAS dryness severity score ranges from 50 to 90.

[0637] 7.18 The method of 7.16 or 7.17, wherein the patient meets all of the criteria (ie, signs of dry eye) (i), (iii), and (iv) in at least one eye.

[0638] 7.19 The method of 7.16 or 7.17, wherein the patient meets all of criteria (i) to (vi).

[0639] 7.20 A method according to 7.16 or 7.17, wherein the patient is characterized by at least one criterion selected from (i), (iii), (iv) (i.e., associated with signs of dry eye disease) and at least one criterion selected from (ii) and (v) (i.e., associated with symptoms of dry eye disease).

[0640] 7.21 A method according to 7.1 to 7.20, wherein the overall ocular surface disease index (OSDI) score is assessed on a scale of 1 to 100, with higher scores indicating greater disability in the patient. 7.22 A method according to 7.1 to 7.21, wherein the patient has a corneal condition characterized by ocular surface damage in one or more zones of the cornea, e.g., the total corneal zone and / or the central corneal zone and / or the nasal corneal zone and / or the temporal corneal zone.

[0641] 7.23 A method according to 7.1 to 7.22 wherein the treatment comprises reducing ocular surface damage in one or more regions of the cornea, for example, the total corneal region and / or the central corneal region and / or the nasal corneal region and / or the temporal corneal region.

[0642] 7.24 The method of 7.23, wherein the patient has a condition of the cornea characterized by ocular surface damage, and wherein the method of treatment comprises treating or reducing the ocular surface damage of:

[0643] i. Total corneal area and central corneal area;

[0644] ii. Total corneal area and nasal corneal area

[0645] iii. Total corneal area and temporal corneal area

[0646] iv. Central corneal area and nasal corneal area

[0647] v. Central corneal area and temporal corneal area

[0648] 7.25 A method according to 7.1 to 7.24, wherein the method comprises treating or reducing ocular surface damage to one or more corneal regions and / or treating or reducing one or more symptoms of dryness in a patient suffering from meibomian gland dysfunction and / or keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0649] 7.26 The method of 7.25, wherein the method comprises treating or reducing ocular surface damage in one or more corneal regions and treating or reducing one or more symptoms of dryness in a patient suffering from keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0650] 7.27 The method of 7.26, wherein the ocular surface damage in one or more corneal regions is selected from (a) the total corneal region, (b) the central corneal region, (c) the nasal corneal region, (d) the temporal corneal region, and (e) any combination thereof.

[0651] 7.28 A method according to 7.22 to 7.27, wherein the ocular surface damage and / or reduction thereof is determined by corneal fluorescein staining, optionally wherein grading of the one or more corneal regions by fluorescein staining is performed using the (National Eye Institute) NEI scale.

[0652] 7.29 A method according to 7.25 to 7.28, wherein the one or more symptoms of dryness are selected from (a) severity of dryness (b) blurred vision, (c) light sensitivity, (d) frequency of dryness; (e) awareness of dryness and (d) any combination thereof.

[0653] 7.30 The method of 7.29, wherein symptoms (a) to (c) are determined on a visual analog scale (VAS) of 0% to 100% representing the patient's discomfort level, and wherein symptoms (d) and (e) are determined on a visual analog scale (VAS) of 0% to 100% representing the percentage of time that the patient experiences said dryness symptoms.

[0654] 7.31 A method according to 7.11 to 7.30, wherein the dryness symptoms and / or reduction thereof are graded using the Overall Ocular Surface Disease Index (OSDI) score.

[0655] 7.32 The method of 7.31, wherein the overall ocular surface disease index (OSDI) score is assessed on a scale of 1 to 100, with higher scores indicating greater disability for the patient.

[0656] 7.33 A method according to 7.1 to 7.32 wherein the composition is effective in reducing the severity of dryness symptoms within 2 weeks of initiation of treatment.

[0657] 7.34 The method of 7.33 wherein the patient's dryness symptoms are reduced in severity by at least 25%.

[0658] 7.35 A method according to 7.1 to 7.34, wherein the patient has keratoconjunctivitis sicca (dry eye) selected from evaporative dry eye, or wherein the patient has keratoconjunctivitis sicca (dry eye) selected from evaporative dry eye caused by meibomian gland dysfunction.

[0659] 7.36 The method of 7.1 to 7.35 wherein the patient does not suffer from aqueous dry eye or aqueous deficient dry eye.

[0660] 7.37 Methods according to 7.1 to 7.36 wherein the treatment is carried out for about at least 1 day, or at least 5 days, or at least 10 days, or at least 30 days, or at least 60 or at least 90 days.

[0661] 7.38 A method according to 7.1 to 7.37, wherein the patient is a human patient.

[0662] 7.39 The method of 7.38, wherein the patient is a female patient.

[0663] 7.40 The method according to 7.38, wherein the patient is a male patient.

[0664] 7.41 A method according to 7.39 or 7.40 wherein the patient is 20-80 years old, e.g. 20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or 30-70 years old, or 40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80 years old, or 50-70 years old at the time of treatment.

[0665] 7.42 A method according to 7.1 to 7.41 wherein the patient has a concomitant disease, e.g., conjunctivitis, hordeolum, chalazion, blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or ocular allergy, or any combination thereof.

[0666] 7.43 A method according to 7.1 to 7.42 wherein the patient has keratoconjunctivitis sicca resulting from treatment of a concomitant disease, e.g., treatment with any one or more of the following: isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, anticholinergics, oral contraceptives, antihistamines, nasal vasoconstrictors, beta-adrenergic antagonists, phenothiazines, atropines, optionally wherein any such treatment is concurrent or prior, and further optionally wherein any such treatment is systemic (e.g., oral or parenteral).

[0667] 7.44 A method according to 7.1 to 7.43 wherein the patient suffers from keratoconjunctivitis sicca resulting from an ophthalmic surgical intervention, e.g., corneal surgery, refractive surgery, LASIK surgery, cataract surgery, optionally wherein any such ophthalmic surgery is concurrent or prior.

[0668] 7.45 A method according to 7.1 to 7.44 wherein the patient is concurrently being treated with another topical ophthalmic medication, e.g., an antibiotic, an antifungal, a corticosteroid, an immunosuppressant, a sympathomimetic, an anesthetic, an antihistamine, or any combination thereof.

[0669] 7.46 A method according to 7.1 to 7.45, wherein the patient is a contact lens wearer.

[0670] 7.47 A method according to 7.1 to 7.46 wherein the patient has not responded or has responded inadequately to prior treatment for keratoconjunctivitis sicca (dry eye).

[0671] 7.48 The method of 7.47 wherein the prior treatment comprises one or more of the following treatment methods: topical aqueous immunosuppressant administration (eg, topical aqueous cyclosporine administration), topical corticosteroid administration, or topical aqueous artificial tears administration.

[0672] In further and related aspects of the seventh aspect, the present disclosure further provides methods of treatment according to the following embodiments:

[0673] 7.49 A method of treating keratoconjunctivitis sicca (dry eye) and / or treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating meibomian gland dysfunction and / or treating a condition of the conjunctiva or cornea, or a method as defined in any one of methods 7.1 to 7.41, wherein the method comprises administering to a patient an ophthalmic composition consisting essentially of 1-perfluorohexyl octane, or a composition as defined in any of the compositions of 7.1 or 7.2, wherein the composition is provided as a kit comprising:

[0674] a. an ophthalmic composition consisting essentially of 1-perfluorohexyloctane, or as defined in 7.1 or 7.2, and

[0675] b. a container, which is used to contain the composition.

[0676] 7.50 A method according to 7.49, wherein the method is as defined in any one of methods 7.1 to 7.48.

[0677] 7.51 A method according to 7.49 wherein the method comprises treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating a condition of the cornea.

[0678] 7.52 A method according to 7.49 to 7.51, wherein the container is suitable for containing at least 600-720

[0679] μl of the composition.

[0680] 7.53 A method according to 7.49 to 7.52 wherein the container is suitable for containing an amount of the composition to support twice daily treatment for at least 30 days.

[0681] 7.54 A method according to 7.49 to 7.53 wherein the kit further comprises a droplet dispenser suitable for dispensing droplets of 10-12 μl in volume, droplets of 10 to 11 μl in volume or droplets of about 11 μl in volume.

[0682] 7.55 A method according to 7.49 to 7.54, wherein the kit further comprises instructions for use, and wherein the instructions for use are in a readable or tangible form, preferably printed (e.g., provided in the form of a brochure or insert in a container label) or in any machine or computer readable form (e.g., a machine readable label, such as a barcode or QR code) indicating daily administration of the composition twice a day according to any of the methods described in 7.1 to 7.48, or optionally according to any of the aforementioned methods 4 or 4.1 to 4.61 or methods 5 or 5.1 to 5.59.

[0683] Although semifluorinated alkanes have been described in the art, for example in EP-A 2 335 735, as useful carriers for ophthalmic drugs for topical treatment of conditions such as keratoconjunctivitis sicca, the present invention is based on the unexpected discovery that semifluorinated alkanes can enrich certain ocular tissues with the semifluorinated alkanes when administered in an appropriate dosage regimen. It has been found that even when administered topically to the corneal surface or conjunctiva, semifluorinated alkanes localize to and enrich certain ocular tissues, such as the meibomian glands of the upper and / or lower eyelids. This results in the accumulation of semifluorinated alkanes in such tissues, forming a "reservoir" that can release the semifluorinated alkanes from the reservoir back to the ocular surface, such as the cornea or conjunctiva. This effect is one of delayed release of the semifluorinated alkane from the ocular tissue reservoir, resulting in the maintenance of a therapeutically effective concentration of the semifluorinated alkane between the administration of a dose of an ophthalmic composition comprising the semifluorinated alkane. In conjunction with the initial dose of the ophthalmic composition, the effect is one of sustained release of the semifluorinated alkane, which sustained release begins shortly after administration of the eye drop and continues until the enriched ocular tissues have exhausted their stores of semifluorinated alkane, or, when a multiple or continuous dosing regimen is followed, each time a new dose of the ophthalmic composition is administered, the ocular tissues are continuously enriched with semifluorinated alkanes.

[0684] The present disclosure is also based on the discovery that the composition comprising a semifluorinated alkane can be administered in a dosage regimen of less than 4 times a day. As a standard treatment regimen, a dosage regimen of 4 times a day with a single drop of 10-11 μl per eye is considered effective. For example, in the dosing instructions accompanying the F6H8 product composition, the subject is instructed to administer drops of the composition of F6H8 4 times a day unless otherwise advised by the physician. Unexpectedly, it has been found that a reduced dosing frequency can also provide similar therapeutic results. Unexpectedly, it has also been found that using a reduced dosing frequency of 2 times a day, under this regimen, the severity of dryness as a symptom experienced by dry eye patients can be significantly reduced within two weeks after starting treatment.

[0685] In one embodiment of the present disclosure, the composition used in the present invention can be administered over a treatment period of at least 2 weeks, or at least 4 weeks, or at least 8 weeks. In another embodiment, when symptoms or signs of dry eye disease, such as ocular surface damage, persist, as determined by any of the methods described herein, the pharmaceutical composition for treating dry eye disease conditions and disorders as described herein can be administered continuously.

[0686] Reducing the amount of the composition comprising the semifluorinated alkane is not only economically beneficial, but also may have the effect of reducing the likelihood of any adverse events (if any) that may occur to the patient while receiving the treatment due to reduced exposure to the compound. The reduced dosing frequency of twice daily dosing (BID) will also be more convenient for the patient compared to a 4 times daily dosing regimen, thus increasing the likelihood of patient compliance. In addition, in cases where dry eye and / or signs and / or symptoms of dry eye caused by meibomian gland dysfunction have been alleviated to the extent that more frequent dosing of the composition is not necessary, BID treatment is convenient for the patient.

[0687] Keratoconjunctivitis sicca is a complex, multifaceted disease or condition as described above. It is also referred to as dry eye syndrome, dry eye disease (DED), or tear dysfunction syndrome. Aqueous DED and evaporative DED are within the scope of keratoconjunctivitis sicca and form specific subtypes thereof. Sjögren's syndrome, tear insufficiency, meibomian gland disease, meibomian gland dysfunction, and other conditions all fall within the scope of keratoconjunctivitis sicca and are direct or indirect causes thereof.

[0688] 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 as an abnormality of the meibomian glands, which is generally characterized by glandular duct obstruction and / or changes (qualitative and / or quantitative) in glandular secretion. In general, conditions or disease states that cause or result in abnormal, reduced or increased delivery of lipids to the tear film can cause keratoconjunctivitis sicca and its associated symptoms.

[0689] Symptoms of keratoconjunctivitis sicca include dryness, itching, gritty or sandy sensation in the eyes; foreign body sensation; pain or soreness; stinging or burning; itching; increased blinking; eye fatigue; photophobia; blurred vision; redness; mucus discharge; contact lens intolerance; excessive reflex tearing. In addition to the described symptoms of keratoconjunctivitis sicca, patients with meibomian gland dysfunction may also experience symptoms of itching, redness, swelling, pain or soreness, accumulation of discharge or crusting, especially at the eyelid margin. It should be understood that not all patients with keratoconjunctivitis sicca exhibit all symptoms at the same time. Therefore, there is currently no uniform standard for diagnosing the disease. It should also be understood that a patient may suffer from one or more subtypes of keratoconjunctivitis sicca, or one or more conditions or disease pathways that cause keratoconjunctivitis sicca. However, it is important to note that within the scope of the present invention, any aspect, symptom or pathophysiological consequence of dry eye disease can be addressed.

[0690] Semifluorinated alkanes are straight or branched alkanes in which some of the hydrogen atoms have been replaced by fluorine. The semifluorinated alkanes (SFA) used in the present invention are composed of at least one non-fluorinated hydrocarbon segment and at least one perfluorinated hydrocarbon segment and have the general formula F(CF 2 ) n (CH 2 ) m H. Another nomenclature that can be used in this article refers to the above SFA with the above two segments, called RFRH, where RF represents a perfluorinated hydrocarbon segment and RH represents a non-fluorinated segment. In addition, these compounds can also be referred to as FnHm, where F represents a perfluorinated hydrocarbon segment, H represents a non-fluorinated segment, and n and m are the number of carbon atoms in each corresponding segment. For example, F6H8 is used to represent 1-perfluorohexyl octane. In addition, this nomenclature is generally used for compounds with linear segments. Therefore, unless otherwise stated, it should be assumed that F3H3 represents 1-perfluoropropylpropane, rather than 2-perfluoropropylpropane, 1-perfluoroisopropylpropane or 2-perfluoroisopropylpropane.

[0691] In some embodiments, the composition comprising a semifluorinated alkane as defined in the context of the present disclosure is free of active ingredients or is a composition free of drugs, i.e., free of any pharmaceutically active drug that can be used for ophthalmic treatment. In a specific embodiment, the composition does not contain or excludes any active ingredient or pharmaceutically active drug substance in a therapeutically effective amount, i.e., any active ingredient or pharmaceutically active drug substance that can be used for ophthalmic treatment, for example. As used herein, an active ingredient refers to any type of pharmaceutically active compound or derivative that can be used for the prevention, diagnosis, stabilization, treatment, or management of a condition or disease in general. A therapeutically effective amount refers to a dose, concentration, or intensity that can be used to produce a desired pharmacological effect. As used herein, a composition of the present disclosure that "does not contain active ingredients" or "does not contain drug substances" or "does not contain any pharmaceutically active drugs that can be used for ophthalmic treatment" or similar variants thereof is a composition that contains at least one or more semifluorinated alkanes, but does not contain any other pharmaceutically active ingredients or drug substances that can be used for ophthalmic treatment or are active for ophthalmic treatment.

[0692] In some embodiments, the SFA of the present invention is of formula F(CF 2 ) n (CH 2 ) m H, especially SFA of formula F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 8 In a specific embodiment, SFA is F(CF 2 ) 6 (CH 2 ) 8 H.

[0693] In other embodiments, the compositions of the present invention may be composed of the semifluorinated alkane 1-perfluorohexyl octane and optionally up to 3 weight percent of 2-perfluorohexyl octane based on the total weight of the composition. 2-Perfluorohexyl octane is of the formula F(CF 2 ) 6 -CH(CH 3)(CH 2 ) 6 In further embodiments, the composition may consist of 1-perfluorohexyl octane and up to 2 weight percent of 2-perfluorohexyl octane or up to 1 weight percent of 2-perfluorohexyl octane. In other embodiments, the composition of the present invention may consist essentially only of the semifluorinated alkane F(CF 2 ) 6 (CH 2 ) 8 H composition.

[0694] As used herein, the term "weight %" refers to the percentage fraction of the weight of a component to the weight of the overall measured composition. Terms preceding a parameter such as weight % include the exact value as well as any value falling within the degree of variability normally observed in the measurement and determination of the parameter, including standard techniques and equipment known in the art.

[0695] In some embodiments, the composition may further include a second SFA of formula F(CF 2 ) n (CH 2 ) m SFA of H, wherein n is an integer in the range of 4 to 8, and m is an integer in the range of 5 to 10, particularly including F(CF 2 ) 4 (CH 2 ) 5 H、F(CF 2 ) 4 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 6 H、F(CF 2 ) 6 (CH 2 ) 8 H、F(CF 2 ) 6 (CH 2 ) 10 H、F(CF 2 ) 8 (CH 2 ) 8 H and F (CF 2 ) 8 (CH 2 ) 10 H. In embodiments comprising two SFAs, the SFAs may be present in a weight ratio of at least about 3:1, e.g., at least about 50:1 or at least about 30:1, or at least about 10:1.

[0696] Liquid SFA is chemically and physiologically inert, colorless and stable. Its typical density is 1.1 to 1.7 g / cm 3 (For example, the density of F6H8 is 1.35g / cm 3 ), and its surface tension can be as low as 19mN / m. F(CF 2 ) n (CH 2 ) m SFAs of type H are insoluble in water but are also somewhat amphiphilic, with the increase in lipophilicity correlating with the increase in the size of the non-fluorinated chain segment.

[0697] RFRH type liquid SFAs have been used commercially for unfolding and reapplying the retina, for long-term tamponade as a vitreous humour substitute (H. Meinert et al., European Journal of Ophthalmology, Vol. 10 (3), pp. 189-197, 2000), and as a flushing fluid for residual silicone oil after vitreoretinal surgery. Experimentally, they have also been used as a blood substitute (H. Meinert et al., Biomaterials, Artificial Cells, and Immobilization Biotechnology, Vol. 21 (5), pp. 583-95, 1993). These applications have established SFAs as physiologically well-tolerated compounds.

[0698] As shown in preclinical testing, SFAs are well tolerated by the eye. In contrast, organic or non-aqueous solvents (with the possible exception of oily compounds) are often very irritating or even severely damaging when administered topically to the eye.

[0699] Furthermore, compared to oily carriers or vehicles in topical ophthalmic compositions, SFAs have a refractive index in the range of 1.29 to 1.35, which is better compatible with the goal of minimally affecting vision, thereby causing little or no blurring.

[0700] When administered to the eye, the SFA compositions of the present invention have several useful functional effects. Semifluorinated alkanes are able to mix and / or dissolve well with non-polar and lipophilic substances. It is suggested that SFA defined in the context of the present invention, for example, is selected from F(CF 2 ) 4 (CH 2 ) 5 H(F4H5), F(CF 2 ) 4 (CH 2 ) 6 H(F4H6), F(CF2 ) 6 (CH 2 ) 6 H(F6H6), F(CF 2 ) 6 (CH 2 ) 8 H(F6H8) and F(CF 2 ) 8 (CH 2 ) 8 An SFA of H(F8H8), e.g., F4H5 or F6H8, or F6H8, may be particularly useful for solubilizing meibum lipids and removing abnormal and obstructive meibum produced in blocked meibomian gland ducts.

[0701] Meibum is the lipid secretion of the meibomian gland ducts and is usually secreted in the form of a clear liquid containing a complex mixture of polar and non-polar lipids such as cholesterol and wax esters, acylglycerides, free fatty acids and phospholipids. In its dysfunctional state, the glands that produce meibum can express secretions with altered composition of those lipids, which exhibit increased viscosity and may also contain granular cellular material. Such secretions can block the glandular ducts and may not effectively form a functionally stable and continuous tear film lipid layer, leading to lipid tear film deficiency and the condition and symptoms of keratoconjunctivitis sicca. As defined in the context of the present invention, the formula F (CF 2 ) n (CH 2 ) m The semifluorinated ophthalmic composition of H effectively dissolves meibum, and in particular effectively dissolves abnormal (eg, sticky) meibum that blocks the meibomian glands and / or meibomian gland ducts.

[0702] In addition, the ophthalmic composition of the present invention can also be used as a substitute, replacement or supplement for the lipid layer of the tear film. For patients suffering from dry eye symptoms, the SFA composition of the present invention can have a lubricating and protective effect. It is believed that the SFA composition can form a protective film on the corneal surface and prevent the aqueous evaporative loss of the tear film.

[0703] In one embodiment, the ophthalmic SFA composition defined in the present disclosure can act as a replacement, substitute or supplement to the lipid layer of the tear film, for example as a lubricant and / or to form a protective film, and also effectively dissolve meibum, especially effectively dissolve abnormal (e.g., sticky) meibum that blocks the meibomian glands and / or meibomian gland ducts.

[0704] In addition, SFAs exhibit significant wetting and spreading behavior, whereby they can quickly and effectively spread on the surface of the cornea and conjunctiva. This significant wetting and spreading behavior allows SFAs to be quickly and completely dispersed from the administered eye drops, further allowing SFAs to enter the meibomian gland ducts on the upper and / or lower eyelids. Due to their high solubility, SFAs can penetrate meibum plugs that are prevalent in meibomian gland dysfunction (MGD) or disease, thereby dissolving and removing the plugs and restoring proper meibomian gland function.

[0705] Wetting refers to the ability of a liquid to establish and maintain contact with a solid surface due to intermolecular interactions when two molecules are close together. The balance between adhesive and cohesive forces determines the degree of wetting. The higher the adhesive force relative to the cohesive force, the more droplets will spread across the surface of the solid material. In contrast, very high cohesive forces within a liquid will cause the droplets to form a spherical shape, thereby avoiding contact with the surface. Similarly, spreading can also occur at the interface of two liquids that are in contact with each other.

[0706] A measure of wetting and spreading is the contact angle θ. The contact angle is the angle at which a liquid-vapor interface meets a solid-liquid or liquid-liquid interface. The tendency of a droplet to spread outward increases as the contact angle decreases. Thus, the contact angle provides an inverse measure of wettability.

[0707] A low contact angle of less than 90° indicates high wetting and / or spreading, while a higher contact angle indicates poor wetting and spreading. Perfect wetting and spreading results in a contact angle of 0°, also recorded as no measurable contact angle.

[0708] The enhanced spreading behavior and stable film properties of this SFA-containing ophthalmic composition are particularly advantageous for treating dry eye disease. Droplets administered to the ocular surface can cause the SFA mixture composition to spread rapidly on the corneal surface and form a film. A stable film that does not break immediately can provide a more lasting lubricating effect for the ocular surface. Effective spreading not only allows SFA to be more effectively distributed on the ocular surface, but also to be distributed to more distant ocular tissues, such as the meibomian glands or lacrimal glands.

[0709] One result of this is a significantly reduced reliance on the patient's blinking mechanism (which may be ineffective or impeded by the diseased state) to allow the composition to spread on the ocular surface. It is believed that the compositions of the present invention can thus be more effectively administered to the ocular surface than conventional formulations that are typically water-based and have poor spreading behavior. Therefore, the use of these compositions can achieve a reduced frequency of dosing for relief of dry eye.

[0710] In particular, the compositions of the present invention described in the above embodiments can be used to treat patients who are unresponsive to traditional physical methods for treating meibomian gland dysfunction or dry eye caused or aggravated by meibomian gland dysfunction, such as physical or forced expression of meibum or meibum obstruction from the meibomian glands, application of heat, such as application of heat to the eyelids (thermotherapy), simultaneous physical expression and thermotherapy, eyelid scrubbing, or intraductal probing of the meibomian gland orifices. Unresponsiveness to treatment can refer to a situation in which the patient's meibomian gland dysfunction and its related symptoms persist, progress, or recur despite a prescribed or recommended treatment period, such as the use of traditional treatment methods. The use of the compositions and treatment methods of the present invention can be used to replace such treatments, or can also be used as an alternative treatment to such traditional methods, which may usually require being performed in a doctor's office and are difficult to tolerate and / or inconvenient due to the pain caused by the application of these physical methods.

[0711] In another aspect, the composition of the present invention can be used to treat the conditions described in the above embodiments, wherein the patient is unresponsive to treatment with an aqueous ophthalmic eye drop composition. In particular, the composition can be used to treat patients with meibomian gland dysfunction, and the patient is unresponsive to treatment with an aqueous-based ophthalmic eye drop composition (e.g., an emulsion or aqueous solution (e.g., a tear supplement or tear substitute)), and the patient may still have a persistent condition, progression, or recurrence of dry eye or MGD or its symptoms despite a course of treatment with such a composition.

[0712] Another advantage of using an ophthalmic composition comprising SFA is that, when dispensed from a conventional dropper (e.g., a conventional eye dropper), SFA is able to form very small droplets, e.g., droplets of about 10-11 μl volume. The droplet volume of about 10-11 μl of F6H8 is converted into a single dose of 13.5-14.85 mg (wherein F6H8 density = 1.35 g / ml). Without being bound by theory, it is believed that the small droplet size is the result of the interaction of the unique properties of SFA in terms of its density, viscosity, and surface tension. It is believed that for topical administration of the eye, small droplets or small volume administration are very advantageous because the lacrimal sac has a very limited capacity to receive and hold fluid. In fact, it is very common that the administration of conventional eye drop formulations based on water or oil immediately results in the discharge of most of the administered drug and some tears. At the same time, there is a risk that some of the administered doses will be systemically absorbed through the nasolacrimal duct.

[0713] The present invention also provides means for formulating non-aqueous ophthalmic compositions that are microbiologically stable. Aqueous ophthalmic compositions are susceptible to bacterial contamination. In contrast, SFAs have bacteriostatic properties and do not support microbial growth. Thus, preservative-free ophthalmic compositions can be formulated that are better tolerated by many patients, particularly those suffering from keratoconjunctivitis sicca. Such compositions also will not promote bacterial infection of the eyelid margin in patients suffering from, for example, obstructed or plugged meibomian glands.

[0714] Ocular tissue includes any surface of the ocular anatomy, or can be topically exposed (i.e., non-surgically). Optionally, the composition is administered as a single drop to the cornea or conjunctiva. Ocular tissue includes, but is not limited to, the cornea, conjunctiva (bulbar and palpebral conjunctiva), lacrimal glands (including lacrimal ducts and lacrimal sacs), meibomian glands, and sclera.

[0715] In some embodiments, the compositions of the present invention can be used to reduce or alleviate ocular disorders or conditions associated with ocular symptoms, including keratoconjunctivitis sicca and meibomian gland dysfunction. For example, the compositions of the present invention can be used in addition to active ingredients containing drugs whose dosing frequency is usually limited by tolerability or safety considerations. The compositions can reduce or alleviate any dryness, irritation, or discomfort in the eye that is not related to the disease. The compositions can be used simultaneously with or in combination with ophthalmic compositions containing pharmaceutical active ingredients (e.g., immunosuppressant eye drops) that are intended to cure or treat the underlying pathogenic pathways of ophthalmic diseases.

[0716] In some embodiments, the composition of the present invention can be used as a cleaning solution for the eye or eye tissue. The composition is used to clean or help remove or wash away any accumulated debris or discharge, such as the meibum secretions of the eyelid, eyelid margin, eyelashes or eye slits. Compared with aqueous preparations, SFA compositions can be spread more easily, so it is possible to reach the more inaccessible area of ​​the eyelid anatomical structure. In a specific embodiment, the composition used as a cleaning solution is formulated into a spray for administration. This can be used for patients who are unwilling or unable to apply the composition by eye drops.

[0717] Optionally, the compositions of the present invention are highly stable, anhydrous, and preservative-free.

[0718] Optionally, one or more other excipients can be used in the SFA composition. In addition to SFA, other excipients may also result in insufficient tear film and tear film lipid layer in patients with keratoconjunctivitis sicca, related conditions and related symptoms thereof. In some embodiments, the excipient is biocompatible and can be tolerated by the eye, and is liquid and / or soluble and miscible in SFA. In particular, the excipient is optionally selected from lipids, oils, lipophilic vitamins, lubricants, viscosity agents, antioxidants, surfactants and mixtures of two or more thereof.

[0719] In some embodiments, the composition may also include other desired or useful excipients, such as acids, bases, electrolytes, buffers, solutes, antioxidants, stabilizers, synergists, and preservatives required in certain circumstances. The composition may be formulated to be administered as a liquid solution, gel, or spray. They may be prepared by known techniques for making the liquid solution, gel, or spray.

[0720] As used herein, the term "enrichment" refers to the temporary storage of SFAs in ocular tissues that are administered and delivered as topical ophthalmic compositions, regardless of whether the tissue in question previously retained or stored any SFAs. Tissues that may be enriched with SFAs optionally include conjunctiva, cornea, lacrimal glands, and / or meibomian glands. As used herein, the weight percentage of tissue enriched SFAs refers to the weight of SFAs measured in the tissue relative to the total weight of the tissue.

[0721] The enrichment of tissues with SFAs depends on the nature of the composition administered, the nature of the tissue to which the composition is administered, and in particular, on the nature of the dosing regimen used to administer the composition. It will be appreciated by the skilled artisan that the prior art does not make it obvious that the administration of a liquid topical ophthalmic composition comprising a semifluorinated alkane results in enrichment of such semifluorinated alkane in any ocular tissue. For example, without being bound by theory, it is contemplated that if the administration of the ophthalmic composition is too rare or the volume is too small, sufficient SFAs may not be delivered to the eye to result in enrichment in ocular tissue. In addition, other components of the composition, such as surfactants or water, may affect the ability of SFAs to be distributed to and enriched in specific ocular tissues. In addition, too large a dose (e.g., too large a droplet, e.g., a droplet volume greater than 30 μl) may result in unnecessary blinking, thereby reducing the ability of SFAs to enrich in ocular tissues.

[0722] The skilled artisan will also recognize that liquid topical ophthalmic compositions typically have a short residence time in the eye. Glands surrounding the eye continuously produce tears and oils, which are continuously washed away from the cornea by the lacrimal apparatus. Mechanical agitation and blinking can further reduce the residence time of such compositions in contact with ocular tissues. This is why many common topical ophthalmic treatments require multiple dosings per day. Enrichment of ophthalmic compositions by ocular tissues to an extent sufficient to allow for continuous, delayed release of the active components of the composition back to the ocular surface alleviates this problem.

[0723] All patents, publications, and other references described herein are incorporated by reference in their entirety.

[0724] Example

[0725] Example 1: After topical administration to rabbit eyes 14 Pharmacokinetics and distribution of C-F6H8

[0726] To evaluate topical ocular administration of dutch striped (pigmented) female rabbits 14 C-1-Perfluorohexyl octane (F6H8, ) after the ocular tissue distribution, this study was conducted.

[0727] On the first day of administration, 5.474 mL of 14 C-F6H8 was combined with 9.526 mL of F6H8. The dosage formulation was magnetically stirred and appeared as a colorless solution. The dosage formulation was divided into vials to provide one vial per day for dosing and stored at about -20°C. Prior to dosing, one vial was thawed per day. Between doses, when not in use, the vials were capped and stored at about 5°C.

[0728] Duplicate weighed aliquots were taken from the dose preparations before and after dosing on Days 1 and 5 and analyzed by liquid scintillation counting (LSC) to determine radioactivity concentration and homogeneity.

[0729] The stability of the test article under the dosing conditions was demonstrated by analyzing pre- and post-dose aliquots by HPLC.

[0730] Animals were not fasted prior to dosing. All animals received a single 35 μL-drop of the dosing formulation per eye, with the right eye dosed first. All collection times were based on the time of the last dosing in the second (left) eye (if applicable).

[0731] The topical ocular dose was administered via a positive displacement micropipette to the center or upper end of the cornea and spread over the entire ocular surface. After administration of the dose, the eyes were allowed to close naturally. Each animal was then restrained for approximately 1 minute to prevent rubbing of the eyes.

[0732] Collecting tears and eye tissue : After the last dose of a single dose or multiple dose regimen, tears were collected from two animals in each group at each time point of 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration. Tears were collected using dye-free TearFlo Test (TFT) strips. One strip was used for each eye at each time point. After collection, the tubes containing the strips were placed on dry ice or stored at a temperature of about -70°C until analysis.

[0733] At sacrifice, both eyes were removed and ocular tissues including aqueous humor, conjunctiva (bulbar conjunctiva), conjunctiva (palpebral conjunctiva), lacrimal gland (accessory lacrimal gland), lacrimal gland (main lacrimal gland), meibomian gland (tarsal plate), choroid-retinal pigment epithelium (choroid-RPE), cornea, iris-ciliary body (ICB), retina, sclera (anterior sclera), sclera (posterior sclera), and vitreous humor were collected.

[0734] Radiometric analysis : The radioactivity of all samples was analyzed for at least 5 minutes or 100,000 counts in a 2900TR liquid scintillation counter (Packard Instrument Company) using Ultima Gold XR or Hionic Fluor scintillation cocktail (Perkin Elmer). Unless the entire sample was used for analysis, each sample was homogenized prior to radioanalysis. If sample size permitted, all samples were analyzed in duplicate.

[0735] For conjunctiva (bulbar and palpebral), cornea, lacrimal gland (main lacrimal gland), meibomian gland, retina, and sclera (anterior and posterior sclera), each sample was digested in 2M sodium hydroxide / ethanol (80:20, v:v) and kept until dissolved at room temperature or in an oven set to no higher than 30° C. Scintillation cocktail was added, samples were shaken, and analyzed directly by LSC.

[0736] For lacrimal glands (accessory lacrimal glands), each sample was digested in 2M sodium hydroxide / ethanol (80:20, v:v) and kept until dissolved at room temperature or in an oven set to no higher than 30° C. Samples were homogenized by mixing and duplicate weighed aliquots were directly analyzed by LSC.

[0737] For tears, at least 10 mL of Ultima Gold XR scintillation cocktail was added, and the samples were then vortexed and analyzed by LSC.

[0738] Quantitative autoradiography Animals were euthanized with sodium pentobarbital and blood was collected by cardiac puncture. Animals were frozen immediately after blood collection for quantitative autoradiography. Frozen heads were embedded in cooled carboxymethylcellulose and frozen into blocks. Appropriate sections were collected on adhesive tape with a thickness of 40 mm in a Leica CM 3600 cryostat. The mounted sections were exposed to a phosphorimaging screen for 4 days together with a fortified blood standard for subsequent calibration of the image analysis software and then scanned using a Typhoon scanner. MCID was obtained using InterFocus Imaging Ltd. TM The Analyzer software acquires the autoradiographic standard image data to create a calibration standard curve. Analyze the specified tissues and fluids. Interpolate tissue concentrations in nanocuries / gram from each standard curve and then convert them to ng equivalents / g based on the specific activity of the test substance.

[0739] Single topical ocular administration, radiometric analysis of ocular tissue : Both eyes of the rabbits received a single topical ocular administration. The target dose level was 45.6 mg / eye (25 μCi / eye). 14After a single topical ocular administration of C-F6H8, two animals were sacrificed at each time point by sparse sampling at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. At sacrifice, ocular tissues were collected from all animals (including tears collected prior to sacrifice).

[0740] Table 1. Single topical ocular administration to female Dutch-banded rabbits 14 Mean radioactivity concentrations in ocular tissues (bulbar conjunctiva, palpebral conjunctiva, cornea, anterior sclera, meibomian glands, accessory lacrimal glands, main lacrimal glands, tears) determined by liquid scintillation counting at specific times after C-F6H8:

[0741]

[0742] Substance related to ocular tissue of female Dutch banded rabbits was observed in the anterior part of the eye 14 The highest mean concentrations of C-F6H8 (determined by radiometric analysis) were between 0.25 and 4 hours after dosing (>1000 ng equivalent 14 The concentration of C-F6H8 / g was in the order of tears (2390000) > meibomian glands (294000) > palpebral conjunctiva (14200) > cornea (8230) > bulbar conjunctiva (5450) > accessory lacrimal glands (4280) > main lacrimal glands (4130) > anterior sclera (2270). The concentration decreased over time, especially within 8 hours after administration in all these tissues, and the background level was still detectable 24 hours after administration.

[0743] Low levels of radioactivity were observed in the vitreous humor and retina, suggesting substance association 14 Some minor distribution of C-F6H8 within these tissues. No radioactivity was detected in the iris-ciliary body and choroid-retinal pigment epithelium. So far, material association has been observed in the tear fluid, meibomian glands, and anterior tissues. 14 Highest exposure for C-F6H8.

[0744] Quantitative autoradiography of ocular tissue after single topical ocular administration : Female Dutch-banded rabbits were given a single topical ocular administration of 35 μl of 14 After C-F6H8, analysis of the entire head by autoradiography showed comparable distribution in the ocular tissues to that observed after radioanalysis. The highest concentrations (>10,000 ng equivalent) were found in the anterior tissues. 14 C-F6H8 / g) is in the order of eyelid margin (443000) > inner eyelid (171000) > cornea (33500). Other tissues with high concentrations are outer eyelid skin, nasolacrimal duct and nasal concha.

[0745] Multiple topical ocular administrationRabbits received 35 μl of the drug twice a day for 4 consecutive days (about 12 hours ± 20 minutes apart) in both eyes. 14 C-F6H8, a single dose was administered to both eyes on the morning of day 5 (9 doses in total). The dose level at each dose was approximately 47 mg / eye, equivalent to 29 mCi / eye. After the last dose on day 5 of the study, two animals were sacrificed at each time point in a sparse sampling manner at 0.25, 0.5, 1, 2, 4, 8 and 24 hours after dosing. At the time of sacrifice, ocular tissues (including tears collected before sacrifice) were collected from all animals.

[0746] Table 2. Multiple topical ocular administration to female Dutch-banded rabbits 14 Mean radioactivity concentrations in ocular tissues (bulbar conjunctiva, palpebral conjunctiva, cornea, anterior sclera, meibomian glands, accessory lacrimal glands, main lacrimal glands, tears) determined by liquid scintillation counting at specific times after C-F6H8:

[0747]

[0748] Multiple topical ocular administrations of 35 μl 14 After C-F6H8, the highest concentrations in ocular tissues were again observed in tears, meibomian glands, bulbar and palpebral conjunctiva, and cornea, suggesting substance relevance 14 Exposure and distribution of C-F6H8 occurred mostly in the anterior part of the eye. Concentrations declined over time, particularly within 8 hours after dosing in all of these tissues, but were still detectable at 24 hours after dosing. The highest mean concentrations (>5000 ng equiv. 14 C-F6H8 / g) was in the order of tears (2330000) > meibomian glands (222000) > cornea (27600) > palpebral conjunctiva (14000) > accessory lacrimal glands (9280) > main lacrimal glands (8890) > bulbar conjunctiva (8290) and was observed between 0.25 and 4 hours after administration. Here, higher concentrations of C-F6H8 / g were detected by multiple topical ocular administration regimens compared to single topical ocular administration. 14 C-F6H8.

[0749] Example 2

[0750] In order to evaluate the The purpose of this study was to investigate the effect of 1-perfluorohexyl-octane (1-PFH-OCT) on tear film thickness in patients with mild to moderate dry eye. Here, the administration of 1-perfluorohexyl-octane was compared with Hydrabak (0.9% sodium chloride, Laboratoires Théa).

[0751] 48 patients (safety population) were randomized (1:1 ratio) to receive F6H8 or Hydrabak. One drop of F6H8 (drop volume = 10-11 μl) or Hydrabak was instilled in each eye 4 times a day for 30 days. DED-related clinical indicators were recorded at the 1st follow-up (day 0, baseline), 2nd follow-up (15±2 days) and 3rd follow-up (30±3 days). The primary outcome variables included tear film thickness (TFT) measured by high-resolution optical coherence tomography (OCT), while secondary outcome variables included lipid layer thickness (LLT) of the tear film (using LipiView interferometer), noninvasive tear breakup time (NITFBUT) using Bon Antares tear topographer, dynamic meibomian gland imaging (DMI) using LipiView interferometer, blink frequency (using LipiView interferometer), dry eye visual analogue scale (VAS), corneal fluorescein staining, conjunctival lissamine green staining, Schirmer I test, tear breakup time (TFBUT), ocular surface disease index (OSDI), adverse events (AEs), etc.

[0752] The study achieved its primary objective by demonstrating that F6H8 increased tear film thickness (TFT) relative to saline solution (Hydrabak) in patients with DED. The initial MMRM analysis showed that for the 48 subjects in the safety population, the relative change (%) in tear film thickness from baseline was significantly greater with F6H8 than with Hydrabak.

[0753] After a single dose at Visit 1, F6H8 transiently increased tear film thickness (TFT) after instillation (see Table 3).

[0754] Table 3: Tear film thickness (TFT) measurements after a single dose at Visit 1 of the study comparing F6H8 and Hydrabak, relative change from pre-dose baseline measurements. An increase in tear film thickness (TFT) was observed immediately after instillation (i.e., 10 minutes), indicating a clear early onset of effect.

[0755]

[0756]

[0757] After multiple administrations, F6H8 gradually increased tear film thickness over time, reaching a maximum effect at the end of the study, after 4 weeks of treatment (visit 3), which is consistent with the mode of action of F6H8 by supporting the lipid layer to prevent evaporation. This potential sustained effect was confirmed by the least square mean error estimated at each follow-up based on the primary efficacy mixed model repeated measures analysis (MMRM) calculated in the post hoc analysis. During the study, these estimates showed that the tear film was more obvious and gradually thickened with F6H8, which was 1.29% at visit 1, 4.33% at visit 2, and reached a significant level of 6.42% at visit 3 for the 48 subjects in the safety population.

[0758] Table 4: Tear film thickness (TFT) measurements based on relative change from baseline pre-dose measurements after multiple doses of F6H8 compared to Hydrabak. After 4 weeks of treatment (Visit 3), a gradual increase in TFT over time was observed, with the greatest effect at the end of the study. The relative change from baseline pre-dose measurements was significant compared to that observed with Hydrabak.

[0759]

[0760] The increase in pre-dose lipid layer thickness (LLT) at the 2nd and 3rd follow-up visits in the F6H8 group further confirmed the overall improvement of the tear film in patients with DED. Post hoc MMRM analysis of the values ​​recorded before instillation showed that the relative change (%) of LLT from baseline was significantly higher for F6H8 than for Hydrabak, with an estimated least square mean error of 16.34%.

[0761] Table 5: Lipid layer thickness (LLT) measurements for F6H8 or Hydrabak based on relative change from baseline pre-dose measurements determined the morning before the first dose of the study. A significant early onset of effect was observed compared to the LLT for Hydrabak at 2 weeks.

[0762]

[0763] Other sign endpoints (fluorescein corneal staining, TFBUT) and symptom endpoints (OSDI, VAS) were improved in both treatment groups compared to baseline. Although the Hydrabak effect in the control part was similar to the F6H8 effect for most parameters at the 3rd follow-up, corneal staining tended to be reduced more strongly in the F6H8 group. Compared with the Hydrabak group, the F6H8 group showed a more sustainable improvement throughout the 4-week study.

[0764] Overall, this study met its primary objective by demonstrating that F6H8 increased tear film thickness and lipid layer thickness. This effect built up over time and reached its apparent maximum at the end of the 4-week study, consistent with F6H8's mode of action of preventing evaporation by replenishing and strengthening the lipid layer. Consistently, the increase in LLT observed in the F6H8 group further confirmed the overall observed improvement in tear film. F6H8 was shown to be safe and well tolerated in patients with DED, as all recorded adverse events / device reactions were mild and of low incidence.

[0765] Example 3

[0766] A phase 2, multicenter, randomized, double-blind, saline-controlled study was conducted to evaluate the effects of 1-perfluorohexyloctane (NOV03; F6H8) on the signs and symptoms of dry eye disease (DED) at two different dosing schedules. The study was conducted in 11 study cities in the United States. The study was reviewed and approved by the appropriate ethics committees and registered at www.clinicaltrials.gov (NCT03333057).

[0767] This study was conducted to evaluate the safety, efficacy, and tolerability of two different dosing regimens of F6H8 compared with saline on the signs and symptoms of dry eye disease.

[0768] Study participants received one of the following treatments during the 4 follow-up periods at days 1, 15, 30, and 60:

[0769] (1) F6H8(NOV03), 4 times a day (QID);

[0770] (2) F6H8(NOV03), twice a day (BID);

[0771] (3) saline solution (0.9% sodium chloride solution), 4 times a day (QID);

[0772] (4) Saline solution (0.9% sodium chloride solution), twice a day (BID).

[0773] In the BID treatment, study subjects instilled one drop bilaterally into each lower eyelid conjunctival fornix twice daily. The volume of F6H8 drops instilled was approximately 10-12 μl, which translates to a single dose of 13.5-16.2 mg (F6H8 density = 1.35 g / ml).

[0774] At each visit, a wide range of DED-related clinical parameters were assessed, including adverse event inquiry, visual acuity, meibomian gland assessment, ocular surface disease index (OSDI), visual analogue scale (VAS) for severity of dryness (burning / stinging, stickiness, foreign body sensation, itching, blurred vision, light sensitivity, and frequency of pain and dryness), tear film break-up time (TFBUT), fluorescein-stained corneal NEI central zone, fluorescein-stained corneal NEI inferior zone, corneal and conjunctival lissamine green staining (Oxford), and Schirmer test I.

[0775] The results showed that BID treatment with F6H8, involving daily administration of 20-24 μl (BID) of F6H8, improved signs and / or symptoms of dry eye disease. In addition, the twice-daily schedule (BID) showed a trend towards fewer adverse effects.

[0776] Inclusion and exclusion criteria for subjects treated twice daily were as follows:

[0777] Inclusion criteria:

[0778] The subject must:

[0779] · Aged 18 or above.

[0780] Provide written informed consent.

[0781] Subjects reported a history of dry eye disease in both eyes for at least 6 months prior to Visit 0.

[0782] Tear film break-up time (TFBUT) ≤ 5 seconds at visit 0 and visit 1.

[0783] Overall ocular surface disease index (OSDI) ≥ 25 at visit 0 and visit 1.

[0784] Schirmer test I ≥ 5 mm at the 0th and 1st follow-up.

[0785] Meibomian gland dysfunction (MGD) was defined as an MGD score ≥ 3 at visit 0 and visit 1 (the secretion of the 5 central glands on the lower eyelid was evaluated and each was scored on a scale of 0-3; 0 =

[0786] Normal, 1 = thick / yellow, whitish, granular 2 = pasty; 3 = none / clogging; total score range 0-15).

[0787] At follow-up 0 and 1, the total corneal fluorescein staining score was 4≤X≤11 (i.e., the sum of the inferior, superior, central, nasal, and temporal corneal areas) according to the National Eye Institute (NEI) classification.

[0788] At least one eye (the same eye) met all of the criteria d, f, g, and h above at both Visit 0 and Visit 1.

[0789] ·Able and willing to follow instructions, including participation in all study assessments and follow-up visits.

[0790] Exclusion criteria : (excerpt)

[0791] Women who are pregnant, breastfeeding or planning to become pregnant

[0792] If of childbearing potential, unwilling to submit to a blood pregnancy test at screening and last follow-up (or to terminate follow-up early), or unwilling to use an acceptable form of birth control

[0793] Clinically significant slit-lamp findings or eyelid anatomy abnormalities at screening

[0794] Malignant tumors of the eye / periocular area

[0795] History of herpetic keratitis

[0796] Active ocular allergy or ocular allergy that is expected to become active during the study

[0797] Persistent eye or systemic infection

[0798] Wearing contact lenses within one month before screening or anticipating contact lens use during the study

[0799] · Had intraocular surgery or ocular laser surgery within the previous 6 months, or is planning to have ocular and / or eyelid surgery during the study period

[0800] Presence of uncontrolled systemic illness

[0801] Known allergies and / or sensitivities to study medications or saline components

[0802] Any use of topical steroid therapy, topical cyclosporine, lifitegrast, serum tears, or topical anti-glaucoma medication within 2 months prior to screening.

[0803] Eligible subjects were randomized to receive one of the following treatments administered bilaterally from Visit 1 to Visit 4:

[0804] After receiving training on how to use the treatments, patients are advised to instill 1 drop of the respective treatment in each eye.

[0805]

[0806] The drop volume of a single drop of NOV03 (ophthalmic composition consisting essentially of 1-perfluorohexyl-octane; d = 1.35 g / ml) involves 10-12 μl, which translates to a single dose of 13.5-16.2 mg per eye, or a daily dose of 27-32.4 mg (20-24 μl) per eye for twice daily treatment (BID).

[0807] The drop volume of a single drop of saline solution (0.9% sodium chloride solution) involves 35-40 μl, which translates to a daily dose of 70-80 μl per eye for twice-daily treatment (BID).

[0808] Hereinafter, the NOV03 (ophthalmic composition consisting essentially of 1-perfluorohexyl-octane) treatment is also referred to as "real drug" and the saline (0.9% sodium chloride solution) treatment is also referred to as "placebo".

[0809] Follow-up arrangements:

[0810] The study consisted of two phases: a 14-day screening period and a 57-day treatment period.

[0811] Screening (Visit 0) : Subjects will be asked to sign an informed consent form before any study-related procedures are completed within 14 days prior to the first visit. At the screening visit, vital signs will be assessed and subjects will donate blood for safety laboratory tests. They will also undergo a battery 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 indicators: tear film breakup time ≤ 5 seconds, Schirmer test ≥ 5mm, and meibomian gland dysfunction (MGD) defined as MGD score ≥ 3 (inclusive).

[0812] Baseline follow-up day 1 (1st follow-up) : On Day 1 (Visit 1), eligible subjects were evaluated for baseline signs and symptoms of dry eye disease. After randomization, subjects provided blood samples for pharmacokinetics (PK) at selected sites. Subjects were given a 14-day supply and self-administered a single drop of study medication to each eye in the clinic. Each subject was given a log book to record the doses they used. The study staff helped subjects understand how to use the log book and when the remaining dose should be used.

[0813] Follow-up2-4: Subjects returned to the clinic on days 15±1 (2nd follow-up), 29±2 days (3rd follow-up), and 57±2 days (4th follow-up) to evaluate signs and symptoms of dry eye disease. During this period, subjects were administered NOV03 or saline solution twice a day (BID). The unused portion of the study drug was returned to the clinic and a new study drug kit was distributed. The record book was checked. At the 4th follow-up, vital signs were evaluated and a second blood draw was performed at selected sites for pharmacokinetics (PK). Record books were collected at the clinic during each follow-up. After completing all 4 follow-up assessments, the subject was removed from the study.

[0814] Patients and examination parameters

[0815] 336 patients who met the inclusion / exclusion criteria were selected by study site. The study population represented a highly symptomatic dry eye disease (DED) population closely associated with MGD; low TFBUT (mean TFBUT approximately 2.9), high total OSDI score (mean total OSDI approximately 56), high VAS dryness severity score (mean VAS dryness severity score approximately 70), and high MGD score (mean MGD score approximately 7.3) at baseline were evident for patients in the BID portion.

[0816] Parameters assessed at baseline and subsequent follow-up included the OSDI questionnaire, 10-item visual analogue scale (VAS) questionnaire, visual acuity (ETDRS), slit-lamp biomicroscopy, TFBUT, NEI grading with fluorescein staining, Oxford scale with lissamine green staining, meibomian gland assessment (MGD score), and Schirmer test I (without anesthesia).

[0817] 323 patients completed the study, of which 110 (NOV03, QID), 105 (NOV03, BID) and 108 (saline, BID+QID). Statistical analysis was performed on the examined parameters to identify statistically significant differences between the real drug and placebo parts. Since there were no statistical differences between the saline BID group and the saline QID group, these groups were combined for some comparisons.

[0818] The parameters evaluated in the study were performed according to the following protocol:

[0819] (a) Corneal fluorescein staining

[0820] 5 μL of 2% preservative-free sodium fluorescein solution was instilled into the inferior conjunctival cul-de-sac of each eye (fluorescein strips may be used, but only at visit 0). For maximum fluorescence, fluorescein staining was evaluated after waiting about 2-3 minutes after instillation. A Wratten #12 yellow filter was used to enhance the ability to grade fluorescein staining. Staining was graded using the NEI (National Eye Institute) grading scale. (See, e.g., Sook Chun Y et al., Am J Ophthalmol. 2014 May; 157(5): 1097-1102). Only corneal staining was graded, without considering any staining of the conjunctiva. Digital images of fluorescein staining were taken for digital analysis.

[0821] According to the NEI / Industry Workshop Scale grade, the ocular surface damage of each of the 5 zones (central corneal zone, upper corneal zone, temporal corneal zone, nasal corneal zone and lower corneal zone) of each eye cornea is scored. According to the NEI grading scale, the surface damage of each zone in the 5 zones (central corneal zone, upper corneal zone, temporal corneal zone, nasal corneal zone and lower corneal zone) of each cornea is defined using a standardized grading system of 0-3. The total corneal staining of each eye is defined by the sum of the scores of each zone in the 5 zones (i.e. the sum of the scores of the central corneal zone, upper corneal zone, temporal corneal zone, nasal corneal zone and lower corneal zone). When there is no fluorescein staining, a grade of 0 will be assigned. The maximum total score for each eye is 15.

[0822] (b) Ocular Surface and Disease Index (OSDI) Questionnaire

[0823] The subjects were asked to fill out a 12-question questionnaire. Questionnaire (e.g., see Schiffman RM, et al., Arch Ophthalmol. 2000; 118: 615-621), and requires answers on a scale of 0 to 4, where 0 corresponds to "never" and 4 corresponds to "all the time". These questions assess the dry eye symptoms experienced by the patient in the past week based on the following ocular symptoms: light sensitivity, sandy sensation, eye pain or soreness, blurriness and poor vision; vision-related functions, problems involving the following aspects: reading, driving at night, working on a computer or bank machine, watching TV; and environmental factors or inducements, i.e., discomfort in the following situations: windy conditions, places with low humidity, and air-conditioned areas. Subtotal all questions and the number of questions answered. The OSDI index is evaluated based on a scale of 0 to 100, with higher scores indicating greater disability. It is calculated by multiplying the sum of the scores by a factor of 25 divided by the total number of questions answered.

[0824] In general, a sum of 0-12 generally indicates normal (e.g., no dry eye), 13 to 22 indicates mild dry eye, 23 to 32 indicates moderate dry eye, and greater than 33 indicates severe dry eye. Therefore, based on a mean OSDI score of 56 (total OSDI score range: 36 to 74), the patients in the study treated twice daily (BID) with NOV03 represented a severe dry eye population.

[0825] (c) Visual Analog Scale (VAS); Eye Dryness Score

[0826] In the 10-item questionnaire, subjects were asked to rate the ocular symptoms (both eyes at the same time) caused by ocular dryness and were asked to place a vertical mark on a horizontal line with a starting value of 0% and an end value of 100% to indicate the level of discomfort (e.g., for dryness symptoms, the mark at 0 corresponds to "no dryness" and 100% corresponds to "maximum dryness"). Subjects were asked about the severity of the following dryness symptoms, i.e., dry eye symptoms: severity of dryness, stickiness, burning / stinging, foreign body sensation, itching, blurred vision, light sensitivity, and pain. Subjects will also be asked about b) their perception of their dry eye symptoms and c) the frequency of dryness. For these questions, a value of 0% corresponds to "never" and a value of 100% corresponds to "all the time." The evaluation line length of the scale is 100 mm (10 cm).

[0827] The values ​​indicated by the patients at each visit were compared relative to the baseline values ​​at the Day 1 visit.

[0828] Patients treated with NOV03 twice daily (BID) in this study represented a highly symptomatic dry eye population based on a mean VAS dryness severity score of 70 at baseline (VAS dryness severity range 36-74).

[0829] (d) Tear film break-up time (TFBUT)

[0830] 5 μL of 2% preservative-free sodium fluorescein solution was instilled into the subconjunctival fornix of each eye (fluorescein strips may be used, but only at Visit 0). To allow the fluorescein to mix well with the tear film, the subject was instructed to blink several times. To obtain maximum fluorescence, TFBUT was evaluated after a waiting time of approximately 30 seconds after instillation.

[0831] The integrity of the tear film was monitored with the aid of a slit lamp, noting the time it took for micelle formation to begin from eye opening. TFBUT was measured in seconds for the right eye and then the left eye using a stopwatch and digital image recording system. A Wratten #12 yellow filter was used to enhance the ability to grade TFBUT.

[0832] For each eye, two measurements were taken and averaged unless the two measurements were >2 seconds apart and <10 seconds each, in which case a third measurement was taken and the two closest of the three were averaged. All values ​​were recorded in the source document.

[0833] Based on a mean TFBUT of 2.9 seconds at baseline (TFBUT range 2-3.8 seconds), patients in the study treated twice daily (BID) with NOV03 represented a dry eye population with evaporative dry eye, with significant associations with MGD and intense tear instability.

[0834] (e) Meibomian gland assessment (MGD score)

[0835] Meibomian gland dysfunction (MGD) is a blockage or other abnormality of the meibomian glands so that not enough oil or meibum is secreted into the tears. MGD can then be a major cause of dry eye syndrome because the tears evaporate too quickly.

[0836] To analyze meibum, a Meibomian Gland Assessment Stick (Korb Tear Science, Morrisville, USA), which allows for repeated use and standard force application (1.25 g / mm2). The MGE-rod was used according to the manufacturer's instructions.

[0837] The assessment was performed as follows: The secretion (meibum) of the 5 central meibomian glands on the lower eyelid was obtained and evaluated by squeezing the glands with a standard force of 1.25 g / mm2 using an MGE-stick. The expressed secretion (meibum) was evaluated and scored on a scale of 0 to 3, 0 = normal, 1 = thick / yellow, whitish, granular; 2 = pasty; 3 = absent / blocked. Therefore, the MGD score represents the sum of the scores of the 5 central meibomian glands, so the total score ranges from 0 to 15.

[0838] In this context, an MGD score of 6 or higher relates to at least 3 of the 5 central meibomian glands being a mushy (thick) substance, or 2 of the 5 central meibomian glands being blocked, after meibum has been expressed from the glands by a standard force of about 1.0-2.0 g / mm2, preferably by a standard force of about 1.25 g / mm2.

[0839] In addition, an MGD score equal to or greater than 7 relates to at least 2 of the 5 central meibomian glands having a mushy (thick) substance after meibum is expressed from the glands with a standard force of about 1.0-2.0 g / mm2, preferably with a standard force of about 1.25 g / mm2, and at least 1 of the 5 central meibomian glands appearing blocked.

[0840] Based on a mean MGD score of 7.3 at baseline (MGD score range 3.6-11), patients in the study treated twice daily (BID) with NOV03 represented a dry eye population with evaporative dry eye, which is closely associated with MGD (abnormal meibum and / or blocked meibomian glands).

[0841] (f) Schirmer test I (without anesthesia)

[0842] The Schirmer Tear Test I will be performed according to the following procedure:

[0843] Do not contaminate before testing

[0844] Using a sterile Schirmer test strip, align the bend in the strip with the notch in the strip.

[0845] Instruct the subject to gaze upward

[0846] Place the Schirmer test strip at the temporal lower eyelid margin of each eye so that the strip fits snugly. Instruct the subject to close their eyes.

[0847] After 5 minutes, remove the Schirmer test strip. Record the length of the wet area in each eye (mm)

[0848] BID Treatment Outcomes

[0849] The parameters examined were compared between twice daily treatments (BID) of NOV03 (an ophthalmic composition consisting essentially of 1-perfluorohexyl-octane; real drug) and placebo (saline solution; 0.9% sodium chloride solution; BID).

[0850] The study demonstrated that, when treated by applying a single 10-12 μl drop of an ophthalmic composition consisting essentially of 1-perfluorohexyl-octane to the eye twice daily, there was a relevant and statistically significant improvement in both the signs (i.e., reduction in ocular surface damage in the corneal region) and the symptoms of dryness in a population with highly symptomatic dry eye disease (DED) closely associated with MGD.

[0851] The study met the pre-specified primary efficacy endpoint of total corneal fluorescein staining, demonstrating that the BID dosing regimen reduced ocular surface damage in total corneal area at 8 weeks.

[0852] In addition, significant improvements were observed for the reduction of ocular surface damage in the central corneal zone, nasal corneal zone, and temporal corneal zone, as evidenced by the corresponding fluorescein staining and subsequent grading of the central corneal zone, nasal corneal zone, temporal corneal zone, and inferior corneal zone according to the NEI scale. It is worth noting that the reduction of ocular surface damage in the central corneal zone is very important because the central corneal area is located at the center of the visual axis, and therefore, the improvement of this ocular surface damage parameter is directly related to the improvement of the patient's visual acuity. In addition, in terms of ocular surface damage, the reduction of ocular surface damage in the superior and inferior corneal zones did not show such significant improvements [see Figure 1 (a) to (d)].

[0853] Sign-related treatment effects, such as reduced ocular surface damage, started unexpectedly early (2 weeks) and were evident throughout follow-up (4 weeks, 8 weeks).

[0854] In addition, the study showed statistically significant improvements in various dryness symptoms compared to the placebo group, as determined by ocular dryness scores on a visual analogue scale (VAS) including "severity of dryness," "frequency of dryness," "awareness of dryness," "blurred vision," and "light sensitivity." No significant improvements were seen in other VAS symptoms [see Figure 2 (a)–(e)].

[0855] Likewise, treatment effects related to symptoms of VAS dryness started unexpectedly early (2 weeks) and were evident throughout the follow-up period (4 weeks, 8 weeks).

[0856] In addition, the study showed statistically significant improvements in various dryness symptoms compared with the placebo group, as determined by the Ocular Surface Disease Index (OSDI) scores, including the total OSDI score [see Figure 3 ].

[0857] Likewise, treatment effects related to OSDI dryness symptoms started unexpectedly early (2 weeks) and were evident throughout the follow-up period (4 weeks, 8 weeks).

[0858] In addition, it was found that the response rate to twice-daily (BID) treatment with NOV03 was unexpectedly high even at early time points after the first administration to patients. When response was defined as a reduction in the severity score of VAS dryness by ≥ 25%, approximately 50% of patients had a positive response to treatment after 2 weeks (see Figure 4 ). Thus, twice-daily (BID) treatment with NOV03 results in a rapid reduction of dryness symptoms at a relatively low daily dose of 27 - 32.4 mg (20 - 24 μl) per eye of a composition consisting essentially of 1-perfluorohexyl-octane.

[0859] In summary, the present invention includes, but is not limited to, the following items:

[0860] 1. An ophthalmic composition consisting of 1-perfluorohexyl-octane (F6H8) for use in a method of treating keratoconjunctivitis sicca (dry eye disease) caused by meibomian gland dysfunction and / or treating a condition of the cornea,

[0861] wherein the method comprises the step of topically administering to the eye of a patient, twice daily, a single drop of a composition consisting essentially of 1-perfluorohexyl octane at a dose of about 10 - 12 μL per eye.

[0862] 2. The composition for use according to item 1, wherein the patient is characterized by at least two of the following criteria:

[0863] vii. Tear film break-up time (TFBUT) of 3.8 seconds or less

[0864] viii. Total corneal fluorescein staining (NEI scale) of 5 to 9

[0865] ix. Schirmer test I of 10 mm or greater

[0866] x. Meibomian gland dysfunction (MGD) score higher than 4

[0867] xi. Total Ocular Surface Disease Index (OSDI) of 36 or higher

[0868] xii. VAS dryness severity score higher than 50.

[0869] 3. The composition for use according to item 1 or 2, wherein the patient is characterized by at least two of the following criteria:

[0870] vii. Tear film break-up time (TFBUT) of 2 to 3.8 seconds

[0871] viii. Total corneal fluorescein staining (NEI scale) of 5 to 9;

[0872] ix. Schirmer test I is 10 mm or greater

[0873] x. Meibomian gland dysfunction (MGD) score of 4 to 11

[0874] xi. Overall ocular surface disease index (OSDI) of 36 to 74

[0875] xii. VAS dryness severity score ranges from 50 to 90.

[0876] 4. A composition for use according to item 2 or 3, wherein the patient is characterized by at least one criterion selected from i., ii., iii. and iv.; and at least one criterion selected from v. and vi.

[0877] 5. A composition for use according to items 2 to 4, wherein the overall ocular surface disease index (OSDI) score is assessed on a scale of 1 to 100, with higher scores indicating greater disability in the patient.

[0878] 6. A composition for use according to items 1 to 5, wherein the method comprises treating or reducing ocular surface damage to one or more corneal regions and treating or reducing one or more dryness symptoms in a patient suffering from keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

[0879] 7. A composition for use according to claim 6, wherein the method comprises treating or reducing ocular surface damage in one or more corneal regions selected from (a) the total corneal region, (b) the central corneal region, (c) the nasal corneal region, (d) the temporal corneal region, and (e) any combination thereof.

[0880] 8. A composition for use according to items 1 to 5, wherein the patient has a corneal condition characterized by ocular surface damage in one or more corneal zones selected from (a) the total corneal zone, (b) the central corneal zone, (c) the nasal corneal zone, (d) the temporal corneal zone, and (e) any combination thereof.

[0881] 9. A composition for use according to items 6 to 8, wherein the ocular surface damage and reduction thereof is determined by corneal fluorescein staining, optionally wherein grading of one or more corneal zones by fluorescein staining is performed using the (National Eye Institute) NEI scale.

[0882] 10. A composition for use according to claim 6 or 7, wherein the method comprises treating or reducing one or more symptoms of dryness selected from: (a) severity of dryness, (b) blurred vision, (c) light sensitivity, (d) frequency of dryness; (e) awareness of dryness, and (f) any combination thereof.

[0883] 11. A composition for use according to claim 10, wherein symptoms (a) to (c) are determined on a visual analogue scale (VAS) of 0% to 100% representing the level of discomfort, and wherein symptoms (d) and (e) are determined on a visual analogue scale (VAS) of 0% to 100% representing the percentage of time that the patient experiences the dryness symptom.

[0884] 12. A composition for use according to any of the preceding items, wherein the composition is administered to the patient's eye as a single drop of 10-11 μL, preferably as a single drop of about 11 μL.

[0885] 13. The composition for use according to any of the preceding items, wherein the composition is administered twice daily at a dose of a single drop per eye in a net volume of 20-24 μL, preferably in a net volume of 20-22 μL or about 22 μL.

[0886] 14. The composition for use according to any one of the preceding items, wherein the patient does not suffer from aqueous dry eye or aqueous deficient dry eye.

[0887] 15. A kit comprising

[0888] a. a composition consisting essentially of 1-perfluorohexyl octane, and

[0889] b. a container for containing the composition,

[0890] The kit is for use in a method for treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating a condition of the cornea as defined in any one of items 1 to 14,

[0891] wherein the container is configured to hold an amount of the composition to support twice-daily treatment for at least 30 days.

[0892] 16. A kit for use according to item 15, wherein the container contains at least 600-720 μl of the composition.

Claims

1. An ophthalmic composition consisting of 1-perfluorohexyl-octane (F6H8) for use in a method for treating keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction and / or treating a condition of the cornea, The method comprises the step of topically administering to the patient's eyes twice daily a single drop of about 10-12 μL per eye of a composition consisting essentially of 1-perfluorohexyl octane.

2. The composition for use according to claim 1, wherein the patient is characterized by at least two criteria selected from the group consisting of: i. Tear film break-up time (TFBUT) is 3.8 seconds or less ii. Total corneal fluorescein staining (NEI scale) of 5 to 9 iii. Schirmer test I is 10 mm or greater iv. Meibomian gland dysfunction (MGD) score higher than 4 v. Overall Ocular Surface Disease Index (OSDI) of 36 or higher vi. VAS dryness severity score is greater than 50.

3. The composition for use according to claim 1 or 2, wherein the patient is characterized by at least two criteria selected from the group consisting of: i. Tear film break-up time (TFBUT) is 2 to 3.8 seconds ii. Total corneal fluorescein staining (NEI scale) of 5 to 9; iii. Schirmer test I is 10 mm or greater iv. Meibomian gland dysfunction (MGD) score of 4 to 11 v. Overall ocular surface disease index (OSDI) of 36 to 74 vi. VAS dryness severity score ranged from 50 to 90.

4. The composition for use according to claim 2 or 3, wherein the patient is characterized by at least one criterion selected from i., ii., iii. and iv.; and at least one criterion selected from v. and vi.

5. The composition for use according to claims 2 to 4, wherein the overall ocular surface disease index (OSDI) score is assessed on a scale of 1 to 100, with higher scores indicating greater disability in the patient.

6. A composition for use according to claims 1 to 5, wherein the method comprises treating or reducing ocular surface damage to one or more corneal regions and treating or reducing one or more symptoms of dryness in a patient suffering from keratoconjunctivitis sicca (dry eye) caused by meibomian gland dysfunction.

7. The composition for use according to claim 6, wherein the method comprises treating or reducing ocular surface damage in one or more corneal regions selected from (a) the total corneal region, (b) the central corneal region, (c) the nasal corneal region, (d) the temporal corneal region, and (e) any combination thereof.

8. The composition for use according to claims 1 to 5, wherein the patient has a corneal condition characterized by ocular surface damage in one or more corneal zones selected from (a) the total corneal zone, (b) the central corneal zone, (c) the nasal corneal zone, (d) the temporal corneal zone, and (e) any combination thereof.

9. The composition for use according to claims 6 to 8, wherein the ocular surface damage and reduction thereof is determined by corneal fluorescein staining, optionally wherein grading of one or more corneal zones by fluorescein staining is performed using the (National Eye Institute) NEI scale.

10. A composition for use according to claim 6 or 7, wherein the method comprises treating or reducing one or more symptoms of dryness selected from the group consisting of: (a) severity of dryness, (b) blurred vision, (c) light sensitivity, (d) frequency of dryness; (e) awareness of dryness, and (f) any combination thereof.

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