Stable peptide composition

Abstract

A stable, low-concentration peptide composition and a kit containing the composition are provided. [Solution] A liquid composition comprising 0.00001 to 0.1%, or 0.001 to 0.05%, of a polypeptide or a pharmaceutically acceptable salt thereof; 0.01 to 0.6% of a buffering agent; no disodium EDTA, or 0.0005 to 0.01% disodium EDTA; no tyloxapol, or 0.01 to 0.1% tyloxapol; and sodium chloride; wherein the pH of the composition is 6.2 to approximately 6.8, and the osmolality of the composition is approximately 250 to 350 mOsm / kg.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority based on U.S. Provisional Application No. 62 / 530,565, filed on July 10, 2017, and U.S. Provisional Application No. 62 / 461,467, filed on February 21, 2017, each of which is incorporated herein by reference in its entirety.

[0002] (Description of Research and Development Sponsored by Federal Government Funds) This invention was made with U.S. government support under R01EY024327 awarded by the National Institutes of Health. The U.S. government may have certain rights in this invention.

[0003] (Reference to Sequence Listing) The attached sequence listing material is incorporated herein by reference. The text file of the attached sequence listing having the name TEAR.003WO.TXT was created on February 14, 2018, and its size is 7.18 KB. The contents of the sequence listing are incorporated herein by reference in their entirety.

[0004] (Field of the Invention) This application relates to the fields of chemistry, biochemistry, and medicine. More specifically, some embodiments of this application relate to stable, low - concentration peptide compositions and kits containing such compositions. In particular, some embodiments of this application describe compositions comprising aqueous solutions of citric acid, EDTA, and peptides that are stable at room temperature (e.g., 20°C to 25°C) with or without surfactants.

Background Art

[0005] Polypeptides are increasingly recognized as promising therapeutic agents. As a result, there is growing interest in the search for polypeptides in pharmaceutical research and development. However, polypeptides are notoriously difficult to formulate, and additives used to preserve or stabilize such formulations can cause, for example, undesirable side effects.

Summary of the Invention

[0006] There is an unmet need for peptide compositions that provide a therapeutic amount of a peptide, are stable at room temperature, and contain only a minimal amount of stabilizer and / or preservative or no preservative at all. To address such needs and others, some embodiments of the present application provide stable polypeptide compositions. Advantageously, in some embodiments, the peptide (or combination of peptides) is stabilized in the compositions of the present application such that long-term storage and / or long-term shipping are enabled. Thus, these peptide compositions are stable at non-refrigerated temperatures without the need for reconstitution and function over a temperature range including temperatures in the range of 0 to 30°C. Indeed, certain embodiments of the present application are based, in part, on the surprising and unexpected finding that low-concentration peptide compositions containing low concentrations of EDTA in combination with a low-concentration citrate buffer contain substantially lower additive levels than are typically found in polypeptide compositions, yet such compositions remain effective after storage at room temperature.

[0007] Some embodiments are compositions (e.g., liquids) comprising, consisting of, or consisting essentially of a polypeptide or a pharmaceutically acceptable salt thereof at about 0.00001% to 0.1%, 0.001% to 0.1% (e.g., 0.01% or 0.005% or 0.001%); a buffer at about 0.03% to 3% (e.g., 0.2888%); free of disodium EDTA or about 0.0001% to 0.01% (e.g., 0% or 0.001%) disodium EDTA; free of tyloxapol or about 0.005% to 0.5% (e.g., 0% or 0.05%) tyloxapol, and sodium chloride (e.g., 0.5%), wherein the pH of the composition is from about 6.2 to about 6.8 and the osmolality of the composition is from about 150 to 500 mOsm / kg or higher (e.g., 250 to 350) mOsm / kg. Liquid compositions include, but are not limited to, combinations, mixtures, solutions, gel compositions, and ointments.

[0008] In some embodiments, the buffer is a citrate buffer. In some embodiments, the citrate buffer contains about 0.001% to 0.1% (e.g., 0.0098%) anhydrous citric acid and about 0.02% to 2% (e.g., 0.279%) sodium citrate dihydrate. In some embodiments, the pH of the composition is about 6.5.

[0009] In some embodiments, the osmolality of the composition is from about 280 to about 320 mOsm / kg. In some embodiments, the osmolality of the composition is about 300 mOsm / kg. In some embodiments, the amount of NaCl is 0.4% to 0.6% (e.g., about 0.5%).

[0010] In some embodiments, the composition further comprises parabens, such as methylparaben (e.g., 0.04% or less). In other embodiments, parabens or other preservatives are not included. In some embodiments, the composition further comprises sodium chlorite.

[0011] Some embodiments provide a kit comprising a plurality of sterile single-use containers, each container comprising a vessel for holding the composition. In some embodiments, the container contains from about 0.03 mL to about 1 mL (e.g., 0.040 mL, 0.050 mL, 0.060 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, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL) of the composition. In some embodiments, the container is for daily use, weekly use, or longer-term use. In one embodiment, containers of 1 mL to 30 mL are used. In some embodiments, the container is a dropper bottle or a gel / ointment tube. In some embodiments, the container comprises a removable seal top for sealing the vessel and a neck portion for interconnecting the vessel and the seal top.

[0012] In some embodiments, the container is made from one or more of the following materials: polyvinyl chloride, polypropylene, polyethylene terephthalate, polyethylene terephthalate, polyethylene terephthalate G, high density polyethylene, low density polyethylene, polybutylene terephthalate, polyurethane, ethylene vinyl acetate, silicone, acrylonitrile-butadiene-styrene, polytetrafluoroethylene, polycarbonate, polystyrene, polymethyl methacrylate, polysulfone, polyvinylidene chloride, or combinations thereof. In some embodiments, a glass container and surface are provided that reduce the adhesion of the composition to the inner surface of the container.

[0013] In some embodiments, the polypeptide is Lacripep having SEQ ID NO: 1 TM , or a pharmaceutically acceptable salt thereof. In some embodiments, the polypeptide is selected from the group consisting of SEQ ID NOs: 2-9, or a pharmaceutically acceptable salt thereof, or one or more fragments. In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof has at least about 80%, 85%, 90%, 95%, or 98% sequence homology to SEQ ID NO: 1 or SEQ ID NOs: 2-9.

[0014] Some embodiments provide a method of administration that includes topically applying the composition to the eye, such as a liquid eye drop from a single-use container. Some embodiments provide a method of administration that includes topically applying the composition to the eye, such as a preservative-free, sterile liquid eye drop from a single-use container.

[0015] Some embodiments provide a method of treating dry eye and / or primary Sjögren's syndrome, comprising administering to the eye of a subject having dry eye and / or primary Sjögren's syndrome a composition described herein, wherein the polypeptide or a pharmaceutically acceptable salt thereof is in an amount of 0.005% or 0.01%, the polypeptide has 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), and administering up to 3 drops per day to the eye of the subject. In some embodiments, the administration improves the fluorescein corneal staining (FCS) total score (on a scale of 0-15 of the NEI / Industry Workshop) in the eye of the subject at least 2 weeks after treatment, or at least 4 weeks after treatment, or at least 6 weeks after the start of 4 weeks of treatment, as compared to a baseline measurement before starting treatment. In some embodiments, the administration improves one or more of the following: dryness of the eye at least 2 weeks after treatment, or at least 4 weeks after treatment, as compared to baseline on a visual analog scale; the SANDE (overall score of SANDE 1) at least 2 weeks after treatment as compared to a baseline measurement before starting treatment; the mean score of the SANDE (overall score of SANDE-1) at least 2 weeks after treatment as compared to a baseline measurement before starting treatment; the individual symptom assessment (instantaneous) at least 2 weeks after treatment as compared to a baseline measurement before starting treatment; the mean score of the individual symptom assessment (reflex) at least 2 weeks after treatment as compared to a baseline measurement before starting treatment; the LGCS in the eye of the subject at least 2 weeks after treatment as compared to a baseline measurement before starting treatment; the Schirmer test under anesthesia in the eye of the subject at least 2 weeks after treatment as compared to a baseline measurement before starting treatment; The TFBUT in the eye of the subject after at least 2 weeks of treatment, compared to the baseline measurement before starting the treatment; The FCS in the eye of the subject after at least 2 weeks of treatment, compared to the baseline measurement before starting the treatment; The SANDE (overall 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 to the baseline measurement before starting the treatment; The individual symptoms (instantaneous) 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 the baseline measurement before starting the treatment; The average score (overall score of 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 to the baseline measurement before starting the treatment; The average score of the individual symptom evaluation (reflex) 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 the baseline measurement before starting the treatment; The FCS, SANDE 1 and individual symptom evaluation (instantaneous) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to the baseline measurement before starting the treatment; The LGCS after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to the baseline measurement before starting the treatment; The Schirmer test result under anesthesia after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to the baseline measurement before starting the treatment; The TFBUT 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 the baseline measurement before starting the treatment. In some embodiments, administration of the composition to the subject population does not result in a statistically higher rate of adverse events compared to the rate of adverse events of administration of a placebo to a similar subject population. In some embodiments, administration of the composition to the subject population does not result in a statistically higher rate of serious adverse events compared to the rate of serious adverse events of administration of a placebo to a similar subject population. In some embodiments, the concentration of the polypeptide or a pharmaceutically acceptable salt thereof is about 0.005%. In some embodiments, the concentration of the polypeptide or a pharmaceutically acceptable salt thereof is about 0.01%. In some embodiments, the subject meets the following criteria: 18 years of age or older; A documented history or current diagnosis of Sjögren's syndrome according to the American-European Consensus Group Sjögren's syndrome criteria, having either 4 out of 6 criteria or 3 out of 4 signs; If the subject is undergoing systemic (oral) treatment for the treatment of Sjögren's syndrome, the subject must be on a stable systemic treatment defined as the same treatment for the previous 90 days; Self-report of a history of dry eye-related eye symptoms and use of over-the-counter eye lubricants within the past 120 days meeting all of the above, and prior to treatment initiation, meeting the following criteria: a) Fluorescein corneal staining (FCS) total score ≥4 and <15 on the National Eye Institute (NEI) / Industry Workshop scale (where 0 = no staining); b) A symptom score of ≥40 using the SANDE questionnaire; c) Schirmer test score under anesthesia ≤5 mm leakage / 5 minutes; d) Lissamine green corneal staining (LGCS) total score ≥5 on the NEI / Industry Workshop scale (where 0 = no staining); meeting all of the above, where the subject must meet all 4 criteria in at least one eye and the same eye at the time of visit. In some embodiments, the subject meets the following criteria: Any active infectious eye condition; Monocular or having a best corrected visual acuity (BCVA) of +1.0 logMAR or less as evaluated by the Early Treatment Diabetic Retinopathy Study (ETDRS), with corrective lenses as needed; Ocular inflammatory conditions not associated with dry eye syndrome (e.g., conjunctivitis, keratitis, anterior blepharitis, etc.); Clinical evidence of cicatricial ocular surface disease, such as cicatricial pemphigoid or Stevens - Johnson syndrome; Unable to discontinue the use of any topical ophthalmic medications (including topical cyclosporine) during treatment with the composition; Used Restasis® (topical ophthalmic cyclosporine) within 60 days before starting treatment with the composition; Used Xiidra® (topical ophthalmic lifitegrast) within 30 - 60 days or within 60 days before starting treatment with the composition; The subject's eye has a total fluorescein corneal staining (FCS) score = 15 or score = 3 in the superior region NEI / Industry Workshop scale, or the subject's eye has FCS with diffuse confluent staining, filaments, or frank epithelial defects; Having active herpetic keratitis or having had its sudden onset within 365 days before starting treatment, or a subject taking chronic oral antiviral medications for herpes disease; Unable to interrupt or discontinue the use of contact lenses during treatment; Having a history of collagen vascular diseases, autoimmune diseases, or rheumatic diseases other than primary Sjögren's syndrome (e.g., lupus, rheumatoid arthritis, etc.); Having a history of or currently having anterior membrane dystrophy; Having undergone corneal transplantation or similar corneal surgeries (DALK, DSEK, DMEK, etc.); Having used or expecting to use amiodarone; Within 30 days before starting treatment, change or anticipate a change in the dosage of tetracycline, omega-3 or omega-6; Within 60 days before starting treatment and / or during the treatment period, change or anticipate a change in the dosage of anticholinergic drugs, antidepressants, oral contraceptives, isotretinoin, oral systemic corticosteroids, oral systemic immunosuppressive drugs; Within 30 days before starting treatment and / or during the test period, used topical ophthalmic antihistamines, ophthalmic, inhaled or intranasal corticosteroids, topical or oral mast cell stabilizers, oral antihistamines, topical or intranasal vasoconstrictors, topical ophthalmic NSAIDs, topical ophthalmic antibiotics; Had punctal cautery in the subject's eye within the past 90 days or had a change (insertion or removal) of punctal plugs before starting treatment; The subject's eye had undergone corneal refractive surgery (LASIK, PRK, RK); Had a history of intraocular surgery within 90 days before starting treatment and a history of any surgical procedure on the ocular surface or eyelids within 365 days before starting treatment; Is pregnant or pregnancy is suspected; Is breastfeeding or plans to breastfeed; Participated in a device or investigational drug trial or clinical trial within 30 days before starting treatment Does not meet one or more of the above.

[0016] In some embodiments of any of the compositions, kits or methods described herein, the polypeptide has the sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2, where "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1). In some embodiments of any of the compositions, kits or methods described herein, the amount of the polypeptide of its pharmaceutically acceptable salt is 0.01% or 0.005%. In some embodiments, a comparison of the vehicle control and treatment with the polypeptide is included instead of or in addition to a comparison with baseline measurements prior to the start of treatment. In some embodiments of any of the compositions, kits or methods described herein, the composition does not contain tyloxapol. In some embodiments of any of the compositions, kits or methods described herein, the composition does not contain EDTA. In some embodiments of any of the compositions, kits or methods described herein, the composition maintains at least about 99.0% of the polypeptide in undegraded form in the composition after storage of the composition for 1 week at 5 ± 3°C or 25 ± 2°C and 25 ± 5% relative humidity. In some embodiments of any of the compositions, kits or methods described herein, the composition maintains at least about 99.0% of the polypeptide in undegraded form in the composition after storage of the composition for 2 weeks at 25 ± 2°C and 25 ± 5% relative humidity. In some embodiments of any of the compositions, kits or methods described herein, the composition maintains at least about 99.0% of the polypeptide in undegraded form in the composition after storage of the composition for 1 month at 5 ± 3°C or 25 ± 2°C and 25 ± 5% relative humidity. In some embodiments of any of the compositions, kits or methods described herein, the composition maintains at least about 99.0% of the polypeptide in undegraded form in the composition after storage of the composition for 2 months at 5 ± 3°C.In some embodiments of any of the compositions, kits or methods described herein, the composition maintains at least about 99.0% of the polypeptide in undegraded form after storage of the composition for 3 months at 5 ± 3 °C or -20 ± 5 °C. In some embodiments of any of the compositions, kits or methods described herein, the composition maintains at least about 99.0% of the polypeptide in undegraded form after storage of the composition for 4 months at 5 ± 3 °C. In some embodiments of any of the compositions, kits or methods described herein, the composition maintains at least about 99.0% of the polypeptide in undegraded form after storage of the composition for 5 months at 5 ± 3 °C. In some embodiments of any of the compositions, kits or methods described herein, the composition maintains at least about 99.5%, 99.9%, or 99.95% of the polypeptide in undegraded form. In some embodiments of any of the compositions, kits or methods described herein, the composition maintains at least about 80% or 90% of the polypeptide in undegraded form after storage of the composition for 12 months at 5 ± 3 °C.

Brief Description of the Drawings

[0017]

Figure 1

[0018]

Figure 2

[0019] Definitions The following are exemplary definitions of terms used herein. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art in light of the entire disclosure. All patents, applications, published applications, and other publications referenced herein are hereby incorporated by reference in their entirety as part of this specification, unless otherwise stated.

[0020] As used herein, the term "about" refers to a quantity, value, number, frequency, percentage, amount, or weight that varies by ± 10% of the recited quantity, value, number, frequency, percentage, amount, or weight.

[0021] Unless otherwise specified, when percentage (%) values are used in this application, the values refer to weight / weight percentage values.

[0022] As used herein, the term "tonicity agent" is given its ordinary meaning and is intended to include substances whose primary purpose is to change the osmolality of a composition. Suitable tonicity agents include, but are not limited to, propylene glycol, polyethylene glycol, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, monosaccharides such as dextrose, fructose, galactose, and / or simple polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, hydrolyzed hydrogenated starch, glycerin, and combinations thereof.

[0023] As used herein, the term "stabilizer" is given its ordinary meaning and is intended to include substances that inhibit chemical reactions with peptides. Stabilizers can include, for example, antioxidants such as sodium pyrosulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene, and combinations thereof.

[0024] As used herein, the term "surfactant" is given its ordinary meaning and is intended to include amphiphilic molecules, meaning that it includes both a hydrophobic group (tail) and a hydrophilic group (head). Thus, a surfactant includes both a water-insoluble (or oil-soluble) component and a water-soluble component. Surfactants used herein can be detergents, wetting agents, emulsifiers, foaming agents, or dispersants. In some embodiments, the polypeptide can act as a surfactant.

[0025] As used herein, the term "chelating agent" is given its ordinary meaning and is intended to 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 such as glutamic acid and histidine, organic diacids such as oxalic acid, malonic acid, succinic acid, etc., and pharmaceutically acceptable salts of the foregoing. In some embodiments, the chelating agent is EDTA, or a pharmaceutically acceptable salt thereof. In some embodiments, the polypeptide can act as a chelating agent.

[0026] As used herein, the term "thickening agent" is given its ordinary meaning and is intended to include substances that affect the viscosity (centipoise, or Cp) of a composition. Examples of thickening 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 acid polymers. Non-limiting examples of thickening agents include polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), and polyacrylic acid (PAA).

[0027] As used herein, the term "ophthalmically acceptable" is given its ordinary meaning and is intended to include substances that are compatible with eye tissue, i.e., that do not cause significant or excessive adverse effects when in contact with eye tissue.

[0028] As used herein, the terms "stable", "stability" or "stabilized" are given their ordinary meaning and are intended to include products and compositions that improve the primary, secondary and / or tertiary structure of a polypeptide. In some embodiments, a stabilized composition may have an acceptable percentage of peptide degradation products, or aggregates, products after a given time. These peptide degradation products can be, for example, the result of oxidation and / or hydrolysis of the peptide.

[0029] As used herein, the terms "peptide", "polypeptide" and "protein" are used interchangeably and are given their ordinary meaning. Unless the context clearly indicates otherwise, the terms described include polymers having at least two or more amino acids linked by peptide bonds. Thus, the terms include oligopeptides, analogs, derivatives, acetylated derivatives, glycosylated derivatives, pegylated derivatives, and the like.

[0030] The term "pharmaceutically acceptable salt" is given its ordinary meaning and includes salts of a compound that do not cause significant irritation to the organism to which it is administered and do not abolish or substantially reduce the biological activity and properties of the compound. In some embodiments, the salt of the compound may improve the biological activity and properties of the compound. In other embodiments, the salt may further improve 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 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 the compound with a base that forms salts such as ammonium salts, alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1- salts of organic bases such as C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. In some embodiments, the polypeptide is an acetate.

[0031] Advantages in Some Embodiments Some embodiments of the present application, described above and herein, provide compositions that are stable at room temperature. In some embodiments, the compositions reduce the concentrations of stabilizers and other additives that can cause undesirable side effects, while still providing the desired stability. In some embodiments, the compositions provide stability in the eye, nasal cavity, oral cavity, epithelium, and other tissues for up to 1, 3, 6, 12, 24, and 48 hours. In some embodiments, the compositions are formulated such that some or all of the components are not evaporated, absorbed, excreted, or otherwise eliminated after application to the eye or other area, but instead remain stable and active for several hours (e.g., 1 - 3 hours, 3 - 6 hours, 6 - 12 hours, 12 - 24 hours, and ranges thereof). In some embodiments, the compositions contain a peptide, such as Lacripep TM or other sequences specified herein, where the peptide is applied to the eye and the peptide is incorporated into the lipid layer of the tear film covering the eye or at the interface between the oily and aqueous components of the tear film, where the peptide stabilizes the tear film and remains in the tear film for at least 1 - 3 hours, at least 3 - 6 hours, or at least 12 - 24 hours, or more than 24 hours. This feature is particularly advantageous because in some embodiments, the active ingredient (e.g., the peptide) can be kept stable and effective for a long period of time. In some embodiments, the reduced dosing frequency results in a reduction in the overall burden of the component on sensitive areas of the body (e.g., the eye).

[0032] Some embodiments herein provide a peptide, but other compounds can be used as active ingredients in addition to or in place of the peptide.

[0033] Peptides are highly selective and effective, while at the same time being relatively safe and well - tolerated. Peptides can be chemically and physically unstable compared to certain small molecule-based therapeutic agents, and thus peptides are particularly well-suited for the compositions described herein. For example, peptides are prone to hydrolysis, oxidation, and aggregation. Polypeptide compositions are typically aqueous solutions containing the active peptide along with a number of stabilizers, preservatives, and other agents that maintain the effectiveness of the peptide. Stabilizers, preservatives, and other agents can maintain the chemical and / or structural integrity of the polypeptide and thus its effectiveness. Certain additives, such as stabilizers and preservatives, can cause undesirable side effects, including allergic reactions, itching, and stinging or burning sensations. However, these additives are required in amounts that cause undesirable results in most peptide compositions in order to maximize the shelf life of the peptide and maintain its effectiveness. Even compositions with all of these additives typically must be refrigerated, making transportation difficult and still having a short shelf life. Furthermore, because peptides degrade and / or aggregate over time (especially upon warming and cooling when going from refrigerated storage for use to room temperature), the by-products can be not only inactive but also toxic and / or immunogenic. Formulators may attempt to increase the potency of peptide compositions by increasing the amount of active peptide in the composition. However, increasing the peptide concentration also increases the rate of peptide aggregation and inactivation.

[0034] Accordingly, some embodiments herein provide peptide compositions that provide a therapeutically effective amount of a peptide, are stable at room temperature, and contain reduced amounts (e.g., only trace amounts) or no stabilizers and / or preservatives.

[0035] In some embodiments, the peptide is: (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, where "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1), and is also referred to as "Lacripep" TM ; and (b) selected from the group consisting of 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, where "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 fragments thereof, optionally with an N-terminally acetylated and / or C-terminally amidated form:

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0036] In some 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, where "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1). In some embodiments, the peptide is Lacripep TM is. In some embodiments, the peptide is any one or more of SEQ ID NOs: 1-9.

[0037] Buffers and pH Buffers stabilize the pH of a solution, i.e., resist changes in pH when acidic or alkaline substances are added to the solution. Suitable buffer compositions for use in the compositions of the present application include, but are not limited to, glycine hydrochloride, sodium acetate, phosphate buffered saline (PBS) (containing monohydrogen phosphate and dihydrogen), citrate buffer (citric acid and sodium citrate), phosphate-citrate buffer, tris(hydroxymethyl)aminomethane (Tris), carbonate buffer (sodium carbonate and sodium bicarbonate), borate buffer, and combinations thereof.

[0038] In some embodiments, the buffer comprises one or more of sodium acetate, phosphate buffered saline (PBS), citrate buffer (citric acid and sodium citrate), and phosphate-citrate buffer. In some embodiments, the buffer is selected from the group consisting of sodium acetate, phosphate buffered saline (PBS), citrate buffer (citric acid and sodium citrate), and phosphate-citrate buffer.

[0039] In some embodiments, the amount of buffer is less than 0.1, 0.2, 0.3, or 0.4%, or limited within the range defined by any two of the aforementioned values.

[0040] In one embodiment, the buffer is a citrate buffer (citric acid and sodium citrate). In one embodiment, the only buffer is the citrate buffer and no other buffers are present in the composition.

[0041] In some embodiments, the pH of the composition is 6 - 7.4; 6.1 - 7.3; 6.2 - 7.2; 6.3 - 7.1; 6.4 - 7.0; 6.5 - 6.9; 6.6 - 6.8; or any pH in between.

[0042] In some embodiments, the pH of the composition is 6; 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, or approximately so.

[0043] In one embodiment, the pH of the composition is 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8, or approximately so.

[0044] The pH of the composition can be adjusted as needed by the addition of a solution of an acid or a base. Any acid or base that is ophthalmically acceptable for the conjugate can be used. The acid includes, for example, hydrochloric acid, and the bases include, for example, sodium hydroxide and potassium hydroxide.

[0045] Chelating agent In some embodiments, the composition further comprises one or more chelating agents. In some embodiments, the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid, disodium edetate (EDTA), ethylenediamine, amino acids such as glutamic acid and histidine, organic diacids such as oxalic acid, malonic acid, succinic acid, etc., 3 - dimercaptopropanesulfonic acid (DMPS), alpha - lipoic acid (ALA), 2,3 - dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfonic acid (TTFD), penicillamine, dimercaptosuccinic acid (DMSA), combinations thereof, and pharmaceutically acceptable salts of the foregoing.

[0046] In some embodiments, a chelating agent, such as 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 included therein. In some embodiments, the chelating agent is present in an amount of 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 less, or is in a range defined by any two of the foregoing values.

[0047] In some embodiments, a chelating agent, such as EDTA, or a pharmaceutically acceptable salt thereof, is present at less than about 0.05% or less than about 0.005% (e.g., about 0.001%).

[0048] Stabilizer Buffers and chelating agents can stabilize the peptide component of a composition by maintaining the pH and reducing the degradation of peptides via metal ions. In some embodiments, the composition further comprises one or more peptide stabilizers in addition to the buffer and / or chelating agent. In some embodiments, the one or more stabilizers in addition to the buffer and / or chelating agent are selected from the group consisting of disaccharides, polysaccharides (e.g., hyaluronic acid), polyols, sugar alcohols, amino acids, proteins (e.g., serum albumin), and combinations thereof. In some embodiments, non-limiting examples of stabilizers include trehalose, sucrose, mannitol, sorbitol, polysorbate 20, polysorbate 80, histidine, glycine, and arginine, and combinations thereof. In one embodiment, the composition does not contain a stabilizer in addition to the buffer and / or chelating agent.

[0049] Polypeptide degradation Polypeptides are susceptible to physical and chemical degradation, such as aggregation, shear, oxidation, deamidation, and hydrolysis. In fact, liquid peptide compositions are at high risk of becoming physically and chemically unstable during manufacture and storage. Reduction of polypeptide degradation is particularly important for low-concentration peptide formulations that initially contain very small amounts of specific peptides. Even a small loss of the initial very small amount can significantly affect the effectiveness of the composition.

[0050] In some embodiments, the stability of the composition is determined by high performance liquid chromatography (HPLC). In some embodiments, the stability of the composition is determined by high performance liquid chromatography - mass spectrometry (HPLC-MS).

[0051] In some embodiments, the stability of the composition is determined after being placed in the dark or under light exposure at room temperature for several days, weeks or months (e.g., 1 - 24 days or months, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 days or months).

[0052] In some embodiments, the stability of the composition is determined after being placed in the dark or under light exposure at 2-8 °C, such as 5 °C, or any value therebetween, for several days, weeks or months (e.g., 1-24 days or months, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 days or months).

[0053] In some embodiments, the stability of the composition is determined after being placed in the dark or under light exposure at -10 to -30 °C, such as -25 °C, or any value therebetween, for several days, weeks or months (e.g., 1-24 days or months, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 days or months).

[0054] In some embodiments, the stability of the composition is determined after being placed in the dark or under light exposure, stored at 2 to 8 °C, or any value therebetween, at room temperature, moved 1, 2 or 3 times per day for 5 minutes, for 1-60 days.

[0055] In some embodiments, after exposure to one or more of the above or herein-described conditions, the composition provides at least 99.99%, 99.95%, 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 of the original amount or activity of the polypeptide or a pharmaceutically acceptable salt thereof in an intact, undegraded or unaggregated form. In one embodiment, the amount or activity of the intact polypeptide or a pharmaceutically acceptable salt thereof is at least 80%, 85%, 90% or 95% of the original amount. In some embodiments, the amount or activity of the intact polypeptide or a pharmaceutically acceptable salt thereof is at least 97% of the original amount.

[0056] In some embodiments, after exposure to one or more of the above or herein-described conditions, the composition contains 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 less of peptide aggregation products or peptide degradation products, or is in a range defined by any two of the foregoing values. In some embodiments, the composition contains about 15% or less, or 20% or less of inactive peptides.

[0057] In some embodiments, after exposure to one or more of the above or herein-described conditions, the composition contains 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 less of the total amount of peptide degradation products and peptide aggregation products, or is in a range defined by any two of the foregoing values.

[0058] In some embodiments, the composition comprises a very low concentration of a buffer in combination with a very low concentration of a chelating agent. In some embodiments, the buffer is a citrate buffer and the chelating agent is EDTA. The combination of a low concentration of citrate buffer (e.g., 0.012% - 0.020%) and EDTA (e.g., 0.0005% - 0.005%) provides the surprising and unexpected benefit of stabilizing a composition containing a low concentration of a peptide (e.g., 0.001 - 0.01%). Such stabilized compositions reduce peptide aggregation and degradation, thereby maintaining the effectiveness of the peptide composition and providing advantages in the manufacture, transport, storage, and use of the peptide composition by reducing the accumulation of undesirable degradation products in the composition.

[0059] In some embodiments, the stabilized composition reduces the rate of formation of degradation and / or aggregation products.

[0060] In some embodiments, the peptide is Lacripep TM and is. In some embodiments, the stabilized composition comprises less than about 5%, 4%, 3%, 2%, or about 1% total degradation products. In some embodiments, the stabilized composition comprises any one degradation product of 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, or 2.0% or less. In some embodiments, the stabilized composition comprises less than about 5%, 4%, 3%, 2%, or about 1% total degradation products and any one degradation product of 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, or 2.0% or less.

[0061] In some embodiments, the aggregation products include dimers, trimers, tetramers, or higher order peptide aggregates.

[0062] Preservative 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 preservatives are provided in reduced amounts. In some embodiments, the one or more preservatives are selected from the group consisting of 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 a preservative. In some embodiments, the composition does not contain a detectable concentration of a preservative. In some embodiments, the polypeptide can be self-preserving, i.e., no additional preservative is necessary to maintain the sterility of the composition.

[0063] In some embodiments, the preservative is present in an amount of 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% or 0.5%, or any value included therein. In some embodiments, the preservative is present in an amount of 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 less, or in a range defined by any two of the foregoing values.

[0064] In some embodiments, the composition is sterile. In some embodiments, the composition is manufactured from sterile components in a sterile environment. In some embodiments, the composition is sterilized prior to packaging. In some embodiments, the composition is sterilized by one or more of (1) addition of one or more quaternary ammonium chlorides to the composition; (2) exposure of the composition to ionizing radiation; (3) filtration of the composition; (4) exposure of the composition to ionizing radiation after packaging; and any combination of the foregoing. In some embodiments, filtration includes passing the composition through a filter (including, but not limited to, a 0.22 μm filter having polyvinylidene fluoride or other suitable membrane (e.g., polyethersulfone)).

[0065] In some embodiments, the peptide is provided in a bacteriostatic and / or bactericidal amount. In some embodiments, the amount of peptide provided in the composition is bacteriostatic and / or bactericidal when 1, 2, or 3 drops of the composition are administered to the surface of the eye. In some embodiments, the peptide is bacteriostatic and / or bactericidal against Gram-positive and / or Gram-negative bacteria, for example when administered to the eye. In some embodiments, the amount of peptide in the composition is sufficient to inhibit bacterial growth by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to a control composition that does not contain the peptide in a standard bacteriological assay. In some embodiments, the bacteria in the bacteriological assay are selected from P. aeruginosa, E. coli, S. epidermidis, S. aureus, or combinations thereof. In some embodiments, the bacteriological assay is selected from a bacterial growth assay, SYTOX Green assay, well diffusion assay, broth or canteen dilution assay, time kill test, antimicrobial gradient assay, ATP bioluminescence assay, or propidium-iodide flow cytometry assay. In some embodiments, the peptide provided in a bacteriostatic and / or bactericidal amount is Lacripep TM is.

[0066] In some embodiments, the bacteriological assay is an assay as per section <51> of the USP or an assay mandated by the FDA. For example, the original product containers contain a peptide solution, and each container is seeded with one of the prepared and standardized inoculum solutions (e.g., P. aeruginosa, E. coli, S. epidermidis, S. aureus, or a combination thereof) and mixed. The amount of the suspended inoculum solution is about 0.5% - 1.0% of the amount of the product, and the concentration of the test preparation immediately after seeding is 1x10 5 ~1x10 6 colony-forming units (CFU) per mL of the product (e.g., measured by the plate count method or another microbial counting test).

[0067] The seeded containers are incubated at 22.5 ± 2.5 °C in a controlled environment and sampled at specific intervals (e.g., 7, 14, and 28 days). For each sampling, changes in appearance are recorded and the CFU / mL is determined. The change in the log 10 value of CFU / mL provides a change over time from the point of logarithmic decrease. The product provides a logarithmic decrease of 1.0 or less from the first calculated number at day 7, a logarithmic decrease of 3.0 or less from the first number at day 14, and does not increase from the number at day 14 at day 28 for bacteria, and does not increase from the first number for yeast and mold. In some embodiments, the peptide provided in a bacteriostatic amount and / or a bactericidal amount is Lacripep TM .

[0068] Surfactant 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, emulsifying agents, foaming agents, dispersing agents, and combinations thereof.

[0069] In some embodiments, the surfactant is an anionic surfactant. An anionic surfactant contains an anionic functional group, such as sulfuric acid, sulfonic acid, phosphoric acid, and carboxylic acid, at its head. In some embodiments, the surfactant is a sulfate ester, sulfonate ester, or phosphate ester, such as a sulfate ester. In some embodiments, the surfactant is selected from the group consisting of or including ammonium lauryl sulfate and sodium lauryl sulfate, such as sodium lauryl sulfate (also known as SDS, sodium dodecyl sulfate). In some embodiments, the surfactant is an alkyl-ether sulfate, such as sodium lauryl ether sulfate (also known as sodium laureth sulfate), and sodium myreth sulfate, and is selected from the group consisting of or including them. In some embodiments, the surfactant is doxate, such as sodium dioctyl sulfosuccinate, perfluorooctanesulfonic acid (PFOS), perfluorobutanesulfonic acid, linear alkylbenzene sulfonic acid (LAB). In some embodiments, the surfactant is a carboxylate, such as an alkyl carboxylate (soap), such as sodium stearate; sodium lauroyl sarcosinate and carboxylic acid-based fluorosurfactants, such as perfluorononanoic acid, perfluorooctanoic acid (PFOA or PFO). In some embodiments, the polypeptide contributes to the surfactant properties of the composition.

[0070] In some embodiments, the surfactant is a cationic surfactant, the charge of which can be pH-dependent, for example a primary, secondary or tertiary amine, such as octenidine dihydrochloride; or a permanently charged quaternary ammonium cation, such as an alkyltrimethylammonium salt, such as cetyltrimethylammonium bromide (CTAB) or cetyltrimethylammonium chloride (CTAC); cetylpyridinium chloride (CPC); benzalkonium chloride (BAC); benzetonium bromide (BZT); 5-bromo-5-nitro-1,3-dioxane; dimethyldioctadecylammonium chloride; or dioctadecyldimethylammonium bromide (DODAB). In some embodiments, the surfactant is an amphoteric surfactant (i.e., having both cationic and anionic centers bonded to the same molecule). The cationic moiety can be based on a primary, secondary or tertiary amine or a quaternary ammonium cation. The anionic moiety can be variable and can include sulfonic acid, such as CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid). Other anionic groups can be thiones exemplified by cocamidopropyl hydroxysultaine; betaines such as cocamidopropyl betaine; and phosphates such as lecithin. In some embodiments, the surfactant can be a nonionic surfactant (not charged).

[0071] Many long-chain alcohols exhibit some surfactant properties and are provided herein as part of the composition in some embodiments. Among these, notable ones are the fatty alcohols, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol (consisting mainly of cetyl 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 monodecyl 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 (polysorbate); sorbitan alkyl esters (span); block copolymers of polyethylene glycol and polypropylene glycol, or poloxamers.

[0072] In some embodiments, the composition may include one or more components found in artificial tears in amounts known in the art, including, but not limited to, carboxymethyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose (also known as HPMC or hypromellose), hydroxypropyl cellulose, hydroxyethyl cellulose (HEC), and hyaluronic acid (also known as hyaluronan, HA), and combinations thereof. In some embodiments, the composition does not contain any of the aforementioned artificial tear components.

[0073] 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 is.

[0074] In some embodiments, the surfactant is tyloxapol (formaldehyde; oxirane; 4-(2,4,4-trimethylpentan-2-yl)phenol). In one embodiment, the only surfactant is tyloxapol and no other surfactants are present in the composition.

[0075] In some embodiments, the surfactant, such as tyloxapol as a non-limiting example, is present in an amount of 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% or 0.5%, or any value included therein. In some embodiments, the surfactant is present in an amount of 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 less than that amount, or within a range defined by any two of the aforementioned values.

[0076] In some embodiments, the composition does not contain a surfactant. In some embodiments, the composition does not contain a detectable concentration of a surfactant.

[0077] Isotonic agents and osmolality In some embodiments, the composition further comprises one or more tonicity agents. Such tonicity agents are added to any polypeptide or buffer having an osmotic pressure modifying effect. In some embodiments, the 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 the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, hydrolyzed hydrogenated starch, glycerin, and combinations thereof.

[0078] 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.

[0079] In some embodiments, the tonicity agent is sodium chloride. In some embodiments, sodium chloride is present at 0.01% - 1%; 0.05% - 0.9%; 0.1% - 0.8%; 0.2% - 0.75%; 0.3% - 0.7%; 0.4% - 0.6%; or any value included therein. In some embodiments, sodium chloride is 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 is present in an amount approximately that, or is a range defined by any two of the foregoing values.

[0080] In some embodiments, the only tonicity agent is sodium chloride and no other tonicity agents are present in the composition.

[0081] In some embodiments, an isotonic agent, such as sodium chloride by way of non-limiting example, is added to the composition to adjust the osmolality to a desired level. In some embodiments, the osmolality of the composition is from about 150 to about 400 mOsm / kg; from about 170 to about 380 mOsm / kg; from about 190 to about 360 mOsm / kg; from about 210 to about 340 mOsm / kg; from about 230 to about 320 mOsm / kg; from about 250 to about 300 mOsm / kg; from about 270 to about 280 mOsm / kg; or any value therebetween. In some embodiments, the osmolality of the composition is from about 250 to about 350 mOsm / kg; from about 260 to about 340 mOsm / kg; from about 270 to about 330 mOsm / kg; from about 280 to about 320 mOsm / kg; from about 290 to about 310 mOsm / kg; or any value therebetween.

[0082] In some embodiments, the osmolality of the composition is 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 approximately so, or is a range defined by any two of the foregoing values.

[0083] In some embodiments, the osmolality of the composition is about 280 mOsm / kg and about 320 mOsm / kg. In one embodiment, the osmolality of the composition is about 300 mOsm / kg. In some embodiments, NaCl is used to adjust the osmolality of the solution to a desired level. In one embodiment, the composition is isotonic or approximately isotonic with human tears.

[0084] Polypeptide and other components 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 included 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 included therein. In some embodiments, the length of the polypeptide or a pharmaceutically acceptable salt thereof is 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, or is in a range defined by any two of the foregoing values, or is approximately so.

[0085] In some embodiments, the C-terminus of the polypeptide or a pharmaceutically acceptable salt thereof is amidated. In some embodiments, the N-terminus of the polypeptide or a pharmaceutically acceptable salt thereof is acetylated. In some embodiments, one or more side chains of the polypeptide or a pharmaceutically acceptable salt thereof are acetylated. In some embodiments, one or more side chains of the polypeptide or a pharmaceutically acceptable salt thereof are amidated. In some embodiments, the N-terminus of the polypeptide or a pharmaceutically acceptable salt thereof is acetylated and the C-terminus of the polypeptide or a pharmaceutically acceptable salt thereof is amidated.

[0086] In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof comprises, consists of, or consists essentially of the 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 by "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 (indicated by "NH2"). In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof comprises, consists of, or consists essentially of a sequence selected from the group of SEQ ID NOs: 3-9, or a fragment thereof or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the amount of the polypeptide or a pharmaceutically acceptable salt thereof in the composition is 0.0001% to 1%; 0.0005% to 0.5%; 0.001% to 0.1%; 0.005% to 0.05%; 0.006% to 0.04%; 0.007% to 0.03%; 0.008% to 0.02%; or 0.009% to 0.01%, or approximately so. In one embodiment, the polypeptide or a pharmaceutically acceptable salt thereof 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).

[0088] In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.0001, 0.00025, 0.0005, 0.00075, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.011, 0.012, 0.013, 0.014, 0.015, 0.020, 0.030, 0.040, 0.050, 0.060, 0.070, 0.080, 0.090, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0%, or in a range defined by any two of the foregoing values, or approximately thereabouts, or more than or less than that amount.

[0089] In some embodiments, the composition is a sterile aqueous composition comprising, consisting essentially of, or consisting of from about 0.001% to about 0.05% polypeptide, such as Lacripep TM or other peptides specified herein, or a pharmaceutically acceptable salt thereof; from about 0.001% to about 0.015% citric acid anhydrous; from about 0.02% to about 0.40% sodium citrate dihydrate; from about 0.0005% to about 0.005% disodium EDTA; from about 0.005% to about 0.15% tyloxapol, and optionally from about 0.005% to about 0.1% methylparaben; wherein the pH of the composition is adjusted to about pH 6.2 to about pH 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is from about 0.1% to about 1%. In one embodiment, the composition does not contain methylparaben. In one embodiment, the composition consists only of the recited components and does not contain additional active ingredients, additives (e.g., thickeners, buffers, chelating agents, stabilizers, preservatives, surfactants, and tonicity agents), carriers, or diluents.

[0090] In some embodiments, the composition comprises about 0.01% ± 0.001% polypeptide, such as Lacripep TMor another peptide specified herein, or a pharmaceutically acceptable salt thereof; a sterile aqueous composition comprising, consisting of, or consisting essentially of 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 0.04% ± 0.004% methylparaben; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%. In one embodiment, the composition is free of methylparaben.

[0091] In some embodiments, the composition comprises about 0.005% ± 0.0005% polypeptide, such as Lacripep TM or another peptide specified herein, or a pharmaceutically acceptable salt thereof; a sterile aqueous composition comprising, consisting of, or consisting essentially of 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 0.04% ± 0.004% methylparaben; wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%. In one embodiment, the composition is free of methylparaben.

[0092] In some embodiments, the composition comprises about 0.001% ± 0.0001% polypeptide, such as Lacripep TMOr another peptide specified in this specification, 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 0.04% ± 0.004% methylparaben, a sterile aqueous composition, wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%. In one embodiment, the composition does not contain methylparaben.

[0093] In some embodiments including but not limited to the above sterile composition, 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 the group of SEQ ID NOs: 3 - 9, or a pharmaceutically acceptable salt or one or more fragments thereof.

[0094] In some embodiments including but not limited to the above sterile composition, the pH of the composition is about 6.5 to about 6.6.

[0095] In some embodiments including but not limited to the above sterile composition, the osmolality of the composition is about 280 to about 320 mOsm / kg. In some embodiments, the osmolality of the composition is about 300 mOsm / kg.

[0096] In some embodiments, the composition contains about 0.01% ± 0.001% Lacripep TM(SEQ ID NO:1) or other peptides specified herein; a sterile aqueous composition comprising about 0.0098% ± 0.001% citric acid anhydrous; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.05% ± 0.005% tyloxapol, wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

[0097] In some embodiments, the composition comprises about 0.005% ± 0.0005% Lacripep TM (SEQ ID NO:1) or other peptides specified herein; a sterile aqueous composition comprising about 0.0098% ± 0.001% citric acid anhydrous; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.05% ± 0.005% tyloxapol, wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

[0098] In some embodiments, the composition comprises about 0.001% ± 0.0001% Lacripep TM(SEQ ID NO:1) or other peptides identified herein; sterile aqueous composition comprising about 0.0098% ± 0.001% citric acid anhydrous; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.05% ± 0.005% tyloxapol, wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

[0099] In one embodiment, including but not limited to the above sterile composition, the composition consists of only the listed components and does not contain additional active ingredients, additives (e.g., thickeners, buffers, chelating agents, stabilizers, preservatives, surfactants, and tonicity agents), carriers or diluents. In some embodiments, the amount of any one or more of the listed components is provided in an amount of 5% and / or ±1% of the listed amount.

[0100] In some embodiments, the compositions described herein are manufactured as solutions, gels or ointments. Gels or ointments may be advantageous or provide other benefits in providing a composition that contacts the eye for a longer period of time than a solution. Thus, in one embodiment, gels or ointments are useful when applied to a subject when the subject is asleep or when the subject's eyes are closed for an extended period of time (e.g., 1, 2, 3, 4, 5 or more hours). Gels or ointments may be used at other times based on the preference of the user.

[0101] Non-limiting exemplary compositions (which may be used in the methods and kits described herein) include the compositions in Tables 1.1, 1.2, 1.3 and 1.4 below. [Table 1] [Table 2]

Table 3

Table 4

[0102] The embodiments of the compositions shown in Tables 1.1 - 1.4 also include compositions having the disclosed components in the range of ±1%, ±2%, ±3%, ±4%, or ±5% of the disclosed amount. In some embodiments, the compositions shown in Tables 1.1 - 1.4 maintain at least about 99.0%, 99.9%, 99.95%, or 99.99% of the Lacripep polypeptide of SEQ ID NO: 1 in the starting undegraded form in the composition after storage of the composition for at least 1 or 2 weeks, 1, 2, 3, 4, or 5 months at -20 ± 5°C, 5 ± 3°C, or 25 ± 2°C and 25 ± 5% relative humidity. In some embodiments, the compositions shown in Tables 1.1 - 1.4 maintain at least about 80% or 90% of the Lacripep polypeptide of SEQ ID NO: 1 in the starting undegraded form in the composition after storage of the composition for at least 12 months at -20 ± 5°C or 5 ± 3°C. In some embodiments, the compositions shown in Tables 1.1 - 1.4 contain about 0.2 - 0.8%, or about 0.5% NaCl.

[0103] Other therapeutic components In some embodiments, the composition includes one or more additional therapeutic agents in addition to the polypeptides described herein. These therapeutic agents can include substances known to those skilled in the art for the treatment of dry eye and related syndromes and conditions including Sjogren's syndrome. A non-exhaustive list of additional therapeutic agents includes cholinergic agents (e.g., pilocarpine, cevimeline), cyclosporine, lifitegrast, dexamethasone (or other corticosteroids, such as prednisone), hyaluronic acid (and its derivatives) with or without chondroitin sulfate, Cyclocut, SI-614, skQ1, Cis-UCA, CycloASol, RGN-259, diclofasol, anakinra, tofacitinib, EBI-005, EGP-437, KP-121, MIM-D3, OTX-DP, levamisoid (OPC-12759), and RU-101. In some embodiments, the additional therapeutic agent is Xiidra (lifitegrast, SAR-1118). In some embodiments, one or more additional therapeutic agents are affected as salts of polypeptides. Artificial tears and other lubricants, including carboxymethylcellulose, polyvinyl alcohol, hydroxypropylmethylcellulose (also known as HPMC or hypromellose), hydroxypropylcellulose, ethylene glycol polymers, and hyaluronic acid (also known as hyaluronan, HA), and ophthalmic ointments such as white petrolatum, mineral oil, and similar lubricants, may also be included in the composition. These additional therapeutic agents may be included in known therapeutic amounts or amounts below the therapeutic amount.

[0104] Containers and Kits In some embodiments, the composition is provided in a kit that includes one or more multi-use containers. In some embodiments, the multi-use container includes a protective cap and a liquid reservoir bottle, where the cap is connected to the bottle via a flexible connector. A blocking plug is disposed at the center of the upper surface of the protective cap. A conical or other suitable shaped liquid outlet is disposed at the center of the bottle cover and mates snugly with the blocking plug of the protective cap. Thus, the sterile composition can be placed in a container for multiple uses.

[0105] In some embodiments, the amount of the composition in the container is 0.1 - 0.5, 0.5 - 1.0, 1 - 2, 2 - 5, 5 - 10, 10 - 20, 20 - 30, or 30 - 60 mL or any range therebetween or approximately so. The container can be a bottle, tube, vial or other suitable container. For reusable containers, instructions may accompany for use up to 12 hours, 24 hours, 2 - 7 day cycles, 1 month cycles or a specified expiration date. Single-use containers can be suitable for use in one or both eyes for a single application cycle.

[0106] In some embodiments, the composition is provided in a kit that includes a single-use container. In some embodiments, the composition is provided in a kit that includes a plurality of single-use containers. In some embodiments, the single-use container includes a vessel for holding the liquid, a removable seal top for sealing the vessel, and a neck portion for interconnecting the vessel and the seal top if desired. In some embodiments, a kit is provided that includes a plurality of single-use containers along with instructions for use.

[0107] In some embodiments, the container includes a pharmaceutically inert material. In some embodiments, the container includes glass, polyvinyl chloride, polypropylene, polyethylene terephthalate, polyethylene terephthalate, polyethylene terephthalate G, high density polyethylene, low density polyethylene, polybutylene terephthalate, polyurethane, ethylene vinyl acetate, silicone, acrylonitrile butadiene styrene, polytetrafluoroethylene, polycarbonate, polystyrene, polymethyl methacrylate, polysulfone, polyvinylidene chloride, or combinations thereof.

[0108] In some embodiments, the container includes polyvinyl chloride, polypropylene, low density polyethylene, polyurethane, ethylene vinyl acetate, silicone, or combinations thereof.

[0109] In some embodiments, the amount of the composition in the container is 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 or approximately therebetween.

[0110] In some embodiments, the amount of the composition in the container is 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 the range defined by any two of the foregoing values or approximately therebetween.

[0111] Eye drops and other administrations In some embodiments, the composition is administered topically to the eye. In some embodiments, the composition is administered for such administration to an individual suffering from any form of dry eye or dry eye (or other symptoms such as dry mouth) associated with Sjogren's syndrome. In some embodiments, it is administered orally as a mouthwash, tablet, patch, spray or lozenge. The compositions described herein can be provided as a liquid (solution, gel, ointment, etc.) or in other forms such as powder or patch, tablet, etc. In some embodiments, the compositions described herein are used to achieve one or more of the following: restore basal tearing, saliva secretion, and wetness of the general mucosa and ocular surface; restore the integrity of the ocular surface and mucosa, rapidly but temporarily promote autophagy, and eliminate pressure, stress or degenerative diseases throughout the eye or in other organs; reduce inflammation, promote wound healing (e.g., corneal and oral wound healing after refractive surgery), stabilize the tear film, and suppress bacterial infection.

[0112] In some embodiments, topical administration to the eye comprises administering one or more drops of the composition to the surface of the eye. For example, in one embodiment, the user is instructed to apply to the surface of the eye rather than wearing contact lenses. In other embodiments, eye drops (or other applications) are suitable for administration while wearing contact lenses. In some embodiments, the composition is administered from a container as a single dose delivered as one drop per eye. In some embodiments, the eye drops are from about 0.020 mL to about 0.050 mL, or any amount therebetween. In some embodiments, the eye drops are about 0.035 mL.

[0113] In some embodiments, administration of the composition to the eye improves one or more patient-reported symptoms or clinical signs of dry eye or Sjogren's syndrome. Improvement of dry eye symptoms or signs can be evaluated by one or more of the following: · Fluorescein corneal staining (FCS) (scaled 0 - 3 by region, for 5 regions, total 0 - 15 scale, using the NEI / Industry Workshop scale) · Lissamine green corneal staining (LGCS) (scaled 0 - 3 by region, total 0 - 18 scale, using the NEI / Industry Workshop scale) · Schirmer test under anesthesia (mm of wetting for 5 minutes), · Tear film break-up time (seconds) · Eye dryness reported by the patient on a visual analog scale and listed as the average change from baseline · Questionnaire on dry eye-related ocular symptoms (SANDE: frequency and severity of 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).

[0114] In some embodiments, the composition comprises from about 0.001% to about 0.05% Lacripep TM(SEQ ID NO:1) or other peptides specified herein; about 0.001% to about 0.015% anhydrous citric acid; about 0.02% to about 0.40% sodium citrate dihydrate; about 0.0005% to about 0.005% disodium EDTA; about 0.005% to about 0.15% tyloxapol, and about 0.005% to about 0.1% methylparaben, comprising, consisting of, or consisting essentially of a sterile aqueous composition, wherein the pH of the composition is adjusted to about pH 6.2 to about pH 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.1% to about 1%. In one embodiment, the composition does not contain methylparaben. In one embodiment, the composition consists of only the listed components and does not contain additional active ingredients, additives (e.g., thickeners, buffers, chelating agents, stabilizers, preservatives, surfactants, and tonicity agents), carriers, or diluents.

[0115] In some embodiments, the composition comprises about 0.001% to about 0.05% Lacripep TM (SEQ ID NO:1) or other peptides specified herein; about 0.001% to about 0.015% anhydrous citric acid; about 0.02% to about 0.40% sodium citrate dihydrate; about 0.0005% to about 0.005% disodium EDTA; and about 0.005% to about 0.15% tyloxapol, comprising, consisting of, or consisting essentially of a sterile aqueous composition, wherein the pH of the composition is adjusted to about pH 6.2 to about pH 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.1% to about 1%. In one embodiment, the composition consists of only the listed components and does not contain additional active ingredients, additives (e.g., thickeners, buffers, chelating agents, stabilizers, preservatives, surfactants, and tonicity agents), carriers, or diluents.

[0116] In some embodiments, the composition is about 0.01% ± 0.001% Lacripep TM (SEQ ID NO: 1) or other peptides specified herein; about 0.0098% ± 0.001% citric anhydride; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.05% ± 0.005% tyloxapol, and is a sterile aqueous composition, wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

[0117] In some embodiments, the composition is about 0.005% ± 0.0005% Lacripep TM (SEQ ID NO: 1) or other peptides specified herein; about 0.0098% ± 0.001% citric anhydride; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.05% ± 0.005% tyloxapol, and is a sterile aqueous composition, wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

[0118] In some embodiments, the composition is about 0.001% ± 0.0001% Lacripep TM(SEQ ID NO:1) or other peptides identified herein; a sterile aqueous composition comprising about 0.0098% ± 0.001% citric acid anhydrous; about 0.279% ± 0.028% sodium citrate dihydrate; about 0.001% ± 0.0001% disodium EDTA; about 0.05% ± 0.005% tyloxapol, wherein the pH of the composition is adjusted to about 6.2 to about 6.8 using NaOH or HCl, and the osmolality of the composition is adjusted to about 250 to about 350 mOsm / kg using NaCl. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

[0119] Some embodiments include methods of treating dry eye and / or primary Sjögren's syndrome, comprising administering the compositions described herein to the eyes of a subject having dry eye and / or primary Sjögren's syndrome. In one embodiment, the compositions described herein are used to treat Sjögren's syndrome. In some embodiments, the compositions described herein are used to treat a subject having one or more of the following criteria: I. Eye symptoms · Symptoms of dry eye for at least 3 months · Foreign body sensation in the eye · Use of artificial tears more than 3 times a day II. Mouth symptoms · Symptoms of dry mouth for at least 3 months · Recurrent or persistent swelling of the salivary glands · Need for liquid to swallow dry foods III. Eye signs · Schirmer test under abnormal anesthesia, (without anesthesia; ≤ 5 mm / 5 minutes) · Positive findings of vital staining on the ocular surface IV. Histopathology · Lip biopsy showing focal lymphocytic sialadenitis (focus score ≥ 1 per 4 mm 2 hit) V. Mouth signs · Unstimulated whole saliva flow rate (≤ 1.5 mL in 15 minutes) · Abnormal parotid sialography · Abnormal salivary scintigraphy VI. Autoantibodies · Anti-SSA(Ro) (anti-Sjögren's syndrome-related antigen A) or anti-SSB(La) (anti-Sjögren's syndrome-related antigen B), or both of them. In one embodiment, the compositions described herein are used to treat a subject having at least one criterion from each of the six categories above. In some embodiments, the polypeptide or a pharmaceutically acceptable salt thereof in the composition is in an amount of 0.005% or 0.01% of Lacripep TM (having the sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH2, where "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1)). In some embodiments, the eye drops contain citric acid (about 0.0098% anhydrous), sodium citrate (about 0.279% of sodium citrate anhydrous), disodium EDTA (about 0.001%), NaCl (to about 300 mOsm / kg), tyloxapol (about 0.05%), NaOH (to about 6.5 pH), USP purified water, in addition to a polypeptide, for example, Lacripep TM In addition. To evaluate efficacy, some embodiments utilize a placebo containing a vehicle eye drop without the polypeptide. In some embodiments, one drop of the composition is administered to the eye up to 3 times a day. In some embodiments, the administration improves the total FCS score (NEI / Industry Workshop scale of 0-15) in the subject's eye at least 2 weeks after treatment, or at least 4 weeks after treatment, or at least 6 weeks after the start of 4 weeks of treatment, compared to the baseline measurement before starting treatment. In some embodiments, the administration improves one or more of the following: Dryness of the eye at least 2 weeks after treatment, or at least 4 weeks after treatment, compared to the baseline on the visual analog scale; The SANDE (overall score of SANDE 1) after at least two weeks of treatment, compared to the baseline measurement before starting the treatment; The average score of the SANDE (overall score of SANDE-1) after at least two weeks of treatment, compared to the baseline measurement before starting the treatment; The individual symptom assessment (instantaneous) after at least two weeks of treatment, compared to the baseline measurement before starting the treatment; The average score of the individual symptom assessment (reflex) after at least two weeks of treatment, compared to the baseline measurement before starting the treatment; The LGCS in the eyes of the subject after at least two weeks of treatment, compared to the baseline measurement before starting the treatment; The Schirmer test under anesthesia in the eyes of the subject after at least two weeks of treatment, compared to the baseline measurement before starting the treatment; The TFBUT in the eyes of the subject after at least two weeks of treatment, compared to the baseline measurement before starting the treatment; The FCS in the eyes of the subject after at least two weeks of treatment, compared to the baseline measurement before starting the treatment; The SANDE (overall score of SANDE 1) after at least two weeks of treatment, or after at least four weeks of treatment, or one week after four weeks of treatment, compared to the baseline measurement before starting the treatment; The individual symptoms (instantaneous) after at least two weeks of treatment, or after at least four weeks of treatment, or one week after four weeks of treatment, compared to the baseline measurement before starting the treatment; The average score (overall score of SANDE-2) after at least two weeks of treatment, or after at least four weeks of treatment, or one week after four weeks of treatment, compared to the baseline measurement before starting the treatment; The average score of the individual symptom assessment (reflex) after at least two weeks of treatment, or after at least four weeks of treatment, or one week after four weeks of treatment, compared to the baseline measurement before starting the treatment; The FCS, SANDE 1, and individual symptom assessment (instantaneous) after at least two weeks of treatment, or after at least four weeks of treatment, compared to the baseline measurement before starting the treatment; LGCS after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to baseline measurements 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 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.

[0120] In some embodiments, the comparison includes, instead of or in addition to, a comparison with a vehicle control.

[0121] In one embodiment, none of the following drugs / therapeutics are co-administered with the composition described herein, and in one embodiment, one or more of the following drugs / therapeutics are co-administered with the composition described herein: Eye drops (any topical ophthalmic drug application) including prescription drugs and over-the-counter (OTC) drugs Contact lenses Any surgical procedure on the ocular surface or eyelid within 365 days before starting treatment, or intraocular surgery within 90 days before starting treatment Amiodarone Topical ophthalmic antihistamines Ophthalmic, inhaled or intranasal corticosteroids Ophthalmic or oral mast cell stabilizers Oral antihistamines Topical or intranasal vasoconstrictors Topical ophthalmic NSAIDs Topical ophthalmic antibiotics Topical cyclosporine, topical lifitegrast within 60 days before and / or during treatment Punctal cautery or punctal plugs or changes to nasolacrimal duct surgery (insertion or removal) within 90 days before and / or during treatment. Chronic oral antiviral drugs for ocular herpes diseases.

Example

[0122] The following are some non-limiting examples of embodiments described in this specification.

[0123] Example 1 Stability of Peptide Composition Some Lacripep TM (SEQ ID NO: 1) eye drop formulations were tested for stability at -20°C, 5°C, 25°C / 25% relative humidity, or 25°C / 60% relative humidity for 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, and 12 months. These formulations are shown in Table 1.5, and the stability data are shown in Table 2 (degradation products shown as w / w% of the starting amount of Lacripep TM ) and Table 3 (12-month data). Under all test conditions, each formulation remained a colorless and clear solution, and the packaging did not leak or discolor. [Table 5] [Table 6] [Table 7]

[0124] Example 2 Comparison of Peptide Stability Lacripep TM (SEQ ID NO: 1) stability was evaluated in PBS at pH 4.5 and 7.0 (Figure 1) and citrate buffer at pH 6.0 and 6.5 (Figure 2). The initial concentration of Lacripep TM was 0.001%, and each test was carried out at 60°C. MALDI TOF mass spectrometry was used to evaluate stability at the start of the experiment (week 0, upper panels of Figures 1 and 2) and after 2 weeks (week 2, upper panels of Figures 1 and 2). After 2 weeks, in PBS at pH 4.5 and 7.0, as indicated by the appearance of a new lower m / e peak, for example, the peak at 993.9 (m / e) (small arrow, lower panel of Figure 1), Lacripep TMSignificant degradation was observed at the peak (large arrow). In contrast, after two weeks in citrate buffer at pH 6.0 and 6.5, Lacripep TM there was no change in the intensity of the peak (large arrow), or the appearance of any new lower m / e peaks (Figure 2, lower panel). This indicates an unexpected improvement in the stability of the peptide in citrate buffer.

[0125] Example 3 Method for Manufacturing a Composition Table 4 summarizes the method described below.

[0126] Add purified water (parts) and methylparaben to a manufacturing vessel of appropriate size. While performing propeller mixing, heat the mixture to 65 °C ± 5 °C until the methylparaben dissolves and a clear solution is obtained, then remove the heat. If necessary to obtain a clear solution, the mixture can be heated to a maximum of 80 °C ± 2 °C.

[0127] While continuing propeller mixing, add citric acid, sodium citrate, and disodium EDTA. Mix until all three components are dissolved to obtain a clear solution, and the temperature of the solution is less than 22 °C ± 2 °C.

[0128] While continuing propeller mixing, add tyloxapol and Lacripep TM (SEQ ID NO: 1) and mix until a clear solution is obtained.

[0129] If necessary, adjust the pH of the bulk solution to 6.5 ± 0.3 with 10% NaOH(aq) or 10% HCl(aq). Mix until the solution is homogeneous.

[0130] If necessary, adjust the osmolality of the solution to 300 ± 20 mOsm / kg with 25% NaCl(aq).

[0131] Add an appropriate amount of purified water (Part II) to the batch to make the batch 100%. Mix with a propeller until the solution is homogeneous. [Table 8]

[0132] Example 4 Method for manufacturing a composition Composition without preservatives Table 5 summarizes the method described below.

[0133] Add purified water (parts) to a production vessel of appropriate size. While performing continuous propeller mixing, add citric acid, sodium citrate, and disodium EDTA. Mix until all three components are dissolved to obtain a clear solution, and the temperature of the solution is less than 22°C ± 2°C.

[0134] While further performing continuous propeller mixing, add tyloxapol and Lacripep TM (SEQ ID NO: 1) and mix until a clear solution is obtained.

[0135] If necessary, adjust the pH of the bulk solution to 6.5 ± 0.3 with 10% NaOH(aq) or 10% HCl(aq). Mix until the solution is homogeneous.

[0136] If necessary, adjust the osmolality of the solution to 300 ± 20 mOsm / kg with 25% NaCl(aq). [Table 9]

[0137] Example 5 Method for manufacturing a composition Table 6 summarizes the method described below.

[0138] Add purified water (parts) to a production vessel of appropriate size. While performing continuous propeller mixing, add citric acid, sodium citrate, and disodium EDTA. Mix until all three components are dissolved to obtain a clear solution, and the temperature of the solution is less than 22°C ± 2°C.

[0139] While further performing continuous propeller mixing, add tyloxapol and LacripepTM Add (Array No. 1) and mix until a clear solution is obtained.

[0140] If necessary, adjust the pH of the bulk solution to 6.5 ± 0.3 with 10% NaOH(aq) or 10% HCl(aq). Mix until the solution becomes homogeneous.

[0141] If necessary, adjust the osmolality of the solution to 300 ± 20 mOsm / kg with 25% NaCl(aq).

Table 10

[0142] For example, the composition contains less than 0.05% of an active ingredient, such as a polypeptide (e.g., 0.001 - 0.02%, 0.001 - 0.05%), or a pharmaceutically acceptable salt thereof; and one or more of (i) less than 0.6% of a buffer (e.g., 0.001 - 0.3%, 0.001 - 0.6%); (ii) less than 0.01% of disodium EDTA (e.g., 0%, 0.001 - 0.005%, 0.001 - 0.01%); and (iii) less than 0.1% of tyloxapol (e.g., 0%, 0.001 - 0.05%, 0.001 - 0.1%), and any other ingredients.

[0143] Furthermore, although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Accordingly, the forms disclosed herein are merely illustrative and not intended to limit the scope of the present disclosure; rather, it is clearly understood that all modifications and alternatives that accompany the true scope and spirit of the embodiments of the present invention are also intended to be encompassed.

[0144] In this application, especially in the claims, the terms and phrases used and their variations should be construed as open-ended, as opposed to limiting, unless otherwise clearly specified. As an example of the foregoing, the term "comprising" should be construed to mean "including without limitation," "including but not limited to," and the like.

[0145] The indefinite articles "a" or "an" do not exclude a plurality. The use of "about" before a number includes the number itself. For example, "about 5" provides explicit support for "5". The present invention includes the following aspects and embodiments. Item 1. 0.00001 to 0.1%, or 0.001 to 0.05% of a polypeptide or a pharmaceutically acceptable salt thereof; 0.01 to 0.6% of a buffer; Free of disodium EDTA, or 0.0005 to 0.01% of disodium EDTA; Free of tyloxapol, or 0.01 to 0.1% of tyloxapol; and Sodium chloride; A liquid composition comprising The pH of the composition is 6.2 to about 6.8, and the osmolality of the composition is about 250 to 350 mOsm / kg. Item 2. The polypeptide or a pharmaceutically acceptable salt thereof is 0.01% or 0.005%; The buffer is 0.25 to 0.31, or 0.2888%; Disodium EDTA is 0.001%; Tyloxapol is 0.05%, The pH of the composition is 6.2 to about 6.8, and the osmolality of the composition is about 250 to 350 mOsm / kg, The polypeptide is Lacripep having SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof. The composition according to Item 1. Item 3. The composition according to any one of Items 1 to 2, wherein the buffer is a citrate buffer. Item 4. The composition according to Item 3, wherein the citrate buffer contains 0.0098% of citric anhydride and 0.279% of sodium citrate dihydrate. Item 5. The composition according to any one of Items 1 to 4, wherein the pH of the composition is about 6.5. Item 6. The composition according to any one of Items 1 to 5, wherein the osmolality of the composition is 280 to 320 mOsm / kg. Item 7. The composition according to any one of Items 1 to 6, wherein the osmolality of the composition is 300 mOsm / kg. Item 8. The composition according to any one of Items 1 to 7, wherein the amount of NaCl is 0.4% to 0.6%. Item 9. The composition according to any one of Items 1 to 8, wherein the amount of NaCl is 0.5%. Item 10. The composition according to any one of Items 1 to 9, further comprising 0.04% of methylparaben. Item 11. The composition according to any one of Items 1 to 10, which is sterile. Item 12. A kit comprising a plurality of single-use containers, each container comprising a vessel for holding the composition according to any one of Items 1 to 11. Item 13. The kit according to Item 12, wherein the container contains about 0.05 mL to about 1 mL of the composition. Item 14. The kit according to any one of claims 12-13, wherein the container comprises a removable seal top for sealing the vessel and a neck portion for interconnecting the vessel and the seal top. Claim 15. The kit according to claim 14, wherein the removable seal top, when removed, renders the vessel non-resealable. Claim 16. The kit according to any one of claims 12-15, wherein the container comprises polyvinyl chloride, polypropylene, polyethylene terephthalate, polyethylene terephthalate, polyethylene terephthalate G, high density polyethylene, low density polyethylene, polybutylene terephthalate, polyurethane, ethylene vinyl acetate, silicone, acrylonitrile-butadiene-styrene, polytetrafluoroethylene, polycarbonate, polystyrene, polymethyl methacrylate, polysulfone, polyvinylidene chloride, or a combination thereof. Claim 17. A method of administration comprising topically applying to the eye one or more drops of the composition according to any one of claims 1-11. Claim 18. The method according to claim 17, wherein the administration further comprises topically applying an eye drop of the composition from a single-use container according to any one of claims 12-16 to the eye. Claim 19. Use of the composition according to any one of claims 1-11 for the treatment of dry eye. Claim 20. Use of the composition according to any one of claims 1-11 for the treatment of one or more symptoms of Sjogren's syndrome. Claim 21. A topical composition comprising 0.005-0.05% polypeptide and one or more of the following: 0.1-0.6% buffering agent; 0.0005-0.01% disodium EDTA; 0.01-0.1% tyloxapol, and sodium chloride wherein the composition is a solution, gel or ointment. Claim 22. The composition according to claim 21, wherein the polypeptide is provided in an amount of 0.001-0.01%. Claim 23. The composition according to claim 21 or 22, wherein the polypeptide is a tear glycoprotein or a fragment thereof. Claim 24. The composition according to any one of claims 21-23, wherein the polypeptide is any one of SEQ ID NOs: 1-9. Claim 25. The composition according to any one of claims 21-24, wherein the polypeptide is Lacripep. Claim 26. Claim 27. The composition according to any one of claims 21-25 for use in treating one or more symptoms of dry eye or Sjogren's syndrome. Claim 28. A method of treating dry eye and / or primary Sjögren's syndrome, comprising administering the composition according to any one of the preceding items to the eye of a subject having dry eye and / or primary Sjögren's syndrome, wherein the polypeptide or a pharmaceutically acceptable salt thereof is in an amount of 0.005% or 0.01%, the polypeptide has the sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH 2 wherein "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1), The method of administering up to 3 drops per day to the eye of the subject. Item 28. The method according to item 27, wherein the administration improves the total FCS score (scale of 0 to 15 of the NEI / Industry Workshop) in the eye of the subject at least 2 weeks after treatment, or at least 4 weeks after treatment, or at least 6 weeks after the start of 4 weeks of treatment, compared to the baseline measurement before starting treatment. Item 29. The administration is as follows: Dryness of the eye at least 2 weeks after treatment, or at least 4 weeks after treatment, compared to the baseline in the visual analog scale; SANDE (total score of SANDE 1) at least 2 weeks after treatment compared to the baseline measurement before starting treatment; The average score of SANDE (total score of SANDE-1) at least 2 weeks after treatment compared to the baseline measurement before starting treatment; Individual symptom assessment (instantaneous) at least 2 weeks after treatment compared to the baseline measurement before starting treatment; The average score of individual symptom assessment (reflex) at least 2 weeks after treatment compared to the baseline measurement before starting treatment; LGCS in the eye of the subject at least 2 weeks after treatment compared to the baseline measurement before starting treatment; The Schirmer test under anesthesia in the eye of the subject at least 2 weeks after treatment compared to the baseline measurement before starting treatment; TFBUT in the eye of the subject at least 2 weeks after treatment compared to the baseline measurement before starting treatment; FCS in the eye of the subject at least 2 weeks after treatment compared to the baseline measurement before starting treatment; The SANDE (overall 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 to the baseline measurement before starting treatment; Individual symptoms (instantaneous) 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 the baseline measurement before starting treatment; The average score (overall score of 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 to the baseline measurement before starting treatment; The average score of individual symptom evaluations (reflex) 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 the baseline measurement before starting treatment; FCS, SANDE 1, and individual symptom evaluations (instantaneous) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to the baseline measurement before starting treatment; LGCS after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to the 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 the baseline measurement before starting treatment; TFBUT 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 the baseline measurement before starting treatment The method according to items 27-28, which improves one of the above. Item 30. The method according to any one of items 27-29, wherein the administration of the composition to the subject group does not result in a significantly higher adverse event rate compared to the adverse event rate of the administration of placebo to the same subject group. Item 31. The method according to any one of items 27-29, wherein the administration of the composition to the subject group does not result in a statistically higher adverse event rate compared to the adverse event rate of the administration of placebo to the same subject group. Item 32. The method according to any one of items 27-29, wherein the administration of the composition to the subject group does not result in a statistically higher severe adverse event rate compared to the severe adverse event rate of the administration of placebo to the same subject group. Item 33. The method according to any one of the preceding items, wherein the concentration of the polypeptide or a pharmaceutically acceptable salt thereof is about 0.005%. Item 34. The method according to any one of the preceding paragraphs, wherein the concentration of the polypeptide or a pharmaceutically acceptable salt thereof is about 0.01%. Item 35. The subject meets the following criteria: 18 years of age or older; A documented history or current diagnosis of Sjögren's syndrome according to the American-European Consensus Group Sjögren's syndrome criteria, having either 4 out of 6 criteria or 3 out of 4 signs; If the subject is undergoing systemic (oral) treatment for the treatment of Sjögren's syndrome, the subject must be on a stable systemic treatment defined as the same treatment for the previous 90 days. Self-report a history of dry eye-related eye symptoms and use of over-the-counter eye lubricants within the past 120 days All of which are met, and Before the start of treatment, the following criteria: a) Fluorescein corneal staining (FCS) total score ≥ 4 and < 15 on the National Eye Institute (NEI) / Industry Workshop scale (where 0 = no staining); b) A symptom score ≥ 40 using the SANDE questionnaire; c) Schirmer test score under anesthesia ≤ 5 mm leakage / 5 minutes; d) Lissamine green corneal staining (LGCS) total score ≥ 5 on the NEI / Industry Workshop scale (where 0 = no staining); All of which are met, The subject must meet all four criteria in at least one eye at the time of presentation to the same eye. The method according to any one of the preceding paragraphs. Item 36. The subject meets the following criteria: Any active infectious eye condition; Monocular or having a best corrected visual acuity (BCVA) of +1.0 logMAR or less as evaluated by the Early Treatment Diabetic Retinopathy Study (ETDRS), using corrective lenses as necessary; Ocular inflammatory conditions not related to dry eye syndrome (e.g., conjunctivitis, keratitis, anterior blepharitis, etc.); Clinical evidence of cicatricial ocular surface disease, such as cicatricial pemphigoid or Stevens-Johnson syndrome; Unable to discontinue the use of any topical ophthalmic drug application (including topical cyclosporine) during treatment with the composition; Used Restasis® (topical ophthalmic cyclosporine) within 60 days before starting treatment with the composition; Used Xiidra® (topical ophthalmic lifitegrast) within 60 days before starting treatment with the composition; The eye of the subject has a total fluorescein corneal staining (FCS) score = 15 or score = 3 on the NEI / Industry Workshop scale in the upper region, or the eye of the subject has FCS with diffuse confluent staining, filaments, or obvious epithelial defects; Subjects who have active herpes keratitis or in whom its sudden onset has occurred within 365 days of starting treatment, or who are taking chronic oral antiviral drugs for herpes disease; Unable to interrupt or discontinue the use of contact lenses during treatment; Having a history of collagen vascular disease, autoimmune disease, or rheumatic disease other than primary Sjögren's syndrome (e.g., lupus, rheumatoid arthritis, etc.); Having a history of or currently having anterior membrane dystrophy; Having undergone corneal transplantation or similar corneal surgery (DALK, DSEK, DMEK, etc.); Having used or expecting to use amiodarone; Changing or expecting to change the dose of tetracycline, omega-3, or omega-6 within 30 days before starting treatment; Changing or expecting to change the dose of anticholinergic drugs, antidepressants, oral contraceptives, isotretinoin, oral systemic corticosteroids, oral systemic immunosuppressive drugs within 60 days before starting treatment and / or during the treatment period; Having used topical ophthalmic antihistamines, eye drops, inhaled or intranasal corticosteroids, topical or oral mast cell stabilizers, oral antihistamines, topical or intranasal vasoconstrictors, topical ophthalmic NSAIDs, topical ophthalmic antibiotics within 30 days before starting treatment and / or during the test period; The eye of the subject having received punctal cautery within the past 90 days or having a change (insertion or removal) to punctal plugs before starting treatment; The eye of the subject having undergone corneal refractive surgery (LASIK, PRK, RK); Having a history of intraocular surgery within 90 days before starting treatment and a history of any surgical method on the ocular surface or eyelid within 365 days before starting treatment; Being pregnant or suspected of being pregnant; Breastfeeding or planning to breastfeed; Having participated in a device or investigational drug trial or clinical trial within 30 days before starting treatment The method according to any one of the preceding paragraphs, not satisfying one or more of the above. Item 37. The polypeptide has a sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH 2 where "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1), the composition, kit or method according to any one of the preceding items. Item 38. The amount of the polypeptide of its pharmaceutically acceptable salt is 0.01% or 0.005%, the composition, kit or method according to any one of the preceding items. Item 39. The composition, kit or method according to any one of the preceding items, including a comparison of the vehicle control and treatment with the polypeptide, instead of or in addition to a comparison with a baseline measurement before the start of treatment. Item 40. The composition comprises 0.001 to 0.05% of the polypeptide or its pharmaceutically acceptable salt; 0.01 to 0.6% of a buffer; 0.0005 to 0.01% of disodium EDTA; 0.01 to 0.1% of tyloxapol, and sodium chloride and the pH of the composition is 6.2 to about 6.8 and the osmolality of the composition is about 250 to 350 mOsm / kg, the composition, kit or method according to any one of the preceding items. Item 41. The polypeptide or its pharmaceutically acceptable salt is 0.01%; the buffer is 0.2888%; disodium EDTA is 0.001%; tyloxapol is 0.05%; the pH of the composition is 6.2 to about 6.8 and the osmolality of the composition is about 250 to 350 mOsm / kg The polypeptide is Lacripep having SEQ ID NO: 1, or its pharmaceutically acceptable salt, the composition, kit or method according to item 40. Item 42. The composition, kit or method according to any one of the preceding items, wherein the composition does not contain tyloxapol. Item 43. The composition, kit or method according to any one of the preceding items, wherein the composition does not contain EDTA. Item 44. The composition, kit or method according to any one of the preceding items, wherein the composition maintains at least about 99.0% of the polypeptide in undegraded form after storage of the composition for 1 week at 5 ± 3°C or 25 ± 2°C and 25 ± 5% relative humidity. Item 45. The composition, kit or method according to any one of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in an undegraded form after storage of the composition for 2 weeks at 25 ± 2 °C and 25 ± 5% relative humidity. Item 46. The composition, kit or method according to any one of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in an undegraded form after storage of the composition for 1 month at 5 ± 3 °C or 25 ± 2 °C and 25 ± 5% relative humidity. Item 47. The composition, kit or method according to any one of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in an undegraded form after storage of the composition for 2 months at 5 ± 3 °C. Item 48. The composition, kit or method according to any one of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in an undegraded form after storage of the composition for 3 months at 5 ± 3 °C or -20 ± 5 °C. Item 49. The composition, kit or method according to any one of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in an undegraded form after storage of the composition for 4 months at 5 ± 3 °C. Item 50. The composition, kit or method according to any one of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in an undegraded form after storage of the composition for 5 months at 5 ± 3 °C. Item 51. The composition, kit or method according to any one of claims 44 - 50, wherein the composition maintains at least about 99.5% of the polypeptide in an undegraded form in the composition. Item 52. The composition, kit or method according to any one of claims 44 - 50, wherein the composition maintains at least about 99.9% of the polypeptide in an undegraded form in the composition. Item 53. The composition, kit or method according to any one of claims 44 - 50, wherein the composition maintains at least about 99.95% of the polypeptide in an undegraded form in the composition. Item 54. The composition, kit or method according to any one of the preceding claims, wherein the composition maintains at least about 80% of the polypeptide in an undegraded form after storage of the composition for 12 months at 5 ± 3 °C. Item 55. The composition, kit or method according to claim 54, wherein the composition maintains at least about 90% of the polypeptide in an undegraded form in the composition.

Claims

1. A polypeptide consisting of SEQ ID NO: 1 at 0.0001 to 0.006% by weight (w / w), or an equivalent pharmaceutically acceptable salt thereof; 0.2 to 0.4 w / w% of a citrate buffer; 0.0005 to 0.005 w / w% of disodium EDTA; Free of tyloxapol, or 0.01 to 0.1 w / w% of tyloxapol; and An isotonic agent An aqueous liquid composition comprising: The pH of the aqueous liquid composition is 6.2 to 6.6, the osmolality of the aqueous liquid composition is 150 to 350 mOsm / kg, and The aqueous liquid composition is sterile.

2. The polypeptide or an equivalent pharmaceutically acceptable salt thereof is 0.0001 to 0.0005 w / w%, 0.00075 to 0.002 w / w% or 0.004 to 0.006 w / w%; Disodium EDTA is 0.0008 to 0.002 w / w%; and Tyloxapol is 0.04 to 0.06 w / w%, The aqueous liquid composition according to Claim 1.

3. The citrate buffer comprises 0.001 to 0.015 w / w% of anhydrous citric acid and 0.02 to 0.40 w / w% of sodium citrate dihydrate, the aqueous liquid composition according to Claim 1 or 2.

4. The pH of the aqueous liquid composition is 6.3 to 6.5, the aqueous liquid composition according to any one of Claims 1 to 3.

5. The osmolality of the aqueous liquid composition is 180 to 210 mOsm / kg, the aqueous liquid composition according to any one of Claims 1 to 4.

6. The amount of NaCl is 0.4 to 0.6 w / w%, the aqueous liquid composition according to any one of Claims 1 to 5.

7. The aqueous liquid composition according to any one of claims 1 to 6, wherein the amount of NaCl is 0.5 w / w%.

8. The aqueous liquid composition according to any one of claims 1 to 7, wherein the N-terminus of the polypeptide is acetylated and the C-terminus of the polypeptide is amidated.

9. The aqueous liquid composition according to any one of claims 1 to 8, wherein the aqueous liquid composition comprises 0.00025 ± 0.000025% w / w, 0.001 ± 0.0001% w / w or 0.005 ± 0.0005% w / w of a polypeptide, or an equivalent amount of a pharmaceutically acceptable salt thereof.

10. The aqueous liquid composition 0.00025 ± 0.000025 w / w%, 0.001 ± 0.0001 w / w% or 0.005 ± 0.0005 w / w% of a polypeptide, or an equivalent amount of a pharmaceutically acceptable salt thereof; 0.279 ± 0.028 w / w% of sodium citrate dihydrate; 0.0098 ± 0.001 w / w% of citric anhydride; 0.001 ± 0.0001 w / w% of disodium EDTA; 0.05 ± 0.005 w / w% of tyloxapol; and 0.50 ± 0.05 w / w% of NaCl and the N-terminus of the polypeptide is acetylated and the C-terminus of the polypeptide is amidated, and the pH of the aqueous liquid composition is 6.4 to 6.6 and the osmolality of the aqueous liquid composition is 190 ± 19 mOsm / kg, the aqueous liquid composition according to claim 1.

11. The aqueous liquid composition according to claim 10, wherein the aqueous liquid composition comprises 0.005 ± 0.0005 w / w% of a polypeptide, or an equivalent amount of a pharmaceutically acceptable salt thereof.

12. The aqueous liquid composition according to claim 10, wherein the aqueous liquid composition comprises 0.001 ± 0.0001 w / w% of a polypeptide, or an equivalent amount of a pharmaceutically acceptable salt thereof. **Claim 13**: The aqueous liquid composition according to claim 10, wherein the aqueous liquid composition contains 0.00025 ± 0.000025 w / w% of a polypeptide or an equivalent amount of a pharmaceutically acceptable salt thereof. **Claim 14**: The aqueous liquid composition according to any one of claims 1 to 13, wherein the polypeptide is an acetate. **Claim 15**: The aqueous liquid composition according to any one of claims 1 to 14, wherein the aqueous liquid composition maintains at least 98% of the polypeptide in an undegraded form in the aqueous liquid composition after storage of the aqueous liquid composition for one week at 5 ± 3°C, or maintains at least 94% of the polypeptide in an undegraded form in the aqueous liquid composition after storage of the aqueous liquid composition for one week at 25 ± 2°C and 25 ± 5% relative humidity. **Claim 16**: The aqueous liquid composition according to any one of claims 1 to 15, wherein the aqueous liquid composition does not contain a thickening agent. **Claim 17**: A kit comprising a plurality of single-use containers, each of the plurality of single-use containers containing the aqueous liquid composition according to any one of claims 1 to 16. **Claim 18**: The kit according to claim 17, wherein the container includes a removable seal top for sealing the vessel and a neck portion for interconnecting the vessel and the seal top. **Claim 19**: The kit according to claim 18, wherein the removable seal top cannot reseal the vessel when removed. **Claim 20**: The kit according to any one of claims 17 to 19, wherein the amount of the aqueous liquid composition in the container is 0.05 to 1 mL. **Claim 21**: The aqueous liquid composition according to any one of claims 1 to 16, for topical application to the eye. **Claim 22**: The aqueous liquid composition according to claim 21, wherein an eye drop of the aqueous liquid composition is topically applied to the eye from a single-use container according to any one of claims 17 to 20.

23. An aqueous liquid composition for treating dry eye and / or primary Sjögren's syndrome, the aqueous liquid composition being administered to the eye of a subject having dry eye and / or primary Sjögren's syndrome, the aqueous liquid composition according to any one of claims 1 to 16.

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