Ophthalmic composition for treating dry eye disease

Abstract

The present invention provides pharmaceutical compositions for the topical treatment of dry eye disease comprising about 0.05 to 0.1% (w / v) cyclosporin dissolved in 1-perfluorobutyl-pentane, and methods of administering and treating the same. The invention also provides kits comprising such compositions.

Description

This application is a divisional application of Chinese patent application No. 201780079941.0 (filed on December 20, 2017, entitled "Ophthalmic Composition for Treating Dry Eye Disease"). Background Technology

[0001] Dry eye syndrome, also known as keratoconjunctivitis sicca or dysfunctional tear film syndrome, is now considered a multifunctional condition affecting both the tear film and the ocular surface, causing discomfort, visual disturbances, and often resulting in ocular surface damage due to tear film instability. Estimates of dry eye prevalence vary widely depending on the criteria used to define the disease, but in the United States, it is estimated that as many as 3.2 million women and 1.7 million men over the age of 50 have dry eye, and the number of affected individuals is projected to increase by 40% by 2030.

[0002] The pharmacological treatment option for dry eye disease is cyclosporine. Cyclosporine is available, at least in the United States, as an ophthalmic (o / w) emulsion (Restasis). ® This is an approved drug in the form of [formula missing]. The product is intended to increase tear production in patients whose tear production is presumably suppressed due to ocular inflammation associated with dry keratoconjunctivitis.

[0003] WO2011 / 073134 A1 discloses a pharmaceutical composition in solution form comprising cyclosporine and a semi-fluorinated alkane as a liquid carrier, which can be applied to a patient's eye, for example, to treat dry keratoconjunctivitis. The pharmaceutical composition, for example, comprises cyclosporine in a semi-fluorinated alkane 1-perfluorobutylpentane (F4H5) in the presence of ethanol as a co-solvent. However, WO2011 / 073134 A1 does not describe administration and treatment regimens for treating dry eye disease, particularly moderate to severe dry eye disease and related conditions.

[0004] Gehlsen et al. (Investigative Ophthalmology & Visual Science June 2015, Vol. 56, 319) described a study testing the use of CsA in SFA (F4H5) as a carrier for topical treatment in a mouse model of experimental dry eye disease. Gehlsen et al. described the use of topical treatment 3x / day (5 μL / eye) in mice with induced experimental dry eye disease in this study. However, Gehlsen et al. did not disclose a treatment or dosing regimen for dry eye disease in human subjects, particularly those with moderate to severe dry eye disease and related conditions.

[0005] Therefore, one object of the present invention is to provide a pharmaceutical composition for treating dry eye disease, particularly moderate to severe dry eye disease and related conditions, comprising cyclosporine and 1-perfluorobutylpentane. Other objects of the invention will become clear based on the following description, examples, and claims. Summary of the Invention

[0006] In a first aspect, the present invention relates to a pharmaceutical composition for use in the topical treatment of dry eye disease, wherein the composition comprises about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, and wherein the amount of cyclosporine applied to each eye in a single dose is about 4 to 12 μg.

[0007] In another aspect, the present invention provides a pharmaceutical composition for treating ocular surface damage in subjects with dry eye disease, and / or for treating reading difficulties in subjects with dry eye disease, preferably wherein the pharmaceutical composition is applied topically to provide an amount of cyclosporine of about 4 μg to 12 μg per eye per single dose. In particular, the subjects may suffer from moderate to severe dry eye disease.

[0008] In another aspect, the present invention provides a kit comprising a pharmaceutical composition for such use, wherein the kit includes a container for holding the pharmaceutical composition and a drop dispenser adapted to administer the composition in volumes of about 8 μl to 12 μl per drop. Detailed Implementation

[0009] In a first aspect, the present invention relates to a pharmaceutical composition for use in the topical treatment of dry eye disease, wherein the composition comprises about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, and wherein the amount of cyclosporine applied to each eye in a single dose is about 4 to 12 μg.

[0010] Dry eye disease (also known as DED, keratoconjunctivitis sicca, dysfunctional tear film syndrome, or dry eye syndrome) is a complex condition that causes discomfort, visual disturbances, and tear film instability, and has the potential to damage the ocular surface. It may be accompanied by increased tear film osmotic pressure and ocular surface inflammation. Patients with keratoconjunctivitis sicca may experience any one or a combination of tear film hyperosmotic pressure, tear film instability, or abnormalities in the lipid layer composition of the tear film.

[0011] Currently, dry eye disease (DED) is classified into two main categories: dehydrating DED and evaporative DED. Within the dehydrating form of DED, two main subtypes can be distinguished: Sjögren and non-Sjögren.

[0012] Sjögren's syndrome is an autoimmune disease in which the lacrimal glands are invaded by activated T cells, leading not only to dry eye but also to dry mouth. Sjögren's syndrome can be a primary disease or caused by other autoimmune disorders, such as systemic lupus erythematosus or rheumatoid arthritis. Non-Sjögren's syndrome patients with dehydrating DED typically have lacrimal gland insufficiency, lacrimal duct obstruction, or reflex hyposecretion.

[0013] The second major category, evaporative dry eye, also exhibits some heterogeneity and may be caused by various underlying factors. One of the main causes is meibomian gland disease or dysfunction, eyelid aperture disorder, blinking disorders (such as in Parkinson's disease), or ocular surface diseases (such as in allergic conjunctivitis).

[0014] Symptoms of dry eye disease can include, but are not limited to, any one or a combination thereof: dryness, scratching, gritty or sandy feeling 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; and excessive reflex tearing. It should be understood that not all patients with dry eye disease will experience all of these symptoms simultaneously.

[0015] As understood herein, the term “dry eye disease” may refer alone to any one or a combination of the subtypes or categories or underlying causes described herein, and may address any symptom or aspect or pathophysiological consequence of dry eye disease.

[0016] Cyclosporine is a pharmacological treatment option for dry eye disease and is available as a prescription drug, for example in the United States as a 0.05% ophthalmic (o / w) emulsion (Restasis). ® It is obtained in the form of [unclear - possibly a specific ingredient or product name]. This product is used to increase tear production in patients whose tear production is presumably suppressed due to ocular inflammation associated with dry keratoconjunctivitis. Restasis ® Apply twice daily to each eye, approximately 12 hours apart. It is packaged in a single vial (prescription information, Restasis). ® ).

[0017] Cyclosporin (synonyms include cyclosporin A, CsA, or cyclosporine) is a cyclic nonribosomal peptide containing 11 amino acids, with the empirical formula C1. 62 H 111 N 11 O 12Cyclosporine has a molecular weight of 1202.61. It is an immunosuppressive drug widely used in post-allergic organ transplantation to reduce the activity of the patient's immune system, thereby reducing the risk of organ rejection. Cyclosporine is usually provided as a colorless or white powder. Cyclosporine is believed to bind to cyclophilin (an immunophilin) ​​in the cytosol of immune-active lymphocytes, especially T lymphocytes. This cyclosporine-cyclophilin complex inhibits calcineurin, which is responsible for activating the transcription of interleukin-2 under normal conditions. It also inhibits the production of lymphokines and the release of interleukins, thus leading to a decrease in the function of effector T cells.

[0018] The pharmaceutical composition according to the present invention uses compound 1-perfluorobutylpentane as a liquid carrier for cyclosporine. 1-Perfluorobutylpentane is a semi-fluorinated alkane having the chemical formula F(CF2)4(CH2)5H. It is an inert, water-insoluble liquid with a density of 1.284 g / cm³ at 25°C. 3 It has a refractive index of 1.3204 at 20°C. Alternative nomenclature for this compound includes F4H5, where F represents a straight-chain perfluorinated alkane segment containing 4 carbon atoms, and H represents a straight-chain, nonfluorinated alkane segment containing 5 carbon atoms. Preferably, 1-perfluorobutylpentane is substantially anhydrous.

[0019] In one embodiment, the pharmaceutical composition for use according to the invention may comprise, based on the total weight of the final pharmaceutical composition (final dosage form), at least about 97% (w / w) or more preferably at least about 98% (w / w) or at least about 99% (w / w) of 1-perfluorobutylpentane and, additionally, cyclosporine at the preferred concentrations defined herein, or composed thereof. In another embodiment, the pharmaceutical composition for use according to the invention may also consist of, based on the total weight of the final composition, about 95.0 to about 99.99% (w / w), or about 96.0 to about 99.99% (w / w), or about 98.0 to 99.99% (w / w), or about 99.999 to about 99.9999% (w / w) of 1-perfluorobutylpentane and, additionally, an amount or concentration of cyclosporine as defined herein.

[0020] In another embodiment, the pharmaceutical composition of the present invention may optionally further comprise 2-perfluorobutylpentane. Preferably, in addition to 1-perfluorobutylpentane, the composition may optionally comprise a small amount of up to 2% (w / w), or up to 1% (w / w), or most preferably, up to 0.5% (w / w) of 2-perfluorobutylpentane.

[0021] The concentration of cyclosporine in the pharmaceutical composition used according to the present invention ranges from about 0.05% to 0.1% (w / v) of the composition. Preferably, the concentration of cyclosporine in the composition is about 0.05% (w / v) or about 0.1% (w / v).

[0022] Unless otherwise stated, the term "% (w / v)" indicates the percentage of a component of the composition by weight relative to the total volume of the composition (where "w" means weight and "v" means volume). For example, 0.05% (w / v) can be understood to refer to 0.5 mg of component in 1 mL of the composition, and 0.1% (w / v) would correspond to 1.0 mg of component in 1 mL of the composition. Unless otherwise stated, the term "% (w / w)" refers to the percentage of a component of the composition by weight relative to the total weight of the composition (where "w" means weight).

[0023] The term “about” as used herein and in connection with parameters (such as the concentration of cyclosporine dissolved in the composition or the amount of cyclosporine characterized by a single dose of the composition) includes precise values ​​as defined and any values ​​falling within the range of variation typically observed when measuring or determining these parameters using existing technology and standard techniques and equipment known in the art.

[0024] Regarding the amount of cyclosporine applied topically for the treatment of dry eye disease, the preferred dosage of the pharmaceutical composition is about 4 to 12 μg of cyclosporine per eye per single dose. In another embodiment, the single dose applied topically to each eye may be about 5 to 10 μg, or more preferably, about 5 μg or about 10 μg.

[0025] Preferably, the total daily dose of cyclosporine in the pharmaceutical composition according to the invention administered to each eye is about 8 to 24 μg / day, or more preferably, about 10 to 20 μg / day, or even more preferably, about 10 μg or 20 μg / day.

[0026] In a preferred embodiment of the present invention for the treatment of dry eye disease, the pharmaceutical composition is administered at a single dose of about 5 μg of cyclosporine per eye, the pharmaceutical composition comprising 0.05% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane and optionally up to about 1.0% (w / w) of ethanol.

[0027] In another preferred embodiment of the invention for the topical treatment of dry eye disease, the pharmaceutical composition is administered at a single dose of about 10 μg of cyclosporine per eye, the pharmaceutical composition comprising 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane and optionally up to about 1.0% (w / w) ethanol.

[0028] In yet another embodiment, the total daily dose of the pharmaceutical composition for use as described in any embodiment of the invention is less than about 28 μg per eye. Preferably, the total daily dose per eye does not exceed about 24 μg. Even more preferably, the total daily dose per eye does not exceed about 20 μg, or about 10 μg.

[0029] Further preferably, the amount of cyclosporine per eye is about 8-12 μl by volume, preferably about 10 μl by volume, of a pharmaceutical composition for the topical treatment of dry eye, the pharmaceutical composition comprising about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, optionally up to about 1.0% (w / w) of ethanol.

[0030] Even more preferably, the amount of cyclosporine per eye is about 8-12 μl by volume, preferably about 10 μl by volume, of a pharmaceutical composition for the topical treatment of dry eye, the pharmaceutical composition comprising about 0.05% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane and optionally up to about 1.0% (w / w) of ethanol.

[0031] Even more preferably, the amount of cyclosporine per eye is applied in the form of a pharmaceutical composition for the topical treatment of dry eye, in the form of about 8-12 μl, preferably about 10 μl, comprising about 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, optionally up to about 1.0% (w / w) of ethanol.

[0032] It has been found that treatment of subjects with dry eye disease with the pharmaceutical composition according to the invention and at a defined dose surprisingly resulted in a reduction of dry eye disease indicators, such as corneal and conjunctival staining and patient questionnaires (see Examples), at an improved level compared to a control product administered at its prescribed dose. Figure 2-4 Subjects receiving and treated with the pharmaceutical composition according to the invention were exposed to a daily dose of cyclosporine that was approximately 30-65% less per eye than that of the control cyclosporine product. Early onset of action was also observed within the first 2 to 4 weeks of treatment. Excellent safety, high tolerability, and patient acceptability were also shown with CyclASol 0.05% and CyclASol 0.1% (see Examples).

[0033] A reduction in the required dose may be beneficial because less active ingredient is needed to achieve the therapeutic goal. This may help reduce cyclosporine-related side effects or reactions in subjects (e.g., for subjects who may require long-term treatment).

[0034] It was found that, compared with 0.05% cyclosporine aqueous (o / w) emulsion (Restasis), treatment of subjects with dry eye disease with the pharmaceutical composition of the present invention at a defined dose surprisingly and indeed resulted not only in a reduction of total adverse reactions (also known as adverse events), but particularly in a reduction of ocular adverse reactions, namely, a reduction in eye irritation, blurred vision, conjunctival hemorrhage, conjunctivitis, and instillation site pain. With the reduction in the occurrence of adverse events, particularly the reduction in ocular adverse reactions as described above, the pharmaceutical composition was found to be safe, well-tolerated, and comfortable in the human eye, and suitable for the treatment methods described herein.

[0035] The pharmaceutical compositions defined herein are preferred not only for treating subjects with dry eye disease, but also for specific conditions associated with it, particularly for subjects with moderate to severe dry eye disease.

[0036] Another aspect of the invention relates to a pharmaceutical composition for treating reading difficulties in subjects suffering from dry eye disease, wherein the composition comprises about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane. The treatment involves topical application of the composition to one or both eyes of a subject suffering from dry eye disease and therefore experiencing reading difficulties.

[0037] Subjects with dry eye disease may experience individual or combined symptoms such as blurred vision, pain, irritation, or damage to the surface of the cornea (e.g., the central cornea), which may lead to visual impairment or difficulty. This visual impairment or difficulty may negatively impact a subject's ability to perform functional tasks in which visual performance and acuity may be essential. In particular, subjects with dry eye disease may experience symptoms that, individually or collectively, lead to poor visual quality or eye comfort, resulting in or causing reading difficulties and an overall reduction in reading ability. Reading difficulties may be due to increased eye discomfort during or related to reading tasks (e.g., exacerbation of any of the dry eye symptoms described herein) and / or difficulties in viewing or perceiving text while reading, such as due to blurred vision or frequent blinking.

[0038] Individuals with dry eye disease and dyslexia will have a score of at least 1.0 or greater on OSDI questions related to reading. Question 6 of the OSDI questionnaire assesses the subject's eyesight in relation to reading ability one week prior to the assessment, with scores ranging from 0 to 4 (0 for no time, 1 for some time, 2 for half the time, 3 for most of the time, and 4 for all the time). Dyslexia can also be assessed by parameters such as the subject's reading speed or acuity on standard text (e.g., silent or aloud reading).

[0039] In a preferred embodiment, the present invention relates to a pharmaceutical composition for treating reading disorders in subjects suffering from dry eye disease, wherein the composition comprises about 0.05 to 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane and optionally up to about 1.0% (w / w) ethanol; and wherein the amount of cyclosporine administered to each eye in a single dose is about 4 to 12 μg.

[0040] In a further preferred embodiment, such pharmaceutical composition can be used to treat reading difficulties in subjects suffering from moderate to severe dry eye disease, and preferably wherein the composition is administered twice daily, or wherein the total daily dose per eye is less than about 28 μg, or preferably wherein the daily dose does not exceed about 24 μg. Even more preferably, the total daily dose per eye is less than about 20 μg, or less than about 10 μg.

[0041] In another embodiment, the single dose applied topically to each eye in treating reading impairment in a subject with dry eye disease may be about 5 to 10 μg, or more preferably about 5 μg or about 10 μg.

[0042] In another preferred embodiment of the invention concerning the treatment of reading impairment in subjects suffering from dry eye disease, the pharmaceutical composition is administered at a dose of about 5 μg cyclosporine per eye, the pharmaceutical composition comprising 0.05% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane and optionally up to about 1.0% (w / w) ethanol.

[0043] In another preferred embodiment of the invention concerning the treatment of reading impairment in subjects suffering from dry eye disease, the pharmaceutical composition is administered at a dose of about 10 μg cyclosporine per eye, the pharmaceutical composition comprising 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane and optionally up to about 1.0% (w / w) ethanol.

[0044] Dyslexia can cause difficulties in many tasks in daily life and employment, where this function is important, and can lead to decreased work efficiency and performance. It has been unexpectedly found that topical ophthalmological treatment of patients with dry eye disease, preferably moderate to severe, using the compositions of the present invention can improve dyslexia scores (e.g., from reference...). Figure 4 OSDI).

[0045] In particular, it has been found that treatment of patients with (moderate to severe) dry eye disease by topical application of the pharmaceutical composition as described herein in the stated amount and method of administration can result in a reduction of reading disorder (e.g., OSDI) scores by at least about 15%, or at least about 25%, or at least about 30%.

[0046] In another aspect, the present invention relates to a pharmaceutical composition for use in treating ocular surface damage in subjects suffering from dry eye disease, wherein the composition comprises about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, and wherein the amount of cyclosporine administered to each eye in a single dose is about 4 to 12 μg.

[0047] In another aspect, the present invention relates to a pharmaceutical composition selected from corneal and / or conjunctival injuries for use in treating subjects suffering from dry eye disease, wherein the composition comprises about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, and wherein the amount of cyclosporine administered to each eye in a single dose is about 4 to 12 μg.

[0048] Damage to the cornea and related tissues is common in patients with dry eye disease, especially those with moderate to severe or acute dry eye. The tear film, with its lipid, aqueous, and mucin layers, normally provides a protective barrier for corneal tissue and epithelium and has a wetting function, preventing dryness / dehydration. It serves as a conduit for supplying oxygen and nutrients to corneal epithelial cells and removing any potential pathogens, debris, and waste. In patients with dry eye disease, the tear film is often unstable or disrupted (e.g., due to reduced water secretion or increased tear film evaporation, or reduced mucin or lipid secretion), thus the corneal tissue and conjunctiva may become less protected, more susceptible to injury, and / or more prone to damage and deterioration.

[0049] The severity of ocular surface damage (characterized by, for example, punctate destruction of the corneal epithelium or surface damage of the bulbar conjunctiva) can be assessed using corneal and conjunctival staining measurements, such as those described herein, namely fluorescein staining (NEI scale) and lissamine green staining (Oxford scale), which particularly highlight and stain dead or damaged corneal and conjunctival cells. Specifically, central corneal fluorescein staining (NEI scale) of the central corneal region (compared to the peripheral corneal region, which includes the lower, upper, nasal, and temporal regions of the cornea) reflects ocular surface damage affecting visual function impairment.

[0050] As used herein, the term “corneal staining” or “total corneal staining,” optionally in conjunction with the fluorescein mentioned, or a dye suitable for or appropriate for corneal staining, refers to the sum total staining observed over all areas of the cornea (i.e., the lower, upper, middle, temporal, and nasal regions). The term “central corneal staining” or similar terms (i.e., beginning with a specific corneal region) and optionally in conjunction with the dye used for staining (e.g., fluorescein) specifically refers to staining observed only in the designated anatomical region.

[0051] As used herein, the terms “conjunctival staining” or “conjunctival staining,” optionally in conjunction with a reference to a fluorescein or a dye suitable for or appropriate for corneal staining, refer to the staining observed as a sum of all areas of the conjunctiva (i.e., the temporal and nasal regions of the conjunctiva). When a term specifying a particular conjunctival region is used (e.g., nasal conjunctival staining), optionally in conjunction with a reference to a dye used for staining, such as lissamine green, it should be understood that this specifically refers to the staining observed in said region.

[0052] In one embodiment, the pharmaceutical composition used according to the invention can be used to treat ocular surface injuries, such as corneal and / or conjunctival injuries, in subjects with dry eye disease. Preferably, the subjects have a total corneal fluorescein staining score of at least 6 (≥6), the score being the sum of scores obtained from the lower, upper, middle, nasal, and temporal regions of the cornea based on the NEI grading scale 0-3. In another embodiment, the pharmaceutical composition used according to the invention can be used to treat ocular surface injuries, such as corneal and / or conjunctival injuries, in subjects with dry eye disease. Preferably, the subjects have central corneal fluorescein staining with a score of at least 1 (≥1) according to the NEI grading scale 0-3. In yet another embodiment, the subjects may also have a total lisamine green conjunctival staining score (the sum of the temporal and nasal regions) of at least 2 (≥2) based on the Oxford scale.

[0053] In a preferred embodiment, the present invention relates to a pharmaceutical composition for treating ocular surface damage in subjects suffering from dry eye disease, wherein the composition comprises about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane and optionally up to about 1.0% (w / w) of ethanol; and wherein the amount of cyclosporine administered in a single dose to each eye is about 4 to 12 μg. In a specific embodiment, this use can be used to treat corneal damage.

[0054] In a further preferred embodiment, such pharmaceutical compositions can be used to treat ocular surface damage in subjects suffering from moderate to severe dry eye disease, preferably wherein the composition is administered twice daily, or wherein the total daily dose administered to each eye is less than about 28 μg, or preferably wherein the daily dose administered does not exceed about 24 μg. Even more preferably, the total daily dose administered to each eye is less than about 20 μg, or less than about 10 μg.

[0055] In another embodiment, the single dose applied topically to each eye for treating ocular surface injury may be about 5 to 10 μg, or more preferably about 5 μg or about 10 μg. In yet another embodiment, the single dose applied topically to each eye for treating ocular surface injury may be about 5 to 10 μg, or more preferably about 5 μg or about 10 μg, wherein the ocular surface injury is corneal injury.

[0056] In yet another preferred embodiment of the invention relating to the treatment of ocular surface damage in subjects suffering from dry eye disease, the pharmaceutical composition is administered at a single dose of about 5 μg of cyclosporine per eye, the pharmaceutical composition comprising 0.05% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane and optionally up to about 1.0% (w / w) of ethanol.

[0057] In another preferred embodiment of the invention concerning the treatment of ocular surface damage in subjects suffering from dry eye disease, the pharmaceutical composition is administered at a single dose of about 10 μg cyclosporine per eye, the pharmaceutical composition comprising 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane and optionally up to about 1.0% (w / w) ethanol.

[0058] In particular, ocular surface injuries such as corneal or conjunctival damage have been found to be effectively treated and reduced, as observed in patients treated with the compositions defined and applied according to the invention (see [link to relevant documentation]). Figure 2 and 3 This is evidenced by a significant reduction in corneal and conjunctival staining compared to that observed in subjects before treatment. Furthermore, earlier efficacy of corneal injury treatment was observed, within two to four weeks of treatment time, compared to the comparative product and carrier.

[0059] Preferably, the pharmaceutical composition and dosage described herein can be used to treat subjects with moderate to severe dry eye disease, optionally wherein the subjects do not respond to treatment with artificial tears.

[0060] The severity of dry eye disease in a subject or patient can be classified and scored using one or more standard tests or combinations thereof. For example, the severity of dry eye disease can be determined using tests based on an assessment of a patient’s perception of eye symptoms and their impact on vision, such as the Ocular Surface Disease Index (OSDI) questionnaire, which has 12 questions focusing on eye irritation symptoms associated with dry eye disease and their impact on daily activities and lifestyle, or the Visual Analogue Scale (VAS) for Dry Eye Symptoms, in which subjects are asked to rate the eye symptoms (both eyes simultaneously) caused by dryness, which is done by placing vertical markers on a horizontal line to indicate the degree of discomfort (0 corresponds to “no dryness”, while 100% corresponds to “maximum dryness”) and the severity of dry eye symptoms, dryness, stickiness, burning / stinging, foreign body sensation, itching, blurred vision, light sensitivity, and pain, as well as the frequency of dryness.

[0061] Dry eye disease can also be assessed and determined using any combination of objective clinical measurements, such as Schirmer test type 1, fluorescein staining and / or lissamine green staining of the cornea and conjunctiva, and tear film breakup time (TBUT) for measuring tear quality.

[0062] In the context of this invention, it should be understood that any one or a combination of these measures for determining the severity of dry eye disease may be applied.

[0063] Preferably, subjects or patients with moderate to severe dry eye may have at least one or a combination of the following prior to treatment with the composition defined herein: a total corneal fluorescein staining score ≥6 according to NEI classification (i.e., the sum of scores for the lower, upper, middle, nasal, and temporal corneal regions equal to or greater than 6); symptomatic (i.e., a score ≥40 according to the Dry Visual Acuity Scale (VAS); or an Ocular Surface Disease Index (OSDI) score ≥20); or a Schirmer's Test I score between ≥2 mm and 8 mm (i.e., equal to or greater than 2 mm, but equal to or less than 8 mm);

[0064] In another embodiment, the pharmaceutical composition used according to the invention can also be used to treat patients with dry eye disease who do not respond to artificial tears.

[0065] Artificial tears, also known as lubricating eye drops or tear substitutes, are used to relieve and treat symptoms of dry eye and are generally available over-the-counter (OTC). These are typically water-based compositions in solution form, but can also be in gel or ointment form. They work by adding moisture to the eye and often contain lubricants (such as hydroxypropyl methylcellulose (HPMC), carbomethylcellulose (CMC), polyvinyl alcohol, liquid polyols such as propylene glycol, polyethylene glycol) and may contain healing-promoting additives (such as hyaluronic acid) or electrolyte compositions that mimic the natural tear film, or additives that promote retention of the composition on the surface of the eye (such as gelling agents like carbomer).

[0066] Preferably, the pharmaceutical composition used according to the invention can be used to treat subjects suffering from dry eye disease, particularly those with moderate to severe dry eye disease, those with persistent dry eye symptoms, and those with related conditions even after a treatment period of at least 2 weeks, or at least 1 month, or at least about 6 months using artificial tears alone.

[0067] The composition used according to the invention and the dosage of the composition as described in any embodiment herein are preferably applied topically to the subject's eye in the form of a single drop. The drops may be applied to the surface of the eye, preferably to any surface area or tissue of the eye that can be topically applied or instilled, such as the cornea or conjunctiva. The single drop composition may be instilled directly onto the surface of the eye, such as the corneal surface, or optionally into the space formed by gently pulling down the lower eyelid, i.e., a sac or eye bag.

[0068] As used herein, the terms "applied to an eye" or "each eye" refer to the administration of a given dose (e.g., a single dose) of the pharmaceutical composition according to the invention to a single eye of a subject. However, the treatment of dry eye disease and dry eye-related conditions as described herein should be understood to be limited to treating a single eye of a subject, but also includes treatment involving the application of the composition according to the invention to each eye (i.e., both eyes) of a subject affected by dry eye disease.

[0069] Preferably, the pharmaceutical composition for any of the purposes described herein is administered four times daily as a single drop per eye. In a more preferred embodiment, the composition is applied to the eye twice daily as a single drop per eye. Thus, a patient receiving bilateral treatment according to this dosing regimen will receive a total of two drops per eye daily for a given treatment period.

[0070] In another embodiment, when the pharmaceutical composition is applied to each eye more than once a day, such as four times a day or twice a day, the time interval between the topical application of the composition to the eye or the surface of the eye is preferably at least 4 hours, or at least 6 hours, or at least 12 hours.

[0071] In another embodiment, the pharmaceutical composition used according to the invention is administered over a treatment period of at least one month (4 weeks), more preferably at least four months (16 weeks). In another embodiment, the pharmaceutical composition for treating dry eye conditions and diseases as described herein can be administered continuously while dry eye symptoms and indicators persist.

[0072] Preferably, the pharmaceutical composition used according to the present invention may contain up to about 1.0% (w / w) of ethanol.

[0073] As used herein, the term “at most about” or “at most,” used in the context of a parameter, such as in relation to the amount of ethanol in the composition, refers to any parameter greater than zero and at most, including, the defined parameter. For example, the amount of “at most about 1.0% (w / w) ethanol” should be understood to include any value greater than zero, ranging at most and including 1.0% (w / w) of ethanol, and will include, for example, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.95%, 0.99% (w / w) of ethanol, where any degree of variation typically observed when measuring or determining the parameter using standard techniques and equipment known in the relevant art is taken into account.

[0074] In one embodiment of the invention, the composition for therapeutic use as described herein may consist essentially of about 0.05% or 0.1% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane and optionally about 1.0% (w / w) ethanol.

[0075] In another embodiment, the composition as described herein is substantially ethanol-free, wherein the composition consists substantially only of cyclosporine in an amount dissolved in 1-perfluorobutylpentane as described in any of the embodiments herein.

[0076] Compared to three-component formulations that also contain a co-solvent (such as ethanol), the absence of an organic co-solvent (such as ethanol) provides the advantage of a simpler two-component formulation. Further inclusion of even one additional component can increase complexity in factors such as cost, manufacturing, processing, packaging, and patient compliance.

[0077] In a preferred embodiment of the invention, the composition used as described herein may preferably comprise or consist of the following components:

[0078] Cyclosporine at a concentration of 0.05 to 0.1% (w / v) soluble in 1-perfluorobutylpentane and 0.5% (w / w) ethanol, or

[0079] Cyclosporine at a concentration of 0.05 to 0.1% (w / v) soluble in 1-perfluorobutylpentane and 1.0% (w / w) ethanol, or

[0080] Cyclosporine soluble in 0.05% (w / v) of 1-perfluorobutylpentane and 0.5% (w / w) ethanol, or

[0081] Cyclosporine soluble in 0.1% (w / v) of 1-perfluorobutylpentane and 0.5% (w / w) ethanol, or

[0082] Cyclosporine soluble in 0.1% (w / v) of 1-perfluorobutylpentane and 1.0% (w / w) ethanol, or

[0083] Cyclosporine 0.05% (w / v) dissolved in 1-perfluorobutylpentane and 1.0% (w / w) ethanol, or

[0084] Cyclosporine dissolved in 0.05 to 0.1% (w / v) of 1-perfluorobutylpentane, or

[0085] Cyclosporine dissolved in 0.1% (w / v) of 1-perfluorobutylpentane, or

[0086] 0.05% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane.

[0087] The compositions of the present invention are preferably provided as a clear solution, wherein cyclosporine is completely dissolved in a 1-perfluorobutylpentane solution (at room temperature, i.e., between 15-25°C). If ethanol is included, the compositions are also provided as a clear solution of cyclosporine dissolved in a solution of 1-perfluorobutylpentane and ethanol. In a preferred embodiment, the compositions are provided in a sterile form.

[0088] In another preferred embodiment, the pharmaceutical composition used according to the invention is substantially free of water and / or substantially free of preservatives. As understood herein, the terms "substantially free" or "truly free" with respect to a composition component mean that the component is present in trace amounts, and if present in trace amounts, the component does not contribute technically to the composition.

[0089] Preferably, the pharmaceutical composition used according to the present invention is substantially free of water, substantially free of preservatives, and effectively inhibits microbial growth.

[0090] In another preferred embodiment, the pharmaceutical compositions used according to the invention are characterized by significant wetting and diffusion behavior, thereby allowing them to spread rapidly and effectively onto ocular surfaces, such as the cornea and / or conjunctiva. Therefore, when small droplets (droplets) of the pharmaceutical compositions used according to the invention are applied to the ocular surface, they result in rapid diffusion of the composition onto the cornea and / or conjunctiva.

[0091] Preferably, when applied using a dropper, the pharmaceutical composition used according to the invention forms small droplets (droplets) ranging from about 8-12 μl, more preferably about 9-11 μl, and most preferably about 10 μl. This distinguishes the composition of the invention from a 0.05% cyclosporine aqueous (o / w) emulsion characterized by a droplet size of about 28.5 μl.

[0092] In another preferred embodiment, the pharmaceutical composition used according to the invention is characterized by administering a relatively low amount of cyclosporine per eye as a single dose, for example, about 4-12 μg of cyclosporine, preferably 5-10 μg of cyclosporine per eye as a single dose. This distinguishes the composition of the invention from a 0.05% cyclosporine aqueous (o / w) emulsion characterized by a droplet size of about 28.5 μl, and thus reduces the total daily dose by about 30 to 65% when using the pharmaceutical composition according to the invention.

[0093] As used herein, the term “consists” and related terms “consisting” or “consist” should be understood to mean that no other features exist besides those features derived from the term. In the case of pharmaceutical compositions, if any other ingredient or component besides those derived from the term is present in the composition, it is present only in trace or residual amounts so as not to impart any technical advantage or relevance to the purpose of the invention, and may be further understood, for example, by the use of the term “substantially” or “substantially” in combination with these terms (e.g., “substantially constitutes”).

[0094] Within the context of this invention, the use of the pharmaceutical composition described in any of the above embodiments in the preparation or formulation of a medicament or medicine for treating a subject in need of any of the preferred dry eye conditions described herein. Further provided within the context of this invention are methods for treating a subject diagnosed with and / or suffering from the dry eye conditions described herein, wherein the methods may include topical application, such as by direct topical instillation of any of the identified compositions, preferably at any of the stated doses or amounts, and / or during any of the identified treatment periods.

[0095] Furthermore, the treatment methods and compositions used for therapeutic purposes are preferably targeted at human subjects diagnosed with and / or suffering from dry eye disease.

[0096] In another aspect, the present invention also provides a kit comprising a pharmaceutical composition used according to the present invention and any of the above embodiments, wherein the kit includes a container for containing the pharmaceutical composition and a drop dispenser suitable for administering the composition in volumes of about 8 to 12 μl per drop.

[0097] In another embodiment, the dropper is adapted to administer approximately 10 μl of the composition per drop.

[0098] As understood herein, a drop dispenser can be a dispenser or applicator device that can be mounted, secured, or connected to a container for containing a pharmaceutical composition. Preferably, the drop dispenser is adapted to dispense a single dose in the form of a single drop of the composition. More preferably, the drop dispenser is adapted to dispense a single dose of 8 μl to 12 μl, or to dispense a single dose of about 10 μl.

[0099] As understood herein, containers for containing pharmaceutical compositions preferably have a volume capable of holding a single dose, but more preferably a volume capable of holding multiple or several doses of the composition. In one embodiment of the invention, the container of the kit can hold up to 160 doses of the pharmaceutical composition used according to the invention.

[0100] The container and / or dropper is preferably made of a thermoplastic material or a polymer. In one embodiment, the container and / or dropper is made of a thermoplastic material selected from polyethylene and polypropylene.

[0101] In one particular embodiment, the dropper is made of polyethylene material, preferably selected from low-density polyethylene and high-density polyethylene, more preferably high-density polyethylene. In another embodiment, the container is made of polypropylene or polyethylene material, more preferably polypropylene.

[0102] In yet another embodiment, the present invention relates to a kit comprising a pharmaceutical composition used according to the invention, the kit comprising a container for containing the pharmaceutical composition and a dropper adapted for administration at about 8 to 12 μl per drop, wherein the container is made of polypropylene and wherein the dropper is made of polyethylene selected from low-density polyethylene and high-density polyethylene, preferably high-density polyethylene.

[0103] Preferably, the container has a volume or internal space that is at least partially filled with the pharmaceutical composition used according to the invention. In another embodiment, the ratio of the volume of the pharmaceutical composition in the container to the total volume of the container is between 0.4 and 0.7. As understood herein, the total volume of the container refers to the total internal volume formed by the internal dimensions of the container. The volume of the pharmaceutical composition in the container refers to the filling volume, i.e., the volume of the pharmaceutical composition contained in the container. For example, in a kit containing a container with a total volume of 3.0 mL, it is preferred that the container contains a volume of 2.0 mL of the pharmaceutical composition according to the invention. Here, the ratio of the volume of the pharmaceutical composition in the container to the total volume of the container is approximately 0.7.

[0104] Particularly preferred are kits comprising the pharmaceutical compositions used according to the invention, wherein the kit, in addition to comprising a dropper suitable for administration at doses of about 8 to 12 μl, comprises any of the following:

[0105] Approximately 2.0 mL of the pharmaceutical composition (i.e., a corresponding ratio of approximately 0.7) is filled into a 3.0 mL container; or

[0106] Approximately 2.0 mL of the pharmaceutical composition (i.e., a corresponding ratio of approximately 0.4) is filled into a 5.0 mL container; or

[0107] Approximately 2.5 mL of the pharmaceutical composition (i.e., a corresponding ratio of approximately 0.5) is filled into a 5.0 mL container.

[0108] Also preferred are kits comprising the pharmaceutical composition used according to the invention, wherein the kit comprises a container for containing the pharmaceutical composition and a dropper suitable for administration at about 8 to 12 μl per drop, and wherein the ratio of the volume of the headspace in the container to the volume of the pharmaceutical composition is between 0.5 and 1.5. As understood herein, the volume of the headspace in the container (or headspace volume) refers to the internal volume of the container formed by the internal dimensions of the container, which is not filled or occupied by the liquid pharmaceutical composition but may contain atmosphere or inert gas.

[0109] For example, in a kit comprising a container holding a pharmaceutical composition used according to the present invention with a filling volume of 2.5 mL, it is preferred that the available headspace volume in the container is about 2.5 mL, wherein the ratio of headspace to pharmaceutical composition filling volume is about 1.0.

[0110] Particularly preferred are kits comprising the pharmaceutical compositions used according to the invention, wherein the kit, in addition to comprising a dropper suitable for administration at about 8 to 12 μl per drop, or preferably about 10 μl per drop, comprises any of the following:

[0111] A container for containing approximately 2.0 mL of a pharmaceutical composition, wherein the container has a headspace of approximately 1.0 mL (i.e., a headspace to fill volume ratio of approximately 0.5); or

[0112] A container for containing approximately 2.0 mL of a pharmaceutical composition, wherein the container has a headspace of approximately 3.0 mL (i.e., a headspace to fill volume ratio of approximately 1.5); or

[0113] A container for containing approximately 2.4 mL of a pharmaceutical composition, wherein the container has a headspace of approximately 2.6 mL (i.e., a headspace to fill volume ratio of approximately 1.1).

[0114] The kit provided according to these embodiments can improve the storage and dispensability of pharmaceutical compositions (i.e., ease and consistency of dispensing).

[0115] Furthermore, the present invention includes items 1 to 37, which relate to methods for treating dry eye disease:

[0116] 1. A method for treating dry eye disease, the method comprising applying topically to the eye of a person suffering from dry eye disease twice daily a composition comprising about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the amount of cyclosporine applied in a single dose to each eye is about 4 to 12 μg of cyclosporine, and wherein the method is therapeutically effective in treating the dry eye disease of the person.

[0117] 2. The method for treating dry eye disease according to claim 1, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0118] 3. The method for treating dry eye disease according to claim 1, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0119] 4. The method for treating dry eye disease according to claim 1, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0120] 5. The method of treating dry eye disease according to claim 1, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0121] 6. The method for treating dry eye disease according to claim 1, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0122] 7. The method of treating dry eye disease according to claim 1, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0123] 8. A method for treating dry eye disease, the method comprising applying topically to the eye of a person suffering from dry eye disease twice daily a composition comprising about 0.05% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is substantially free of water and substantially free of preservatives, wherein the amount of cyclosporine applied per eye in a single dose is about 5 μg of cyclosporine, and wherein the method is therapeutically effective in treating the person's dry eye disease.

[0124] 9. The method of treating dry eye disease according to claim 8, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0125] 10. The method for treating dry eye disease according to claim 8, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0126] 11. The method of treating dry eye disease according to claim 8, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0127] 12. The method of treating dry eye disease according to claim 8, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0128] 13. The method for treating dry eye disease according to claim 8, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0129] 14. The method of treating dry eye disease according to claim 8, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0130] 15. The method for treating dry eye disease according to any one of claims 8 to 14, wherein corneal staining is reduced.

[0131] 16. The method for treating dry eye disease according to item 15, wherein a reduction in corneal staining is achieved during a 4-month treatment period.

[0132] 17. A method for treating dry eye disease according to any one of claims 8 to 14, wherein a reduction in central corneal staining and / or a reduction in any one or combination of lower, upper, nasal, or temporal corneal staining is achieved.

[0133] 18. The method for treating dry eye disease according to any one of claims 8 to 14, wherein early onset of action is achieved.

[0134] 19. The method of treating dry eye disease according to item 18, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0135] 20. A method for treating dry eye disease according to any one of claims 8 to 14, wherein visual impairment associated with dry eye disease is reduced.

[0136] 21. The method for treating dry eye disease according to any one of claims 8 to 14, wherein ocular surface damage associated with dry eye disease is reduced.

[0137] 22. The method of treating dry eye disease according to any one of claims 8 to 14, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0138] 23. A method for treating dry eye disease, the method comprising applying topically to the eye of a person suffering from dry eye disease twice daily a composition comprising about 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is substantially free of water and substantially free of preservatives, wherein the amount of cyclosporine applied in a single dose to each eye is about 10 μg of cyclosporine, and wherein the method is therapeutically effective in treating the person's dry eye disease.

[0139] 24. The method of treating dry eye disease according to claim 23, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0140] 25. The method of treating dry eye disease according to claim 23, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0141] 26. The method of treating dry eye disease according to claim 23, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0142] 27. The method of treating dry eye disease according to claim 23, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0143] 28. The method for treating dry eye disease according to claim 23, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0144] 29. The method of treating dry eye disease according to claim 23, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0145] 30. The method for treating dry eye disease according to any one of claims 23 to 29, wherein corneal staining is reduced.

[0146] 31. The method for treating dry eye disease according to item 30, wherein a reduction in corneal staining is achieved during a 4-month treatment period.

[0147] 32. The method of treating dry eye disease according to any one of claims 23 to 29, wherein a reduction in central corneal staining and / or a reduction in any one or combination of lower, upper, nasal, or temporal corneal staining is achieved.

[0148] 33. The method for treating dry eye disease according to any one of claims 23 to 29, wherein early onset of action is achieved.

[0149] 34. The method of treating dry eye disease according to item 33, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0150] 35. The method of treating dry eye disease according to any one of claims 23 to 29, wherein visual impairment associated with dry eye disease is reduced.

[0151] 36. The method for treating dry eye disease according to any one of claims 23 to 29, wherein ocular surface damage associated with dry eye disease is reduced.

[0152] 37. The method of treating dry eye disease according to any one of claims 23 to 29, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0153] Furthermore, the present invention includes the following items 38 to 72, which relate to methods for reducing reading difficulties associated with dry eye disease:

[0154] 38. A method for reducing reading impairment associated with dry eye disease, the method comprising applying topically to the eye of a person suffering from dry eye disease twice daily a composition comprising about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the amount of cyclosporine applied in a single dose to each eye is about 4 to 12 μg of cyclosporine, and wherein said method is effective in reducing reading impairment in said person.

[0155] 39. The method for reducing reading difficulties according to claim 38, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0156] 40. The method for reducing reading difficulties according to claim 38, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0157] 41. The method for reducing reading difficulties according to claim 38, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0158] 42. The method for reducing reading difficulties according to claim 38, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0159] 43. The method for reducing reading difficulties according to claim 38, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0160] 44. The method for reducing reading difficulties according to claim 38, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0161] 45. A method for reducing reading impairment associated with dry eye disease, the method comprising applying topically to the eye of a person suffering from dry eye disease twice daily a composition comprising about 0.05% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is substantially free of water and substantially free of preservatives, wherein the amount of cyclosporine applied in a single dose to each eye is about 5 μg of cyclosporine, and wherein the method is effective in reducing reading impairment in the person.

[0162] 46. ​​The method for reducing reading difficulties according to claim 45, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0163] 47. The method for reducing reading difficulties according to claim 45, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0164] 48. The method for reducing reading difficulties according to claim 45, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0165] 49. The method for reducing reading difficulties according to claim 45, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0166] 50. The method for reducing reading difficulties according to claim 45, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0167] 51. The method for reducing reading difficulties according to claim 45, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0168] 52. The method for reducing reading difficulties according to any one of claims 45 to 51, wherein a reduction in corneal staining is achieved.

[0169] 53. The method for reducing reading difficulties according to claim 52, wherein the reduction of corneal staining is achieved during a 4-month treatment period.

[0170] 54. The method for reducing reading difficulties according to any one of claims 45 to 51, wherein a reduction in central corneal staining and / or a reduction in any one or combination of lower, upper, nasal, or temporal corneal staining is achieved.

[0171] 55. The method for reducing reading difficulties according to any one of claims 45 to 51, wherein early onset of action is achieved.

[0172] 56. The method for reducing reading difficulties according to claim 55, wherein the early onset of effect is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0173] 57. The method for reducing reading difficulties according to any one of claims 45 to 51, wherein ocular surface damage associated with dry eye disease is reduced.

[0174] 58. The method for reducing reading difficulties according to any one of claims 45 to 51, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0175] 59. A method for reducing reading impairment associated with dry eye disease, the method comprising applying topically to the eye of a person suffering from dry eye disease twice daily a composition comprising about 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is substantially free of water and substantially free of preservatives, wherein the amount of cyclosporine applied in a single dose to each eye is about 10 μg of cyclosporine, and wherein the method is effective in reducing reading impairment in the person.

[0176] 60. The method for reducing reading difficulties according to claim 59, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0177] 61. The method for reducing reading difficulties according to claim 59, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0178] 62. The method for reducing reading difficulties according to claim 59, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0179] 63. The method for reducing reading difficulties according to claim 59, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0180] 64. The method for reducing reading difficulties according to claim 59, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0181] 65. The method for reducing reading difficulties according to claim 59, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0182] 66. The method for reducing reading difficulties according to any one of claims 59 to 65, wherein a reduction in corneal staining is achieved.

[0183] 67. The method for reducing reading difficulties according to claim 66, wherein the reduction of corneal staining is achieved during a 4-month treatment period.

[0184] 68. The method for reducing reading difficulties according to any one of claims 59 to 65, wherein a reduction in central corneal staining and / or a reduction in any one or combination of lower, upper, nasal, or temporal corneal staining is achieved.

[0185] 69. The method for reducing reading difficulties according to any one of claims 59 to 65, wherein early effectiveness is achieved.

[0186] 70. The method for reducing reading difficulties according to claim 69, wherein the early onset of effect is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0187] 71. The method for reducing reading difficulties according to any one of claims 59 to 65, wherein ocular surface damage associated with dry eye disease is reduced.

[0188] 72. The method for reducing reading difficulties according to any one of claims 59 to 65, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0189] Furthermore, the present invention includes the following items 73 to 107, which relate to methods for reducing reading difficulties associated with dry eye disease:

[0190] 73. A method for reducing ocular surface damage associated with dry eye disease, the method comprising applying topically to the eye of a person suffering from dry eye disease twice daily a composition comprising about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the amount of cyclosporine applied in a single dose to each eye is about 4 to 12 μg of cyclosporine, and wherein said method is effective in reducing ocular surface damage in said person.

[0191] 74. The method for reducing ocular surface damage according to claim 73, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0192] 75. The method for reducing ocular surface damage according to claim 73, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0193] 76. The method for reducing ocular surface damage according to claim 73, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0194] 77. The method for reducing ocular surface damage according to claim 73, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0195] 78. The method for reducing ocular surface damage according to claim 73, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0196] 79. The method for reducing ocular surface damage according to claim 73, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0197] 80. A method for reducing ocular surface damage associated with dry eye disease, the method comprising applying topically to the eye of a person suffering from dry eye disease twice daily a composition comprising about 0.05% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is substantially free of water and substantially free of preservatives, wherein the amount of cyclosporine applied per eye in a single dose is about 5 μg of cyclosporine, and wherein the method is effective in reducing ocular surface damage in the person.

[0198] 81. The method for reducing ocular surface damage according to claim 80, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0199] 82. The method for reducing ocular surface damage according to claim 80, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0200] 83. The method for reducing ocular surface damage according to claim 80, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0201] 84. The method for reducing ocular surface damage according to claim 80, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0202] 85. The method for reducing ocular surface damage according to claim 80, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0203] 86. The method for reducing ocular surface damage according to claim 80, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0204] 87. The method for reducing ocular surface damage according to any one of claims 80 to 86, wherein a reduction in corneal staining is achieved.

[0205] 88. The method for reducing ocular surface damage according to claim 87, wherein the reduction of corneal staining is achieved during a 4-month treatment period.

[0206] 89. The method for reducing ocular surface damage according to any one of claims 80 to 86, wherein a reduction in central corneal staining and / or a reduction in any one or combination of lower, upper, nasal, or temporal corneal staining is achieved.

[0207] 90. The method for reducing ocular surface damage according to any one of claims 80 to 86, wherein early onset of action is achieved.

[0208] 91. The method for reducing ocular surface damage according to claim 90, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0209] 92. The method for reducing ocular surface damage according to any one of claims 80 to 86, wherein visual impairment associated with dry eye disease is reduced.

[0210] 93. The method for reducing ocular surface damage according to any one of claims 80 to 86, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0211] 94. A method for reducing ocular surface damage associated with dry eye disease, the method comprising applying topically to the eye of a person suffering from dry eye disease twice daily a composition comprising about 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is substantially free of water and substantially free of preservatives, wherein the amount of cyclosporine applied in a single dose to each eye is about 10 μg of cyclosporine, and wherein the method is effective in reducing ocular surface damage in the person.

[0212] 95. The method for reducing ocular surface damage according to claim 94, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0213] 96. The method for reducing ocular surface damage according to claim 94, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0214] 97. The method for reducing ocular surface damage according to claim 94, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0215] 98. The method for reducing ocular surface damage according to claim 94, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0216] 99. The method for reducing ocular surface damage according to claim 94, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0217] 100. The method for reducing ocular surface damage according to claim 94, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0218] 101. The method for reducing ocular surface damage according to any one of claims 94 to 100, wherein corneal staining is reduced.

[0219] 102. The method for reducing ocular surface damage according to claim 101, wherein the reduction of corneal staining is achieved during a 4-month treatment period.

[0220] 103. The method for reducing ocular surface damage according to any one of claims 94 to 100, wherein a reduction in central corneal staining and / or a reduction in any one or combination of lower, upper, nasal, or temporal corneal staining is achieved.

[0221] 104. The method for reducing ocular surface damage according to any one of claims 94 to 100, wherein early onset of action is achieved.

[0222] 105. The method for reducing ocular surface damage according to claim 104, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0223] 106. The method for reducing ocular surface damage according to any one of claims 94 to 100, wherein visual impairment associated with dry eye disease is reduced.

[0224] 107. The method for reducing ocular surface damage according to any one of claims 94 to 100, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0225] Furthermore, the present invention includes items 108 to 140, which relate to a method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease:

[0226] 108. A method for reducing the total daily dose of cyclosporine applied topically to a person treating dry eye disease, the method comprising applying a composition twice daily as a single drop per eye to the eye of said person, said composition comprising about 0.05% to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the amount of cyclosporine applied as a single dose per eye is about 4 to 12 μg of cyclosporine, and wherein the method reduces the total daily dose of cyclosporine by about 30% to 65% compared to applying 0.05% (w / v) cyclosporine aqueous (o / w) emulsion topically twice daily as a single drop per eye, and is at least therapeutically effective in treating dry eye disease; or

[0227] The amount of cyclosporine administered as a single dose per eye is approximately 5 to 10 μg of cyclosporine, and the method reduces the total daily dose of cyclosporine by approximately 30% to 65% compared to topical application of 0.05% (w / v) cyclosporine aqueous (o / w) emulsion twice daily per eye as a single drop per eye, and is at least therapeutically effective in treating dry eye disease.

[0228] 109. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease as described in claim 108, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0229] 110. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 108, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0230] 111. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 108, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0231] 112. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 108, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0232] 113. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 108, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0233] 114. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 108, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0234] 115. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye according to any one of claims 108 to 114, wherein a single drop of the composition has a drop dose of about 10 μl and a single drop of the emulsion has a drop dose of about 28.5 μl.

[0235] 116. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye according to any one of claims 108 to 114, wherein systemic exposure to cyclosporine is reduced compared to topical application of 0.05% (w / v) cyclosporine aqueous (o / w) emulsion twice daily by single drop.

[0236] 117. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye according to any one of claims 108 to 114, wherein one or more side effects are reduced compared to topical application of 0.05% (w / v) cyclosporine aqueous (o / w) emulsion twice daily by single drop.

[0237] 118. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease, as described in claim 117, wherein the side effects are selected from blurred vision, eye pain, and eye irritation.

[0238] 119. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease, the method comprising applying a composition twice daily by single drop to the eye of a person suffering from dry eye disease, the composition comprising about 0.05% (w / v) cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is substantially free of water and substantially free of preservatives, wherein the amount of cyclosporine applied as a single dose per eye is about 5 μg of cyclosporine, and wherein the method reduces the total daily dose of cyclosporine by about 65% and is at least therapeutically effective in treating dry eye disease compared to applying 0.05% (w / v) cyclosporine aqueous (o / w) emulsion topically twice daily by single drop per eye.

[0239] 120. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease, as described in claim 119, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0240] 121. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 119, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0241] 122. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 119, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0242] 123. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 119, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0243] 124. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 119, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0244] 125. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 119, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0245] 126. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye according to any one of claims 119 to 125, wherein a single drop of the composition has a drop dose of about 10 μl and a single drop of the emulsion has a drop dose of about 28.5 μl.

[0246] 127. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye according to any one of claims 119 to 125, wherein systemic exposure to cyclosporine is reduced compared to topical application of 0.05% (w / v) cyclosporine aqueous (o / w) emulsion twice daily by single drop.

[0247] 128. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye according to any one of claims 119 to 125, wherein one or more side effects are reduced compared to topical application of 0.05% (w / v) cyclosporine aqueous (o / w) emulsion twice daily by single drop.

[0248] 129. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to any one of claims 119 to 125, wherein said side effects are selected from blurred vision, eye pain, and eye irritation.

[0249] 130. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease, the method comprising applying a composition twice daily by single drop to the eye of a person suffering from dry eye disease, the composition comprising about 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is substantially free of water and substantially free of preservatives, wherein the amount of cyclosporine applied as a single dose per eye is about 10 μg of cyclosporine, and wherein the method reduces the total daily dose of cyclosporine by about 30% and is at least therapeutically effective in treating dry eye disease compared to applying 0.05% (w / v) of cyclosporine aqueous (o / w) emulsion topically twice daily by single drop per eye.

[0250] 131. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease, as described in claim 130, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0251] 132. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 130, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0252] 133. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 130, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0253] 134. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 130, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0254] 135. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 130, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0255] 136. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease according to claim 130, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0256] 137. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye according to any one of claims 130 to 136, wherein a single drop of the composition has a drop dose of about 10 μl and a single drop of the emulsion has a drop dose of about 28.5 μl.

[0257] 138. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye according to any one of claims 130 to 136, wherein systemic exposure to cyclosporine is reduced compared to topical application of 0.05% (w / v) cyclosporine aqueous (o / w) emulsion twice daily by single drop.

[0258] 139. A method for reducing the total daily amount of cyclosporine applied topically to a person treating dry eye according to any one of claims 130 to 136, wherein one or more side effects are reduced compared to topical application of 0.05% (w / v) cyclosporine aqueous (o / w) emulsion twice daily by single drop.

[0259] 140. The method of reducing the total daily amount of cyclosporine applied topically to a person treating dry eye disease as described in claim 139, wherein the side effects are selected from blurred vision, eye pain, and eye irritation.

[0260] Furthermore, the present invention includes items 141 to 177 relating to compositions for treating dry eye disease:

[0261] 141. A composition for treating dry eye disease comprising about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is therapeutically effective in treating dry eye disease in patients when applied topically twice daily at a single dose of about 4 to 12 μg of cyclosporine per eye.

[0262] 142. The composition according to claim 141, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0263] 143. The composition according to claim 141, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0264] 144. The composition according to claim 141, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0265] 145. The composition according to claim 141, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0266] 146. The composition according to claim 141, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0267] 147. The composition according to claim 141, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0268] 148. The composition according to claim 141, wherein the concentration of cyclosporine is about 0.05% (w / v) of cyclosporine, and the single dose per eye is about 5 μg of cyclosporine, and wherein the composition is substantially free of water and substantially free of preservatives.

[0269] 149. The composition according to claim 148, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0270] 150. The composition according to claim 148, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0271] 151. The composition according to claim 148, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0272] 152. The composition according to claim 148, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0273] 153. The composition according to claim 148, wherein the composition comprises cyclosporine dissolved in about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0274] 154. The composition according to claim 148, wherein the composition comprises cyclosporine dissolved in at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0275] 155. The composition according to any one of claims 148 to 154, wherein the composition is effective in reducing corneal staining.

[0276] 156. The composition according to claim 155, wherein the reduction in corneal staining is achieved within a 4-month treatment period.

[0277] 157. The composition according to any one of claims 148 to 154, wherein the composition is effective in reducing central corneal staining and / or in reducing any one or a combination of lower, upper, nasal, or temporal corneal staining.

[0278] 158. The composition according to any one of claims 148 to 154, wherein the composition effectively achieves early onset of action.

[0279] 159. The composition according to claim 130 or 158, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0280] 160. The composition according to any one of claims 148 to 154, wherein the composition is effective in reducing visual impairment associated with dry eye disease.

[0281] 161. The composition according to any one of claims 148 to 154, wherein the composition is effective in reducing ocular surface damage associated with dry eye.

[0282] 162. The composition according to any one of claims 148 to 154, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0283] 163. The composition according to claim 141, wherein the concentration of cyclosporine is about 0.10% (w / v) of cyclosporine, and the single dose per eye is about 10 μg of cyclosporine, and wherein the composition is substantially free of water and substantially free of preservatives.

[0284] 164. The composition according to claim 163, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0285] 165. The composition according to claim 163, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0286] 166. The composition according to claim 163, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0287] 167. The composition according to claim 163, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0288] 168. The composition according to claim 163, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0289] 169. The composition according to claim 163, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0290] 170. The composition according to any one of claims 163 to 169, wherein the composition is effective in reducing corneal staining.

[0291] 171. The composition according to claim 170, wherein the reduction in corneal staining is achieved within a 4-month treatment period.

[0292] 172. The composition according to any one of claims 163 to 169, wherein the composition is effective in reducing central corneal staining and / or in reducing any one or a combination of lower, upper, nasal, or temporal corneal staining.

[0293] 173. The composition according to any one of claims 163 to 169, wherein the composition effectively achieves early onset of action.

[0294] 174. The composition according to claim 173, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0295] 175. The composition according to any one of claims 163 to 169, wherein the composition is effective in reducing visual impairment associated with dry eye disease.

[0296] 176. The composition according to any one of claims 163 to 169, wherein the composition is effective in reducing ocular surface damage associated with dry eye.

[0297] 177. The composition according to any one of claims 163 to 169, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0298] Furthermore, the present invention includes items 178 to 214, which relate to compositions for the effective treatment of human dry eye disease, wherein the total daily dose of cyclosporine is reduced:

[0299] 178. A composition for the effective treatment of human dry eye disease, wherein the total daily dose of cyclosporine applied topically to the human is reduced, the composition comprising about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is applied topically as a single dose of about 4 to 12 μg of cyclosporine per eye twice daily, and wherein the total daily dose of cyclosporine is reduced by about 30% to 65% compared to a 0.05% (w / v) cyclosporine aqueous (o / w) emulsion applied topically as a single drop per eye twice daily.

[0300] 179. The composition according to claim 178, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0301] 180. The composition according to claim 178, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0302] 181. The composition according to claim 178, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0303] 182. The composition according to claim 178, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0304] 183. The composition according to claim 178, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0305] 184. The composition according to claim 178, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0306] 185. The composition according to claim 178, wherein the concentration of said cyclosporine is about 0.05% (w / v) cyclosporine, wherein said composition is substantially free of water and substantially free of preservatives, wherein the single dose per eye is about 5 μg of cyclosporine, the single drop volume is about 10 μl, and wherein the total daily amount of cyclosporine is about 65% less than that of a 0.05% (w / v) cyclosporine aqueous (o / w) emulsion having a volume of about 28.5 μl when applied topically twice daily as a single drop per eye.

[0307] 186. The composition according to claim 185, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0308] 187. The composition according to claim 185, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0309] 188. The composition according to claim 185, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0310] 189. The composition according to claim 185, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0311] 190. The composition according to claim 185, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0312] 191. The composition according to claim 185, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0313] 192. The composition according to any one of claims 185 to 191, wherein the composition is effective in reducing corneal staining.

[0314] 193. The composition according to claim 192, wherein the reduction in corneal staining is achieved within a 4-month treatment period.

[0315] 194. The composition according to any one of claims 185 to 191, wherein the composition is effective in reducing central corneal staining and / or in reducing any one or a combination of lower, upper, nasal, or temporal corneal staining.

[0316] 195. The composition according to any one of claims 185 to 191, wherein the composition effectively achieves early onset of action.

[0317] 196. The composition according to claim 195, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0318] 197. The composition according to any one of claims 185 to 191, wherein the composition is effective in reducing visual impairment associated with dry eye disease.

[0319] 198. The composition according to any one of claims 185 to 191, wherein the composition is effective in reducing ocular surface damage associated with dry eye.

[0320] 199. The composition according to any one of claims 183 to 189 or 185 to 191, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0321] 200. The composition according to claim 178, wherein the concentration of said cyclosporine is about 0.10% (w / v) cyclosporine, wherein said composition is substantially free of water and substantially free of preservatives, wherein the single dose per eye is about 10 μg of cyclosporine, the single drop volume is about 10 μl, and wherein the total daily amount of cyclosporine is about 30% less than that of a 0.05% (w / v) cyclosporine aqueous (o / w) emulsion having a volume of about 28.5 μl when applied topically twice daily as a single drop per eye.

[0322] 201. The composition according to claim 200, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0323] 202. The composition according to claim 200, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0324] 203. The composition according to claim 200, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0325] 204. The composition according to claim 200, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0326] 205. The composition according to claim 200, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0327] 206. The composition according to claim 200, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0328] 207. The composition according to any one of claims 200 to 206, wherein the composition is effective in reducing corneal staining.

[0329] 208. The composition according to claim 207, wherein the reduction in corneal staining is achieved within a 4-month treatment period.

[0330] 209. The composition according to any one of claims 200 to 206, wherein the composition is effective in reducing central corneal staining and / or in reducing any one or a combination of lower, upper, nasal, or temporal corneal staining.

[0331] 210. The composition according to any one of claims 200 to 206, wherein the composition effectively achieves early onset of action.

[0332] 211. The composition according to claim 210, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0333] 212. The composition according to any one of claims 200 to 206, wherein the composition is effective in reducing visual impairment associated with dry eye disease.

[0334] 213. The composition according to any one of claims 200 to 206, wherein the composition is effective in reducing ocular surface damage associated with dry eye.

[0335] 214. The composition according to any one of claims 200 to 206, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0336] Furthermore, the present invention includes items 215 to 251, which relate to compositions for reducing reading difficulties associated with dry eye disease:

[0337] 215. A composition for reducing reading impairment associated with dry eye disease, comprising about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is effective in reducing reading impairment in persons with dry eye disease when administered topically twice daily at a single dose of about 4 to 12 μg of cyclosporine per eye.

[0338] 216. The composition according to claim 215, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0339] 217. The composition according to claim 215, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0340] 218. The composition according to claim 215, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0341] 219. The composition according to claim 215, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0342] 220. The composition according to claim 215, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0343] 221. The composition according to claim 215, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0344] 222. The composition according to claim 215, wherein the concentration of cyclosporine is about 0.05% (w / v) of cyclosporine, and the single dose per eye is about 5 μg of cyclosporine, and wherein the composition is substantially free of water and substantially free of preservatives.

[0345] 223. The composition according to claim 222, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0346] 224. The composition according to claim 222, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0347] 225. The composition according to claim 222, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0348] 226. The composition according to claim 222, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0349] 227. The composition according to claim 222, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0350] 228. The composition according to claim 222, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0351] 229. The composition according to any one of claims 222 to 228, wherein the composition is effective in reducing corneal staining.

[0352] 230. The composition according to claim 229, wherein the reduction in corneal staining is achieved within a 4-month treatment period.

[0353] 231. The composition according to any one of claims 222 to 228, wherein the composition is effective in reducing central corneal staining and / or in reducing any one or a combination of lower, upper, nasal, or temporal corneal staining.

[0354] 232. The composition according to any one of claims 222 to 228, wherein the composition effectively achieves early onset of action.

[0355] 233. The composition according to claim 232, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0356] 234. The composition according to any one of claims 222 to 228, wherein the composition is effective in reducing visual impairment associated with dry eye disease.

[0357] 235. The composition according to any one of claims 222 to 228, wherein the composition is effective in reducing ocular surface damage associated with dry eye.

[0358] 236. The composition according to any one of claims 222 to 228, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0359] 237. The composition according to claim 215, wherein the concentration of cyclosporine is about 0.10% (w / v) of cyclosporine, and the single dose per eye is about 10 μg of cyclosporine, and wherein the composition is substantially free of water and substantially free of preservatives.

[0360] 238. The composition according to claim 237, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0361] 239. The composition according to claim 237, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0362] 240. The composition according to claim 237, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0363] 241. The composition according to claim 237, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0364] 242. The composition according to claim 237, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0365] 243. The composition according to claim 237, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0366] 244. The composition according to any one of claims 237 to 243, wherein the composition is effective in reducing corneal staining.

[0367] 245. The composition according to claim 244, wherein the reduction in corneal staining is achieved within a 4-month treatment period.

[0368] 246. The composition according to any one of claims 237 to 243, wherein the composition is effective in reducing central corneal staining and / or in reducing any one or a combination of lower, upper, nasal, or temporal corneal staining.

[0369] 247. The composition according to any one of claims 237 to 243, wherein the composition effectively achieves early onset of action.

[0370] 248. The composition according to claim 247, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0371] 249. The composition according to any one of claims 237 to 243, wherein the composition is effective in reducing visual impairment associated with dry eye disease.

[0372] 250. The composition according to any one of claims 237 to 243, wherein the composition is effective in reducing ocular surface damage associated with dry eye.

[0373] 251. The composition according to any one of claims 237 to 243, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0374] Furthermore, the present invention includes items 252 to 288, which relate to compositions for reducing ocular surface damage associated with dry eye disease:

[0375] 252. A composition for reducing ocular surface damage associated with dry eye disease, comprising about 0.05 to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, wherein the composition is effective in reducing ocular surface damage in persons with dry eye disease when administered topically twice daily at a single dose of about 4 to 12 μg of cyclosporine per eye.

[0376] 253. The composition according to claim 252, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0377] 254. The composition according to claim 252, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0378] 255. The composition according to claim 252, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0379] 256. The composition according to claim 252, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0380] 257. The composition according to claim 252, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0381] 258. The composition according to claim 252, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0382] 259. The composition according to claim 252, wherein the concentration of cyclosporine is about 0.05% (w / v) of cyclosporine, and the single dose per eye is about 5 μg of cyclosporine, and wherein the composition is substantially free of water and substantially free of preservatives.

[0383] 260. The composition according to claim 259, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0384] 261. The composition according to claim 259, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0385] 262. The composition according to claim 259, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0386] 263. The composition according to claim 259, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0387] 264. The composition according to claim 259, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0388] 265. The composition according to claim 259, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0389] 266. The composition according to any one of claims 259 to 265, wherein the composition is effective in reducing corneal staining.

[0390] 267. The composition according to claim 266, wherein the reduction in corneal staining is achieved within a 4-month treatment period.

[0391] 268. The composition according to any one of claims 259 to 265, wherein the composition is effective in reducing central corneal staining and / or in reducing any one or a combination of lower, upper, nasal, or temporal corneal staining.

[0392] 269. The composition according to any one of claims 259 to 265, wherein the composition effectively achieves early onset of action.

[0393] 270. The composition according to claim 269, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0394] 271. The composition according to any one of claims 259 to 265, wherein the composition is effective in reducing visual impairment associated with dry eye disease.

[0395] 272. The composition according to any one of claims 259 to 265, wherein the composition is effective in reducing ocular surface damage associated with dry eye.

[0396] 273. The composition according to any one of claims 259 to 265, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0397] 274. The composition according to claim 252, wherein the concentration of cyclosporine is about 0.10% (w / v) of cyclosporine, and the single dose per eye is about 10 μg of cyclosporine, and wherein the composition is substantially free of water and substantially free of preservatives.

[0398] 275. The composition according to claim 274, wherein the composition further comprises up to about 1% (w / w) of ethanol.

[0399] 276. The composition according to claim 274, wherein the composition comprises cyclosporine dissolved in a solution of about 99% (w / w) of 1-perfluorobutylpentane and about 1% (w / w) of ethanol.

[0400] 277. The composition according to claim 274, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99% (w / w) of 1-perfluorobutylpentane and at most about 1% (w / w) of ethanol.

[0401] 278. The composition according to claim 274, wherein the composition further comprises up to about 0.5% (w / w) of ethanol.

[0402] 279. The composition according to claim 274, wherein the composition comprises cyclosporine dissolved in a solution of about 99.5% (w / w) of 1-perfluorobutylpentane and about 0.5% (w / w) of ethanol.

[0403] 280. The composition according to claim 274, wherein the composition comprises cyclosporine dissolved in a solution of at least about 99.5% (w / w) of 1-perfluorobutylpentane and at most about 0.5% (w / w) of ethanol.

[0404] 281. The composition according to any one of claims 274 to 280, wherein the composition is effective in reducing corneal staining.

[0405] 282. The composition according to claim 281, wherein the reduction in corneal staining is achieved within a 4-month treatment period.

[0406] 283. The composition according to any one of claims 274 to 280, wherein the composition is effective in reducing central corneal staining and / or in reducing any one or a combination of lower, upper, nasal, or temporal corneal staining.

[0407] 284. The composition according to any one of claims 274 to 280, wherein the composition effectively achieves early onset of action.

[0408] 285. The composition according to claim 284, wherein the early onset of action is measured by a reduction in corneal and conjunctival staining and is achieved within approximately 2 to 4 weeks.

[0409] 286. The composition according to any one of claims 274 to 280, wherein the composition is effective in reducing visual impairment associated with dry eye disease.

[0410] 287. The composition according to any one of claims 274 to 280, wherein the composition is effective in reducing ocular surface damage associated with dry eye.

[0411] 288. The composition according to any one of claims 274 to 280, wherein the composition is safe, well tolerated and comfortable for the human eye.

[0412] The present invention also includes items 289 to 303, which relate to:

[0413] 289. A pharmaceutical composition for use in the topical treatment of dry eye disease, wherein the composition comprises about 0.05% to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, and wherein the amount of cyclosporine administered as a single dose per eye is about 4 μg to 12 μg.

[0414] 290. A pharmaceutical composition for use in treating ocular surface damage in a subject suffering from dry eye disease, wherein the composition comprises about 0.05% to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, and wherein the amount of cyclosporine administered as a single dose per eye is about 4 μg to 12 μg.

[0415] 291. A pharmaceutical composition for use in treating reading disorders in subjects suffering from dry eye disease, wherein the composition comprises about 0.05% to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane.

[0416] 292. The pharmaceutical composition for use according to claim 291, wherein the amount of cyclosporine administered as a single dose per eye is from about 4 μg to 12 μg.

[0417] 293. The pharmaceutical composition for use according to any one of claims 289 to 292, wherein the total daily dose administered to each eye is less than about 28 μg.

[0418] 294. The pharmaceutical composition for use according to any one of claims 289 to 293, wherein the amount of cyclosporine administered in a single dose per eye is about 5 μg or about 10 μg.

[0419] 295. The pharmaceutical composition for use according to any one of claims 289 to 294, wherein the dose of said composition is administered as a single drop to the eye of a subject.

[0420] 296. The pharmaceutical composition for use according to any one of claims 289 to 295, wherein the dry eye disease is moderate to severe, and optionally wherein the subject is unresponsive to treatment with artificial tears.

[0421] 297. A pharmaceutical composition for use according to any one of claims 289 to 296, wherein the composition comprises up to about 1.0% (w / w) of ethanol.

[0422] 298. A pharmaceutical composition for use according to any one of claims 289 to 297, wherein the composition comprises essentially about 0.05% or 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane and optionally about 1.0% (w / w) of ethanol.

[0423] 299. The pharmaceutical composition for use according to any one of claims 289 to 298, wherein the composition is administered twice daily.

[0424] 300. A kit comprising a pharmaceutical composition for use according to any one of claims 289 to 299, wherein the kit comprises a container for containing the pharmaceutical composition and a drop dispenser adapted to administer a volume of the composition of about 8 μl to 12 μl per drop.

[0425] 301. The kit according to claim 300, wherein the container and / or dropper is made of a thermoplastic material, preferably selected from polyethylene or polypropylene.

[0426] 302. The kit according to claim 301, wherein the container is made of polypropylene, and wherein the dropper is made of polyethylene selected from low-density polyethylene or high-density polyethylene.

[0427] 303. The kit according to any one of claims 300 to 302, wherein the ratio of the volume of the pharmaceutical composition in the container to the total volume of the container is between 0.4 and 0.7, or wherein the ratio of the volume of the top space of the container to the volume of the pharmaceutical composition is between 0.5 and 1.5. Attached Figure Description

[0428] Figure 1 The study plan was outlined, including screening and a two-week adjustment period (providing subjects with lubricating eye drops), followed by a four-month treatment period.

[0429] Figure 2 The following corneal fluorescein staining (National Eye Institute (NEI) scale) results are shown for patients with moderate to severe dry eye treated with the following medications: a) 0.05% (w / v) cyclosporine solution (CyclASol 0.05%) in 1-perfluorobutylpentane and 1.0% (w / v) ethanol; b) 0.1% (w / v) cyclosporine solution (CyclASol 0.1%) in 1-perfluorobutylpentane and 1.0% (w / v) ethanol; c) Restasis ®(Containing 0.05% (w / v) cyclosporine) and d) a separate carrier (1-perfluorobutylpentane and 1.0% (w / w) ethanol). Changes in the total corneal fluorescein staining score (NEI scale) over time were described for visits V2 (2-week follow-up), V3 (4-week follow-up), V4 (12-week follow-up), and V5 (16-week follow-up), compared to the baseline score obtained before treatment initiation (V1, day 1). Here, changes in the corneal fluorescein staining score (NEI scale) compared to the open-labeled restasis were observed. ® In comparison, both CyclASol 0.05% and CyclASol 0.1% offer earlier onset of action and higher efficacy. This is surprising, as it is similar to Restasis. ® Compared to 28.5 μl, administering a smaller volume (10 μl) to patients means a 30% to 65% reduction in daily exposure to cyclosporine A, while producing even greater efficacy.

[0430] Figure 3 This study presents results based on conjunctival lissamine green staining (Oxford scale) after treatment with CyclASol 0.05%, CyclASol 0.1%, Restasis®, and a carrier. Changes in the total conjunctival lissamine green staining score (Oxford scale) were described compared to baseline (V1, day 1) for visits V2 (2-week follow-up), V3 (4-week follow-up), V4 (12-week follow-up), and V5 (16-week follow-up). Changes were observed in the total conjunctival lissamine green staining score (Oxford scale) compared to the open-label comparison with Restasis®. ® In comparison, both CyclASol 0.05% and CyclASol 0.1% showed earlier onset of action and higher efficacy. This is surprising, as it is similar to Restasis. ® Compared to 28.5 μl, administering a smaller volume (10 μl) to patients means that daily exposure to cyclosporine A is reduced by 30%–65%, while producing even greater efficacy.

[0431] Figure 4 This study shows the efficacy of treatment with CyclASol 0.05% and CyclASol 0.1% in patients with moderate to severe dry eye disease, based on data obtained from the reading assessment section of the OSDI (Ocular Surface Disease Index) questionnaire. The questionnaire ranges from 0 to 4 (0 indicating no reading problems, and 4 indicating the most severe reading problems). Figure 4In this study, relative reading impairment (expressed as a percentage) observed in patients treated with CyclASol 0.05% and CyclASol 0.1% at baseline (V1, day 1) was compared with that observed at visits V2 (2-week follow-up), V3 (4-week follow-up), V4 (12-week follow-up), and V5 (16-week follow-up). Negative relative values ​​indicate improvement in reading impairment. The comparisons showed that patients treated with CyclASol 0.05% and CyclASol 0.1% experienced improved reading ability compared to those treated with the carrier at visit V5 (16-week follow-up), resulting in reductions in reading impairment of 28% and 31%, respectively.

[0432] Figure 5 The following images show central corneal fluorescein staining (National Eye Institute (NEI) scale) in patients with moderate to severe dry eye treated with the following medications: a) 0.05% (w / v) cyclosporine solution (CyclASol 0.05%) in 1-perfluorobutylpentane and 1.0% (w / v) ethanol; b) 0.1% (w / v) cyclosporine solution (CyclASol 0.1%) in 1-perfluorobutylpentane and 1.0% (w / v) ethanol; c) Restasis ® (Containing 0.05% (w / v) cyclosporine) and d) a separate carrier (1-perfluorobutylpentane and 1.0% (w / w) ethanol). Changes in central corneal fluorescein staining score (NEI scale) over time were described for visits V2 (2-week follow-up), V3 (4-week follow-up), V4 (12-week follow-up), and V5 (16-week follow-up), compared to the baseline score obtained before treatment initiation (V1, day 1). Here, changes in the central corneal fluorescein staining score (NEI scale) compared to the open marker Restasis were observed. ® In comparison, both CyclASol 0.05% and CyclASol 0.1% offer earlier onset of action and higher efficacy. This is surprising, as it is similar to Restasis. ® Compared to 28.5 μl, administering a smaller volume (10 μl) to patients means a 30% to 65% reduction in daily exposure to cyclosporine A, while producing even greater efficacy.

[0433] The following examples are used to illustrate the present invention, but should not be construed as limiting the scope of the invention.

[0434] Example

[0435] Example 1

[0436] Research settingsA phase 2, multicenter, randomized, double-blind, placebo-controlled clinical study using an open-labeled comparator group will be conducted to evaluate the efficacy, safety, and tolerability of topical CyclASol for the treatment of dry eye disease. The dose-finding trial in patients with moderate to severe dry eye who are unresponsive to artificial tears will be set up as a four-group randomized, parallel, double-blind, carrier-controlled study using two doses of CyclASol (0.05% and 0.1%) and an open-labeled comparator group.

[0437] CyclASol is a clear ophthalmic solution of cyclosporine A dissolved in 1-perfluorobutylpentane. 1-Perfluorobutylpentane, usually abbreviated as F4H5, is used as the carrier. The only other component in the formulation is ethanol (1.0% (w / w)) as a co-solvent.

[0438] In addition to the blinded vector control group, the study also included an open-label treatment group consisting of Restasis®, enabling a head-to-head comparison of the efficacy of CyclASol and Restasis®. ® It is an approved dry eye medication containing 0.05% cyclosporine A, formulated as an aqueous emulsion.

[0439] Research Plan

[0440] CyclASol 0.05% = 0.05% (w / v) cyclosporine A, soluble in 1-perfluorobutylpentane (F4H5) and 1% (w / w) ethanol.

[0441] CyclASol 0.1% = 0.1% (w / v) cyclosporine A, soluble in 1-perfluorobutylpentane (F4H5) and 1% (w / w) ethanol.

[0442] Support = solution of 1-perfluorobutylpentane (F4H5) and 1% (w / w) ethanol

[0443] research group

[0444] A total of 207 patients (153 women and 54 men) were included. Participants reported a history of bilateral dry eye disease and met all other study eligibility criteria, with similar age and sex distributions across groups. Participants were randomized to receive 0.05% CyclASol, 0.1% CyclASol, a carrier, or Restasis® in a 1:1:1:1 ratio. The study consisted of two phases: a 14-day adjustment period and a 112-day treatment period.

[0445] Patients included in the study must meet the following criteria:

[0446] (a) Be 18 years of age or older;

[0447] (b) Provide written informed consent;

[0448] (c) Subjects reported a history of bilateral dry eye disease at least 6 months prior to the 0th visit;

[0449] (d) At the time of visit 0, the patient was currently using (within 30 days prior to visit 0) over-the-counter and / or prescription eye drops for dry eye symptoms;

[0450] (e) At the 0th and 1st visits, the score is ≥40 according to the dry visual simulation score;

[0451] (f) At the 0th and 1st visits, a total corneal fluorescein staining score of ≥6 according to the NEI classification (e.g., the sum of the lower, upper, central, nasal and temporal regions);

[0452] (g) At the 0th and 1st visits, a total Lissamine Green conjunctival score (sum of temporal and nasal) of ≥2 according to the Oxford classification;

[0453] (h) Schirmer's TestI score between ≥2mm and ≤8mm at the 0th and 1st visits;

[0454] (i) At least one eye (the same eye) satisfies all of the criteria (f), (g) and (h) above;

[0455] (j) Able and willing to follow instructions, including participating in all research assessments and visits.

[0456] During the 112-day treatment period, the patient will be examined according to the following schedule:

[0457] Instructions for use

[0458] Instruct study participants to administer one dose (one single drop) twice daily (in the morning and before bedtime) into each eye.

[0459] Compared with the administration of a single dose of Restasis ®Compared to a 0.05% aqueous (o / w) emulsion (28.5 μL, see Restasis NDA21-023, Clinical Pharmacology Biopharmaceutics Review(s)), the application volume of CyclASol 0.05% and CyclASol 0.1% solutions and carriers per single dose (10 μL) was significantly reduced, as was the amount of active ingredient.

[0460]

[0461] Research Analysis

[0462] At each visit during the 112-day treatment period, treatment efficacy for each subject was assessed using tests including corneal fluorescein staining (NEI grading); conjunctival staining (Lissamine, Oxford grading); and subject symptom assessment questionnaires such as the Ocular Surface Disease Index (OSDI, see Schiffman RM et al. 2000; 118:615-621.) questionnaire (including questions related to reading difficulties 6) and the Visual Analogue Scale (VAS) for dryness severity.

[0463] For corneal staining (Sook Chun Y et al., Am J Ophthalmol. 2014 May; 157(5):1097-102), 5 μl of 2% preservative-free sodium fluorescein solution was instilled into the conjunctival sac of each eye. To obtain maximum fluorescence, fluorescein staining was assessed only about 3–5 minutes after instillation. A Wratten #12 yellow filter was used to enhance the ability to grade fluorescein staining.

[0464] Staining was graded using the NEI grading system (National Eye Institute grading system), with grading performed only on the cornea. A corneal fluorescein staining score was obtained for each of the inferior, superior central, temporal, and nasal regions of the cornea based on a 0-3 scale, where a score of 0 indicates no staining was observed. The term "total corneal fluorescein staining score" (see [link to relevant documentation]) is used. Figure 2 The score is the sum of scores from the lower, upper, central, temporal, and nasal regions of the cornea.

[0465] Conjunctival lisamine green staining (Bron AJ et al., Cornea. 2003; 22:640-650) was performed by instilling 10 μl of lisamine green solution into the inferior conjunctival fornix of the subject. After approximately 30 seconds, the staining was assessed. The subject was instructed to blink several times to disperse the lisamine green. The staining was graded using the Oxford Grading Scale. Here, lisamine staining is represented by dots on a series of plates (AEs). The staining range for each plate is 0-5, while for the total exposed intrapalpebral conjunctiva, the staining range is 0-10. The nasal and temporal regions were graded separately. A score of 0 indicates no staining. A total conjunctival lisamine green staining score was obtained, which is the sum of the scores for the temporal and nasal regions of the conjunctiva.

Claims

1. A pharmaceutical composition for use in the topical treatment of a subject suffering from dry eye disease, wherein the composition comprises about 0.05% to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, and wherein the amount of cyclosporine administered as a single dose per eye is about 4 μg to 12 μg.

2. A pharmaceutical composition for use in treating ocular surface damage in a subject suffering from dry eye disease, wherein the composition comprises about 0.05% to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, and wherein the amount of cyclosporine administered as a single dose per eye is about 4 μg to 12 μg.

3. A pharmaceutical composition for use in treating reading impairment in a subject suffering from dry eye disease, wherein the composition comprises about 0.05% to 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane, and wherein the amount of cyclosporine administered as a single dose per eye is about 4 μg to 12 μg.

4. The pharmaceutical composition for use according to any one of the preceding claims, wherein the subject is a human subject.

5. The pharmaceutical composition for use according to any one of the preceding claims, wherein the total daily dose administered to each eye is less than about 28 μg.

6. The pharmaceutical composition for use according to any one of the preceding claims, wherein the dose of the composition is administered as a single drop to the eye of a subject.

7. The pharmaceutical composition for use according to any one of the preceding claims, wherein the dry eye disease is moderate to severe, and optionally wherein the subject is unresponsive to treatment with artificial tears.

8. A pharmaceutical composition for use according to any one of the preceding claims, wherein the composition comprises up to about 1.0% (w / w) of ethanol.

9. A pharmaceutical composition for use according to any one of the preceding claims, wherein the composition comprises substantially about 0.05% or 0.1% (w / v) of cyclosporine dissolved in 1-perfluorobutylpentane and optionally about 1.0% (w / w) of ethanol.

10. The pharmaceutical composition for use according to any one of the preceding claims, wherein the composition is administered twice daily.

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