Stable peptide compositions and methods of treating medium / high dry eye related ocular conditions using

Abstract

The present application generally relates to stable peptide compositions and kits comprising low levels of buffers and chelating agents, and methods of using the same to treat patients suffering from moderate / severe or severe dry eye.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Serial No. 63 / 357,638, filed on July 1, 2022, and U.S. Serial No. 63 / 390,550, filed on July 19, 2023, each of which is incorporated herein by reference in its entirety. Background Art

[0003] field

[0004] The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, several embodiments of the present application relate to stable diluted peptide compositions and kits containing such compositions for treating ocular disorders, particularly moderate / severe or severe dry eye.

[0005] Description of Related Technology

[0006] Although dry eye treatments are commercially available, there remains a need for effective treatments for dry eye in general, particularly in patients with moderate / severe or severe dry eye symptoms. Summary of the invention

[0007] There is an unmet need for effective treatment of dry eye, particularly in patients with moderate / severe dry eye symptoms as disclosed herein, e.g., those patients with a dry eye score of at least 60. In addition, there is an unmet need for peptide compositions that provide therapeutic amounts of peptides, are stable at room temperature, and contain only trace amounts of stabilizers and / or preservatives or no stabilizers and / or preservatives at all.

[0008] Non-limiting embodiments of the present disclosure include the following numbered embodiments:

[0009] 1. A method for treating ocular symptoms associated with moderate / severe dry eye, comprising:

[0010] Identifying subjects with moderate / severe dry eye-related ocular symptoms; and

[0011] administering to a subject a liquid composition comprising:

[0012] 0.0001% to 0.005% (w / v) of a polypeptide or a pharmaceutically acceptable salt thereof, the polypeptide having a sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2 (SEQ ID NO: 1), wherein "Ac" represents an acetyl group and the C-terminus is amidated;

[0013] 0.01% to 0.6% (w / v) buffer;

[0014] 0.0005% to 0.01% (w / v) disodium EDTA;

[0015] 0.0001% to 0.01% (w / v) or 0.0001% to 0.05% (w / v) tyloxapol;

[0016] and 0.1% to 1.0% (w / v) sodium chloride,

[0017] wherein the pH of the composition is from about 6.2 to about 6.8,

[0018] One drop of the composition is applied to the eye of the subject up to three times per day.

[0019] 2. The method of embodiment 1, wherein the subject meets at least one criterion selected from the group consisting of:

[0020] a) Total FCS score ≥ 4 and < 15 on the NEI / Industry Workshop scale;

[0021] b) Using VAS instantaneous measure, dry eye score ≥60;

[0022] c) Schirmer 1 test score ≤ 5 mm wetting / 5 minutes under anesthesia; and

[0023] d) LGCS total score ≥ 5 (where 0 = no staining) using the NEI / Industry Workshop Scale.

[0024] 3. The method of embodiment 1 or 2, wherein the subject's dry eye score is ≥ 60 using VAS instantaneous measurement.

[0025] 4. The method of embodiment 1 or 2, wherein the subject meets all 4 criteria in one eye.

[0026] 5. The method of any one of embodiments 1 to 4, wherein the subject does not suffer from Sjögren's syndrome.

[0027] 6. The method according to any one of the preceding embodiments, wherein the polypeptide or a pharmaceutically acceptable salt thereof is present in the liquid composition at 0.00025% to 0.005% (w / v) or at 0.0001% to 0.001% (w / v).

[0028] 7. The method according to any one of the preceding embodiments, wherein the polypeptide or a pharmaceutically acceptable salt thereof is present in the liquid composition at 0.00025% or 0.001% (w / v).

[0029] 8. The method according to any one of the preceding embodiments, wherein tyloxapol is present in the liquid composition at 0.0005% to 0.01% (w / v) or 0.0005% to 0.05% (w / v).

[0030] 9. The method of any one of the preceding embodiments, wherein tyloxapol is present in the liquid composition at about 0.001% (w / v), or about 0.01% (w / v), or about 0.05% (w / v).

[0031] 10. The method of any of the preceding embodiments, wherein the pH of the composition is from about 6.0 to about 7.0, or from about 6.4 to about 6.6.

[0032] 11. The method of embodiment 9 or 10, wherein the pH of the composition is about 6.5.

[0033] 12. The method of any of the preceding embodiments, wherein the amount of NaCl is from about 0.4% to about 0.6% (w / v).

[0034] 13. The method according to any of the preceding embodiments, wherein the amount of NaCl is about 0.5% (w / v).

[0035] 14. The method of embodiment 11 or 13, wherein the composition has an osmotic pressure concentration of about 190 mOsm / kg to 210 mOsm / kg.

[0036] 15. The method according to any one of the preceding embodiments, wherein the buffer is a citrate buffer.

[0037] 16. The method of embodiment 13 or 15, wherein the citric acid buffer comprises 0.0098% anhydrous citric acid and 0.279% sodium citrate dihydrate.

[0038] 17. The method according to any of the preceding embodiments, wherein the amount of EDTA is from about 0.0005% to about 0.005% (w / v).

[0039] 18. The method according to any of the preceding embodiments, wherein the amount of EDTA is about 0.001% (w / v).

[0040] 19. The method according to any one of the preceding embodiments, wherein the composition further comprises 0.04% methylparaben.

[0041] 20. The method according to any one of the preceding embodiments, wherein the composition is sterile.

[0042] 21. The method of any of the preceding embodiments, further comprising determining that the subject has a history of one or more ocular symptoms associated with dry eye.

[0043] 22. The method according to any one of the preceding embodiments, wherein the one or more ocular symptoms associated with dry eye include use of an ocular wetting agent by the subject within the last 6 months.

[0044] 23. The method according to any one of the preceding embodiments, wherein the composition is administered three times a day.

[0045] 24. The method according to any one of the preceding embodiments, wherein the composition is administered up to three times per day for at least one week.

[0046] 25. The method according to any one of the preceding embodiments, wherein the composition is administered up to three times per day for 1 week to 6 weeks.

[0047] 26. The method of any of the preceding embodiments, wherein administration improves the subject's total FCS score (NEI / Industry Workshop 0 to 15 scale) of the eye after at least two weeks of treatment, or after at least four weeks of treatment, or after at least six weeks from four weeks of treatment, compared to a baseline measurement before starting treatment.

[0048] 27. The method of any one of the preceding embodiments, wherein administration improves one or more of:

[0049] dry eyes after at least two weeks of treatment or after at least four weeks of treatment compared with baseline on a visual analog scale;

[0050] SANDE after at least two weeks of treatment compared with baseline measurements before starting treatment (global score SANDE 1);

[0051] The mean SANDE score after at least two weeks of treatment compared with the baseline measurement before starting treatment (Global Score SANDE-1);

[0052] Individual symptom assessments (momentary) after at least two weeks of treatment compared with baseline measurements before starting treatment;

[0053] Mean scores on individual symptom assessments (reflective) after at least two weeks of treatment compared with baseline measurements before starting treatment;

[0054] LGCS in subjects' eyes after at least two weeks of treatment compared to baseline measurements before starting treatment;

[0055] Schirmer testing under anesthesia in the eyes of subjects after at least two weeks of treatment compared to baseline measurements before starting treatment;

[0056] TFBUT of the subject's eye after at least two weeks of treatment compared to baseline measurement before starting treatment;

[0057] FCS in the subject's eye after at least two weeks of treatment compared to baseline measurements before starting treatment;

[0058] SANDE (Global Score of SANDE 1) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared with the baseline measurement before starting treatment;

[0059] Individual symptoms (momentary) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared to baseline measurements before starting treatment;

[0060] Mean score (Global Score SANDE-2) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared with the baseline measurement before starting treatment;

[0061] Mean scores on individual symptom assessments (reflective) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared to baseline measurements before starting treatment;

[0062] FCS and SANDE 1 and individual symptom assessments (momentary) after at least 2 weeks of treatment, or after at least 4 weeks of treatment compared to baseline measurements before starting treatment;

[0063] LGCS after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared with baseline measurement before starting treatment;

[0064] Schirmer test results under anesthesia after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to baseline measurements before starting treatment;

[0065] TFBUT was measured at 1 week after at least 2 weeks of treatment, or at least 4 weeks of treatment, or after 4 weeks of treatment, compared to the baseline measurement before starting treatment.

[0066] 28. The method of embodiment 27, wherein the improvement is, is about, is at least, is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the measured or estimated value or a range defined by any two of the foregoing values.

[0067] 29. The method of any of the preceding embodiments, wherein the subject also meets all of the following criteria:

[0068] 18 years of age or older;

[0069] Documented prior history or current diagnosis of dry eye-related ocular symptoms; and

[0070] History of dry eye-related ocular symptoms and self-reported use of over-the-counter ocular lubricants in the past 120 days.

[0071] 30. The method of any of the preceding embodiments, wherein the subject does not meet one or more of the following criteria:

[0072] Any active infectious eye condition;

[0073] monocular or with best-corrected visual acuity (BCVA) of +1.0 logMAR or worse, using corrective lenses as needed, as assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS);

[0074] Ocular inflammatory conditions not related to dry eye syndrome (e.g., conjunctivitis, keratitis, anterior blepharitis, etc.);

[0075] Clinical evidence of scarring ocular surface disease, such as scarring ocular pemphigoid or Stevens-Johnson syndrome;

[0076] The use of any topical ophthalmic medications other than the investigational product (including topical cyclosporine) should not be suspended during the run-in and treatment periods;

[0077] Used within 60 days before starting treatment with the composition (topical ophthalmic cyclosporine);

[0078] Used within 60 days before starting treatment with the composition (topical ophthalmic lifalast);

[0079] The subject's eye has a total fluorescein corneal staining (FCS) score of 15 or a score of 3 in the superior zone on the NEI / Industry Workshop scale, or the subject's eye has a FCS with diffuse confluent staining, filaments, or epithelial defects;

[0080] Subjects who have active herpetic keratitis or have had an outbreak of herpetic keratitis within 365 days of starting treatment or are receiving chronic oral antiviral agents for herpetic disease;

[0081] Do not suspend or give up using contact lenses during treatment;

[0082] have used or are planning to use amiodarone;

[0083] Changes in the dose of the following or anticipated changes in the dose of the following within 30 days prior to starting treatment: tetracycline, omega 3, or omega 6;

[0084] Changes in the doses of the following within 60 days before starting treatment and / or during the duration of treatment or anticipated changes in the doses of the following: anticholinergics, antidepressants, oral contraceptives, isotretinoin, oral systemic corticosteroids, oral systemic immunosuppressants,

[0085] Have used topical ophthalmic antihistamines, ophthalmic, inhaled or intranasal corticosteroids, topical or oral mast cell stabilizers, oral antihistamines, topical or nasal vasoconstrictors, topical ophthalmic NSAIDs, topical ophthalmic antibiotics within 30 days before starting treatment and / or during the duration of treatment;

[0086] In the subject's eye, and within the past 90 days, the puncta have been cauterized or one or more punctal plugs have been changed (inserted or removed) prior to starting treatment;

[0087] In the subject's eye, corneal refractive surgery (LASIK, PRK, RK) had been performed;

[0088] Any history of surgery on the ocular surface or eyelid within 365 days before starting treatment, or any history of intraocular surgery within 90 days before starting treatment;

[0089] Pregnancy or suspected pregnancy;

[0090] Are breastfeeding or intend to breastfeed;

[0091] Has any physical or mental impairment that would interfere with the ability to participate and give informed consent; and

[0092] Have participated in a device or investigational drug study or clinical trial within 30 days of starting treatment.

[0093] 31. The method of any of the preceding embodiments, wherein the subject does not meet at least one of the following criteria in one or both eyes:

[0094] a) Total FCS score <4 or ≥15 in the NEI / Industry Workshop Scale,

[0095] b) Using VAS instantaneous dry eye score <60,

[0096] c) Schirmer 1 test score > 5 mm wetting / 5 minutes under anesthesia, or

[0097] d) LGCS total score <5 (where 0 = no staining) using the NEI / Industry Workshop scale.

[0098] 32. The method according to any one of the preceding embodiments, wherein the subject is identified as having severe dry eye, but not moderate / severe dry eye.

[0099] 33. The method of embodiment 32, wherein the subject has a dry eye score of ≥70 in at least one eye using VAS instantaneous measurement.

[0100] 34. The method of any of the preceding embodiments, wherein the composition comprises, consists of, or consists essentially of a composition selected from the group consisting of the formulations in Table A, Table B, Table C, Table 1.1, Table 1.2, and Table 1.3.

[0101] 35. A liquid composition for treating moderate / severe dry eye-related ocular symptoms in an eye of a subject, the composition comprising:

[0102] 0.0001% to 0.006% (w / v) of a polypeptide or a pharmaceutically acceptable salt thereof, the polypeptide having a sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2 (SEQ ID NO: 1), wherein "Ac" represents an acetyl group, and the C-terminus is amidated;

[0103] 0.01% to 0.6% (w / v) buffer;

[0104] 0.0005% to 0.01% (w / v) disodium EDTA;

[0105] 0.0001% to 0.01% (w / v) or 0.0001% to 0.05% (w / v) tyloxapol;

[0106] and 0.1% to 1.0% (w / v) sodium chloride,

[0107] wherein the pH of the composition is from about 6.2 to about 6.8.

[0108] 36. The liquid composition of embodiment 35, wherein the composition comprises, consists of, or consists essentially of a composition selected from the group consisting of the compositions of the formulations in Table A, Table B, Table C, Table 1.1, Table 1.2, and Table 1.3.

[0109] 37. The liquid composition of any one of embodiments 35 to 36, wherein the subject meets at least one criterion selected from the group consisting of:

[0110] a) Total FCS score ≥4 and <15 in the NEI / Industry Workshop Scale;

[0111] b) Using VAS instantaneous measurement, dry eye score ≥60;

[0112] c) Schirmer 1 test score ≤ 5 mm wetting / 5 minutes under anesthesia; and

[0113] d) LGCS total score ≥ 5 (where 0 = no staining) using the NEI / Industry Workshop Scale.

[0114] 38. The liquid composition of any one of embodiments 35 to 37, wherein the subject's dry eye score is ≥ 60 using VAS instantaneous measurement.

[0115] 39. The liquid composition of any one of embodiments 35 to 38, wherein the subject meets all 4 criteria in one eye.

[0116] 40. The liquid composition of any one of embodiments 35 to 39, wherein the subject does not suffer from Sjögren's syndrome.

[0117] 41. The liquid composition of any one of embodiments 35 to 40, wherein the subject does not meet at least one of the following criteria in one or both eyes:

[0118] a) Total FCS score <4 or ≥15 in the NEI / Industry Workshop Scale,

[0119] b) Using VAS instantaneous dry eye score <60,

[0120] c) Schirmer 1 test score > 5 mm wetting / 5 minutes under anesthesia, or

[0121] d) LGCS total score <5 (where 0 = no staining) using the NEI / Industry Workshop scale.

[0122] 42. The liquid composition of any one of embodiments 35 to 41, wherein the subject is identified as suffering from severe dry eye but not suffering from moderate / severe dry eye.

[0123] 43. The liquid composition of embodiment 42, wherein the subject has a dry eye score of ≥ 70 in at least one eye using VAS instantaneous measurement. BRIEF DESCRIPTION OF THE DRAWINGS

[0124] Figure 1 is a schematic diagram depicting an embodiment of a method of treating a subject having moderate / severe dry eye symptoms according to some non-limiting embodiments of the present disclosure.

[0125] Figure 2 It is displayed with Lacripep TM Schematic representation of the study design for the treatment of ocular surface disease associated with primary Sjögren's syndrome.

[0126] Figure 3 It was shown that in patients with primary Sjögren's syndrome, daily ocular administration of 22 μM Lacripep TM Plot of the change from baseline in lower CFS at 14 and 28 days after 3 visits.

[0127] Figure 4A The study showed that daily ocular administration of placebo, 22 μM, or 44 μM Lacripep in patients with primary Sjögren's syndrome TM Plot of the change from baseline in lower CFS after 3 visits, at days 14 and 28, and at the post-treatment follow-up (day 42).

[0128] Figure 4B In a subgroup of patients with primary Sjögren's syndrome with EDS ≥ 60, daily ocular administration of placebo, 22 μM, or 44 μM Lacripep TM Plot of the change from baseline in lower CFS after 3 visits, at 14 or 28 days, and at the post-treatment follow-up (Day 42).

[0129] Figure 5A The study showed that daily ocular administration of placebo, 22 μM, or 44 μM Lacripep in patients with primary Sjögren's syndrome TM Graph of the change from baseline in burning / stinging symptoms after 3 visits, at 14 or 28 days, and at the post-treatment follow-up (Day 42).

[0130] Figure 5B In a subgroup of patients with primary Sjögren's syndrome with an EDS ≥ 60, daily ocular administration of placebo, 22 μM, or 44 μM Lacripep TM Graph of the change from baseline in burning / stinging symptoms after 3 visits, at 14 or 28 days, and at the post-treatment follow-up (Day 42).

[0131] Figure 6 is an implementation of a VAS questionnaire for measuring the eye dryness score (EDS).

[0132] Figure 7 is an embodiment of a schematic diagram showing the division of the corneal surface for measuring the total fluorescein corneal staining (FCS) score.

[0133] Figure 8 is an embodiment of a schematic diagram showing the division of the conjunctival surface for measuring the lissamine green conjunctival staining (LGCS) total score. DETAILED DESCRIPTION

[0134] the term

[0135] The following are illustrative definitions of terms used herein. Unless otherwise expressly stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art upon reading the entire specification. Unless otherwise stated, all patents, applications, published applications, and other publications cited herein are incorporated herein by reference in their entirety.

[0136] As used herein, the term "about" refers to a quantity, value, number, frequency, percentage, amount or weight that varies by + / - 10% relative to a reference quantity, value, number, frequency, percentage, amount or weight.

[0137] Unless otherwise indicated, when a percentage (%) value is used in this application, the value refers to a weight / volume (w / v) percentage value.

[0138] The term "tonicity agent" as used herein should be given its ordinary meaning and should include materials whose primary purpose is to change the osmolality of the composition. Suitable tonicity agents include, but are not limited to, propylene glycol, polyethylene glycol, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose and / or simple polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, hydrogenated starch hydrolysates, glycerol, and combinations of the foregoing.

[0139] The term "stabilizer" as used herein should be given its ordinary meaning and should include materials that inhibit chemical reactions with peptides. Stabilizers can include, for example, antioxidants such as sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene, and combinations of the foregoing.

[0140] As used herein, the term "surfactant" should be given its ordinary meaning and should include amphiphilic molecules, meaning that they contain both a hydrophobic group (tail) and a hydrophilic group (head). Thus, surfactants contain both a water-insoluble (or oil-soluble) component and a water-soluble component. As used herein, a surfactant can be a detergent, a wetting agent, an emulsifier, a foaming agent, or a dispersant. In some embodiments, a polypeptide can serve as a surfactant.

[0141] The term "chelating agent" as used herein should be given its ordinary meaning and should include compounds that can form two or more bonds with metal ions, i.e., multidentate ligands. Chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), ethylenediamine, amino acids (e.g., glutamic acid and histidine), organic diacids (e.g., oxalic acid, malonic acid, succinic acid, etc.), and the aforementioned pharmaceutically acceptable salts. In several embodiments, the chelating agent is EDTA or a pharmaceutically acceptable salt thereof. In some embodiments, the polypeptide can serve as a chelating agent.

[0142] As used herein, the term "viscosity building agent" should be given its ordinary meaning and should include materials that affect the viscosity (centipoise or Cp) of the composition. Examples of viscosity enhancing agents include, but are not limited to, polysaccharides such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family (and their derivatives), vinyl polymers, and acrylic polymers. Non-limiting examples of viscosity building agents include polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), and polyacrylic acid (PAA).

[0143] As used herein, the term "ophthalmically acceptable" shall be given its ordinary meaning and shall include materials that are compatible with ocular tissue; that is, it does not cause significant or undue deleterious effects when in contact with ocular tissue.

[0144] As used herein, the terms "stable", "stability" or "stabilized" should be given their ordinary meaning and should include products and compositions that enhance the primary, secondary and / or tertiary structure of a polypeptide. In some embodiments, a stabilized composition may have an acceptable percentage of peptide degradation or aggregation products after a given period of time. These peptide degradation products may be the result of, for example, oxidation and / or hydrolysis of the peptide.

[0145] As used herein, the terms "peptide," "polypeptide," and "protein" are used interchangeably and should be given their ordinary meanings. Unless otherwise clear from the context, the term refers to polymers having at least two amino acids linked by a peptide bond. Thus, the term includes oligopeptides, analogs, derivatives, acetylated derivatives, glycosylated derivatives, pegylated derivatives, and the like.

[0146] The term "pharmaceutically acceptable salt" should be given its ordinary meaning, and should include salts of compounds that do not cause significant stimulation to the organism to which it is applied and do not eliminate or significantly reduce the biological activity and properties of the compound. In some embodiments, the salt of the compound can enhance the biological activity and properties of the compound. In other embodiments, the salt can additionally enhance the structural integrity or chemical stability of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with an inorganic acid such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid or phosphoric acid. Pharmaceutical salts can also be obtained by reacting the compound with an organic acid, such as an aliphatic or aromatic carboxylic acid or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as an ammonium salt, an alkali metal salt (e.g., a sodium salt or a potassium salt), an alkaline earth metal salt (e.g., a calcium salt or a magnesium salt), a salt of an organic base (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine) and a salt with an amino acid (e.g., arginine and lysine). In some embodiments, the polypeptide is an acetate.

[0147] Provided herein is a method for treating ocular symptoms associated with dry eye by administering a therapeutic amount of a polypeptide to the eye of a subject in need thereof. As used herein, "ocular symptoms associated with dry eye" has its conventional and common meaning, as understood by those of ordinary skill in the art in accordance with the present disclosure. Ocular symptoms may include one or more symptoms associated with dry eye (or keratoconjunctivitis sicca). Dry eye is a multifactorial disease of the ocular surface characterized by loss of tear film homeostasis. It may be accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and sensory nerve abnormalities play a role in etiology. Ocular symptoms associated with dry eye may include, but are not limited to, blurred vision, light sensitivity, sandy or gritty sensation, eye irritation, eye pain, burning or discomfort, eye stinging, and eye itching. In some embodiments, the subject does not suffer from Sjögren's syndrome (primary or secondary). As used herein, "moderate / severe" or "moderate to severe" relating to dry eye or symptoms are used interchangeably and have their conventional and common meanings understood by those of ordinary skill in the art in accordance with the present disclosure. In some embodiments, a subject has moderate / severe dry eye and / or dry eye symptoms when the subject meets all of the following criteria in at least one eye:

[0148] a) Total FCS score in the NEI / Industry Workshop Scale is ≥ 4 and < 15,

[0149] b) Using VAS instantaneous dry eye score ≥ 60,

[0150] c) Schirmer 1 test score ≤ 5 mm wetting / 5 minutes under anesthesia, and

[0151] d) LGCS total score ≥ 5 (where 0 = no staining) using the NEI / Industry Workshop scale. As used herein, "severe" with respect to dry eye disease or symptoms has its conventional and ordinary meaning as understood by one of ordinary skill in the art in light of this disclosure. In some embodiments, a subject has severe dry eye and / or dry eye symptoms when the subject scores ≥ 70 in at least one eye using the VAS instantaneous measurement.

[0152] The therapeutic polypeptides disclosed herein include lacritin and / or therapeutically active fragments thereof, such as Lacripep TM The present application discloses the surprising discovery that when the polypeptide is administered in a composition at a concentration of no more than 22 μM (corresponding to about 0.005% w / v), or more preferably at a concentration of 4 μM (corresponding to about 0.001% w / v) or 1 μM (corresponding to about 0.00025% w / v), Lacripep is more effective than when administered at a higher concentration (e.g., 44 μM, corresponding to about 0.01% w / v). TM The therapeutic effect may be greater in alleviating symptoms in subjects with moderate / severe dry eye, and optionally those with severe dry eye.In some embodiments, the subject does not have Sjögren's syndrome (primary or secondary).

[0153] As described above and herein, several embodiments of the present application provide compositions stable at room temperature. In several embodiments, the composition has a reduced level of stabilizers and other additives that may cause undesirable side effects, and still provides desired stability. In some embodiments, the composition provides stability of up to 1 hour, 3 hours, 6 hours, 12 hours, 24 hours and 48 hours in the eye, nasal cavity, mouth, epithelium and other tissues. In some embodiments, the composition is formulated so that some or all of the ingredients do not evaporate, are not absorbed, are not discharged or otherwise eliminated after being applied to the eye or other areas, but remain stable and active for several hours (e.g., 1 hour to 3 hours, 3 hours to 6 hours, 6 hours to 12 hours, 12 hours to 24 hours and the range therein). In some embodiments, the composition comprises a peptide, such as Lacripep TMOr other sequences identified herein, wherein the peptide is administered to the eye and the peptide is integrated into the lipid layer of the tear covering the eye, or into the junction of the lipid and aqueous components of the tear, wherein the peptide stabilizes the tear and remains in the tear for at least 1 hour to 3 hours, at least 3 hours to 6 hours, or at least 12 hours to 24 hours, or for a period of more than 24 hours. In several embodiments, this feature is particularly advantageous because it allows the active ingredient (e.g., peptide) to remain stable and effective over an extended period of time. In some embodiments, the reduced frequency of application results in an overall reduction in the overall burden of ingredients on sensitive areas of the body (e.g., eyes).

[0154] Although peptides are provided in several embodiments herein, other compounds besides peptides may be used as active ingredients.

[0155] Peptides are highly selective and effective, and at the same time, relatively safe and well tolerated. Peptides are particularly suitable for compositions as described herein, because relative to some small molecule-based therapeutic agents, peptides may be chemically and physically unstable. For example, peptides are susceptible to hydrolysis, oxidation and aggregation. Peptide compositions are typically aqueous solutions containing active peptides and a variety of stabilizers, preservatives and other agents to maintain the efficacy of peptides. Stabilizers, preservatives and other agents can maintain the chemical and / or structural integrity of polypeptides, thereby maintaining their efficacy. Some additives (such as stabilizers and preservatives) may cause undesirable side effects, including hypersensitivity, itching and tingling or burning. However, in order to maximize the shelf life of peptides and maintain efficacy, these additives are needed in most peptide compositions, and their amounts cause undesirable results. Even in compositions with all these additives, peptide therapeutic agents must be refrigerated usually, making transportation difficult, and even if refrigerated, still have a short shelf life. Furthermore, as peptides degrade and / or aggregate over time (particularly when used from cold storage to room temperature, by warming and cooling), the byproducts may not only be inactive, they may be toxic and / or immunogenic. Formulators can attempt to increase the potency of peptide compositions by increasing the amount of active peptide in the composition. However, increased peptide concentration also increases the rate of peptide aggregation and inactivation.

[0156] Thus, several embodiments herein provide peptide compositions that provide therapeutic amounts of peptides, are stable at room temperature, and contain reduced (eg, only trace amounts) stabilizers and / or preservatives, or none at all.

[0157] In some embodiments, the peptide is selected from: (a) the amino acid sequence KQFIENGSEFAQKLLKKFS, Ac-KQFIENGSEFAQKLLKKFS-NH2 or Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2, wherein "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1), also referred to herein as "Lacripep TM ”; and, (b) the amino acid sequence KQFIENGSEFAQKLLKKFSLLKPWA, Ac-KQFIENGSEFAQKLLKKFSLLKPWA-NH2 or Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-Leu-Leu-Lys-Pro-Trp-Ala-NH2, wherein “Ac” represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 2). In other embodiments, the peptide has one of the following amino acid sequences or a fragment thereof, optionally with N-terminal acetylation and / or C-terminal amidation:

[0158] <210> SEQ ID NO 3

[0159] <211> Length: 138

[0160] <212> Type: PRT

[0161] <213> Organism: Homo sapiens

[0162] <400> Sequence: 3

[0163]

[0164] <210> SEQ ID NO 4

[0165] <211> Length: 119

[0166] <212> Type: PRT

[0167] <213> Organism: Homo sapiens

[0168] <400> Sequence: 4

[0169]

[0170] <210> SEQ ID NO 5 <211> Length: 114

[0171] <212> Type: PRT <213> Organism: Homo sapiens <400> Sequence: 5

[0172]

[0173] <210> SEQ ID NO 6 <211> Length: 114

[0174] <212> Type: PRT <213> Organism: Homo sapiens <400> Sequence: 6

[0175]

[0176] <210> SEQ ID NO 7 <211> Length: 109

[0177] <212> Type: PRT <213> Organism: Homo sapiens <400> Sequence: 7

[0178]

[0179] <210> SEQ ID NO 8 <211> Length: 104

[0180] <212> Type: PRT <213> Organism: Homo sapiens <400> Sequence: 8

[0181]

[0182] <210> SEQ ID NO 9

[0183] <211> Length: 14

[0184] <212> Type: PRT

[0185] <213> Organism: Homo sapiens

[0186] <400> Sequence: 9

[0187]

[0188] In several embodiments, the peptide is represented by the amino acid sequence Ac-KQFIENGSEFAQKLLKKFS-NH2 or Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2, wherein "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1). In some embodiments, the peptide is Lacripep TMIn some embodiments, the peptide is any one or more of SEQ.ID 1-9.

[0189] Buffer and pH

[0190] Buffers stabilize the pH of a solution, i.e., resist changes in pH when acidic or alkaline materials are added to the solution. Suitable buffers for use in the present composition include, but are not limited to, glycine hydrochloride, sodium acetate, phosphate buffered saline (PBS) (including monohydrogen phosphate and dihydrogen phosphate), citric acid buffer (citric acid and sodium citrate), phosphate-citric acid buffer, tris (hydroxymethyl) aminomethane (Tris), carbonate buffer (sodium carbonate and sodium bicarbonate), boric acid buffer, and combinations thereof.

[0191] In some embodiments, the buffer comprises one or more of sodium acetate, phosphate buffered saline (PBS), citric acid buffer (citric acid and sodium citrate) and phosphate-citric acid buffer. In some embodiments, the buffer is selected from sodium acetate, phosphate buffered saline (PBS), citric acid buffer (citric acid and sodium citrate) and phosphate-citric acid buffer.

[0192] In some embodiments, the amount of buffer is limited to less than 0.1%, 0.2%, 0.3% or 0.4%, or within a range defined by any two of the foregoing values.

[0193] In embodiments, the buffer is a citrate buffer (citric acid and sodium citrate). In embodiments, the only buffer is a citrate buffer and no other buffering agents are present in the composition.

[0194] In some embodiments, the pH of the composition is between 6.0 and 7.4; 6.1 and 7.3; 6.2 and 7.2; 6.3 and 7.1; 6.4 and 7.0; 6.5 and 6.9; 6.6 and 6.8; or any pH therebetween.

[0195] In some embodiments, the pH of the composition is or is about 6.0; 6.1; 6.2; 6.3; 6.4; 6.5; 6.6; 6.7; 6.8; 6.9; 7; 7.1; 7.2; 7.3; 7.4, or a range defined by any two of the foregoing values, for example, 6.0 to 7.0, 6.2 to 6.5, 6.3 to 6.5, 6.0 to 6.5, 6.3 to 6.7, or 6.3 to 7.0. In some embodiments, the pH of the composition is or is about 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8. In some embodiments, the pH of the composition is or is about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5. In some embodiments, the pH of the composition is or is about 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8.

[0196] The pH of the composition can be adjusted as needed by adding a solution of an acid or base. Any acid or base whose conjugate is ophthalmically acceptable can be used. Acids include, for example, hydrochloric acid, and bases include, for example, sodium hydroxide and potassium hydroxide.

[0197] In some embodiments, USP <791> Methods Measurement of pH.

[0198] Chelating agents

[0199] In some embodiments, the composition further comprises one or more chelating agents. In some embodiments, the chelating agent is selected from ethylenediaminetetraacetic acid, disodium edetate (EDTA), ethylenediamine, amino acids (e.g., glutamic acid and histidine), organic diacids (e.g., oxalic acid, malonic acid, succinic acid, etc.), 3-dimercaptopropanesulfonic acid (DMPS), alpha lipoic acid (ALA), 2,3-dimercaptopropanesulfonic acid (DMPS), tetrahydrofurfurylthiamine disulfide (TTFD), penicillamine, dimercaptosuccinic acid (DMSA), combinations thereof, and pharmaceutically acceptable salts thereof.

[0200] In some embodiments, the chelating agent (as a non-limiting example EDTA) or a pharmaceutically acceptable salt thereof is present at 0.0001% to 0.1%; 0.0005% to 0.05%; 0.0006% to 0.04%; 0.0007% to 0.003%; 0.0008% to 0.002%; 0.0009% to 0.001%; ​​or any value or range subsumed therein. In some embodiments, the chelating agent is present in an amount equal to or less than 0.1%; 0.09%; 0.08%; 0.07%; 0.06%; 0.05%; 0.04%; 0.03%; 0.02%; 0.01%; 0.009%; 0.008%; 0.007%; 0.006%; 0.005%; 0.004%; 0.003%; 0.002%; 0.001%; ​​0.0009%; 0.0008%; 0.0007%; 0.0006%; 0.0005%; 0.0004%; 0.0003%; 0.0002%; or 0.0001%, or within a range defined by any two of the foregoing values.

[0201] In some embodiments, the chelating agent (eg, EDTA, etc.) or a pharmaceutically acceptable salt thereof is present at less than about 0.05% or less than about 0.005% (eg, about 0.001%).

[0202] Stabilizer

[0203] Buffer and chelating agent can stabilize the peptide components of composition by maintaining pH and reducing metal ion-mediated peptide degradation.In some embodiments, except buffer and / or chelating agent, composition further comprises one or more peptide stabilizers.In some embodiments, except buffer and / or chelating agent, one or more stabilizers are selected from disaccharides, polysaccharides (for example, hyaluronic acid), polyols, sugar alcohols, amino acids, proteins (for example, serum albumin) and combinations thereof.In some embodiments, the limiting examples of stabilizer include trehalose, sucrose, mannitol, sorbitol, polysorbate 20, polysorbate 80, histidine, glycine and arginine and combinations thereof.In embodiments, except buffer and / or chelating agent, composition does not include stabilizer.

[0204] Peptide degradation

[0205] Polypeptides are susceptible to physical and chemical degradation, e.g., aggregation, shearing, oxidation, deamidation, and hydrolysis. In fact, liquid peptide compositions have a high risk of physical and chemical instability during manufacture and storage. Reducing polypeptide degradation is particularly important for diluted peptide formulations that initially contain very small amounts of a particular peptide. Even very small losses of the initial small amount can significantly affect the efficacy of the composition.

[0206] In some embodiments, composition stability is determined by high performance liquid chromatography (HPLC). In some embodiments, composition stability is determined by high performance liquid chromatography-mass spectrometry (HPLC-MS).

[0207] In some embodiments, composition stability is determined after a sealed container of the composition has been in the dark, or exposed to light, at room temperature for days, weeks, or months (e.g., 1-24 days or 1-24 months, e.g., 1 day or 1 month, 2 days or 2 months, 3 days or 3 months, 4 days or 4 months, 5 days or 5 months, 6 days or 6 months, 7 days or 7 months, 8 days or 8 months, 9 days or 9 months, 10 days or 10 months, 11 days or 11 months, 12 days or 12 months, 13 days or 13 months, 14 days or 14 months, 15 days or 15 months, 16 days or 16 months, 17 days or 17 months, 18 days or 18 months, 19 days or 19 months, 20 days or 20 months, 21 days or 21 months, 22 days or 22 months, 23 days or 23 months, 24 days or 24 months).

[0208] In some embodiments, composition stability is determined after a sealed container of the composition has been in the dark, or exposed to light, at 2°C to 8°C (e.g., 5°C), or any value therebetween, for days, weeks, or months (e.g., 1-24 days or 1-24 months, e.g., 1 day or 1 month, 2 days or 2 months, 3 days or 3 months, 4 days or 4 months, 5 days or 5 months, 6 days or 6 months, 7 days or 7 months, 8 days or 8 months, 9 days or 9 months, 10 days or 10 months, 11 days or 11 months, 12 days or 12 months, 13 days or 13 months, 14 days or 14 months, 15 days or 15 months, 16 days or 16 months, 17 days or 17 months, 18 days or 18 months, 19 days or 19 months, 20 days or 20 months, 21 days or 21 months, 22 days or 22 months, 23 days or 23 months, 24 days or 24 months).

[0209] In some embodiments, composition stability is determined after a sealed container of the composition has been in the dark, or exposed to light, at -10°C to -30°C (e.g., -25°C), or any value in between, for days, weeks, or months (e.g., 1-24 days or 1-24 months, e.g., 1 day or 1 month, 2 days or 2 months, 3 days or 3 months, 4 days or 4 months, 5 days or 5 months, 6 days or 6 months, 7 days or 7 months, 8 days or 8 months, 9 days or 9 months, 10 days or 10 months, 11 days or 11 months, 12 days or 12 months, 13 days or 13 months, 14 days or 14 months, 15 days or 15 months, 16 days or 16 months, 17 days or 17 months, 18 days or 18 months, 19 days or 19 months, 20 days or 20 months, 21 days or 21 months, 22 days or 22 months, 23 days or 23 months, 24 days or 24 months).

[0210] In some embodiments, composition stability is determined after a sealed container of the composition has been in the dark, or exposed to light, and moved from 2°C to 8°C (storage), or any value in between, to room temperature for 5 minutes, once, twice, or three times a day, for 1 day to 60 days.

[0211] In some embodiments, after exposure to one or more of the conditions described above and herein, the composition provides at least 99.99%; 99.95%; 99.9%; 99.9%; 99%; 98%; 97%; 96%; 95%; 94%; 93%; 92%; 91%; 90%; 89%; 88%; 87%; 86%; 85%; 84%; 83%; 82%; 81%; 80%; 79%; 78%; 77%; 76%; 75%; 74%; 73%; 72%; 71%; 70%; or any value therebetween. In some embodiments, the amount or activity of the intact polypeptide or its pharmaceutically acceptable salt is at least 80%, 85%, 90% or 95% of the original amount. In some embodiments, the amount or activity of the intact polypeptide or its pharmaceutically acceptable salt is at least 97% of the original amount.

[0212] In some embodiments, after exposure to one or more of the conditions described above and herein, the composition comprises no more than 30%; 29%; 28%; 27%; 26%; 25%; 24%; 23%; 22%; 21%; 20%; 19%; 18%; 17%; 16%; 15%; 14%; 13%; 12%; 11%; 10%; 9%; 8%; 7%; 6%; 5%; 4%; 3%; 2%; 1%; or within a range defined by any two of the foregoing values. In some embodiments, the composition comprises no more than about 15%, or no more than 20% inactive peptide.

[0213] In some embodiments, after exposure to one or more of the conditions described above and herein, the composition comprises no more than 30%; 29%; 28%; 27%; 26%; 25%; 24%; 23%; 22%; 21%; 20%; 19%; 18%; 17%; 16%; 15%; 14%; 13%; 12%; 11%; 10%; 9%; 8%; 7%; 6%; 5%; 4%; 3%; 2%; 1%; or the total amount of peptide degradation products and peptide aggregation products within the range defined by any two of the foregoing values.

[0214] In some embodiments, the composition comprises a very low level of buffer, combined with a very low level of chelating agent. In some embodiments, the buffer is a citric acid buffer, and the chelating agent is EDTA. The combination of a low level of citric acid buffer (e.g., 0.012% to 0.020%) and EDTA (e.g., 0.0005% to 0.005%) provides a surprising and unexpected benefit of stabilizing a composition containing a low level of peptide (e.g., 0.001% to 0.01%). Such stabilized compositions provide advantages in the manufacture, transportation, storage and use of peptide compositions by reducing peptide aggregation and degradation, thereby maintaining the efficacy of the peptide composition and reducing the accumulation of undesirable decomposition products in the composition.

[0215] In some embodiments, the stabilized composition reduces the rate of formation of decomposition and / or aggregation products.

[0216] In some embodiments, the peptide is Lacripep TM . In some embodiments, the stabilized composition comprises less than about 5%, 4%, 3%, 2%, or about 1% of total degradation products. In some embodiments, the stabilized composition comprises no more than 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, or 2.0% of any single degradation product. In some embodiments, the stabilized composition comprises less than about 5%, 4%, 3%, 2%, or about 1% of total degradation products and no more than 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, or 2.0% of any single degradation product.

[0217] In some embodiments, the aggregation products include dimers, trimers, tetramers, or larger peptide aggregates.

[0218] preservative

[0219] In some embodiments, the composition further comprises one or more preservatives to prevent the growth of microorganisms in the composition. In some embodiments, the composition further comprises one or more preservatives to maintain the sterility of the composition. In some embodiments, the composition further comprises one or more preservatives to prevent the growth of microorganisms and maintain the sterility of the composition. However, in many embodiments, the preservative is provided in a reduced amount. In some embodiments, one or more preservatives are selected from benzalkonium chloride, cetylpyridinium chloride, chlorobutanol, benzalkonium bromide, methylparaben, propylparaben, phenylethyl alcohol, sodium perborate, disodium edetate, chlorobutanol, sorbic acid, benzethonium chloride, sodium acetate, polyquaternium-1, phenylmercuric nitrate, phenylmercuric borate, sodium propionate, chlorhexidine, thimerosal and combinations thereof. In some embodiments, the composition does not contain preservatives. In some embodiments, the composition does not contain preservatives of detectable levels. In some embodiments, the polypeptide can be self-preservative, that is, no additional preservative is needed to maintain the sterility of the composition.

[0220] In some embodiments, the preservative is present at 0.0001% to 1%; 0.01% to 0.9%; 0.05% to 0.8%; 0.1% to 0.7%; 0.2% to 0.3%; 0.4% to 0.5%, or any value subsumed therein. In some embodiments, the preservative is present in an amount equal to or less than 1%; 0.9%; 0.8%; 0.7%; 0.6%; 0.5%; 0.4%; 0.3%; 0.2%; 0.1%; 0.09%; 0.08%; 0.07%; 0.06%; 0.05%; 0.04%; 0.03%; 0.02%; 0.01%; 0.009%; 0.008%; 0.007%; 0.006%; 0.005%; 0.004%; 0.003%; 0.002%; or 0.001%, or in an amount within the range defined by any two of the foregoing values.

[0221] In some embodiments, the composition is sterile. In some embodiments, the composition is manufactured from sterile ingredients in a sterile environment. In some embodiments, the composition is sterilized before packaging. In some embodiments, the composition is sterilized by one or more of the following methods: (1) adding one or more quaternary ammonium chlorides to the composition; (2) exposing the composition to ionizing radiation; (3) filtering the composition; (4) exposing the composition to ionizing radiation after packaging; and any combination of the foregoing. In some embodiments, filtering includes passing the composition through a filter (including but not limited to a 0.22 micron filter with polyvinylidene fluoride or other suitable membrane (e.g., polyethersulfone)).

[0222] In some embodiments, the peptide is provided in an amount that is bacteriostatic and / or bactericidal. In some embodiments, when one, two or three drops of the composition are applied to the surface of the eye, the amount of the peptide provided in the composition is bacteriostatic and / or bactericidal. In some embodiments, for example, when applied to the eye, the peptide is bacteriostatic and / or bactericidal to Gram-positive and / or Gram-negative bacteria. In some embodiments, in a standard bacteriological assay, relative to a control composition that does not include the peptide, the amount of the peptide in the composition is sufficient to inhibit bacterial growth by at least 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, the bacteria in the bacteriological assay are selected from Pseudomonas aeruginosa (P.aeruginoa), Escherichia coli (E.coli), Staphylococcus epidermidis (S.epidermis), Staphylococcus aureus (S.aureus) or a combination thereof. In some embodiments, the bacteriological assay is selected from a bacterial growth assay, a SYTOX Green assay, a well diffusion assay, a broth or agar dilution assay, a time kill test, an antimicrobial gradient assay, an ATP-bioluminescence assay, or a propidium iodide flow cytometry assay. In some embodiments, the peptide provided in a bacteriostatic and / or bactericidal amount is Lacripep TM .

[0223] In some embodiments, the bacteriological assay is USP Section <51> Assay or FDA-mandated assay. For example, the original product container, containing the peptide solution, is inoculated with one of the prepared and standardized inocula (e.g., Pseudomonas aeruginosa, Escherichia coli, Staphylococcus epidermidis, Staphylococcus aureus, or a combination thereof) and mixed. The volume of the suspended inoculum should be approximately 0.5% to 1.0% of the product volume, and the concentration of the test preparation immediately after inoculation is 1×10 5 to 1×10 6 Colony forming organisms (CFU) / mL of product (by, for example, the plate count method or another microbial enumeration test).

[0224] Incubate the inoculated containers at 22.5 ± 2.5 °C in a controlled environment and take samples at specified intervals, such as 7 days, 14 days, and 28 days. At each sampling, record any changes in appearance and determine the CFU / mL. The log of CFU / mL 10 The change in the value provides a change over time regarding the log reduction. The product has a reduction of not less than 1.0 log from the initial calculated count at 7 days, a reduction of not less than 3.0 log from the initial count at 14 days, and no increase in counts at 28 days from 14 days for bacteria, and no increase from the initial counts for yeast and mold. In some embodiments, the peptide provided in a bacteriostatic and / or bactericidal amount is Lacripep TM .

[0225] Surfactants

[0226] In some embodiments, the composition further comprises one or more surfactants. In some embodiments, the one or more surfactants are selected from detergents, wetting agents, emulsifiers, foaming agents, dispersants, and combinations thereof.

[0227] In some embodiments, the surfactant is an anionic surfactant. Anionic surfactants contain anionic functional groups in their heads, such as sulfate, sulfonate, phosphate and carboxylate. In some embodiments, the surfactant is sulfate ester, sulfonate ester or phosphate ester, such as sulfate ester. In some embodiments, the surfactant is selected from the group comprising ammonium lauryl sulfate and sodium lauryl sulfate (e.g., sodium lauryl sulfate (also referred to as SDS, sodium dodecyl sulfate)) or consisting of it. In some embodiments, the surfactant is an alkyl ether sulfate, such as selected from the group comprising sodium lauryl polyoxyethylene ether sulfate (also referred to as sodium lauryl ether sulfate) and myristyl polyoxyethylene ether sodium sulfate or consisting of it. In some embodiments, the surfactant is docusate, such as dioctyl sodium sulfosuccinate, perfluorooctane sulfonate (PFOS), perfluorobutane sulfonate, linear alkylbenzene sulfonate (LAB). In some embodiments, the surfactant is a carboxylate, such as an alkyl carboxylate (soap), such as sodium stearate; sodium lauroyl sarcosinate and carboxylate-based fluorosurfactants, such as perfluorononanoate, perfluorooctanoate (PFOA or PFO). In some embodiments, the polypeptide contributes to the surfactant properties of the composition.

[0228] In some embodiments, the surfactant is a cationic surfactant, the charge of which may be pH-dependent, such as a primary, secondary or tertiary amine, such as octenidine dihydrochloride; or may contain a permanently charged quaternary ammonium cation, such as an alkyl trimethylammonium salt, such as hexadecyl trimethylammonium bromide (CTAB) or hexadecyl trimethylammonium chloride (CTAC); hexadecylpyridinium chloride (CPC); benzalkonium chloride (BAC); benzethonium chloride (BZT); 5-bromo-5-nitro-1,3-dioxane; dimethyldi(octadecyl) ammonium chloride; or dioctadecyl dimethyl ammonium bromide (DODAB). In some embodiments, the surfactant is a zwitterionic surfactant (i.e., having both cationic and anionic centers attached to the same molecule). The cationic portion may be based on a primary, secondary or tertiary amine or a quaternary ammonium cation. The anionic portion may be more variable and include sulfonates, such as CHAPS (3-[(3-cholamidopropyl) dimethylammonium]-1-propane sulfonate). Other anionic groups are sultaines exemplified by cocamidopropyl hydroxysultaine; betaines, such as cocamidopropyl betaine; phosphates, such as lecithin. In some embodiments, the surfactant may be a nonionic surfactant (uncharged).

[0229] Many long chain alcohols exhibit some surfactant properties and are provided as part of the composition in some embodiments. Prominent among them are the fatty alcohols cetyl alcohol, stearyl alcohol and cetearyl alcohol (consisting primarily of cetyl alcohol and stearyl alcohol) and oleyl alcohol. Other surfactants include cocamide MEA, cocamide DEA, dodecyl dimethyl amine oxide and polyethoxylated tallow amine (POEA). Examples of nonionic surfactants include polyoxyethylene glycol alkyl ethers, such as octaethylene glycol monododecyl ether or pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ethers; glucoside alkyl ethers, such as decyl glucoside, lauryl glucoside or octyl glucoside; polyoxyethylene glycol octylphenol ethers, such as Triton X-100; polyoxyethylene glycol alkylphenol ethers, such as nonoxynol-9; glycerol alkyl esters, such as glyceryl laurate; polyoxyethylene glycol sorbitan alkyl esters (polysorbates); sorbitan alkyl esters (Spans); block copolymers of polyethylene glycol and polypropylene glycol, or poloxamers.

[0230] In some embodiments, the composition may contain one or more ingredients found in artificial tears in an amount known in the art, including, but not limited to: carboxymethylcellulose, polyvinyl alcohol, hydroxypropyl methylcellulose (also known as HPMC or hydroxypropyl methylcellulose), hydroxypropyl cellulose, hydroxyethyl cellulose (HEC) and hyaluronic acid (also known as hyaluronic acid (hyaluronan), HA), and combinations thereof. In some embodiments, the composition does not contain any of the aforementioned artificial tears ingredients.

[0231] In some embodiments, the surfactant is another peptide or protein. In some embodiments, as a non-limiting example, the surfactant is human serum albumin. In some embodiments, as another non-limiting example, the surfactant is Lacripep TM .

[0232] In several embodiments, the surfactant is tyloxapol (formaldehyde; ethylene oxide; 4-(2,4,4-trimethylpentan-2-yl)phenol). In embodiments, the only surfactant is tyloxapol, and no other surfactants are present in the composition.

[0233] In some embodiments, the surfactant (as a non-limiting example, tyloxapol) is present at 0.01% to 1%; 0.05% to 0.9%; 0.1% to 0.8%; 0.2% to 0.7%; 0.3% to 0.6%; 0.4% to 0.5%, or any value subsumed therein. In some embodiments, the surfactant is present in an amount equal to or less than 1%; 0.9%; 0.8%; 0.7%; 0.6%; 0.5%; 0.4%; 0.3%; 0.2%; 0.1%; 0.09%; 0.08%; 0.07%; 0.06%; 0.05%; 0.04%; 0.03%; 0.02%; 0.01%; 0.009%; 0.008%; 0.007%; 0.006%; 0.005%; 0.004%; 0.003%; 0.002%; or 0.001%, or in an amount within the range defined by any two of the foregoing values.

[0234] In some embodiments, the composition includes tyloxapol in an amount of or about 0.0001%, 0.0002%, 0.0005%, 0.001%, 0.002%, 0.005%, 0.01%, 0.02%, or 0.05% (w / v), or a percentage of a range bounded by any two of the foregoing values ​​(e.g., 0.0001% to 0.05%, 0.0001% to 0.02%, 0.001% to 0.01%, 0.0001% to 0.05%, 0.0002% to 0.002%, 0.0005% to 0.002%, 0.0002% to 0.001%, 0.001% to 0.01%, 0.001% to 0.05%, or 0.001% to 0.005%, etc.). In some embodiments, tyloxapol is present in the liquid composition at 0.0001% to 0.002% (w / v). In some embodiments, tyloxapol is present in the liquid composition at 0.0005% to 0.005% (w / v). In some embodiments, tyloxapol is present in the liquid composition at 0.001% to 0.01% (w / v). In some embodiments, tyloxapol is present in the liquid composition at about 0.001% (w / v). In some embodiments, tyloxapol is present in the liquid composition at about 0.01% (w / v). In some embodiments, tyloxapol is present in the liquid composition at about 0.05% (w / v).

[0235] In some embodiments, the composition contains no surfactant.In some embodiments, the composition contains no detectable levels of surfactant.

[0236] Tonicity Agents and Osmolality

[0237] In some embodiments, the composition further comprises one or more tonicity agents. Such tonicity agents are tonicity agents other than any polypeptide or buffer having a tonicity regulating effect. In some embodiments, one or more tonicity agents are selected from propylene glycol, polyethylene glycol, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, monosaccharides such as dextrose, fructose, galactose and / or simple polyols such as sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, hydrogenated starch hydrolysate, glycerol and combinations thereof.

[0238] In some embodiments, the one or more tonicity agents are selected from sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose, mannitol, and combinations thereof.

[0239] In some embodiments, the tonicity agent is sodium chloride. In some embodiments, sodium chloride is present at 0.01% to 1%; 0.05% to 0.9%; 0.1% to 0.8%; 0.2% to 0.75%; 0.3% to 0.7%; 0.4% to 0.6%; or any value subsumed therein. In some embodiments, sodium chloride is present in an amount that is or is about 1%; 0.95%; 0.9%; 0.85%; 0.8%; 0.75%; 0.7%; 0.65%; 0.6%; 0.55%; 0.5%; 0.45%; 0.4%; 0.35%; 0.3%; 0.25%; 0.2%; 0.15%; 0.1%; 0.09%; 0.08%; 0.07%; 0.06%; 0.05%; 0.04%; 0.03%; 0.02%; or 0.01%; or in an amount within a range defined by any two of the foregoing values.

[0240] In some embodiments, the only tonicity agent is sodium chloride, and no other tonicity agents are present in the composition.

[0241] In some embodiments, a tonicity agent (as a non-limiting example, sodium chloride) is added to the composition to adjust the osmotic pressure concentration to a desired level. In some embodiments, the osmotic pressure concentration of the composition is about 150mOsm / kg to about 400mOsm / kg; about 170mOsm / kg to about 380mOsm / kg; about 190mOsm / kg to about 360mOsm / kg; about 210mOsm / kg to about 340mOsm / kg; about 230mOsm / kg to about 320mOsm / kg; about 250mOsm / kg to about 300mOsm / kg; about 270mOsm / kg to about 280mOsm / kg; or any value therebetween. In some embodiments, the osmolality of the composition is about 250 mOsm / kg to about 350 mOsm / kg; about 260 mOsm / kg to about 340 mOsm / kg; about 270 mOsm / kg to about 330 mOsm / kg; about 280 mOsm / kg to about 320 mOsm / kg; about 290 mOsm / kg to about 310 mOsm / kg; or any value therebetween. In some embodiments, the osmolality of the composition is from about 150 mOsm / kg to about 300 mOsm / kg; from about 150 mOsm / kg to about 250 mOsm / kg; from about 160 mOsm / kg to about 230 mOsm / kg; from about 170 mOsm / kg to about 220 mOsm / kg; from about 180 mOsm / kg to about 220 mOsm / kg; from about 190 mOsm / kg to about 210 mOsm / kg; from about 190 mOsm / kg to about 200 mOsm / kg; from about 170 mOsm / kg to about 210 mOsm / kg; from about 180 mOsm / kg to about 200 mOsm / kg; or any value therebetween.

[0242] In some embodiments, the osmolality of the composition is or is about 150 mOsm / kg; 160 mOsm / kg; 170 mOsm / kg; 180 mOsm / kg; 190 mOsm / kg; 200 mOsm / kg; 210 mOsm / kg; 220 mOsm / kg; 230 mOsm / kg; 240 mOsm / kg; 250 mOsm / kg; 260 mOsm / kg; 270 mOsm / kg; 280 mOsm / kg; 290 mOsm / kg; 300 mOsm / kg; 310 mOsm / kg; 320 mOsm / kg; 330 mOsm / kg; 340 mOsm / kg; or 350 mOsm / kg, or is within a range defined by any two of the foregoing values.

[0243] In some embodiments, the weight-gram molecular osmotic pressure concentration of the composition is about 280mOsm / kg to about 320mOsm / kg. In some embodiments, the weight-gram molecular osmotic pressure concentration of the composition is about 300mOsm / kg. In some embodiments, NaCl is used to adjust the weight-gram molecular osmotic pressure concentration of the solution to the desired level. In embodiments, the composition is isotonic or approximately isotonic with human tears.

[0244] In some embodiments, USP <785> Methods Osmolality was measured.

[0245] Peptides and other ingredients

[0246] In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof has 10 to 150 amino acids; 10 to 50 amino acids; 100 to 150 amino acids; 30 to 70 amino acids; or any number subsumed therein. In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof has 10 to 30 amino acids; 11 to 29 amino acids; 12 to 28 amino acids; 13 to 27 amino acids; 14 to 26 amino acids; 15 to 25 amino acids; 16 to 24 amino acids; 17 to 23 amino acids; 18 to 22 amino acids; 19 to 21 amino acids; or any number subsumed therein. In some embodiments, the polypeptide, or a pharmaceutically acceptable salt thereof, is or is about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acids in length, or a range bounded by any two of the foregoing values.

[0247] In some embodiments, the C-terminus of a polypeptide or a pharmaceutically acceptable salt thereof is amidated. In some embodiments, the N-terminus of a polypeptide or a pharmaceutically acceptable salt thereof is acetylated. In some embodiments, one or more side chains of a polypeptide or a pharmaceutically acceptable salt thereof are acetylated. In some embodiments, one or more side chains of a polypeptide or a pharmaceutically acceptable salt thereof are amidated. In some embodiments, the N-terminus of a polypeptide or a pharmaceutically acceptable salt thereof is acetylated and the C-terminus of a polypeptide or a pharmaceutically acceptable salt thereof is amidated.

[0248] In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof comprises, consists of, or consists essentially of the following amino acid sequence: Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-Leu-Leu-Lys-Pro-Trp-Ala-NH2 (SEQ ID NO:2), wherein "Ac" represents an acetyl group and the C-terminus is amidated (indicated as "NH2"). In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof comprises the amino acid sequence: Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2 (SEQ ID NO: 1), wherein "Ac" represents an acetyl group, and the C-terminus is amidated (denoted as "NH2"). In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof comprises, consists of, or consists essentially of a sequence selected from SEQ ID NO: 3-9, or a fragment or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, the amount of the polypeptide or its pharmaceutically acceptable salt in the composition is or is about 0.0001% to 0.005%; 0.0005% to 0.005%; or 0.001% to 0.005%. In embodiments, the polypeptide or its pharmaceutically acceptable salt is present in the composition at about 0.003% to 0.09% (e.g., 0.005%, 0.01%, 0.02%, 0.03% and ranges thereof).

[0250] In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof is present in the composition in an amount that is, is about, is more than, or is less than 0.0001%, 0.00025%, 0.0005%, 0.00075%, 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, or 0.006%, or a range defined by any two of the foregoing values. In some embodiments, the composition comprises the polypeptide or a pharmaceutically acceptable salt thereof in an amount of or about 0.0001%, 0.0002%, 0.00025%, 0.0003%, 0.0005%, 0.00075%, 0.001%, 0.002%, 0.005% or 0.006% (w / v), or a percentage of a range defined by any two of the foregoing values ​​(e.g., 0.00025% to 0.006%, 0.00025% to 0.005%, 0.00025% to 0.001%, 0.0001% to 0.001%, 0.0001% to 0.002%, or 0.001% to 0.005%). In some embodiments, the composition comprises the polypeptide or a pharmaceutically acceptable salt thereof in an amount of 0.00025% to 0.005% (w / v). In some embodiments, the composition comprises a polypeptide or a pharmaceutically acceptable salt thereof in an amount of 0.0001% to 0.002% (w / v). In some embodiments, the composition comprises a polypeptide or a pharmaceutically acceptable salt thereof in an amount of about 0.00025% (w / v). In some embodiments, the composition comprises a polypeptide or a pharmaceutically acceptable salt thereof in an amount of about 0.001% (w / v). In some embodiments, the composition comprises a polypeptide or a pharmaceutically acceptable salt thereof in an amount of about 0.005% (w / v). In some embodiments, the amount of the polypeptide or its pharmaceutically acceptable salt is, is about, is at least, is at least about, does not exceed, does not exceed about 0.1 μM, 0.5 μM, 1.0 μM, 1.5 μM, 2.0 μM, 2.5 μM, 3.0 μM, 3.5 μM, 4.0 μM, 4.5 μM, 5.0 μM, 10 μM, 15 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM or 25 μM, or a range defined by any two of the foregoing values ​​(e.g., 0.1 μM to 25 μM, 0.1 μM to 6.0 μM, 0.1 μM to 4.0 μM, 1.0 μM to 5.0 μM, 1.0 μM to 22 μM, or 1.0 μM to 4.0 μM). In some embodiments, the composition comprises the polypeptide or its pharmaceutically acceptable salt in an amount of about 1.0 μM. In some embodiments, the composition comprises the polypeptide or a pharmaceutically acceptable salt thereof in an amount of about 4.0 μM. In some embodiments, the composition comprises the polypeptide or a pharmaceutically acceptable salt thereof in an amount of about 22 μM.In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof has a sequence consisting of or consisting essentially of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2 (SEQ ID NO: 1), wherein "Ac" represents an acetyl group and the C-terminus is amidated.

[0251] In some embodiments, the composition comprises: 0.0001% to 0.005% (w / v) of a polypeptide having a sequence consisting of or consisting essentially of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2 (SEQ ID NO: 1), wherein "Ac" represents an acetyl group and the C-terminus is amidated; 0.01% to 0.6% (w / v) of a buffer; 0.0005% to 0.01% (w / v) disodium EDTA; 0.0001% to 0.02% or 0.0001% to 0.06% (w / v) tyloxapol; and about 0.1% to 1.0% NaCl; wherein the pH of the composition is about 6.0 to about 7.0, and the osmolality is 170 mOsm / kg to 210 mOsm / kg. In some embodiments, the composition is a sterile aqueous composition.

[0252] In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of: about 0.005% ± 0.0005% of a polypeptide, such as Lacripep TM (SEQ ID NO.1) or other peptides identified herein, or a pharmaceutically acceptable salt thereof; about 0.0098% ± 0.001% anhydrous citric acid; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.001% ± 0.0001% tyloxapol; about 0.50% ± 0.05% NaCl; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the weight-gram molecular osmotic pressure concentration is 170mOsm / kg to 210mOsm / kg. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of: about 0.005% ± 0.0005% of a polypeptide, such as Lacripep TM(SEQ ID NO.1) or other peptides identified herein, or a pharmaceutically acceptable salt thereof; about 0.0098% ± 0.001% anhydrous citric acid; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.01% ± 0.001% tyloxapol; about 0.50% ± 0.05% NaCl; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the weight-gram molecular osmotic pressure concentration is 170mOsm / kg to 210mOsm / kg. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of: about 0.005% ± 0.0005% of a polypeptide, such as Lacripep TM (SEQ ID NO.1) or other peptides identified herein, or a pharmaceutically acceptable salt thereof; about 0.0098% ± 0.001% anhydrous citric acid; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.05% ± 0.005% tyloxapol; about 0.50% ± 0.05% NaCl; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the weight-gram molecular osmotic pressure concentration is 170mOsm / kg to 210mOsm / kg. In an embodiment, the pH is about 6.3 to about 6.5 and the weight-gram molecular osmotic pressure concentration is 180mOsm / kg to 200mOsm / kg. In an embodiment, the composition consists solely of the listed ingredients and does not contain any additional active ingredients, excipients (eg, viscosity building agents, buffers, chelating agents, stabilizers, preservatives, surfactants and tonicity agents), carriers or diluents.

[0253] In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of: about 0.001% ± 0.0001% of a polypeptide, such as Lacripep TM(SEQ ID NO.1) or other peptides identified herein, or a pharmaceutically acceptable salt thereof; about 0.0098% ± 0.001% anhydrous citric acid; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.001% ± 0.0001% tyloxapol; about 0.50% ± 0.05% NaCl; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the weight-gram molecular osmotic pressure concentration is 170mOsm / kg to 210mOsm / kg. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of: about 0.001% ± 0.0001% of a polypeptide, such as Lacripep TM (SEQ ID NO.1) or other peptides identified herein, or a pharmaceutically acceptable salt thereof; about 0.0098% ± 0.001% anhydrous citric acid; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.01% ± 0.001% tyloxapol; about 0.50% ± 0.05% NaCl; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the weight-gram molecular osmotic pressure concentration is 170mOsm / kg to 210mOsm / kg. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of: about 0.001% ± 0.0001% of a polypeptide, such as Lacripep TM (SEQ ID NO.1) or other peptides identified herein, or a pharmaceutically acceptable salt thereof; about 0.0098% ± 0.001% anhydrous citric acid; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.05% ± 0.005% tyloxapol; about 0.50% ± 0.05% NaCl; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the weight-gram molecular osmotic pressure concentration is 170mOsm / kg to 210mOsm / kg. In an embodiment, the pH is about 6.3 to about 6.5 and the weight-gram molecular osmotic pressure concentration is 180mOsm / kg to 200mOsm / kg. In an embodiment, the composition consists solely of the listed ingredients and does not contain any additional active ingredients, excipients (eg, viscosity building agents, buffers, chelating agents, stabilizers, preservatives, surfactants and tonicity agents), carriers or diluents.

[0254] In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of: about 0.00025% ± 0.000025% of a polypeptide, such as Lacripep TM (SEQ ID NO.1) or other peptides identified herein, or a pharmaceutically acceptable salt thereof; about 0.0098% ± 0.001% anhydrous citric acid; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.001% ± 0.0001% tyloxapol; about 0.50% ± 0.05% NaCl; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the weight-gram molecular osmotic pressure concentration is 170mOsm / kg to 210mOsm / kg. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of: about 0.00025% ± 0.000025% of a polypeptide, such as Lacripep TM (SEQ ID NO.1) or other peptides identified herein, or a pharmaceutically acceptable salt thereof; about 0.0098% ± 0.001% anhydrous citric acid; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.01% ± 0.001% tyloxapol; about 0.50% ± 0.05% NaCl; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the weight-gram molecular osmotic pressure concentration is 170mOsm / kg to 210mOsm / kg. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of: about 0.00025% ± 0.000025% of a polypeptide, such as Lacripep TM(SEQ ID NO.1) or other peptides identified herein, or a pharmaceutically acceptable salt thereof; about 0.0098% ± 0.001% anhydrous citric acid; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.05% ± 0.005% tyloxapol; about 0.50% ± 0.05% NaCl; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the weight-gram molecular osmotic pressure concentration is 170mOsm / kg to 210mOsm / kg. In an embodiment, the pH is about 6.3 to about 6.5 and the weight-gram molecular osmotic pressure concentration is 180mOsm / kg to 200mOsm / kg. In an embodiment, the composition consists solely of the listed ingredients and does not contain any additional active ingredients, excipients (eg, viscosity building agents, buffers, chelating agents, stabilizers, preservatives, surfactants and tonicity agents), carriers or diluents.

[0255] In some embodiments, including but not limited to the above-mentioned sterile compositions, the polypeptide is Lacripep having SEQ ID NO: 1. TM or a pharmaceutically acceptable salt thereof. In some embodiments, the polypeptide is a polypeptide having SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof. In some embodiments, the polypeptide is a polypeptide having a sequence selected from SEQ ID NO: 3-9 or a pharmaceutically acceptable salt thereof or one or more fragments thereof.

[0256] In some embodiments, including but not limited to the above sterile compositions, the pH of the composition is about 6.5 to about 6.6. In some embodiments, including but not limited to the above sterile compositions, the pH of the composition is about 6.3 to about 6.5. In some embodiments, including but not limited to the above sterile compositions, the pH of the composition is about 6.5.

[0257] In some embodiments, including but not limited to the above-mentioned sterile compositions, the weight-gram molecular osmotic pressure concentration of the composition is about 270mOsm / kg to about 210mOsm / kg. In some embodiments, including but not limited to the above-mentioned sterile compositions, the weight-gram molecular osmotic pressure concentration of the composition is about 180mOsm / kg to about 200mOsm / kg. In some embodiments, the weight-gram molecular osmotic pressure concentration of the composition is about 190mOsm / kg.

[0258] In embodiments, including but not limited to the above-mentioned sterile compositions, the composition consists solely of the listed ingredients and does not contain any additional active ingredients, excipients (e.g., viscosity building agents, buffers, chelating agents, stabilizers, preservatives, surfactants, and tonicity agents), carriers, or diluents. In some embodiments, the amounts of any one or more of the listed ingredients are provided in amounts of ±5% and / or ±1% of the listed amounts.

[0259] In some embodiments, compositions disclosed herein are prepared as solutions, gels or ointments. Gels or ointments are advantageous in providing compositions that are in contact with the eye for a longer time period than solutions or in providing other benefits. Therefore, in some embodiments, when the composition is applied to the object when the object will sleep or when the object's eyes will close an extended time period (e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or more hours), gels or ointments are useful. Based on the user's preference, gels or ointments can be used at other times.

[0260] Non-limiting exemplary compositions that can be used in the methods and kits disclosed herein include the following compositions in Table A, Table B, and Table C below, and the compositions in Table 1.1, Table 1.2, and Table 1.3 in the Examples.

[0261] Table A

[0262]

[0263] Table B

[0264]

[0265] Table C

[0266]

[0267] Embodiments of the compositions of Table A and / or Table B and / or Table C (and Table 1.1 and / or Table 1.2 and / or Table 1.3) also include compositions having a pH of 6.3 to 6.5. Embodiments of the compositions of Table A and / or Table B and / or Table C (and Table 1.1 and / or Table 1.2 and / or Table 1.3) also include compositions having an amount of the disclosed ingredients within a range of ±1% of the disclosed amounts, within a range of ±2% of the disclosed amounts, within a range of ±3% of the disclosed amounts, within a range of ±4% of the disclosed amounts, or within a range of ±5% of the disclosed amounts. In some embodiments, after the composition is stored at -20±5°C, 5±3°C or 25±2°C and 25±5% relative humidity for at least 1 week or 2 weeks, 1 month, 2 months, 3 months, 4 months or 5 months, the composition of Table A and / or Table B and / or Table C (and Table 1.1 and / or Table 1.2 and / or Table 1.3) maintains its original undegraded form of Lacripep 1 of SEQ ID NO: 1.TM At least about 99.0%, 99.9%, 99.95% or 99.99% of the polypeptide in the composition. In some embodiments, after the composition is stored at -20±5°C or 5±3°C for at least 12 months, the composition of Table A and / or Table B and / or Table C (and Table 1.1 and / or Table 1.2 and / or Table 1.3) maintains its original undegraded form of Lacripep of SEQ ID NO: 1. TM The polypeptide comprises at least about 80% or 90% of the composition.

[0268] Other therapeutic ingredients

[0269] In some embodiments, in addition to the polypeptide disclosed herein, the composition further comprises one or more additional therapeutic agents. These therapeutic agents may include substances known to those skilled in the art for treating dry eye and related syndromes and conditions (including general dry eye). Additional therapeutic ingredients may treat a disease, syndrome, or condition, or may alleviate symptoms associated with a disease, syndrome, or condition. A non-exhaustive list of additional therapeutic agents includes: cholinergics (e.g., pilocarpine, cevimeline), cyclosporine, lifalast, dexamethasone (or other corticosteroids, such as prednisolone), hyaluronic acid (and its derivatives) with or without chondroitin sulfate, Cyclokat, SI-614, skQ1, Cis-UCA, CycloASol, RGN-259, diquafosol, anakinra, tofacitinib, EBI-005, EGP-437, KP-121, MIM-D3, OTX-DP, rebamipat (OPC-12759), and RU-101. In some embodiments, the additional therapeutic agent is Xiidra (lifalast, SAR-1118). In some embodiments, one or more additional therapeutic agents are provided as salts of the polypeptide. Compositions may also include artificial tears and other lubricants containing one or more of carboxymethylcellulose, polyvinyl alcohol, hydroxypropylmethylcellulose (also known as HPMC or hydroxypropylmethylcellulose), hydroxypropylcellulose, glycol polymers, and hyaluronic acid (also known as hyaluronan, HA), as well as tear ointments such as white petrolatum, mineral oil, and similar lubricants. These additional therapeutic agents may be included in known therapeutic or subtherapeutic amounts.

[0270] Containers and kits

[0271] In some embodiments, the composition is provided with a package product comprising one or more reusable containers. In some embodiments, the reusable container comprises a protective cap and a liquid storage bottle, wherein the cap is connected to the bottle via a flexible connector. A plug is arranged in the middle of the protective cap top surface. A taper or other suitable liquid outlet is arranged in the middle of the bottle cap, and is closely matched with the plug of the protective cap. Therefore, the sterile composition can be placed in a container for multiple use.

[0272] In some embodiments, the amount of the composition in the container is or is about: 0.1 mL to 0.5 mL, 0.5 mL to 1.0 mL, 1 mL to 2 mL, 2 mL to 5 mL, 5 mL to 10 mL, 10 mL to 20 mL, 20 mL to 30 mL, or 30 mL to 60 mL, or a range therebetween. The container can be a bottle, tube, vial, or other suitable container. Multiple use containers can be accompanied by instructions for use for 12 hours, 24 hours, 2 days to 7 days, a monthly cycle, or until a specified expiration date. Single use containers can be suitable for use in one eye or both eyes in a single application cycle.

[0273] In some embodiments, the composition is provided in a package comprising a single-use container. In some embodiments, the composition is provided in a package comprising a plurality of single-use containers. In some embodiments, the single-use container comprises a vessel for holding a liquid, a removable sealing top for sealing the vessel, and optionally a neck portion interconnecting the vessel and the sealing top. In several embodiments, a package comprising a plurality of single-use containers and instructions for use is provided.

[0274] In some embodiments, the container comprises a pharmaceutically inert material. In some embodiments, the container comprises glass, polyvinyl chloride, polypropylene, polyethylene terephthalate, polyethylene terephthalate, polyethylene terephthalate G, high density polyethylene, low density polyethylene, polybutylene terephthalate, polyurethane, polyethylene vinyl acetate, silicone, acrylonitrile butadiene styrene, polytetrafluoroethylene, polycarbonate, polystyrene, polymethyl methacrylate, polysulfone, polyvinylidene chloride, or a combination thereof.

[0275] In some embodiments, the container comprises polyvinyl chloride, polypropylene, low density polyethylene, polyurethane, polyethylene vinyl acetate, silicone, or a combination thereof.

[0276] In some embodiments, the amount of composition in the container is or is about 0.02 mL; 0.05 mL to 1 mL; 0.1 mL to 0.95 mL; 0.15 mL to 0.8 mL; 0.2 mL to 0.85 mL; 0.25 mL to 0.8 mL; 0.3 mL to 0.75 mL; 0.35 mL to 0.7 mL; 0.4 mL to 0.65 mL; 0.45 mL to 0.6 mL; 0.5 mL to 0.55 mL; or any amount therebetween.

[0277] In some embodiments, the amount of the composition in the container is or is about 0.02 mL; 0.025 mL; 0.030 mL; 0.035 mL; 0.040 mL; 0.045 mL; 0.050 mL; 0.055 mL; 0.060 mL; 0.065 mL; 0.070 mL; 0.075 mL; 0.1 mL; 0.15 mL; 0.2 mL; 0.25 mL; 0.3 mL; 0.35 mL; 0.4 mL; 0.45 mL; 0.5 mL; 0.55 mL; 0.6 mL; 0.65 mL; 0.7 mL; 0.75 mL; 0.8 mL; 0.85 mL; 0.9 mL; 0.95 mL; or 1 mL of the composition, or an amount within a range defined by any two of the foregoing values.

[0278] Ophthalmic and other applications

[0279] Provided herein are methods of treating ocular symptoms associated with moderate / severe dry eye by administering a polypeptide as described herein to an eye of a subject identified as having moderate / severe dry eye and in need thereof. In some embodiments, the subject is identified as having severe dry eye. In some embodiments, the subject does not have Sjögren's syndrome (primary or secondary). Reference Figure 1 , a method of treating moderate / severe ocular symptoms associated with dry eye in a subject (e.g., a subject suffering from general dry eye) is provided. Method 100 may include, at block 110, identifying a subject suffering from one or more moderate / severe ocular symptoms associated with dry eye (e.g., suffering from general dry eye, and optionally not suffering from Sjögren's syndrome (primary or secondary)) and meeting one or more (e.g., 1, 2, 3, or 4) of the following criteria:

[0280] a) Total FCS score in the NEI / Industry Workshop Scale is ≥ 4 and < 15,

[0281] b) Using VAS instantaneous dry eye score ≥ 60,

[0282] c) Schirmer 1 test score ≤ 5 mm wetting / 5 minutes under anesthesia, and

[0283] d) LGCS total score ≥ 5 (where 0 = no staining) using the NEI / Industry Workshop Scale.

[0284] In some embodiments, the subject with moderate / severe dry eye meets all four of the above criteria in at least one eye.In some embodiments, the subject is identified as having severe dry eye by a SANDE score of ≥ 60 (not shown).

[0285] At block 120, the method includes administering to a subject a composition of the disclosure, e.g., comprising an amount of a polypeptide of the disclosure (e.g., Lacripep TM (SEQ ID NO: 1)) or a pharmaceutically acceptable salt thereof, such as a composition in Table A, Table B or Table C, or Table 1.1, Table 1.2 or Table 1.3.

[0286] In some embodiments, a subject does not have moderate / severe or severe dry eye and / or dry eye symptoms in at least one eye when the subject meets at least one of the following criteria in at least one eye:

[0287] a) Total FCS score <4 or ≥15 in the NEI / Industry Workshop Scale,

[0288] b) Using VAS instantaneous dry eye score <60,

[0289] c) Schirmer 1 test score > 5 mm wetting / 5 minutes under anesthesia, or

[0290] d) LGCS total score <5 (where 0 = no staining) using the NEI / Industry Workshop scale.

[0291] In some embodiments, when the total FCS score in the NEI / industry seminar scale is <4 in at least one eye, the subject does not have moderate / severe or severe dry eyes and / or dry eye symptoms in at least one eye. In some embodiments, when the VAS moment is used in at least one eye, the dry eye score is <60, and the subject does not have moderate / severe or severe dry eyes and / or dry eye symptoms in at least one eye. In some embodiments, when the Schirmer 1 test score under anesthesia in at least one eye is >5mm wetting / 5 minutes, the subject does not have moderate / severe or severe dry eyes and / or dry eye symptoms in at least one eye. In some embodiments, when the NEI / industry seminar scale is used in at least one eye, the LGCS total score is <5 (where 0 = no staining), the subject does not have moderate / severe or severe dry eyes and / or dry eye symptoms in at least one eye.

[0292] Subjects suffering from one or more moderate / severe ocular symptoms associated with dry eyes can be identified using any suitable selection. In some embodiments, based at least on the assessment of one or more ocular symptoms associated with dry eyes (such as but not limited to pain, stinging, burning, or itching) of the subject, the subject is identified as suffering from moderate / severe ocular symptoms associated with dry eyes. In some embodiments, based at least on the assessment of stinging and / or burning in the eyes of the subject, the subject is identified as suffering from moderate / severe ocular symptoms associated with dry eyes. In some embodiments, the assessment of symptoms is an instantaneous assessment of the subject's symptoms. In some embodiments, symptoms are rated on a visual analog scale (VAS), for example, on a scale of 0 mm to 100 mm, 0 mm is the minimum intensity and 100 mm is the maximum intensity, to provide an eye dryness score (EDS) (e.g., on a scale of 0 mm to 100 mm, 0 mm is the minimum score and 100 mm is the maximum score). EDS can be obtained by assessing the subject's symptoms on a questionnaire, for example, such as Figure 6 As shown. Using the VAS, the assessment of the subject's symptoms reported on the linear dimension of the scale is measured in millimeters (e.g., the left end of each line is taken as 0) to provide the EDS. (See Schaumberg D, et al. Development and Validation of a Short Global Dry Eye Symptom Index. The Ocular Surface. January 2007, Vol 5; 1; 50-57, which is incorporated herein by reference in its entirety). The EDS score is a VAS questionnaire (e.g., Figure 6 The value of the “Dry eyes” row in the questionnaire in the .

[0293] In some embodiments, at least when the subject has an EDS equal to or higher than a predetermined EDS threshold, the subject is identified as suffering from moderate / severe dry eye-related ocular symptoms. In some embodiments, the EDS threshold is determined based on the distribution of EDS in a patient group known to suffer from moderate / severe dry eye. In some embodiments, the EDS threshold is determined based on the distribution of EDS in a subject group known not to have moderate / severe dry eye. In some embodiments, the EDS threshold is 60, 65, 70, 75, 80, 85, 90 or more, or a value within a range (e.g., 60 to 90, 60 to 80, 60 to 70, or 60 to 100) defined by any two of the foregoing values. In some embodiments, one or more dry eye-related ocular symptoms include an EDS equal to or greater than 60. In some embodiments, the subject suffers from general dry eye. In some embodiments, the subject does not suffer from Sjögren's syndrome (primary or secondary).

[0294] In some embodiments, the method includes using at least the subject's responses to one or more questionnaires designed to measure, for example, but not limited to, one or more of the following: ocular surface discomfort or visual symptoms associated with dry eye; the impact of dry eye on daily function; and health-related quality of life, which can be used instead of or in addition to the subject's momentary assessment of one or more dry eye-related ocular symptoms on the VAS scale as discussed above to identify the subject as suffering from dry eye-related ocular symptoms. In some embodiments, the questionnaire includes, but is not limited to, one or more of the following: 1) Ocular Surface Disease Index (OSDI); 2) Impact of Dry Eye on Daily Life (IDEEL); 3) National Eye Institute-Visual Function Questionnaire (NEIVFQ); 4) Symptom Assessment of Dry Eye (SANDE); 5) Dry Eye Related Quality of Life Score Questionnaire (DEQS); 6) McMonnies Dry Eye Questionnaire; 7) Women's Health Study Questionnaire; 8) Dry Eye Questionnaire (DEQ); 9) North Carolina Dry Eye Management Scale (UNC DEMS); 10) Subjective Evaluation of Symptoms of Dryness (SESoD); 11) Standardized Patient Evaluation of Dry Eye (SPEED); 12) Dry Eye Epidemiology Project Questionnaire (DEEP); 13) Canadian Dry Eye Epidemiology Study (CANDEES); 14) Salisbury Eye Evaluation; 15) Melbourne Vision Impairment Project; 16) Bjerrum Questionnaire; 17) Japanese Dry Eye Awareness Study. Suitable non-limiting examples of questionnaires are summarized in Stapleton et al.TFOSDEWS II Epidemiology Report.Ocul Surf.2017Jul; 15(3):334-365, and Wolffsohn et al.TFOSDEWS II Diagnostic Methodology report.Ocul Surf.2017Jul; 15(3):539-574, each of which is incorporated herein by reference in its entirety. In some embodiments, at least when the measurement of the symptoms by any suitable questionnaire (e.g., as discussed above) is at or above a threshold measurement, the subject is identified as suffering from moderate / severe dry eye-related ocular symptoms, the threshold measurement corresponding to the EDS threshold of the instantaneous assessment of one or more dry eye-related ocular symptoms of the subject in the VAS scale. In some embodiments, the subject does not suffer from Sjögren's syndrome (primary or secondary).

[0295] In some embodiments, subjects with one or more moderate / severe ocular symptoms associated with dry eye are identified at least by one or more ocular measurements (e.g., one or more ocular symptoms that are not measured based on the subject's report). Any suitable ocular measurement can be used to identify a subject as suffering from one or more ocular symptoms associated with dry eye. In some embodiments, the symptoms of dry eye are determined based on at least, but not limited to, measurements of one or more of tear film stability, tear secretion, tear volume, tear film composition, ocular surface damage, ocular surface inflammation, and eyelid function. In some embodiments, the symptoms of dry eye are determined at least by, but not limited to, one or more of increased corneal staining, increased conjunctival staining, shortened tear breakup time, and reduced Schirmer tear test scores (anesthetized or unanesthetized). Suitable non-limiting examples of ocular measurements are summarized in Stapleton et al. TFOSDEWS II Epidemiology Report. Ocul Surf. 2017 Jul; 15(3): 334-365, and Wolffsohn et al. TFOSDEWS II Diagnostic Methodology report. Ocul Surf. 2017 Jul; 15(3): 539-574, each of which is incorporated herein by reference in its entirety. In some embodiments, the subject does not suffer from Sjögren's syndrome (primary or secondary).

[0296] In some embodiments, symptoms of moderate / severe dry eyes are determined by at least one or more of, but not limited to, the Schirmer test (e.g., Schirmer test under anesthesia), lissamine green conjunctival staining (LGCS), and fluorescein corneal staining (FCS). "Fluorescein corneal staining," "FCS," "corneal fluorescein staining," and "CFS" are used interchangeably herein. In some embodiments, the method includes measuring ocular surface staining, such as FCS or LGCS, to determine whether the subject has one or more ocular symptoms associated with dry eyes. In some embodiments, ocular surface staining is scored using the National Eye Institute (NEI) / Industry Workshop scale. In some embodiments, the FCS of the NEI / Industry Workshop scale is scored by a trained physician (e.g., a trained ophthalmologist) by scoring the CFS level within a grid that divides the corneal area into five sections (e.g., as Figure 7The LGCS of the NEI / Industry Workshop scale is determined by assigning a score (or grade) from zero to 3 to each section, depending on the amount and distribution of staining. A score / grade of 0 indicates no staining in the section. In the NEI / Industry Workshop scale, the total FCS score can range from 0 / 15 (indicating the absence of corneal epithelial lesions) to 15 / 15 (indicating severe epithelial lesions). In some embodiments, the LGCS of the NEI / Industry Workshop scale is determined by a trained physician (e.g., a trained ophthalmologist) by scoring the level of LGCS within a grid that divides the conjunctival area into six sections (superior limbal, inferior limbal, peripheral area of ​​both the nasal and temporal sections) (e.g., as Figure 8 ), assigning each section a score (or grade) from zero to 3, based on the amount and distribution of staining. A score / grade of 0 indicates no staining in the section. In the NEI / Industry Workshop scale, the total LGCS score can range from 0 / 18 to 18 / 18.

[0297] Ocular surface staining can be scored using any suitable equivalent selection to the NEI / industry workshop scale detailed above. In some embodiments, ocular surface staining is scored according to one or more of the following grading scales: van Bijsterveld system, collaborative longitudinal evaluation of keratoconus (CLEK) scheme, Oxford scheme, area-density combined index, and international collaborative clinical alliance eye staining score for Sjögren's syndrome. Suitable non-limiting examples of scoring ocular surface staining are summarized in Wolffsohn et al. TFOSDEWS II Diagnostic Methodology report. OculSurf. 2017 Jul; 15 (3): 539-574, which is incorporated herein by reference in its entirety.

[0298] In some embodiments, at least when the total FCS score of the object is above the FCS threshold, the object is identified as suffering from moderate / severe ocular symptoms associated with dry eye. In some embodiments, one or more ocular symptoms associated with dry eye include a total FCS score of ≥ about 4 and < about 15 in the NEI / industry workshop scale. In some embodiments, the FCS threshold in the NEI / industry workshop scale is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, or a range defined by any two of the foregoing values ​​(e.g., 4 to 14, 6 to 12, 4 to 10, 6 to 8, 6 to 14, 8 to 14, 8 to 12 or 4 to 6), wherein 0 indicates no staining. In some embodiments, at least when the total FCS score of the object determined using the alternative scoring option is equal to or higher than a threshold value corresponding to a threshold value defined using the NEI / industry workshop standard, the object is identified as suffering from ocular symptoms associated with dry eye.

[0299] In some embodiments, at least when the object's lissamine green conjunctival staining (LGCS) score is higher than the LGCS threshold, the object is identified as suffering from moderate / severe dry eye-related ocular symptoms. In some embodiments, one or more dry eye-related ocular symptoms include an LGCS score of ≥5 in the National Eye Institute (NEI) / industry workshop scale, where 0 indicates no staining. In some embodiments, in the NEI / industry workshop scale, the LGCS threshold is at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or higher, or a range defined by any two of the aforementioned values ​​(e.g., 5 to 14, 5 to 12, 8 to 14, 5 to 8, 10 to 14 or 5 to 6), where 0 indicates no staining. In some embodiments, at least when the LGCS score of the object determined using the alternative scoring option is equal to or higher than the threshold value corresponding to the threshold value defined using the NEI / industry workshop scale, the object is identified as suffering from dry eye-related ocular symptoms.

[0300] In some embodiments, based at least on the measurement of tear secretion, the subject is identified as suffering from moderate / severe dry eye-related ocular symptoms. In some embodiments, tear secretion is measured using the Schirmer test or its variants. The Schirmer test can be any suitable form of the Schirmer test. In some embodiments, one or more dry eye-related ocular symptoms include a Schirmer test score of ≤5 mm wet / 5 minutes under anesthesia. In some embodiments, the Schirmer test is not limited to Schirmer 1, Schirmer 2, Schirmer 3, thread method or 1 minute Schirmer test under anesthesia. In some embodiments, one or more dry eye-related ocular symptoms include a Schirmer test score below the Schirmer test threshold, for example, a Schirmer 1 test score under anesthesia below the Schirmer 1 test threshold under anesthesia. Suitable Schirmer tests and their variants and corresponding thresholds are summarized in Savini et al. The challenge of dry eye diagnosis. Clin Ophthalmol. 2008 Mar; 2 (1): 31-55, which is incorporated herein by reference in its entirety. In some embodiments, the Schirmer test is a Schirmer 1 test under anesthesia. In some embodiments, one or more ocular symptoms associated with dry eye include a Schirmer test score of ≤5 mm wetness / 5 minutes under anesthesia. In some embodiments, any of the Schirmer test variants (including Schirmer 1 under anesthesia) can be used to identify subjects with one or more moderate / severe ocular symptoms associated with dry eye.

[0301] In some embodiments, a subject is identified as having severe dry eye as having a SANDE score of ≥60, rather than moderate / severe dry eye.

[0302] In some embodiments, object has the medical history of the ocular symptoms related to moderate / severe dry eye.In some embodiments, method includes determining that object has the medical history of the ocular symptoms related to one or more moderate / severe dry eyes.In some embodiments, object is identified as suffering from one or more ocular symptoms related to dry eyes at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 16 months, 20 months, 24 months, 30 months, 36 months or longer, or in the time length within the range limited by any two of the aforementioned values ​​(for example, 1 month to 36 months, 1 month to 24 months, 1 month to 12 months, 3 months to 30 months, 3 months to 24 months, 6 months to 12 months, 6 months to 24 months) has been experienced or has been diagnosed with one or more previous moderate / severe dry eye related ocular symptoms. In some embodiments, the subject's one or more moderate / severe dry eye-related ocular symptoms include the subject's use of an ocular lubricant (e.g., artificial tears) within the last 6 months, 5 months, 4 months, 3 months, 2 months, or 1 month, or for a length of time within a range defined by any two of the foregoing values ​​(e.g., 1 month to 6 months, 2 months to 6 months, 3 months to 5 months).

[0303] In some embodiments, the subject is at least 18 years old. In some embodiments, the subject is 18 to 25 years old, 25 to 40 years old, 40 to 55 years old, 55 to 60 years old, 60 to 65 years old, 65 to 70 years old, 70 to 75 years old, 75 to 80 years old, 80 to 85 years old, or older.

[0304] In some embodiments, subjects who meet one or more of the following are excluded:

[0305] 1. Subjects with any active infectious ocular condition.

[0306] 2. Subjects with monocular or BCVA of +1.0 logMAR or worse (using corrective lenses as needed) as assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS).

[0307] 3. Subjects suffering from ocular inflammatory conditions not associated with dry eye syndrome (eg, conjunctivitis, keratitis, anterior blepharitis, etc.).

[0308] 4. Subjects with clinical evidence of scarring ocular surface disease (e.g., scarring ocular pemphigoid or Stevens Johnson syndrome).

[0309] 5. Subjects must not discontinue use of any topical ophthalmic medications (including topical cyclosporine) other than the Composition during the run-in and treatment periods.

[0310] 6. Used within 60 days before the first visit (topical ophthalmic cyclosporine).

[0311] 7. Used within 60 days before the first visit (topical ophthalmic ritahest).

[0312] 8. Subjects with a total fluorescein corneal staining (FCS) score = 15 or a score = 3 in the superior region in the treated eye according to the NEI / Industry Workshop scale, or subjects with FCS of diffuse confluent staining, filaments, or epithelial defects.

[0313] 9. Subjects who have active herpetic keratitis or have had an outbreak of herpetic keratitis within 365 days prior to identification, or subjects who are receiving chronic oral antiviral agents for herpetic disease.

[0314] 10. Subjects who cannot suspend or give up using contact lenses during the administration period.

[0315] 11. Subjects who have used or are expected to use amiodarone.

[0316] 12. Subjects who have had or are expected to have had their doses changed within 30 days prior to evaluation: tetracycline, omega 3, or omega 6.

[0317] 13. Subjects who have changed or are expected to change the following doses within 60 days prior to evaluation and during the duration of treatment: anticholinergics, antidepressants, oral contraceptives, isotretinoin, oral systemic corticosteroids, oral systemic immunosuppressants.

[0318] 14. Subjects who have used topical ophthalmic antihistamines, ophthalmic, inhaled or intranasal corticosteroids, topical or oral mast cell stabilizers, oral antihistamines, topical or nasal vasoconstrictors, topical ophthalmic NSAIDs, topical ophthalmic antibiotics within 30 days prior to evaluation and for the duration of treatment.

[0319] 15. Subjects who have had a punctum cauterized or one or more punctal plugs changed (inserted or removed) in the treated eye within the past 90 days prior to assessment. Note: If a punctal plug is placed at randomization / baseline and becomes dislodged, it should be replaced as soon as possible.

[0320] 16. Subjects who have undergone corneal refractive surgery (LASIK, PRK, RK) in the treated eye.

[0321] 17. Subjects with a history of any surgical procedure to the ocular surface or eyelid in the treated eye within 365 days prior to evaluation or a history of intraocular surgery within 90 days prior to evaluation.

[0322] 18. Subjects who are pregnant or suspected of being pregnant and subjects who are breastfeeding or intending to breastfeed. Female subjects of childbearing potential are required to have a negative urine pregnancy test at screening and must agree to use an acceptable method of contraception from the time of signing the informed consent until the end of treatment. Medically acceptable methods of contraception include intrauterine devices; barrier methods such as diaphragms, condoms, cervical caps, or sponges used with spermicides; or hormonal contraception.

[0323] 19. Subjects with any physical or mental impairment that would interfere with the ability to participate and give informed consent.

[0324] 20. Subjects who have participated in a device or investigational drug study or clinical trial within 30 days of identification. They may not participate in another study or trial during treatment.

[0325] In some embodiments, the subject does not have Sjögren's syndrome (primary or secondary).

[0326] In some embodiments, the composition is topically applied to the eye. In some embodiments, the composition is applied to an individual suffering from (e.g., identified as suffering from) any form of moderate / severe dry eye for treatment thereof. In some embodiments, the subject does not suffer from Sjögren's syndrome (primary or secondary). The composition described herein can be provided as a liquid (solution, gel, ointment, etc.) or other suitable form, such as a powder or on a patch, tablet, etc. In some embodiments, the composition described herein is used to achieve one or more of the following: restore basal tears, general mucosa and ocular surface moistening; restore ocular surface and mucosal homeostasis, quickly but briefly promote autophagy to eliminate pressure, stress or degenerative diseases in the entire eye and other organs; reduce inflammation, promote wound healing (e.g., corneal or oral wound healing after refractive surgery), stabilize the tear lipid layer and inhibit bacterial infection.

[0327] In some embodiments, topical application to the eye includes applying one or more drops of the composition to the surface of the eye. For example, in some embodiments, the user is instructed to apply to the ocular surface, rather than to contact lenses. In other embodiments, the drops (or other applications) are suitable for application when wearing contact lenses. In some embodiments, the composition is applied from a container as a single dose, delivered to each eye as a single drop. In some embodiments, the drop is about 0.020mL to about 0.050mL, or any volume therebetween. In some embodiments, the drop is about 0.035mL.

[0328] Composition can be applied to object with any suitable dosing frequency and volume.In some embodiments, composition is applied to the eye (for example, ocular surface) of object as one or more drops (for example, 1 drop, 2 drops, 3 drops, 4 drops, 5 drops or more drops).In some embodiments, each application is applied to the eye of object by a drop of composition.In some embodiments, a drop of composition comprises about 0.005ml, about 0.01ml, about 0.02ml, about 0.03ml, 0.04ml, about 0.05ml, about 0.06ml, about 0.07ml, about 0.08ml, about 0.09ml, about 0.1ml, about 0.2ml, about 0.5ml or more volume, or in the range (for example, 0.005ml to 0.5ml, 0.01ml to 0.1ml, 0.02ml to 0.08ml, 0.03ml to 0.07ml etc.) of any two defined by aforementioned values. In some embodiments, one or more drops of the composition are applied to the eye of the subject up to three times a day, for example, once, twice or three times a day. In some embodiments, one or more drops of the composition are applied to the eye of the subject up to three times a day, up to three times every other day, up to three times every three days, up to three times every four days, up to three times every five days, up to three times a week or longer. In some embodiments, one or more drops of the composition are applied to the eye of the subject up to three times a day for at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 10 weeks, at least 3 months, at least 4 months, at least 6 months, at least 8 months, at least 12 months, at least 18 months, at least 24 months or longer, or for a period of time within the range defined by any two of the aforementioned values ​​(e.g., 5 days to 24 months, 1 week to 24 months, 1 week to 6 weeks, 1 week to 12 months, 6 weeks to 10 weeks, 3 months to 12 months, etc.).

[0329] In some embodiments, the composition is applied to one eye of the subject, for example, to an eye that exhibits one or more of the ocular symptoms associated with moderate / severe dry eye. In some embodiments, the composition is applied to both eyes of the subject. In some embodiments, the composition is applied to one eye of the subject, for example, to an eye that exhibits one or more of the ocular symptoms associated with severe dry eye. In some embodiments, the composition is applied to both eyes of the subject. In some embodiments, the subject does not suffer from Sjögren's syndrome (primary or secondary).

[0330] In some embodiments, the subject is identified as having severe dry eye, rather than moderate / severe dry eye. In some embodiments, the subject has severe dry eye and / or dry eye symptoms when the subject has a dry eye score of ≥70 in at least one eye using VAS instantaneous measurement.

[0331] In some embodiments, applying the composition to the eye improves one or more patient-reported symptoms or clinical signs of moderate / severe dry eye. In some embodiments, the subject does not suffer from Sjögren's syndrome (primary or secondary). Improvement of dry eye symptoms or signs can be assessed by one or more of the following:

[0332] Fluorescein corneal staining (FCS) (0 to 3 scale x region, 0 to 15 scale for 5 regions total, using NEI / industry workshop scale)

[0333] Lissamine green conjunctival staining (LGCS) (0 to 3 points x area, 0 to 18 points total, using the NEI / Industry Workshop scale)

[0334] Schirmer test under anesthesia (mm wetted within 5 minutes),

[0335] Tear film breakup time (seconds)

[0336] Dry eye, as reported by patients on a visual analogue scale and tabulated as mean change from baseline

[0337] • Dry Eye Related Ocular Symptoms Questionnaire (SANDE: How Frequent and How Severe Are Dry Eye Symptoms), (Schaumberg D, et al. Development and Validation of a Short Global Dry Eye Symptom Index. The Ocular Surface. January 2007, Vol 5; 1; 50-57, incorporated herein by reference in its entirety).

[0338] In some embodiments, the assessment of improvement in moderate / severe or severe dry eye symptoms or signs includes reflective and / or instantaneous assessment of symptoms. In some embodiments, the reflective assessment includes assessing the difference in symptoms experienced by the subject after treatment compared to before treatment. In some embodiments, the reflective assessment of symptoms includes assessing the difference in symptoms currently experienced by the subject compared to the last day of treatment (e.g., the first day of treatment). In some embodiments, the reflective assessment of symptoms includes assessing the difference in symptoms currently experienced by the subject compared to the last day of assessment of dry eye symptoms. In some embodiments, the measured or assessed improvement in a symptom or sign of dry eye (e.g., those listed above) is, is about, is at least, is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the measured or assessed value, or a range bounded by any two of the foregoing values.

[0339] In some embodiments, the composition administered to a subject with moderate / severe dry eye symptoms is a sterile aqueous composition comprising, consisting of, or consisting essentially of a composition disclosed herein. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of a formulation in Table A, Table B, or Table C. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of a formulation A in Table A. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of a formulation B in Table A. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of a formulation C in Table A. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of a formulation D in Table B. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of Formulation E in Table B. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of Formulation F in Table B. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of Formulation G in Table C. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of Formulation H in Table C. In some embodiments, the composition is a sterile aqueous composition comprising, consisting of, or consisting essentially of Formulation I in Table C.

[0340] Some embodiments include a method for treating moderate / severe dry eye, the method comprising applying a composition disclosed herein to the eye of a subject suffering from moderate / severe dry eye. In some embodiments, the subject does not suffer from Sjögren's syndrome (primary or secondary). In some embodiments, the composition described herein is used to treat a subject with moderate / severe dry eye symptoms. In some embodiments, the subject is identified as moderate / severe dry eye by meeting 1, 2, 3, or 4 of the following criteria:

[0341] a) Total FCS score in the NEI / Industry Workshop Scale is ≥ 4 and < 15,

[0342] b) Using VAS instantaneous dry eye score ≥ 60,

[0343] c) Schirmer 1 test score ≤ 5 mm wetting / 5 minutes under anesthesia, and

[0344] d) LGCS total score ≥ 5 (where 0 = no staining) using the NEI / Industry Workshop Scale.

[0345] In some embodiments, the compositions described herein are used to treat subjects with all four criteria from the above list. In some embodiments, the compositions described herein are used to treat subjects with all four criteria from the above list in at least one eye (e.g., in one or both eyes). In some embodiments, the subject does not suffer from Sjögren's syndrome (primary or secondary). In some embodiments, the subject does not meet 1, 2, 3, or 4 of the following criteria in one or both eyes: a) FCS total score <4 or ≥15 in the NEI / Industry Workshop scale; b) using VAS instant, dry eye score <60; c) Schirmer 1 test score under anesthesia> 5mm wetting / 5 minutes; and d) using the NEI / Industry Workshop scale, LGCS total score <5 (where 0 = no staining). In some embodiments, the polypeptide or pharmaceutically acceptable salt thereof in the composition is Lacripep TM (having a sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2, wherein "Ac" represents an acetyl group, and the C-terminus is amidated (SEQ ID NO: 1)), the amount thereof is 0.005%, 0.001%, or 0.00025% (w / v). In some embodiments, in addition to the polypeptide (e.g., Lacripep TM), the ophthalmic solution further comprises citric acid (about 0.0098% anhydrous), sodium citrate (about 0.279% sodium citrate dehydrate), disodium EDTA (about 0.001%), NaCl (about 0.5%), tyloxapol (about 0.001%, 0.01% or 0.05%), NaOH or HCl (to about 6.5 pH), purified water, USP. In some embodiments, a sterile aqueous composition comprising, consisting of, or consisting essentially of Formula A, Formula B, Formula C, Formula D, Formula E, Formula F, Formula G, Formula H, or Formula I in Table A, Table B, and Table C, or Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, or Formula 9 in Table 1.1, Table 1.2, and Table 1.3 is administered to a subject having moderate / severe dry eye symptoms. To evaluate efficacy, some embodiments utilize a placebo comprising a vehicle ophthalmic solution without the polypeptide. In some embodiments, one drop of the composition is applied to the subject's eye up to three times a day. In some embodiments, the subject is identified as having severe dry eye, rather than moderate / severe dry eye. In some embodiments, the subject has severe dry eye and / or dry eye symptoms when the subject's dry eye score in at least one eye is ≥70 using VAS instantaneous measurement.

[0346] In some embodiments, the method includes measuring the change in one or more ocular symptoms associated with dry eye after administration compared to before administration. In some embodiments, the method includes measuring the score of one or more of dry eye (EDS), SANDE, LGCS, FCS, Schirmer test (e.g., Schirmer test under anesthesia), and TBUT after administration, and comparing with the corresponding score before administration.

[0347] In some embodiments, administration improves the subject's total FCS score (NEI / Industry Workshop 0 to 15 scale) in the eye after at least two weeks of treatment, or after at least four weeks of treatment, or after at least six weeks from four weeks of treatment, compared to a baseline measurement before initiation of treatment. In some embodiments, administration improves one or more of the following:

[0348] dry eyes after at least two weeks of treatment or after at least four weeks of treatment compared with baseline on a visual analog scale;

[0349] SANDE after at least two weeks of treatment compared with baseline measurements before starting treatment (global score SANDE 1);

[0350] The mean SANDE score after at least two weeks of treatment compared with the baseline measurement before starting treatment (Global Score SANDE-1);

[0351] Individual symptom assessments (momentary) after at least two weeks of treatment compared with baseline measurements before starting treatment;

[0352] Mean scores on individual symptom assessments (reflective) after at least two weeks of treatment compared with baseline measurements before starting treatment;

[0353] LGCS in subjects' eyes after at least two weeks of treatment compared to baseline measurements before starting treatment;

[0354] Schirmer testing under anesthesia in the eyes of subjects after at least two weeks of treatment compared to baseline measurements before starting treatment;

[0355] TFBUT of the subject's eye after at least two weeks of treatment compared to baseline measurement before starting treatment;

[0356] FCS in the subject's eye after at least two weeks of treatment compared to baseline measurements before starting treatment;

[0357] SANDE (Global Score of SANDE 1) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared with the baseline measurement before starting treatment;

[0358] Individual symptoms (momentary) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared to baseline measurements before starting treatment;

[0359] Mean score (Global Score SANDE-2) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared with the baseline measurement before starting treatment;

[0360] Mean scores on individual symptom assessments (reflective) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared to baseline measurements before starting treatment;

[0361] FCS and SANDE 1 and individual symptom assessments (momentary) after at least 2 weeks of treatment, or after at least 4 weeks of treatment compared to baseline measurements before starting treatment;

[0362] LGCS after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared with baseline measurement before starting treatment;

[0363] Schirmer test results under anesthesia after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to baseline measurements before starting treatment;

[0364] TFBUT was measured at 1 week after at least 2 weeks of treatment, or at least 4 weeks of treatment, or after 4 weeks of treatment, compared to the baseline measurement before starting treatment.

[0365] In some embodiments, the measured or assessed improvement in a symptom or symptom of dry eye (e.g., those listed above) is, is about, is at least, is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the measured or assessed value, or a range bounded by any two of the foregoing values.

[0366] In some embodiments, the comparison alternatively comprises a comparison to a vehicle control, or further comprises a comparison to a vehicle control.

[0367] In some embodiments, any one or more of the following drugs / therapies are not co-administered with the compositions described herein, and in some embodiments, any one or more of the following drugs / therapies are co-administered with the compositions described herein:

[0368] 1. Ophthalmic medications (any topical ophthalmic medication) including prescription and over-the-counter [OTC] medications

[0369] 2. Contact lenses

[0370] 3. Any ocular surface or eyelid surgery within 365 days before the start of treatment or any intraocular surgery within 90 days before the start of treatment.

[0371] 4.Amiodarone.

[0372] 5. Topical ocular antihistamines

[0373] 6. Ophthalmic, inhaled, or intranasal corticosteroids

[0374] 7. Topical or oral mast cell stabilizers

[0375] 8. Oral antihistamines

[0376] 9. Topical or nasal vasoconstrictors

[0377] 10. Topical ophthalmic NSAIDs

[0378] 11. Topical ocular antibiotics

[0379] 12. Within 60 days before treatment and / or during treatment: topical cyclosporine, topical lifilamistat

[0380] 13. Within 90 days before treatment and / or during treatment: punctal cauterization or change (insertion or removal) of one or more punctal plugs or nasolacrimal duct surgery.

[0381] 14. Long-term oral antiviral medication for ocular herpetic disease.

[0382] Example

[0383] The following are non-limiting examples of some of the embodiments described herein.

[0384] Example 1 - Treatment of moderate / severe dry eyes

[0385] A randomized, placebo-controlled, double-blind, parallel-group study was conducted to determine the efficacy of 0.005% (22 μM), 0.001% (4 μM), or 0.00025% (1 μM) Lacripep TM Effect of treatment in a patient group identified with moderate / severe dry eye-related symptoms.

[0386] Exclusion and inclusion criteria

[0387] Select objects that meet the following criteria:

[0388] 1. Subjects who were 18 years of age or older when informed consent was obtained.

[0389] 2. Subjects with a history of dry eye-related ocular symptoms and self-reported use of over-the-counter ocular moisturizers in the past 120 days.

[0390] 3. Subjects who meet the following criteria at both the screening and the second visit (randomization / baseline) examinations:

[0391] a) Total FCS score in the NEI / Industry Workshop Scale is ≥ 4 and < 15,

[0392] b) Using VAS instantaneous dry eye score (EDS) ≥ 60,

[0393] c) Schirmer 1 test score under anesthesia ≤ 5 mm wetting / 5 minutes,

[0394] d) LGCS total score ≥ 5 (where 0 = no staining) using the NEI / Industry Workshop Scale.

[0395] NOTE: Subjects must meet all criteria and qualifying scores for FCS, EDS, Schirmer, and LGCS in at least one eye and must be in the same eye at the time of the visit.

[0396] The FCS was scored by a trained ophthalmologist who scored the level of corneal fluorescein staining in a grid that divided the corneal area into five sections ( Figure 7 ), each section is assigned a score (or grade) from zero to 3, depending on the amount and distribution of staining. A score / grade of 0 indicates no staining in the section. The total FCS score is determined in the range of 0 / 15 (indicating the absence of corneal epithelial lesions) to 15 / 15 (indicating severe epithelial lesions).

[0397] The LGCS was scored by trained ophthalmologists who scored the level of lissamine green conjunctival staining in a grid that divided the conjunctival area into six sections (superior paralimbal, inferior paralimbal, peripheral area for both nasal and temporal regions) ( Figure 8 ), assigning a score (or grade) from zero to 3 to each section, depending on the amount and distribution of staining. A score / grade of 0 indicates that there is no staining in the section. The total FCS score ranges from 0 / 15 (indicating the absence of corneal epithelial lesions) to 15 / 15 (indicating severe epithelial lesions), assigning a score (or grade) from zero to 3 to each section, depending on the amount and distribution of staining. A score / grade of 0 indicates that there is no staining in the section. The total FCS score is determined in the range of 0 / 18 to 18 / 18.

[0398] Through Figure 6 EDS is scored based on a momentary assessment of the subject's symptoms reported on the questionnaire shown. In the questionnaire, the subject is asked to rate their dry eye symptoms by marking an "X" on each row. EDS is the value of the "Dry Eyes" row of the questionnaire.

[0399] The Schirmer test was performed by folding a Schirmer paper strip (5 mm x 35 mm) at the notch and hooking the folded end over the temporal third of the lower eyelid margin. The score was the wetted length measured from the notch after a 5 minute period. For Schirmer test scoring under anesthesia, anesthesia was applied to the subject's eye before applying the Schirmer paper strip.

[0400] Subjects who met any of the following criteria at Visit 1 (Screening) or Visit 2 (Randomization / Baseline) were excluded:

[0401] 1. Subjects with any active infectious ocular condition.

[0402] 2. Subjects with monocular or BCVA of +1.0 logMAR or worse (using corrective lenses as needed) as assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS).

[0403] 3. Subjects suffering from ocular inflammatory conditions not associated with dry eye syndrome (eg, conjunctivitis, keratitis, anterior blepharitis, etc.).

[0404] 4. Subjects with clinical evidence of scarring ocular surface disease (e.g., scarring ocular pemphigoid or Stevens Johnson syndrome).

[0405] 5. Subjects cannot discontinue use of any topical ophthalmic medications (including topical cyclosporine) other than the investigational product during the run-in and study treatment periods.

[0406] 6. Used within 60 days before the first visit (topical ophthalmic cyclosporine).

[0407] 7. Used within 60 days before the first visit (topical ophthalmic ritahest).

[0408] 8. Subjects with a total fluorescein corneal staining (FCS) score = 15 or a score = 3 in the superior region in the study eye according to the NEI / Industry Workshop scale, or subjects with FCS of diffuse confluent staining, filaments, or epithelial defects.

[0409] 9. Subjects with active herpetic keratitis or a previous outbreak of herpetic keratitis within 365 days of visit 1, or subjects receiving chronic oral antiviral agents for herpetic disease.

[0410] 10. Subjects who cannot suspend or give up the use of contact lenses from the screening visit (Visit 1) to the end of the study (Visit 5).

[0411] 11. Subjects who have used or are expected to use amiodarone.

[0412] 12. Subjects who have had or are planning to have their doses changed within 30 days prior to visit 1: tetracycline, omega 3, or omega 6.

[0413] 13. Subjects who have changed or are expected to change the following doses within 60 days prior to Visit 1 and during the duration of the study: anticholinergics, antidepressants, oral contraceptives, isotretinoin, oral systemic corticosteroids, oral systemic immunosuppressants.

[0414] 14. Subjects who have used topical ophthalmic antihistamines, ophthalmic, inhaled or intranasal corticosteroids, topical or oral mast cell stabilizers, oral antihistamines, topical or nasal vasoconstrictors, topical ophthalmic NSAIDs, topical ophthalmic antibiotics within 30 days prior to Visit 1 and for the duration of the study.

[0415] 15. Subjects who have had a punctum cauterized or one or more punctal plugs changed (inserted or removed) in the study eye within the past 90 days prior to Visit 1. Note: If a punctal plug was placed at randomization / baseline and becomes dislodged, it should be replaced as soon as possible.

[0416] 16. Subjects who have undergone corneal refractive surgery (LASIK, PRK, RK) in the study eye.

[0417] 17. Subjects with a history of any surgical procedure to the ocular surface or eyelid within 365 days prior to Visit 1 or a history of intraocular surgery within 90 days prior to Visit 1 in the study eye.

[0418] 18. Subjects who are pregnant or suspected of being pregnant and subjects who are breastfeeding or intending to breastfeed. Female subjects of childbearing potential are required to have a negative urine pregnancy test at screening and must agree to use an acceptable method of contraception from the time of signing the informed consent until the end of treatment. Medically acceptable methods of contraception include intrauterine devices; barrier methods such as diaphragms, condoms, cervical caps, or sponges used with spermicides; or hormonal contraception.

[0419] 19. Subjects with any physical or mental impairment that would interfere with the ability to participate and give informed consent.

[0420] 20. Subjects who have participated in device or investigational drug research or clinical trials within 30 days of the first visit. No other activities are allowed during treatment.

[0421] Eligible subjects were randomly assigned to one of four treatment groups: three Lacripep TM ophthalmic solution concentration (0.005% (Formulation 1 or 4), 0.001% (Formulation 2 or 5), or 0.00025% (Formulation 3 or 6) w / v) or placebo (corresponding vehicle). Each study group included 65 subjects, for a total of 260 subjects. Lacripep TM The formulations are shown in Table 1.1, Table 1.2 and Table 1.3.

[0422] One drop of the study product is applied three times daily (TID) to both eyes for one, two, four, or six weeks. Efficacy and safety are evaluated at predetermined intervals.

[0423] Table 1.1: Lacripep TM preparation

[0424]

[0425] *pH 6.3 to 6.5 (target = 6.5)

[0426] Table 1.2: Lacripep TM preparation

[0427]

[0428] *pH 6.3 to 6.5 (target = 6.5)

[0429] Table 1.3: Lacripep TM preparation

[0430]

[0431] *pH 6.3 to 6.5 (target = 6.5)

[0432] Efficacy: All efficacy assessments were performed in both eyes and by the same person when possible. Corneal fluorescein staining (CFS) was assessed in 5 areas (central, inferior, superior, temporal, and nasal) using a 0 to 3 scale (total 0 to 15). Lissamine green conjunctival staining (LGCS) was assessed in 6 areas using a 0 to 3 scale (total 0 to 18). All sites were trained and tested on the NEI scoring method.

[0433] The Schirmer test under anesthesia was performed after instillation of approximately 50 μL (one drop) of 0.5% proparacaine after drying the inferior conjunctival sac, and the wetting was recorded for 5 minutes in mm. The tear film breakup time (TBUT) was measured in seconds. The visual analog scale was used to measure patient-rated symptom severity and frequency in the Dry Eye Symptom Evaluation (SANDE) Checklist Version 1 and Version 2. The Individual Symptom Assessment (Momentary and Reflective) measured patient-reported symptoms on a visual analog scale (VAS). The SANDE Version 2 and Individual Symptom Assessment (Reflective) asked patients to rate the difference in their symptoms compared to their last clinical visit and were administered to subjects on Days 14, 28, and 42 of treatment.

[0434] The primary efficacy measure was the mean change in the total CFS score (NEI / Industry Workshop 0 to 15 scale, 0 to 3 scale in each of the 5 domains) in the study eyes from baseline to Day 28. The key secondary efficacy measure was the mean change from baseline to Day 28 in the dryness score from the individual symptom assessment (VAS from 0 mm to 100 mm).

[0435] Changes in CFS from baseline to Day 14 and to post-treatment follow-up (Day 42) were additional secondary measures. Other secondary measures included changes in LGCS score, TFBUT, and Schirmer test from baseline to Day 14 and Day 28. Secondary symptom measures included changes from baseline to Day 14 and Day 28 in each of the SANDE and individual symptom assessments.

[0436] Study results will demonstrate significant improvement in one or more symptoms relative to vehicle treatment.

[0437] Example 2 - Treatment of Primary Sjögren's Syndrome

[0438] The primary objective of this study was to evaluate the efficacy of 22 μM and 44 μM Lacripep in subjects with a history of ocular surface disease associated with primary Sjögren's syndrome, including subjects with mild dry eye symptoms. TM Safety and tolerability of ophthalmic solution versus placebo (vehicle), applied three times daily for 28 days. In addition, a number of dry eye signs and symptoms were assessed.

[0439] Lacripep TMis a synthetic 19 amino acid peptide fragment of the tear protein (SEQ ID NO: 1). Proteomic studies have revealed that the active, monomeric form of the tear protein is downregulated in the tears of patients with many forms of dry eye disease, including aqueous deficiency, evaporative, and contact lens-associated dry eye, but most dramatically in patients with primary and secondary Sjögren's syndrome.

[0440] Study Design

[0441] This was a multicenter, randomized, placebo-controlled, double-blind, parallel-group study conducted at 35 sites in the United States and approved by the local institutional review board. Written informed consent was obtained from all subjects after review of the risks and benefits of participation. The study was conducted in accordance with the Health Insurance Portability and Accountability Act of 1996 and the Declaration of Helsinki of 1996 and is registered with ClinicalTrials.gov: NCT 03226444.

[0442] The study duration was 56 days, including a 14-day run-in period, a 28-day active treatment period, and a 14-day follow-up period (washout) (see Figure 2 ). Measurements were collected at five scheduled visits.

[0443] Study plan

[0444] Screening and Eligibility: At Visit 1 (Screening), informed consent was obtained from subjects and eligibility was determined, which required documentation of primary Sjögren's syndrome according to the American-European Consensus Group Sjögren's Syndrome Criteria. Subjects were at least 18 years of age and had a history of dry eye-related symptoms and use of ocular lubricants in the past 120 days. Major inclusion criteria at Screening and subsequent baseline visits included:

[0445] 1. Total CFS score ≥ 4 and < 15 on the National Eye Institute Industry Workshop (NEI) scale (Appendix 6 of the protocol)

[0446] 2. Symptom severity score ≥ 40 using the Symptom Assessment of Dry Eyes (SANDE) questionnaire

[0447] 3. Schirmer test score under anesthesia ≤ 5 mm wetting / 5 minutes

[0448] 4. Using the NEI scale, the total LGCS score is ≥ 5

[0449] Exclude objects that have:

[0450] 1. Active infectious eye conditions.

[0451] 2. Ocular inflammatory conditions not related to dry eye syndrome.

[0452] 3. Clinical evidence of scarring ocular surface disease

[0453] 4. Use within 14 days before the first visit (topical ophthalmic cyclosporine) or (Topical ophthalmic ritast).

[0454] 5. History of collagen vascular disease, autoimmune disease, or rheumatic disease other than primary Sjögren's syndrome (e.g., lupus, rheumatoid arthritis, etc.)

[0455] 6. History or current anterior membrane dystrophy, corneal transplant, corneal refractive surgery, or other recent ophthalmic procedures.

[0456] 7. Those with childbearing potential and unwilling to use contraceptive measures, or who are pregnant or breastfeeding.

[0457] 8. Any physical or mental impairment that would interfere with the ability to participate and give informed consent.

[0458] Those subjects who qualified entered a 14-day run-in period consisting of one drop of single-blind placebo (vehicle) instilled three times daily in each eye.

[0459] Randomization and Treatment: Eligibility was confirmed at Visit 2 (Baseline / Randomization). All criteria were met in the same study eye. For each subject, the study eye was the one that was eligible for study inclusion, or if both were eligible, the one with the higher baseline corneal fluorescein staining total score, or the right eye if both eyes showed the same baseline score. Eligible subjects were randomly assigned to one of three treatment groups: two Lacripep TM One of the ophthalmic solution concentrations (22 μM or 44 μM) or placebo (vehicle).

[0460] One drop of study product was applied to both eyes three times daily (TID) for 28 days. Efficacy and safety evaluations were performed at Visit 3 (Week 2) and Visit 4 (Week 4). Subjects who discontinued before Visit 4 underwent Visit 4 evaluations (early termination).

[0461] 14-Day Follow-up Period: After discontinuation of the study product, there was a 14-day follow-up period during which subjects instilled one drop of Refresh in each eye three times a day (TID) (Allergan, Dublin Ireland).

[0462] At Visit 5 (Week 6 follow-up), efficacy and safety evaluations were performed.

[0463] Concomitant Medication / Therapy: Subjects with records indicating use of prohibited medications (topical, topical ophthalmic, systemic, and / or injectable) during the appropriate pre-study washout period and / or during the 14-day vehicle run-in period prior to randomization were excluded from efficacy analyses prior to database lock.

[0464] Subjects did not receive any study medications or devices within 30 days of screening, nor did they receive any study medications or devices during the study except as per protocol. Subjects receiving systemic (oral) therapy for Sjögren's syndrome must be on stable systemic therapy, defined as the same therapy for the immediately preceding 90 days. Cyclosporine (mixed or Allergan, Irvine CA or Cequa, Sun Pharmaceuticals, Mumbai, India) or ritalidomide ( Novartis, Basel, CH). Subjects did not have any changes (insertion or removal) of punctal plugs in the study eye within 14 days prior to the screening examination and throughout the study period.

[0465] Topical or systemic medications known to exacerbate dry eye were prohibited during the study.

[0466] Study Blinding: Subjects were randomly assigned to receive either placebo or study drug. During the double-blind treatment period, placebo (vehicle) and Lacripep TM The containers were identical in appearance. Study subjects and investigators and their staff were blinded to the identity of the treatments until the final database lock.

[0467] Outcome measures

[0468] Efficacy: All efficacy assessments were performed in both eyes and by the same person when possible. Corneal fluorescein staining (CFS) was assessed in 5 areas (central, inferior, superior, temporal, and nasal) using a 0 to 3 scale (total 0 to 15). Lissamine green conjunctival staining (LGCS) was assessed in 6 areas using a 0 to 3 scale (total 0 to 18). All sites were trained and tested on the NEI scoring method.

[0469] The Schirmer test under anesthesia was performed after instillation of approximately 50 μL (one drop) of 0.5% proparacaine after drying the inferior conjunctival sac, and the wetting was recorded for 5 minutes in mm. The tear breakup time (TBUT) was measured in seconds. The visual analog scale was used to measure the severity and frequency of symptoms rated by patients in the Dry Eye Symptom Evaluation (SANDE) Checklist Version 1 and Version 2. The Individual Symptom Assessment (Momentary and Reflective) measured patient-reported symptoms on a visual analog scale (VAS). The SANDE Version 2 and Individual Symptom Assessment (Reflective) asked patients to rate the difference in their symptoms compared to their last clinic visit and were administered to subjects on Days 14, 28, and 42 of treatment.

[0470] The primary efficacy measure was the mean change in the total CFS score (NEI / Industry Workshop 0 to 15 scale, 0 to 3 scale in each of the 5 domains) in the study eyes from baseline to Day 28. The key secondary efficacy measure was the mean change from baseline to Day 28 in the individual symptom assessment dryness score (VAS from 0 mm to 100 mm).

[0471] Changes in CFS from baseline to Day 14 and post-treatment follow-up (Day 42) were additional secondary measures. Other secondary measures included changes in LGCS score, TFBUT, and Schirmer test from baseline to Day 14 and Day 28. Secondary symptom measures included changes from baseline to Day 14 and Day 28 in each of the SANDE and individual symptom assessments.

[0472] Safety: Safety measurements included external ocular examination, dilated ophthalmoscopy, intraocular pressure (IOP), slit-lamp biomicroscopy, and best corrected visual acuity (BCVA). If a subject was diagnosed or noted to have meibomian gland disease (MGD), severity was assessed.

[0473] All treatment-emergent adverse events (TEAEs), their severity and relatedness to study drug were recorded.

[0474] Statistical analysis: All analyses were performed using SAS (version 9.4, SAS Institute, Cary NC).

[0475] Analysis Set: The Intent-to-Treat (ITT) set included all subjects who received at least one dose of study product, as indicated by the dosing record. All safety variables were analyzed using the Safety Analysis Set, and only observed data were included (ie, missing data remained missing for safety analyses).

[0476] The Full Analysis (FAS) set consisted of all subjects in the ITT set that met the predefined inclusion criteria. Prior to database lock, several subjects were excluded from the FAS based on anticipated eligibility exclusions and / or anticipated defined protocol violations.

[0477] Baseline and Safety Analyses: Demographics and baseline efficacy assessment parameters are summarized by treatment group. Baseline ocular assessments of the study eyes are summarized. Adverse events are classified according to the Medical Dictionary for Regulatory Activities (MedDRA version 20.0, MedDRA MSSA, McLean, VA). Adverse events and any adverse findings from standard safety tests are listed. Adverse event counts and percentages are summarized by treatment group as well as the presence of any serious adverse events. Safety data are examined for trends across treatment groups.

[0478] Prespecified efficacy analyses: Prespecified primary and secondary endpoint analyses were performed on FAS.

[0479] The primary endpoint, the difference in the change from baseline to Day 28 in the total CFS score between placebo and each of the two active dose groups, was tested first. A Bonferroni correction was used to control for overall type 1 error (i.e., these were formally tested to a significance level of p < 0.025). A Bonferroni gating procedure was used, i.e., if the primary endpoint was met, the key secondary endpoint (dry eye score) was tested similarly.

[0480] Next, key secondary analyses were performed, where statistical inferences depended on the primary inferences via the Bonferroni gating procedure. Any trends in other secondary efficacy endpoints in the treatment groups were examined. All inferential summaries of these analyses were used for descriptive purposes. Point estimates and 95% confidence intervals (CI) for treatment differences and p-values ​​for treatment comparisons were calculated using t-tests.

[0481] All two-sample t tests performed in the analyses did not assume equal variances, and the Satterthwaite approximation was used to compare different sample sizes. Last observation carried forward (LOCF) was used to impute missing values ​​before day 28, except in reflective individual symptom assessments, where patients explicitly compared symptoms to previous visits.

[0482] Post hoc efficacy analysis: Post hoc, analysis of covariance (ANCOVA) was used to assess the treatment effect control for baseline dry eye score (EDS) for all primary and secondary endpoints. All ANCOVA models were fitted using the Proc Mixed procedure in SAS. Post hoc analyses were also performed using data from all observations in the ITT set without interpolation. Trends and significant efficacy signals for data from the ITT set were examined using endpoint mean ± standard error and p-values ​​from nonparametric Wilcoxon rank sum tests as descriptions of statistical strength. Subgroups were then evaluated according to baseline EDS.

[0483] result

[0484] Subject Disposition: The study screened 350 subjects, of whom 204 subjects were enrolled for treatment, 68 in each of three treatment groups (ITT sets). FAS excluded 27 subjects based on exclusion criteria or protocol violations. Excluded treatment subjects reported use of prohibited medications during the run-in period, such as cyclosporine or rituximab, or showed signs of comorbid autoimmune / connective tissue disease characteristic of secondary Sjögren's syndrome.

[0485] The FAS consisted of 177 subjects, of which 60 were in the placebo group and 22 μM Lacripep TM The group consisted of 57 patients, and 44 μM Lacripep TM The number of subjects in the efficacy analysis set was 60. Five subjects in the efficacy analysis set failed to complete the study: three failed to complete the 28-day active treatment course, and two failed to complete the follow-up period. In the prespecified analyses, LOCF was used to impute missing values ​​for patients who dropped out early.

[0486] Subject Demographics: A detailed summary of demographic data is provided in Table 2.1. Females comprised 96% of the subjects. The mean age of the subjects was 60 years, with 87% identifying as Caucasian, with the majority not being Hispanic or Latino. There were no significant differences in demographics between the three study groups.

[0487] Baseline disease characteristics are summarized in Table 2.1. The subject reported a baseline CFS total score of 9.0 ± 2.7 (mean ± SD). The baseline dry eye score was 65.5 ± 25.5 (mean ± SD). All three groups had similar baseline disease characteristics. Similar baseline characteristics were observed for the ITT set and FAS.

[0488] Table 2.1. Demographic Information and Baseline Characteristics of Treatment Groups - Intention-to-Treat Set

[0489]

[0490]

[0491] Post hoc efficacy analyses: Secondary endpoints yielded signals of potential treatment effects in change in lower-region CFS and change in burning / stabbing symptoms. These were repeated with ANCOVA analyses using the ITT set, showing a highly significant effect of baseline EDS. To illustrate, Figure 3 The lower region CFS (ICFS) is shown for the entire ITT set and for the subgroup with baseline EDS from ≥40 to ≥80. The subgroup with baseline EDS ≥60 showed the strongest treatment effect, with 74 / 129 subjects (57%) remaining in the sample set. Endpoints were reassessed in the subset of ITT subjects with EDS ≥60 at baseline. Significant treatment effects were observed in total CFS and in the subregions of lower CFS, burning / stinging symptoms, and conjunctiva using the LGCS.

[0492] Figure 3 :In post hoc analysis, according to the baseline dry eye score (EDS), the lower corneal fluorescein staining (ICFS) score of the ITT population subset was calculated. The mean and standard error of the results were drawn for each subset. The number of patients in each subset is indicated above the bar. The EDS≥60 subgroup showed the strongest effect statistically (p=0.0001 at 14 days, and p=0.026 at the 28th day). For their descriptive values, the p value level from the post-hoc Wilcoxon test is indicated in the bar (*p<0.05, **p<0.005, ***p<0.0005).

[0493] Corneal staining: at 22 μM Lacripep TM In the pre-specified analysis of the 500 mg / dL group versus placebo, the improvement in the lower domain CFS score from baseline to day 14 was statistically significant. Post hoc analysis showed a 0.4 improvement, p=0.005 (see Figure 4A ). In the subset of patients with baseline EDS ≥ 60, the effect was more pronounced (0.8 improvement, p = 0.0001), and a significant effect was also observed at day 28 (0.4 improvement, p = 0.026). Positive (although not statistically significant) differences were observed in the higher dose groups (see Figure 4B ).

[0494] In the set of baseline EDS ≥ 60, the pre-specified primary endpoint of total CFS score at Day 14 was significantly improved in the 22 μM dose group compared to placebo (1.2, p=0.03).

[0495] Figure 4A , Figure 4B : Post hoc analysis of CFS signs. Figure 4A The primary endpoint of CFS score was not met at day 28, but there was a significant treatment effect at day 14 in the inferior corneal area at the 22 μM dose. Figure 4B In the subset of subjects with baseline EDS ≥ 60, significant treatment effects were observed at Days 14 and 28 for the 22 μM dose, declining after washout at Day 42; a positive but non-significant effect was observed in the 44 μM dose group.

[0496] Individual symptom assessment (burning / stinging): Improvement in burning / stinging symptoms from baseline to day 14 (reflective VAS rating) at 22 μM Lacripep TM The difference was statistically significant in the prespecified analysis of the 100% group versus placebo. A post hoc analysis of the change in momentary rating of burning / stinging showed an improvement of 11.6 mm VAS versus placebo, p=0.006 (see Figure 5AIn the subset of patients with baseline EDS ≥ 60, a significant effect was shown at the same time point (14.0 mm improvement, p = 0.027) and also in the higher dose group (14.2 mm, p = 0.038, see Figure 5B At days 28 and 42, both dose groups tended to perform better than the placebo group (not statistically significant).

[0497] Figure 5A , Figure 5B : Post hoc analysis of burning / stinging symptoms. Figure 5A In the case of burning / stinging symptoms, the 22 μM dose had a significant therapeutic effect on day 14. Figure 5B In the subset of subjects with baseline EDS ≥ 60, a significant treatment effect was observed for both doses at Day 14. A positive but non-significant effect was observed for both dose groups at Day 28.

[0498] Lissamine staining: The improvement in LGCS was not statistically significant in the pre-specified secondary endpoint analysis. However, in the subset of patients with baseline EDS ≥ 60, a significant effect was observed. 22 μM Lacripep TM The change from baseline in the LCGS total score for the tamoxifen group versus placebo was 1.5 (p=0.017) at day 14. The same dose and time point showed significant improvements in segments 1 (0.4, p=0.049) and 5 (0.4, p=0.038).

[0499] In addition, although the foregoing has been described in considerable detail by way of illustration and example for purposes of clarity and understanding, it will be appreciated by those skilled in the art that many and various modifications may be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but also cover all modifications and substitutions that fall within the true scope and spirit of the embodiments of the present invention.

[0500] Unless otherwise expressly stated, the terms and phrases used in this application and their variations, especially in the appended claims, should be interpreted as open-ended and non-restrictive. As an example of the foregoing, the term "including" should be considered to mean "including but not limited to", "including but not limited to", etc.

[0501] The indefinite article "a" or "an" does not exclude a plurality. Use of "about" before a number includes the number itself. For example, "about 5" provides clear support for "5".

Claims

1. A method for treating ocular symptoms associated with moderate / severe dry eye, comprising: Identify subjects with moderate / severe dry eye-related ocular symptoms; and administering to the subject a liquid composition comprising: 0.0001% to 0.005% (w / v) of a polypeptide having a sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2 (SEQ ID NO: 1), wherein "Ac" represents an acetyl group and the C-terminus is amidated, or a pharmaceutically acceptable salt thereof; 0.01% to 0.6% (w / v) buffer; 0.0005% to 0.01% (w / v) disodium EDTA; 0.0001% to 0.01% or 0.0001% to 0.05% (w / v) tyloxapol; and 0.1% to 1.0% (w / v) sodium chloride, wherein the pH of the composition is from about 6.2 to about 6.8, wherein one drop of the composition is applied to the eye of the subject up to three times per day.

2. The method of claim 1, wherein the subject satisfies at least one criterion selected from the group consisting of: a) Total FCS score ≥4 and <15 in the NEI / Industry Workshop Scale; b) Using VAS instantaneous measurement, dry eye score ≥60; c) Schirmer 1 test score ≤ 5 mm wetting / 5 minutes under anesthesia; and d) LGCS total score ≥ 5 (where 0 = no staining) using the NEI / Industry Workshop Scale.

3. The method of claim 1 or 2, wherein the subject has a dry eye score of ≥60 using VAS instantaneous measurement.

4. The method of claim 1 or 2, wherein the subject meets all four criteria in one eye.

5. The method of any one of claims 1 to 4, wherein the subject does not suffer from Sjögren's syndrome.

6. The method of any one of the preceding claims, wherein the polypeptide or a pharmaceutically acceptable salt thereof is present in the liquid composition at 0.00025% to 0.005% (w / v) or at 0.0001% to 0.001% (w / v).

7. The method of any one of the preceding claims, wherein the polypeptide or a pharmaceutically acceptable salt thereof is present in the liquid composition at 0.00025% or 0.001% (w / v).

8. The method of any one of the preceding claims, wherein the tyloxapol is present in the liquid composition at 0.0005% to 0.01% (w / v) or 0.0005% to 0.05% (w / v).

9. The method of any one of the preceding claims, wherein the tyloxapol is present in the liquid composition at about 0.001% (w / v), or about 0.01% (w / v), or about 0.05% (w / v).

10. The method of any of the preceding claims, wherein the pH of the composition is from about 6.0 to about 7.0, or from about 6.4 to about 6.

6.

11. The method of claim 10, wherein the pH of the composition is about 6.

5.

12. The method of any one of the preceding claims, wherein the amount of NaCl is from about 0.4% to about 0.6% (w / v).

13. The method of any one of the preceding claims, wherein the amount of NaCl is about 0.5% (w / v).

14. The method of claim 13, wherein the composition has an osmolality of about 190 mOsm / kg to 210 mOsm / kg.

15. The method of any one of the preceding claims, wherein the buffer is a citrate buffer.

16. The method of claim 15, wherein the citric acid buffer comprises 0.0098% anhydrous citric acid and 0.279% sodium citrate dihydrate.

17. The method of any one of the preceding claims, wherein the amount of EDTA is from about 0.0005% to about 0.005% (w / v).

18. The method of any one of the preceding claims, wherein the amount of EDTA is about 0.001% (w / v).

19. The method of any preceding claim, wherein the composition further comprises 0.04% methylparaben.

20. The method of any one of the preceding claims, wherein the composition is sterile.

21. The method of any of the preceding claims, further comprising determining that the subject has a history of one or more ocular symptoms associated with dry eye.

22. The method of any of the preceding claims, wherein the one or more ocular symptoms associated with dry eyes include use of an ocular wetting agent by the subject within the last 6 months.

23. The method of any one of the preceding claims, wherein the composition is administered three times daily.

24. The method of any one of the preceding claims, wherein the composition is administered up to three times per day for at least one week.

25. The method of any one of the preceding claims, wherein the composition is administered up to three times daily for 1 to 6 weeks.

26. The method of any of the preceding claims, wherein the administering improves the subject's FCS total score (NEI / Industry Workshop 0 to 15 scale) of the eye after at least two weeks of treatment, or after at least four weeks of treatment, or after at least six weeks from four weeks of treatment, compared to a baseline measurement prior to initiation of treatment.

27. The method of any one of the preceding claims, wherein the administering improves one or more of: dry eyes after at least two weeks of treatment or after at least four weeks of treatment compared with baseline on a visual analog scale; SANDE after at least two weeks of treatment compared with baseline measurements before starting treatment (global score SANDE 1); The mean SANDE score after at least two weeks of treatment compared with the baseline measurement before starting treatment (Global Score SANDE-1); Individual symptom assessments (momentary) after at least two weeks of treatment compared with baseline measurements before starting treatment; Mean scores on individual symptom assessments (reflective) after at least two weeks of treatment compared with baseline measurements before starting treatment; LGCS in the subject's eye after at least two weeks of treatment compared to a baseline measurement before starting treatment; Schirmer testing under anesthesia in the subject's eyes after at least two weeks of treatment compared to baseline measurements before starting treatment; TFBUT of the subject's eye after at least two weeks of treatment compared to a baseline measurement before starting treatment; the FCS of the subject's eye after at least two weeks of treatment compared to a baseline measurement before starting treatment; SANDE (Global Score of SANDE 1) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared with the baseline measurement before starting treatment; Individual symptoms (momentary) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared to baseline measurements before starting treatment; Mean score (Global Score SANDE-2) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared with the baseline measurement before starting treatment; Mean scores on individual symptom assessments (reflective) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks of treatment, compared to baseline measurements before starting treatment; FCS and SANDE1 and individual symptom assessments (momentary) after at least 2 weeks of treatment, or after at least 4 weeks of treatment compared to baseline measurements before starting treatment; LGCS after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared with baseline measurement before starting treatment; Schirmer test results under anesthesia after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to baseline measurements before starting treatment; TFBUT was measured at 1 week after at least 2 weeks of treatment, or at least 4 weeks of treatment, or after 4 weeks of treatment, compared to the baseline measurement before starting treatment.

28. The method of claim 27, wherein the improvement is, is about, is at least, is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the measured or assessed value or a range defined by any two of the foregoing values.

29. The method of any of the preceding claims, wherein the subject further meets all of the following criteria: 18 years of age or older; Documented prior history or current diagnosis of dry eye-related ocular symptoms; and History of dry eye-related ocular symptoms and self-reported use of over-the-counter ocular lubricants in the past 120 days.

30. The method of any of the preceding claims, wherein the subject does not meet one or more of the following criteria: Any active infectious eye condition; monocular or with best-corrected visual acuity (BCVA) of +1.0 logMAR or worse, using corrective lenses as needed, as assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS); Ocular inflammatory conditions not related to dry eye syndrome (e.g., conjunctivitis, keratitis, anterior blepharitis, etc.); Clinical evidence of scarring ocular surface disease, such as scarring ocular pemphigoid or Stevens-Johnson syndrome; The use of any topical ophthalmic medications other than the investigational product (including topical cyclosporine) should not be suspended during the run-in and treatment periods; Used within 60 days before starting treatment with the composition (topical ophthalmic cyclosporine); Used within 60 days before starting treatment with the composition (topical ophthalmic lifalast); The subject's eye has a total fluorescein corneal staining (FCS) score of 15 or a score of 3 in the superior zone on the NEI / Industry Workshop scale, or the subject's eye has a FCS with diffuse confluent staining, filaments, or epithelial defects; Subjects who have active herpetic keratitis or have had an outbreak of herpetic keratitis within 365 days of starting treatment or are receiving chronic oral antiviral agents for herpetic disease; Do not suspend or give up using contact lenses during treatment; have used or are planning to use amiodarone; Changes in the dose of the following or anticipated changes in the dose of the following within 30 days prior to starting treatment: tetracycline, omega 3, or omega 6; Changes in the doses of the following within 60 days before starting treatment and / or during the duration of treatment or anticipated changes in the doses of the following: anticholinergics, antidepressants, oral contraceptives, isotretinoin, oral systemic corticosteroids, oral systemic immunosuppressants, Have used topical ophthalmic antihistamines, ophthalmic, inhaled or intranasal corticosteroids, topical or oral mast cell stabilizers, oral antihistamines, topical or nasal vasoconstrictors, topical ophthalmic NSAIDs, topical ophthalmic antibiotics within 30 days before starting treatment and / or during the duration of treatment; In the subject's eye and within the past 90 days, the puncta have been cauterized or one or more punctal plugs have been changed (inserted or removed) prior to starting treatment; In the subject's eye, corneal refractive surgery (LASIK, PRK, RK) has been performed; Any history of surgery on the ocular surface or eyelid within 365 days before starting treatment, or any history of intraocular surgery within 90 days before starting treatment; Pregnancy or suspected pregnancy; Are breastfeeding or intend to breastfeed; Has any physical or mental impairment that would interfere with the ability to participate and give informed consent; and Have participated in a device or investigational drug study or clinical trial within 30 days of starting treatment.

31. The method of any of the preceding claims, wherein the subject does not meet at least one of the following criteria in one or both eyes: a) Total FCS score <4 or ≥15 in the NEI / Industry Workshop Scale, b) Using VAS instantaneous dry eye score <60, c) Schirmer 1 test score > 5 mm wetting / 5 minutes under anesthesia, or d) LGCS total score <5 (where 0 = no staining) using the NEI / Industry Workshop scale.

32. The method of any of the preceding claims, wherein the subject is identified as having severe dry eye, but not moderate / severe dry eye.

33. The method of claim 32, wherein the subject has a dry eye score of ≥ 70 in at least one eye using VAS instantaneous measurement.

34. The method of any of the preceding claims, wherein the composition comprises, consists of, or consists essentially of a composition selected from the group consisting of the formulations in Table A, Table B, Table C, Table 1.1, Table 1.2, and Table 1.

3.

35. A liquid composition for treating moderate / severe dry eye-related ocular symptoms in an eye of a subject, the composition comprising: 0.0001% to 0.006% (w / v) of a polypeptide having a sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2 (SEQ ID NO: 1), wherein "Ac" represents an acetyl group and the C-terminus is amidated, or a pharmaceutically acceptable salt thereof; 0.01% to 0.6% (w / v) buffer; 0.0005% to 0.01% (w / v) disodium EDTA; 0.0001% to 0.01% (w / v) or 0.0001% to 0.05% (w / v) tyloxapol; and 0.1% to 1.0% (w / v) sodium chloride, wherein the composition has a pH of about 6.2 to about 6.

8.

36. The liquid composition of claim 35, wherein the composition comprises, consists of, or consists essentially of a composition selected from the group consisting of the compositions of the formulations in Table A, Table B, Table C, Table 1.1, Table 1.2, and Table 1.

3.

37. The liquid composition of any one of claims 35 to 36, wherein the subject meets at least one criterion selected from the group consisting of: a) Total FCS score ≥4 and <15 in the NEI / Industry Workshop Scale; b) Using VAS instantaneous measurement, dry eye score ≥60; c) Schirmer 1 test score ≤ 5 mm wetting / 5 minutes under anesthesia; and d) LGCS total score ≥ 5 (where 0 = no staining) using the NEI / Industry Workshop Scale.

38. The liquid composition of any one of claims 35 to 37, wherein the subject has a dry eye score of ≥ 60 using VAS instantaneous measurement.

39. The liquid composition of any one of claims 35 to 38, wherein the subject meets all four criteria in one eye.

40. The liquid composition of any one of claims 35 to 39, wherein the subject does not suffer from Sjögren's syndrome.

41. The liquid composition of any one of claims 35 to 40, wherein the subject does not meet at least one of the following criteria in one or both eyes: a) Total FCS score <4 or ≥15 in the NEI / Industry Workshop Scale, b) Using VAS instantaneous dry eye score <60, c) Schirmer 1 test score > 5 mm wetting / 5 minutes under anesthesia, or d) LGCS total score <5 (where 0 = no staining) using the NEI / Industry Workshop scale.

42. The liquid composition of any one of claims 35 to 41, wherein the subject is identified as having severe dry eye but not moderate / severe dry eye.

43. The liquid composition of claim 42, wherein the subject has a dry eye score of ≥ 70 in at least one eye using VAS instantaneous measurement.

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