Treatment of Dry Eye Using Antioxidants Targeting Mitochondria

Abstract

Formulations and methods are provided that use a mitochondria-targeted antioxidant (SkQ) to improve dry eye symptoms in subjects with a tear production volume of 7 mm or more as measured by the Schirmer test. These methods provide benefits to subjects in a particular population but do not provide benefits to subjects with a tear production volume of less than 7 mm as measured by the Schirmer test.

Description

Technical Field

[0001] The present invention relates to formulations and methods using an antioxidant (SkQ) targeting mitochondria.

Background Art

[0002] For the diagnosis of dry eye disease by a healthcare provider, no specific signs measured by the healthcare provider are required. Subjects with dry eye disease may report various symptoms to the healthcare provider, such as a decrease in tear production, a decrease in visual acuity or visual field defects, eye pain, a sandy sensation, photosensitivity, eye redness, itching, etc. The various symptoms may worsen in dry environments, dusty environments, or smoky environments, as well as in situations such as air conditioning, reading, or using a computer. The symptoms may worsen over time, although some subjects experience the worst symptoms immediately after waking up in the morning. The diagnosis can be made based solely on the subject's symptoms.

[0003] The healthcare provider may use a questionnaire such as the Ocular Surface Disease Index (OSDI) questionnaire, in which 12 questions are described and each answer is scored on a scale from 0 ("none") to 4 ("always"), to evaluate the subject's symptoms. The healthcare provider may measure the signs of dry eye disease and prescribe medications. Prescription medications include anti-inflammatory drugs that reduce eyelid inflammation and immunosuppressive drugs such as cyclosporine and corticosteroids that suppress corneal inflammation. An eyeball or lacrimal duct implant may also be prescribed. Many subjects rely on over-the-counter medications such as artificial tears and eye drops to suppress eye redness, but since artificial tears do not target the cause of dry eye disease, they may cause further irritation to the eyes. There is a need for improved methods to treat and prevent the signs and symptoms of dry eye disease and to improve the short-term and long-term outcomes of subjects.

Summary of the Invention

Problems to be Solved by the Invention

[0004] The present technology provides a population-specific formulation and method for using a mitochondria-targeted antioxidant (SkQ) to assist in the treatment or prevention of the signs and symptoms of dry eye disease (DED).

Means for Solving the Problems

[0005] The methods disclosed herein are based on unexpected findings in two consecutive clinical studies, VISTA-1 (NCT03764735) and VISTA-2 (NCT04206020), for a population of subjects with a tear production of 7 mm or more as measured by the Schirmer test prior to clinical trials. The active pharmaceutical substance in these trials is an SkQ-type antioxidant that targets mitochondria. The formulations used in this method contain SkQ at a concentration of 0.5 μg / mL or higher.

[0006] The present technology can be further summarized by the following list of features. 1. A method of assisting in the treatment of a dry eye condition, the method comprising administering to a subject in need thereof a formulation comprising a compound of formula I:

Chemical formula

Chemical formula

[0007] 2. The method according to feature 1, wherein SkQ comprises the compound SkQ1 in its reduced or oxidized form as shown below:

Chemical formula

Chemical formula

[0008] 3. The method according to any of the preceding features, wherein the preparation is an eye drop or an eye drop gel preparation and is applied topically to the eye and / or one or more appendages of the eye. 4. The method according to any of the preceding features, wherein one or more of the signs of dry eye disease is a corneal staining grade greater than 0 in the whole or a part of the cornea. 5. The method according to any of the preceding features, wherein one or more symptoms of dry eye disease include a visual field defect index ≥ 1 or a visual acuity reduction index ≥ 1, and / or a reduction in the visual acuity of the eye. 6. The method according to any of the preceding features, wherein the preparation is applied topically to the eye, the preparation spreads on the surface of the eye, and the preparation contacts one or more appendages of the eye by blinking, eye movement, or a combination thereof. 7. The method according to any of the preceding features, wherein one or more of the signs of dry eye disease is a corneal staining grade greater than 0 in the whole or a part of the cornea, and one or more of the symptoms of dry eye disease is a reduction in the visual acuity of the eye.

[0009] 8. Further comprising the following: administering fluorescein staining to the eye after a certain period of time, and measuring the grade of fluorescein staining in the central part of the cornea; and repeating administering a compound of formula I, performing fluorescein staining, and measuring the grade of central fluorescein staining, whereby a decrease or complete disappearance of the grade of central corneal fluorescein staining of the eye is achieved, A method according to any of the preceding features, comprising. 9. The method of feature 8, wherein the grade of fluorescein staining in the central part of the cornea is initially >0 and finally =0. 10. The method according to any of the preceding features, wherein the subject has been reported to have a visual field defect index of 1 or more or a visual acuity decrease index of 1 or more and / or a decrease in the visual acuity of the eye before administration of the compound of formula I, and the method results in an improvement in the visual acuity of the eye.

[0010] 11. The method of feature 10, wherein the improvement in visual acuity is an improvement in the best corrected visual acuity (BCVA) of the eye, and the improvement in BCVA is an improvement of about >0.3 in BCVA. 12. The method of feature 11, wherein BCVA is measured as the logarithm of the minimum angle of a resolution chart measurement. 13. The method according to any of features 11-12, wherein the improvement in BCVA further includes an improvement in the index of visual field defect and / or the index of visual acuity decrease. 14. The method according to any of features 10-13, wherein the reported visual field defect index is an evaluation on a scale of 0-4 based on the subject's visual field defect experience in the week before administration, where 0 = none, 1 = sometimes, 2 = half the time, 3 = most of the time, 4 = always. 15. The method according to any of features 10-13, wherein the reported visual acuity decrease index is an evaluation on a scale of 0-4 by the subject of the subject's visual acuity decrease experience in the week before administration, where 0 = none, 1 = sometimes, 2 = half the time, 3 = most of the time, 4 = always.

[0011] 16. Any method of the preceding features, wherein one or more signs and / or one or more symptoms of dry eye disease include that the amount of tear production in the eye by the Schirmer test is 7 mm or more, the grade of fluorescein staining at the center of the cornea exceeds 0, the total fluorescein corneal staining score is 2 or more, the total lissamine green conjunctival staining score is 2 or more, corneal hypersensitivity, conjunctival congestion, eyelid margin congestion, corneal damage, the subject's eye irritation, eye itching or discomfort, visual acuity decline, and one or more of the visual field defect, visual acuity decline, eye pain, photophobia, or eye pain reported by the subject. 17. Any method of the preceding features, wherein the administration is carried out over a period of about 14 days to about 90 days. 18. Any method of the preceding features, wherein one or more signs and / or one or more symptoms of dry eye disease are associated with a condition including one or more of the following: eye fatigue caused by reading, night driving, observing a display screen, or wearing contact lenses, exposure to environmental eye irritants, hormone replacement therapy, exposure to wind or dry air, allergies, ophthalmic surgery, side effects of drugs, thyroid diseases, diseases due to aging, infectious diseases, exposure keratitis, vitamin deficiency, Sjogren's syndrome, and conditions accompanied by dry keratoconjunctivitis, dry keratitis, or immune system disorders. 19. The method of feature 18, wherein the infection is any of a bacterial infection, a fungal infection, or a viral infection.

[0012] 20. Any method of the preceding features, wherein SkQ is selected from the group consisting of the following compounds, including one or more compounds in an oxidized or reduced form, or a mixture thereof:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0013] 21. A pharmaceutically acceptable anion Z - is acetate, bromide, camphorate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, dihydrogen phosphate dodecahydrate, dihydrogen phosphate dihydrate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprinate, caproate, caprylate, dodecyl sulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, or a combination thereof, in any of the preceding methods. 22. The SkQ optionally contains one or more water molecules bound to A, L, Sk + , and / or Z - via hydrogen bonds and / or ionic bonds, in any of the preceding methods. 23. The administration to the subject is at least one drop or at least about 0.05 mL of the formulation administered to the eye and / or one or more appendages of the eye at least once every 24 hours, in any of the preceding methods.

[0014] 24. A method according to any of the preceding features, wherein the formulation comprises one or more of benzalkonium chloride, hypromellose, sodium chloride, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dodecahydrate, and water. 25. A method according to any of the preceding features, wherein the Schirmer test score is a Schirmer test score without anesthesia. 26. A method according to any of the preceding features, wherein one or more symptoms of dry eye disease include one or more symptoms reportable by the subject. 27. A method according to any of the preceding features, wherein one or more signs and / or one or more symptoms of dry eye disease result from a progressive dry eye disease over a period longer than about 2 months.

[0015] 28. The method of feature 27, wherein the central corneal damage is indicated by a central corneal fluorescein staining of grade 1 or more. 29. A method according to any of the preceding features, wherein the formulation comprises SkQ at a concentration of 1 μg / mL or more. 30. A kit for treating one or more signs and / or one or more symptoms of dry eye disease, comprising: A dispensing container containing an eye drop or eye gel formulation containing SkQ at a concentration of 0.5 μg / mL or more; and instructions for use. 31. The kit of feature 28, wherein the eye drop or eye gel formulation contains SkQ at a concentration of 1 μg / mL or more.

[0016] As used herein, the term "dry eye disease" can be used interchangeably with the term "dry eye syndrome". As used herein, the term "about" refers to a range within plus or minus 10%, 5%, 1%, or 0.5% of the stated value. As used herein, "consisting essentially of" allows for the inclusion of materials or steps that do not substantially affect the basic and novel characteristics of the claims. Any recitation herein of the term "comprising" may, especially in the description of the components of a composition or the elements of an apparatus, be exchanged with the alternative recitations "consisting of" or "consisting essentially of".

[0017] Detailed Description The present technology provides a population-specific formulation and method for treating and preventing the signs or symptoms of DED using a formulation containing SkQ at 0.5 μg / mL or more. In two consecutive clinical studies, VISTA-1 and VISTA-2, an unexpected benefit is shown in a specific population of subjects with a pre-treatment (baseline) tear production of 7 mm or more as measured by the Schirmer test. The formulation is administered to this population for a defined period. After the defined period has elapsed, the formulation provides a benefit. Examples of such benefits include, unexpectedly depending on the tear production measured at the baseline of the subject, improvement in vision and healing of the central and overall cornea.

[0018] For example, subjects with a Schirmer score of 7 mm or more at baseline show a statistically significant improvement in the grade of central corneal staining and a significant improvement in vision, compared to the vehicle. Surprisingly, subjects with a Schirmer score of less than 7 mm at baseline do not show such improvement compared to the vehicle. Clinical data using a formulation containing SkQ at 1 μg / mL or more have demonstrated that the presence of a tear volume at a level of Schirmer score of 7 mm or more is important for the effectiveness of the formulation against the signs and symptoms of DED.

[0019] The Schirmer test can be used to measure whether sufficient tears are secreted to keep the eyes moist. The Schirmer test can be performed by a healthcare provider applying an approved sterile test strip without anesthesia to the lower eyelid of each eye of the subject for 5 minutes. Approved Schirmer test strips can also be purchased over the counter (without a prescription), and the test strips may have millimeter graduations or may come with instructions for the subject to perform a self-diagnosis of the Schirmer test.

[0020] Without anesthesia, the Schirmer test can also evaluate the ability of the eye surface to respond to surface irritation. Before performing the Schirmer test, a healthcare provider can use topical ophthalmic anesthesia. Using anesthesia allows for the evaluation of basal tear secretion without considering the ability of the eye surface to respond to surface irritation without anesthesia. The Schirmer test described here can be performed with or without anesthesia.

[0021] The Schirmer test strip is inserted into the lower conjunctival sac at the junction of the outer and middle thirds without touching the cornea, and the length of wetting of the test strip (in millimeters) is recorded after 5 minutes. The subject can blink normally during the test. After 5 minutes, the test strip is removed and the degree of wetness of each strip is measured. The results of tear secretion by the Schirmer test are evaluated as follows: wet area > 25 mm = excessive tear secretion, 15 - 24 mm = normal tear secretion, 10 - 14 mm = mild tear secretion dysfunction, 5 - 9 mm = moderate tear secretion dysfunction, and < 5 mm = severe tear secretion dysfunction (Brzhesky, et al., 2015).

[0022] SkQ1-type antioxidants targeting mitochondria have been reported to have a certain level of effect against pathological DED in a wide range of subject populations. Brzhesky, et al., 2015 and Petrov, et al., 2016 showed that SkQ1 treatment may protect the corneas of patients with a wide range of Schirmer test scores and improve certain signs and symptoms of DED. The pathogenesis of DED and the progression of signs and symptoms may vary depending on the patient cohort. Brzhesky and Petrov did not propose specific treatments for DED according to the subjects of population-specific groups or the type and stage of the disease of the subjects.

[0023] According to Brzhesky and Petrov, pathological DED-related damage in the central part of the cornea of DED patients may be reduced by SkQ1 treatment. Surprisingly, this observation has not been confirmed in the comprehensive analysis population of the following VISTA-1 clinical trial (Example 1). Since the central part of the cornea plays a role in supporting vision, the healing of damage in the central part of the cornea is an important issue for the treatment of DED. The cornea functions as the outermost lens of the eye. This important role of the cornea in providing vision is recognized by the Food and Drug Administration (FDA).

[0024] Analysis of the data collected in the VISTA-1 and VISTA-2 clinical trials has shown that in certain populations with a baseline tear production of 7 mm or more as measured by the Schirmer test, specific signs and symptoms of DED improve after administration of a formulation containing SkQ. For example, surprisingly, in the population-specific groups, tear production may be at a mild to moderate level. In population-specific groups, subjects with progressive or long-term DED may experience excessive tear secretion with dry eye, which may occur due to excessive reflex tear secretion as a response to corneal surface disease due to DED (Shen, et al., 2016; Messmer, 2015). When using the Schirmer test for measurement, the baseline tear production can be in the range of ≧7 mm, or in the range of ≧7 mm to ≦50 mm, ≧7 mm to ≦40 mm, ≧7 mm to ≦30 mm, ≧7 mm to ≦25 mm, ≧7 mm to ≦20 mm, ≧7 mm to ≦15 mm, ≧7 mm to ≦14 mm, ≧7 mm to ≦13 mm, ≧7 mm to ≦12 mm, ≧7 mm to ≦11 mm, or ≧7 mm to ≦10 mm.

[0025] For population-specific subjects to benefit from the methods disclosed herein, administration of a formulation containing SkQ to the subject's eye must be carried out over a period of administration or an initial period of administration. After the first period of administration, one or more subsequent periods of administration may follow. The period can be in the range of 14 days to about 120 days, about 21 days to about 100 days, about 30 days to 90 days, about 30 days to about 60 days, about 30 days to about 40 days, or about 30 days to about 35 days. In the studies of SkQ1, the no-observed-adverse-effect level (NOAEL) for ocular toxicity has been shown to be 4.5 μg per eye per day (4.5 μg / eye / day). Mild ocular toxicity of SkQ1 is observed at 45 μg / eye / day (Petrov et al., 2016). One drop of the aqueous formulation contains approximately 0.05 mL. One drop of the gel formulation contains approximately 0.05 mL to approximately 0.1 mL. At a high concentration administration dose of 0.1 mL (0.1 mL x 1.55 μg / mL, twice a day = 0.31 μg / eye / day), the amount of SkQ1 instilled into one eye falls within a safety margin of 10 of the systemic exposure observed at the OAEL for ocular toxicity (i.e., <4.5 μg / eye / day). The methods disclosed herein can include administering a formulation comprising SkQ at a concentration in the range from 0.5 μg / mL to less than about 22.5 μg / mL, from 0.5 μg / mL to about 20.0 μg / mL or less, from 0.5 μg / mL to about 15.0 μg / mL or less, from 0.5 μg / mL to about 10.0 μg / mL or less, from 0.5 μg / mL to about 7.5 μg / mL or less, from 0.5 μg / mL to about 5.0 μg / mL or less, from 0.5 μg / mL to about 2.5 μg / mL or less, or from 0.5 μg / mL to about 2.0 μg / mL or less. The methods disclosed herein can include administering a formulation comprising SkQ at a concentration in the range from 1 μg / mL to less than about 22.5 μg / mL, from 1 μg / mL to about 20.0 μg / mL or less, from 1 μg / mL to about 15.0 μg / mL or less, from 1 μg / mL to about 10.0 μg / mL or less, from 1 μg / mL to about 7.5 μg / mL or less, from 1 μg / mL to about 5.0 μg / mL or less, from 1 μg / mL to about 2.5 μg / mL or less, or from 1 μg / mL to about 2.0 μg / mL or less.

[0026] When using a topical formulation comprising SkQ in the range from 1 μg / mL to ≤ about 5.0, administration of the formulation can be carried out once every two days per eye, once a day per eye, twice a day (BID), three times a day per eye, four times a day per eye, or five times a day per eye. For formulations comprising a higher concentration of SkQ, administration of the formulation can be carried out once every two days per eye, once a day per eye, or BID.

[0027] This formulation can be applied topically to the eye and / or one or more appendages of the eye. Examples of appendages include the orbit, extraocular muscles, eyelids, part of the lacrimal apparatus, optic nerve, or combinations thereof.

[0028] This formulation can be administered systemically (or non-topically). This formulation can be administered intradermally or subcutaneously as a liquid / gel formulation at a higher SkQ concentration. For example, in intradermal / subcutaneous administration, a formulation with an osmotic pressure in the range of about 200 mOsm / L to about 600 mOsm / L, in the range of about 250 mOsm / L to about 450 mOsm / L, or in the range of about 275 mOsm / L to about 325 mOsm / L can be used without causing harmful irritation. The formulation can be administered with a carrier formulation, such as a transdermal patch or an ocular carrier, and can include a polymer, adhesive, coating, or insert as needed.

[0029] In other examples, the formulation can be administered systemically by various methods such as single injection, daily injection, intravenous (IV) drip, self-injection, etc. The IV injection formulation is isotonic (e.g., adjusted osmotic pressure / osmolality with appropriate salts), and the pH is monitored as further described below. The formulation can be administered systemically in the form of a nasal spray formulation, or in the form of an oral formulation or a drug capsule (DC). For example, the oral formulation can be manufactured using one or more excipients selected from an emulsion or lactic acid, propylene glycol, and pure water.

[0030] The formulation of SkQ can be a formulation of SkQ containing water as a solvent for SkQ. The formulation can be individually packaged in a sterile disposable dispenser package. The formulation can be provided in a multi-purpose dispensing container that holds a formulation of eye drops or eye gel. The formulation of SkQ containing water can be sterilized, for example, by ionizing radiation, filtration, heat, or microwaves. The formulation of SkQ can include excipients or additional components such as hypromellose, sodium chloride, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dodecahydrate, osmotic pressure regulator, pH buffer, etc.

[0031] The eye drops or eye gel formulations of SkQ can include preservatives such as benzalkonium chloride and polyquaternium-1. The formulations of SkQ can include one or more gelling agents such as methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, alginate or sodium alginate, poloxamer, carbomer polymer, and thiolated chitosan. The one or more gelling agents can be formulated as a fluid (non-viscous) solution that forms a gel (viscous solution) only after contact with the eye, for example, by adding sodium chloride to the gelling agent or by reducing the hydroxypropyl molar substitution of the gelling agent. In this example, the temperature of the eye can be utilized to induce gelling of the formulation.

[0032] The eye drops or eye gel formulations of SkQ can be adjusted to a pH value in the range of about 3.5 to about 6.9, about 4 to about 6.9, about 5 to about 6.9, about 5.5 to about 6.9, or about 6 to about 6.9. The formulation of SkQ can include an osmotic pressure regulator (such as sugar or NaCl). The osmotic pressure can be measured, for example, by the freezing point osmometry method. The normal tear osmotic pressure is about 289 mOsm / L, but this value may change in subjects with signs or symptoms of DED. The formulation can be adjusted to an osmotic pressure in the range of about 50 mOsm / L to about 1000 mOsm / L, about 100 mOsm / L to 700 mOsm / L, about 150 mOsm / L to about 600 mOsm / L, or about 200 mOsm / L to about 500 mOsm / L.

[0033] The methods disclosed herein can result in one or more improvements in the grade of corneal staining across the entire cornea or a portion (zone) of the cornea. Fluorescent or visual staining methods can be used to grade damage in five different regions of the cornea (central, superior, inferior, nasal, temporal) on a scale ranging from 0 - 3 (0 = no damage, 3 = maximum damage) or a scale ranging from 0 - 4 (0 = no damage, 4 = maximum damage). At grade 3 or 4 (most damaged), confluence or severe staining in that zone may occur. The grade of damage across the entire cornea can be calculated as the total damage score, which is the sum of the zone scores. In this example, the maximum possible grade of the total corneal damage score is 15 or 20 respectively. Alternatively, damage in three different regions of the cornea (central, upper, lower) can be graded on a scale ranging from 0 - 3 (0 = no damage, 3 = maximum damage) or a scale ranging from 0 - 4 (0 = no damage, 4 = maximum damage). In this example, the maximum possible grade of the total corneal damage score is 9 or 12 respectively. A total score of 2 or more, 3 or more, 4 or more is considered abnormal.

[0034] Dyes used for staining include, for example, fluorescein, lissamine green dye, or rose bengal dye (Begley et al., 2019). The National Eye Institute / Industry Workshop Scale (NEI scale) can be utilized. The NEI scale is a four - step scale ranging from 0 = no staining to 3 = strong staining. The grade of staining in the central part of the cornea is assigned on a scale of 0 - 3 or 0 - 4, where grade 0 is no staining and grade 4 is strong or confluent staining. The grade of conjunctival staining can be calculated by summing the grades in the temporal and nasal regions of the cornea. During grading of damage across the entire cornea or staining in the central part of the cornea, if acute severe damage (such as punctate epithelial erosions) is observed, grade 3 or 4 can be assigned immediately.

[0035] The method of the present invention can provide, for a selected population, an average reduction in the grade of fluorescein staining at the corneal center that is greater than about 0.1, greater than about 0.2, greater than about 0.3, greater than about 0.4, or optionally in the range of about 0.1 to about 1. Healthcare providers can measure the blink frequency of a subject as a sign of DED. Blinks can be further classified into various types of blinks (such as spontaneous, incomplete, associated with reading, or not associated with reading, etc.). In an example of the total number of all blinks, the average blink rate can be about 2 times higher in dry eyes than in non-dry eyes, that is, about 28 blinks per minute in dry eyes and about 13 blinks per minute in normal eyes, or it can be in the range of about 20 or more blinks per minute in dry eyes and about 10 - 15 blinks per minute in normal eyes. The range of about 15 to 20 blinks per minute can be further investigated.

[0036] Healthcare providers can evaluate the conjunctival congestion of a subject's eyes using a 3 - 5 point scale where the highest score indicates the most severe condition. The redness of the eyelid margin can be evaluated using a 3 or 4 point scale, with the highest score being the most severe. The Schirmer test discussed here, or the signs and / or symptoms discussed here, can be measured regardless of the implementation of controlled measurement conditions. The eye discomfort score is subjectively evaluated by the subject according to the discomfort scale (0 - 4, 0 = no discomfort, 4 = continuous discomfort) for each eye. A similar scale can be used, for example, in the range of 0 - 3, where 0 is no discomfort and 3 is continuous or severe discomfort.

[0037] Tear break-up time (TBUT) is a test used to evaluate the signs of evaporative DED. To measure TBUT, a dye (such as fluorescein) is instilled into the subject's tear film, and the subject is asked not to blink while observing the tear film under a cobalt blue broad beam of light. TBUT is recorded as the number of seconds elapsed from the last blink until the first dry area appears in the tear film. A TBUT of less than about 10 seconds is considered an abnormal sign indicating DED.

[0038] By measuring the vision of a medical provider, signs of DED can be known. The vision can be the best corrected visual acuity (BCVA) of one or both eyes. For example, the BCVA can be measured using a logarithm of the minimum angle of resolution (LogMAR) chart such as the Bailey Lovie chart or the Early Treatment Diabetic Retinopathy Study chart. The number of characters correctly read by the subject can be converted into a LogMAR score.

[0039] To measure the BCVA, a Snellen chart or a Golovin-Sivtsev chart can be used. When using the Golovin-Sivtsev chart, a score of 1.0 = good vision (equivalent to 20 / 20 on the Snellen chart), close to 0.0 = poor vision (e.g., 0.1 = 20 / 200 on the Snellen chart). For example, vision can be measured using a Robin-Sivtsev chart with illumination of 600 - 1000 lux at a distance of 5 meters. In another example, the Snellen score 6 / 6 (20 / 20) indicates that the subject can resolve fine parts with an angular resolution of about 1 minute, which corresponds to LogMAR 0 (for example, the logarithm of 1 to the base 10 is 0). The Snellen score 6 / 12 (20 / 40) indicates that the subject can resolve fine parts with an angular resolution of about 2 minutes, which corresponds to LogMAR 0.3 (for example, the logarithm of 2 to the base 10 is approximately 0.3). Instead of or in addition to charts and tables, an electronic vision test or a computer vision test can be applied. An extended fundus examination or an extended pupil examination (fundus) can be performed by a medical provider. Fundus examination includes examination of the vitreous body, retina, macula, choroid, and optic nerve. Each examination can be recorded as normal, non-clinically significant abnormality (NCS), or clinically significant abnormality (CS). The evaluation scale described above (e.g., 0 - 3 or 0 - 4) can be used.

[0040] The grade of the symptoms of dry eye disease can be calculated by the sum of individual symptoms, situations or conditions, and problems reported by the subject. To receive reports of symptoms from the subject, a questionnaire or an interview by a medical provider can be used. Subjects may report one or more symptoms of dry eye disease. Examples of symptoms include eyes being sensitive to light (photophobia), eyes becoming dry, having a gritty feeling, eyes being painful, eyes being uncomfortable, or eye pain, decreased vision, decreased tear production, eyes becoming red, and itching. Each symptom may be reported individually or evaluated using a numerical index by the subject or during an interview by a healthcare provider. For example, this index may be represented on a scale of 0 to 4, where 0 indicates never, 1 indicates sometimes, 2 indicates half the time, 3 indicates most of the time, and 4 indicates always.

[0041] Subjects may report that their eyes feel uncomfortable depending on the situation or conditions. Examples of conditions include strong wind, low humidity, and effective air conditioning. Each symptom can be reported or evaluated individually using a numerical index that indicates the degree of discomfort by the subject. For example, this index may be represented on a scale of 0 to 4, where 0 indicates never, 1 indicates sometimes, 2 indicates half the time, 3 indicates most of the time, and 4 indicates always. Subjects may report one or more problems related to the symptoms of dry eye disease. Examples of problems include reading, night driving, working on a computer screen, and watching movies. Each problem may be reported individually by the subject or evaluated using a numerical index. For example, this index may be represented on a scale of 0 to 4, where 0 indicates never, 1 indicates sometimes, 2 indicates half the time, 3 indicates most of the time, and 4 indicates always.

[0042] The diagnosis of DED is made based only on the report of one or more symptoms, one or more situations or conditions that cause discomfort, or one or more problems by the subject. The diagnosis of DED can be made based only on the signs of dry eye disease, including one or more signs provided by the diagnosis of a healthcare provider. The diagnosis of DED may include an estimate of the period during which the subject has suffered from DED. For example, damage to the central part of the cornea may indicate that the subject has DED, that its cause has been long-term, and / or that DED is progressing.

[0043] The percentage of dry eye disease symptoms can be calculated by the composite or possible total of those symptoms, situations or conditions, and problems reported by the subject. Severe dry eye disease can be about 50% or more of the total possible. Moderate dry eye disease ranges from about 30% or more to less than 50% of the total possible. Mild dry eye disease is greater than about 10% and less than 30%. Normal eyes can be 10% or less of the possible total. Weights can be assigned to each score. For example, the OSDI is a questionnaire or interview that has been validated to distinguish normal, mild to moderate, and severe dry eye disease using a comprehensive disease severity score (Bakkar et al., 2021). The use of the survey or OSDI has been demonstrated in numerous clinical trials and clinic diagnoses.

[0044] Oxidative stress may be involved in various diseases including eye symptoms such as macular degeneration, uveitis, cataracts, corneal and ocular surface inflammation, DED. Paradoxically, subjects with progressive or long-term DED may complain of excessive tearing in dry eye, which can occur due to excessive reflex tear secretion as a response to corneal surface disease due to DED (Shen et al., 2016; Messmer, 2015). The population-specific method disclosed herein can be applied to a group of subjects with a baseline Schirmer score of 7 mm or more that occurred at least in part due to increased tear outflow due to etiology and progression of long-term or progressive DED. Applying this method to a specific group of subjects with a Schirmer score of 7 mm or more at baseline is thought to be at least in part because SkQ acts to enhance the natural antioxidant components of tears that may have been depleted by DED.

[0045] If the Schirmer test score at baseline is 7 mm or more, it can be combined with the estimated value of DED progression in a population-specific group. This method can be applied to subjects with a Schirmer test score of 7 mm or more at baseline and having one or more corneal staining grades, abnormal blink rate, conjunctival or eyelid margin congestion, abnormal eye discomfort score, TBUT, or visual acuity in the whole cornea or a part of the cornea. In one example, the population-specific method can be applied to patients with progressive DED (e.g., corneal central damage grade ≧ 1) and a Schirmer test score ≧ 7 mm at baseline, which at least partially results from DED and has continued for about 2 weeks or more, about 1 month or more, about 2 months or more, about 3 months or more, about 6 months or more, about 1 year or more, or about 2 years or more (Shen et al., 2016; Messmer, 2015). The role of SkQ in these methods is to be able to address oxidative stress and damage to the corneal center in long-term DED.

[0046] The methods disclosed herein can be combined with one or more other combination therapies. One or more other combination therapies may be associated with DED or one or more different diseases or symptoms. DED can be associated with exposure to one or more of various diseases such as dry keratoconjunctivitis and dry keratitis. DED may be a multifactorial disease of the ocular surface. The aging process generally results in a decrease in tear production and flow, and specific hormonal changes (e.g., menopause) are the main causes of DED. Oxidative stress is involved in the natural aging process. There are numerous environmental and lifestyle causes of DED, including side effects of stress-related diseases, air quality indices in suburban areas, exposure to low humidity outdoors or indoors, tobacco smoke, wind, sun (ultraviolet or heat), ozone, a dusty work environment, side effects of specific drugs such as antihistamines, antidepressants, beta blockers, other eye diseases (such as blepharitis, allergic conjunctivitis), rheumatoid arthritis, Sjogren's syndrome, cataract surgery, specific medical conditions such as contact dermatitis, etc. The use of contact lenses and activities with a reduced number of blinks such as long-term computer use and reading may contribute to DED.

[0047] Examples [Example 1] VISTA-1 Clinical Study In the VISTA-1 clinical study (NCT03764735), eyedrops containing different concentrations of SkQ1 were evaluated in terms of various aspects of safety and efficacy in the treatment of various signs and symptoms of DED, compared with placebo (vehicle). The vehicle was an artificial tear treatment used as a control. In the VISTA-1 study, changes in corneal fluorescein staining levels from baseline to day 57 were reported. The levels on the corneal fluorescein scale ranged from 0 to 4, with level 0 = none and level 4 = severe. In VISTA-1, changes in symptoms such as grittiness reported by the subjects were reported from baseline to day 57, and the scale for each symptom ranged from 0 to 5, with 0 = none and 5 = worst. The study subjects were carefully monitored to ensure that no adverse events occurred. An exemplary aspect of the VISTA-1 study design is summarized in Table 1 below.

[0048] [Table 1]

[0049] VISTA-1 Study Results The mean change from baseline in central corneal fluorescein staining values in all treatment groups was -0.31 in the 0.155 μg / mL SkQ1 eyedrop group, -0.20 in the 1.55 μg / mL SkQ1 eyedrop group, and -0.26 in the placebo group. Since the mean difference between the active ingredient and placebo was not statistically significant, it was shown that SkQ1 eyedrops did not produce a statistically significant beneficial therapeutic effect on the central fluorescein staining signs of dry eye. Table 2 shows an overview of the change from baseline (after 57 days) in central corneal fluorescein staining in the mITT population of VISTA-1.

[0050] [Table 2]

[0051] [Example 2] VISTA-1 Clinical Study In the VISTA-2 (NCT04206020) clinical study, the results of a dose of 1.55 μg / mL SkQ1 compared to placebo (vehicle) were reported. In VISTA-2, measured changes in the eye discomfort scale were reported. The scale ranges from 0 to 4, where 0 = no discomfort and 4 = discomfort persists from baseline to day 57. VISTA-2 reported measured changes in the conjunctival fluorescein staining level (total of temporal and nasal regions). The scale for each region ranges from 0 to 4, where 0 = no staining and 4 = confluent staining from baseline to day 57. Study subjects were carefully monitored to ensure no adverse events occurred. An exemplary aspect of the VISTA-2 study design is summarized in Table 3 below.

[0052]

Table 3

[0053] [Example 3] Composite analysis of VISTA-1 and VISTA-2 clinical studies In addition to the reported data, observational data collected during the VISTA-1 and VISTA-2 clinical trials were analyzed in the ITT subgroup by Schirmer test without anesthesia of 7 mm or more at baseline. (Initial evaluation) In both VISTA-1 and VISTA-2, a post hoc analysis was performed on the observational data of the ITT subgroup, including subjects with a Schirmer test score of 7 mm or more without anesthesia at baseline, and the observational data were only for evaluating the change from baseline in central fluorescence staining. Table 4 summarizes the results of subjects with a Schirmer test score of 7 mm or more without anesthesia at baseline. In VISTA-1, when using 1.55 μg / mL SkQ1, a significant improvement was seen in the change from baseline in central fluorescein staining (p ANCOVA = 0.023). In VISTA-2, due to the increased sample size, a significant improvement was confirmed in this subgroup (p ANCOVA(=0.0168). In Table 4, the change from baseline in central fluorescein staining in the ITT subgroup with a baseline Schirmer test score of 7 mm or more without anesthesia is provided only by the observational data.

[0054] [Table 4]

[0055] Similar subgroups as described above were also analyzed in post hoc analyses for both VISTA-1 and VISTA-2, and the proportion of subjects in whom central corneal fluorescein staining disappeared was evaluated. Table 5 summarizes the results for subjects with a baseline Schirmer test score of 7 mm or more without anesthesia. In VISTA-1, a numerical improvement was seen in these subjects (p ピアソンカイ2乗 =0.0336). In VISTA-2, with the increase in sample size, a significant improvement was confirmed (p ロジスティック回帰 =0.0049, p ピアソンカイ2乗 =0.0033, p フィッシャーの正確検定 =0.0037). In Table 5, the population of study subjects in whom corneal fluorescein staining in the central corneal part disappeared in the ITT subgroup with a baseline Schirmer test score of 7 mm or more without anesthesia is provided only by the observed data.

[0056] [Table 5]

[0057] In VISTA-2, in the ITT subgroup including subjects with a baseline Schirmer test score of 7 mm or more, a decrease in visual acuity [OSDI4] of 1 or more, and a decrease in visual acuity [OSDI5] of 1 or more, the change from baseline in BCVA using logMAR (BCVA-logMAR) at Visit 3 was evaluated. Table 6 summarizes the results of VISTA-2. In VISTA-2, p ANCOVAA significant improvement was shown at = 0.0143. Table 6 summarizes the change in BCVA - logMAR from baseline when comparing 1.55 μg / mL SkQ1 with placebo for the ITT subgroup that included subjects with a Schirmer test score ≥ 7 mm, poor vision [OSDI4] ≥ 1, and visual acuity decline [OSDI5] ≥ 1 at baseline.

[0058]

Table 6

[0059] Importantly, in the subgroup that included subjects with a Schirmer test score < 7 mm without anesthesia at baseline, no statistically significant improvement was seen for either corneal staining or visual acuity (compared to the vehicle). Tables 7 and 8 summarize the lack of efficacy (compared to the vehicle) for subjects with a test score < 7 mm without anesthesia at baseline. Table 7 summarizes the change in central full - fluorescein staining from baseline using only observational data for the ITT subgroup with a Schirmer test score < 7 mm without anesthesia at baseline.

[0060]

Table 7

[0061] Table 8 summarizes the change in BCVA - logMAR from baseline when comparing 1.55 μg / mL SkQ1 with placebo for the ITT subgroup that included subjects with a Schirmer test score < 7 mm, poor vision [OSDI4] ≥ 1, and visual acuity decline [OSDI5] ≥ 1 at baseline.

[0062]

Table 8

[0063] OSDI (registered trademark), Cornea Disease Index (registered trademark), AbbVie, Allergan plc, Irvine, California NCT03764735, (ClinicalTrials.gov Identifier: NCT03764735). NCT04206020, (ClinicalTrials.gov Identifier: NCT04206020). FDA, (fda.gov / medical-devices / lasik / what-lasik). Petrov, A., et al., SkQ1 eye drops for the treatment of dry eye: Results of a phase 2 safety and efficacy clinical study during challenge in the environment and controlled adverse environment models. Advances in therapy, 2016. 33(1): p. 96-115. Brzheskiy, VV, et al., Results of a multicenter, randomized, double-blind, placebo-controlled clinical study on the efficacy and safety of Visomitin eye drops in patients with dry eye syndrome. Adv Ther, 2015. 32(12): p. 1263-79. Bakkar MM, El-Sharif AK, AlQadire M. Validation of the Arabic version of the Cornea Disease Index Questionnaire. Int J Ophthalmol. 2021;14(10):1595-1601. Published 2021 Oct 18. doi:10.18240 / ijo.2021.10.18. Begley C, Caffery B, Chalmers R, Situ P, Simpson T, Nelson JD. Review and analysis of grading scales for ocular surface staining. Ocul Surf. 2019 Apr;17(2):208-220. doi:10.1016 / j.jtos.2019.01.004. Epub 2019 Jan 14. PMID: 30654024. Shen GL, Ng JD, Ma XP. Outcomes, diagnosis, management, and results of referrals for epiphora to oculoplastic surgery. Int J Ophthalmol. 2016;9(12):1751-1755. Published December 18, 2016. doi:10.18240 / ijo.2016.12.08. Messmer, Elisabeth M. "Pathophysiology, diagnosis, and treatment of dry eye disease." Deutsches Arzteblatt international vol. 112, 5 (2015): 71-81; quiz 82. doi:10.3238 / arztebl.2015.0071.

Claims

1. A formulation comprising a compound of formula I: 【Chemical 1】 wherein A is a quinone antioxidant having the following structure: [Chemical 2] and / or its reduced quinol form, where m is an integer from 1 to 3, and each Y is C １～６ alkyl and C １～６ alkoxy (—OC １～６ ), independently selected from the group consisting of wherein L is a linker group comprising: a) a linear or branched hydrocarbon chain, optionally substituted with one or more substituents and optionally containing one or more double or triple bonds, and / or b) a natural isoprene chain n is an integer from 1 to 40; B is Sk + Z ー is a target group containing, where Sk + is a lipophilic cation and Z - is a pharmaceutically acceptable anion; wherein the formulation contains SkQ at a concentration of 0.5 μg / mL or more; the formulation is suitable for assisting in the treatment of a subject in a dry eye state, and the eyes of the subject have a tear production amount measured by the Schirmer test of 7 mm or more, resulting in an improvement in one or more signs and / or one or more symptoms of dry eye disease, the formulation.

2. The formulation according to claim 1, wherein the SkQ comprises compound SkQ1 or a combination thereof in its reduced or oxidized form as shown below: [Chemical Formula 3] 【Chemical 4】

3. The formulation according to claim 1 or 2, wherein the formulation is an eye drop or an eye gel formulation and is suitable for topical application to the eye and / or one or more adnexa of the eye.

4. The formulation according to any one of claims 1 to 3, wherein the one or more signs of dry eye disease are such that the grade of corneal staining in the whole or a part of the cornea is greater than 0.

5. The formulation according to any one of claims 1 to 4, wherein the one or more symptoms of dry eye disease include a visual field defect index ≥ 1 or a visual acuity reduction index ≥ 1, and / or a reduction in visual acuity of the eye.

6. The formulation according to any one of claims 1 to 5, wherein the formulation is topically applied to the eye, and the formulation is suitable for contacting one or more adnexa of the eye by spreading on the surface of the eye, blinking, eye movement, or a combination thereof.

7. The formulation according to any one of claims 1 to 6, wherein one or more of the signs of dry eye disease are such that the grade of corneal staining in the whole or a part of the cornea is greater than 0, and one or more of the symptoms of dry eye disease include a reduction in visual acuity of the eye.

8. A formulation according to any one of claims 1 to 7, wherein the formulation is suitable for use in a method comprising: a) performing fluorescein staining on the eye; b) measuring the grade of fluorescein staining in the central part of the cornea; c) repeatedly treating the eye with the formulation after a) and b). Thereby, the grade of fluorescein staining of the central cornea of the eyeball is reduced or completely disappears. The preparation.

9. The preparation according to claim 8, wherein the grade of fluorescein staining of the central part of the cornea is initially >0 and finally =0.

10. The preparation according to any one of claims 1 to 9, wherein the subject has a visual field defect index of 1 or more or a visual acuity reduction index of 1 or more, and / or the vision of the eye is reduced before treatment with the preparation, and the preparation brings about an improvement in the vision of the eye after the treatment.

11. The preparation according to claim 10, wherein the improvement in vision is an improvement in the best corrected visual acuity (BCVA) of the eye, and the improvement in BCVA is an improvement of about 0.3 or more in BCVA.

12. The preparation according to claim 11, wherein the BCVA is measured as the logarithm of the minimum angle in the resolution chart measurement.

13. The preparation according to any one of claims 11 or 12, wherein the improvement in BCVA further includes an improvement in the index of visual field defect and / or the index of visual acuity reduction.

14. The preparation according to any one of claims 10 to 13, wherein the reported visual field defect index is an evaluation in a scale range of 0 to 4 based on the subject's visual field defect experience during the week before treatment with the preparation, where 0 = none, 1 = sometimes, 2 = half, 3 = most of the time, 4 = always.

15. The preparation according to any one of claims 10 to 13, wherein the reported visual acuity reduction index is an evaluation in a scale range of 0 to 4 based on the subject's visual acuity reduction experience during the week before treatment with the preparation, where 0 = none, 1 = sometimes, 2 = half, 3 = most of the time, 4 = always.

16. One or more signs and / or one or more symptoms of dry eye disease include that the amount of tear production of the eye by the Schirmer test is 7 mm or more, the grade of fluorescein staining of the central cornea exceeds 0, the total fluorescein corneal staining score is 2 or more, the total lissamine green conjunctival staining score is 2 or more, corneal hypersensitivity, conjunctival congestion, eyelid margin congestion, corneal damage, the subject's eye irritation, eye itching or discomfort, visual acuity reduction, and one or more of the visual field defect, visual acuity reduction, eye pain, photosensitivity of the eye, or eye pain reported by the subject. The preparation according to any one of claims 1 to 15.

17. The preparation according to any one of claims 1 to 16, which is suitable for treating the eyes of a subject over a period of about 14 days to about 90 days.

18. One or more signs and / or one or more symptoms of dry eye disease are accompanied by a condition including one or more of the following: eye fatigue caused by reading, night driving, observing a display screen, or wearing contact lenses, exposure to environmental eye irritants, hormone replacement therapy, exposure to wind or dry air, allergies, ophthalmic surgery, side effects of drugs, thyroid diseases, diseases due to aging, infections, exposure keratitis, vitamin deficiencies, Sjogren's syndrome, and conditions associated with dry keratoconjunctivitis, dry keratitis, or immune system disorders. The preparation according to any one of claims 1 to 16.

19. The preparation according to claim 18, wherein the infection is a bacterial infection, a fungal infection, or a viral infection.

20. The preparation according to any one of claims 1 to 19, wherein the SkQ contains one or more compounds in an oxidized or reduced form, or a mixture thereof, and is selected from the group consisting of the following compounds: 【Chemical Formula 5】 [Chemical Formula 6] 【Chemical 7】 【Chemical Formula 8】 【Chemical Formula 9】 【Chemical Formula 10】 【Chemical 11】 【Chemical Formula 12】 【Chemical 13】 【Chemical 14】 As well as 【Chemical Formula 15】

21. the pharmaceutically acceptable anion Z － The preparation according to any one of claims 1 to 20, wherein － is acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, monobasic phosphate dodecahydrate, monobasic phosphate dihydrate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprinate, caproate, caprylate, dodecyl sulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, or a combination thereof.

22. wherein SkQ optionally contains a hydrate containing one or more water molecules bonded to A, L, Sk + , and / or Z － via hydrogen bonds and / or ionic bonds, the pharmaceutical preparation according to any one of claims 1 to 21.

23. The preparation according to any one of claims 1 to 22, which is suitable for treating a subject by administering the preparation to the eye and / or one or more appendages of the eye at a dose of at least one drop or at least about 0.05 mL of the preparation at least once every 24 hours.

24. The preparation according to any one of claims 1 to 23, which contains one or more of benzalkonium chloride, hypromellose, sodium chloride, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dodecahydrate, and water.

25. The preparation according to any one of claims 1 to 24, wherein the Schirmer test score is a Schirmer test score without anesthesia.

26. The preparation according to any one of claims 1 to 25, wherein one or more symptoms of dry eye disease include one or more symptoms reportable by a subject.

27. The preparation according to any one of claims 1 to 26, wherein the one or more signs and / or the one or more symptoms of dry eye disease result from a progressive dry eye disease over a period longer than about 2 months.

28. The preparation according to claim 27, wherein the damage to the central cornea is indicated by a grade of central corneal fluorescein staining of 1 or more.

29. The preparation according to any one of the preceding claims, wherein the preparation contains SkQ at a concentration of 1 μg / mL or more.

30. A kit for treating one or more signs and / or one or more symptoms of dry eye disease, comprising: A dispensing container containing an eye drop or eye gel preparation containing SkQ at a concentration of 0.5 μg / mL or more; and Instructions for use.

31. The kit according to claim 28, wherein the eye drop or eye gel preparation contains SkQ at a concentration of 1 μg / mL or more.

32. Treating or preventing dry eye syndrome in a subject in need thereof using the preparation according to any one of claims 1 to 29 or the kit according to claim 30 or 31.

33. The use according to claim 32, wherein the amount of tear production measured by the Schirmer test in the eye of the subject is 7 mm or more.

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