Adiponectin peptidomimetics formulations

Abstract

To provide therapeutic agents for eye diseases associated with inflammation.SOLUTION: Disclosed are compositions and methods for the use of adiponectin peptidomimetics in therapeutic applications. The compositions can include a peptide, for example, D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH2, a solubilizer, a surfactant, a buffer, optionally boric acid and optionally mannitol. The osmolality of the composition can be between 260 to 330 mOsm / kg and the pH can be between 4.5 to 5.5. Methods of using the compositions in treating certain eye diseases are also disclosed.SELECTED DRAWING: None

Description

Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 62 / 749,861, filed October 24, 2018, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Disclosed herein are compositions for treating ocular disorders. More specifically, disclosed are compositions and methods for the use of adiponectin peptidomimetics in therapeutic applications.

[0003] For the majority of patients with inflammation-associated dry eye and ocular diseases, there are few effective treatment options. Thus, there is a high need for effective and safe therapies. Adiponectin is a protein secreted primarily from adipose tissue and is associated with inflammatory responses. Adiponectin exerts immunomodulatory effects by increasing levels of the anti-inflammatory cytokines IL-10 and IL-1RA and decreasing levels of the proinflammatory proteins IL-6, TNF-α, and IFN-γ. Topical application of adiponectin in experimental models of dry eye reduces inflammation of the ocular surface and lacrimal gland. Low molecular weight (1-2 kDa) peptide compounds that mimic the activity or function of adiponectin protein are useful as therapeutics to treat patients with inflammation-associated dry eye and ocular diseases.

[0004] However, low molecular weight adiponectin peptide mimetics are susceptible to degradation by fragmentation, deamidation, oxidation, and hydrolysis. Thus, the challenges in developing compositional strategies for these small peptides require a balance of physicochemical variables that allow chemical stabilization into peptide compositions that allow for routine use and long-term storage at room temperature conditions, solubilization to therapeutically relevant peptide concentrations under refrigerated conditions, ensuring that the resulting solutions are non-irritating, and preventing aggregation of the peptides due to loss / fragmentation of hydrophilic sequences.

[0005] The formulation of adiponectin peptidomimetics has three main objectives: (a) to prevent aggregation, (b) to minimize degradation, and (c) to minimize irritation. The aggregation behavior of peptides is due to their high hydrophobicity. At higher pH, deamidation of the peptide occurs, converting the overall positively charged peptide into a neutral peptide. The other amino acid residues of the peptide are hydrophobic, so the absence of charge leads to microdisintegration of the peptide chain and precipitation. The compositions of the present invention address these challenges. Summary of the Invention

[0006] One aspect of the present invention is a composition comprising a therapeutically effective amount of a peptide of 1 kDa to 2 kDa, a solubilizing agent generally recognized as safe, one or more surfactants generally recognized as safe, a buffer recognized as generally recognized as safe, optionally boric acid and optionally mannitol, the composition having an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5. When boric acid or mannitol is added, the composition may include a composition in which boric acid is generally 0.05% to 1.0%, or 0.05% to 0.2%, and mannitol is generally 0.5% to 5.0%, or 2.0% to 4.0% of the total composition.

[0007] One aspect of the present invention is a composition comprising a therapeutically effective amount of an adiponectin peptide mimetic of 1 kDa to 2 kDa, a solubilizing agent generally recognized as safe, one or more surfactants generally recognized as safe, and a buffering agent generally recognized as safe, optionally including boric acid, and optionally including mannitol, wherein the composition has an osmolality of 260 to 330 mOsm / kg and a pH of 4.5 to 5.5.

[0008] One aspect of the invention is a method of treating a disease in a patient by administering to the patient a composition comprising: a therapeutically effective amount of a 1 kDa to 2 kDa peptide; a solubilizing agent generally recognized as safe; a surfactant generally recognized as safe; and a buffering agent generally recognized as safe, optionally boric acid and optionally mannitol, having an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5.

[0009] One aspect of the invention is a method of treating a disease in a patient by administering to the patient a composition comprising a therapeutically effective amount of a 1 kDa to 2 kDa adiponectin peptide mimetic, a solubilizing agent generally recognized as safe, one or more surfactants generally recognized as safe, a buffer generally recognized as safe, optionally boric acid and optionally mannitol, having an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5. [Brief description of the drawings]

[0010] FIG. 1 shows the corneal staining results of use of the compositions of the present invention in test rabbit eyes.

[0011] FIG. 2 shows the tear-away disintegration time (TBUT) results of the use of the compositions of the present invention in the eyes of test rabbits.

[0012] FIG. 3 shows the tear volume (TV) results of use of the compositions of the present invention in the eyes of test rabbits.

[0013] Figures 4A-4C show the overall response versus baseline (integrated AUC response) for the corneal staining, TBUT, and TV test results as shown in Figures 1-3.

[0014] definition As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0015] As used herein, the terms "a," "an," or "the" include not only embodiments of one element, but also embodiments of two or more elements. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0016] The term "dry eye", as defined in "Definition and Classification of Dry Eye Disease, Guidelines from the 2007 International Dry Eye Workshop", Ocul Surf, 2007, 5(2), 75-92, refers to a multifactorial disorder of the tears and ocular surface (including the cornea, conjunctiva, and eyelids) that causes symptoms of discomfort, visual disturbance, and tear film instability. Dry eye may be accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Dry eye includes dry eye syndrome, keratoconjunctivitis sicca (KCS), dysfunctional tear syndrome, lacrimal keratoconjunctivitis, evaporative tear deficiency, aqueous tear deficiency, and LASIK-induced neurotrophic epitheliopathy (LE).

[0017] The term "ocular disease associated with inflammation" refers to a disease or disorder of the eye in which inflammation causes damage to the ocular surface system. As used herein, the "ocular surface system" includes the cornea, conjunctiva, lacrimal gland, meibomian gland, nasolacrimal duct, and their associated tear and connective tissue matrix, as well as the eyelids and eyelashes, including the endocrine, immune, and vascular systems, all integrated by a continuous epithelium and interconnected nerves.

[0018] The term "symptom" refers to a subjective sign or observation of a disorder or disease experienced or perceived by a patient.

[0019] The term "clinical sign" refers to an objective sign, observation, or evidence of a disorder or disease that can be detected or interpreted by a clinician.

[0020] The term "adiponectin" refers to a polypeptide that is mainly derived from adipocytes. The adiponectin polypeptide consists of 244 amino acid residues, including a short non-collagenous N-terminal segment (about 130 amino acids), followed by a collagen-like sequence (Maeda et al., BBRC, 1996, 221, 286-289). The amino acid sequence of the human adiponectin polypeptide is, for example, sequence number NP004788.1 in NCBI Ref. or NO.Q15848 in UniPro Ref. Adiponectin can form homotrimers of similar size and overall structure that complement the protein Clq, with a particularly high homology to Clq (about 65-70% homology) in the C-terminal globular domain. This globular domain (about 130 amino acids) is thought to be essential for the biological activity of native (natural) adiponectin. The crystal structure of adiponectin shows even greater structural similarity between this same globular domain and TNFα (approximately 60% homology).

[0021] The term "adiponectin peptide mimetic" refers to an oligopolyamide compound consisting of natural and / or non-natural amino acid residues that mimics the activity or function of the adiponectin protein. Adiponectin peptide mimetics may have the ability to bind to or interact with one or more adiponectin receptors (AdipoR1 and AdipoR2) or variants thereof. Peptide mimetics may be backbone-modified peptides, any polyamide or other polymeric structure that resembles a peptide, a peptide containing non-natural amino acid residues, or a peptide derivative.

[0022] The term "peptide" refers to an organic compound containing a chain of two or more amino acids covalently linked by peptide bonds. Peptides are sometimes referred to in terms of the number of constituent amino acids: a dipeptide contains two amino acid residues, a tripeptide contains three amino acid residues, and so on.

[0023] The term "amino acid" as used herein refers to an organic compound that contains both a basic amino group and an acidic carboxyl group. Included in the term are natural amino acids (such as L-amino acids), modified and unusual amino acids (such as D-amino acids), and amino acids that are known to occur biologically in free or bound forms but are normally present, but do not occur in proteins. The term includes modified and unusual amino acids, for example, as disclosed in Roberts and Vellaccio (1983) The Peptides, 5, 342-429, the teachings of which are incorporated herein by reference. Natural protein amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine. Naturally occurring non-protein amino acids include, but are not limited to, argininosuccinic acid, citrulline, cysteine ​​sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3-monoiodotyrosine, 3,5-diiodotriosine, 3,5,5'-triiodothyronine, and 3,3',5,5'-tetraiodothyronine.Modified or unusual amino acids that can be used to practice the present invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, N-Cbz protected amino acids, 2,4-diaminobutyric acid, homoarginine, N-methyl-arginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, beta-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, norvaline, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.

[0024] The term "side chain" refers to a group attached to the peptide backbone, typically the alpha carbon of an alpha-amino acid. For example, the side chains of proteinogenic amino acids include methyl (alanine), hydroxymethyl (butyric acid), benzyl (phenylalanine), mercaptomethyl (cysteine), and carboxymethyl (aspartic acid).

[0025] The term "unnatural amino acid" can be used to refer to an amino acid that does not occur in nature by itself, but is synthesized or created by man. Examples of unnatural amino acids include, but are not limited to, iodized tyrosine, methylated tyrosine, glycosylated serine, glycosylated threonine, azetidine-2-carboxylic acid, 3,4-dehydroproline, perthiaproline, canavanine, ethionine, norleucine, selenomethionine, animohexanoic acid, telluromethionine, homoallyl and homopropargyl glycine. D-amino acids are also examples of unnatural amino acids.

[0026] "Nva" corresponds to the unnatural amino acid norvaline, also known as 2(L)-aminopentanoic acid. "NvaNH2" corresponds to 2(L)-aminopentanamide. "Aca" corresponds to the unnatural amino acid 6-aminocaproic acid, also known as 6-aminohexanoic acid. "AcpNH2" corresponds to 6-aminocapramide, also known as 6-aminohexanamide. "Dap(Ac)" corresponds to N2(3)-acetyl-diaminopropionic acid. "Dbu" corresponds to 2,4-diaminobutyric acid. "Glc" corresponds to glucose. "betaGlc" corresponds to beta-glucose. "Serbeta(Glc)" corresponds to serine glycosylated with a beta-glucosyl residue at the alcohol hydroxyl group. "Thr("GalNAc")" corresponds to threonine glycosylated with an N-acetylgalactosaminyl residue at the alcohol hydroxyl group. "Tyr(I2)" corresponds to 3,5-diiodotyrosine. "N-MeArg" corresponds to N-methyl-arginine. "betaAla" corresponds to beta-alanine, also known as 3-aminopropanoic acid. "betaAla-NH2" corresponds to the amide derivative of beta-alanine, also known as 3-aminopropanamide. "(D)-Ser" corresponds to D-serine. "Apa" corresponds to aminopentanoic acid. "AlloThr" corresponds to allo-threonine, also known as (2S,3S)-2-amino-3-hydroxybutanoic acid. "3Hyp" corresponds to 3-hydroxyproline. "4Hyp" corresponds to 4-hydroxyproline.

[0027] As used herein, the term "hydroxylated acyclic amino acid" refers to an acyclic amino acid that contains at least one alcohol hydroxyl group in its structure.Preferably, but not exclusively, examples of hydroxylated acyclic amino acids are serine, (D)-serine, threonine, (D)-threonine, (L)-allo-threonine, (D)-allo-threonine, (L)-isoserine, (D)-isoserine, (D)-β-homoserine, (D)-P-homoserine, (L)-homoserine, and (D)-homoserine.

[0028] The term "peptide transduction domain" refers to a peptide or derivative thereof that is capable of crossing a cell membrane and directing the transport of a peptide, protein, or molecule associated with the protein transduction domain from outside the cell through the cytoplasmic membrane of the cell to the cytoplasm of the cell.

[0029] The term "conjugated" referring to the bond between two peptides means that the two peptides are covalently linked to each other. The bond can be achieved directly through the formation of an amide bond between the carboxyl group of one peptide and the amino group of the other peptide, or by a linking group, where the linking group has a covalent bond to each peptide. For example, the linking group can be a peptide chain, an amino acid, or any group that has at least two functional groups and can form a covalent bond to each of the two peptide chains.

[0030] "Generally Recognized as Safe" (GRAS) is a U.S. Food and Drug Administration (FDA) designation that a chemical or substance added to food is considered safe by experts and is exempt from the usual Federal Food, Drug, and Cosmetic Act (FFDCA) food additive tolerance requirements.

[0031] The term "therapeutically effective amount", "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to ameliorate a disorder, as described above. For example, for a given parameter, a therapeutically effective amount will show an increase or decrease in therapeutic effect of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. The therapeutic effect may be expressed as a "fold" increase or decrease. For example, a therapeutically effective amount may have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. In the context of the present invention, the effective amount of an adiponectin peptidomimetic compound may vary depending on the co-administration of other therapeutic agents or the individual's disease profile (among other factors, such as age, disease severity, etc.).

[0032] The terms "treatment", "treat" and "amelioration" refer to a reduction in the severity of symptoms. When treating an ocular disorder, such as dry eye, the term may refer to the addition of artificial tears, conserving tears, reducing tear evaporation, increasing tear production, reducing eyelid or ocular surface inflammation, reducing ocular symptoms to dry eye, and the like. As used herein, the terms "treat" and "prevent" are not intended to be absolute terms. Treatment refers to delaying the onset, improving symptoms, improving the quality of life of the patient, and the like. The effect of treatment can be compared to an individual or a collection of individuals not receiving the treatment, or the same patient at different times before or during treatment. In some embodiments, the severity of the disease is reduced by at least 10%, for example, compared to an individual before administration or a control individual not receiving the treatment. In some aspects, the severity of the disease is reduced by at least 25%, 50%, 75%), 80%), or 90%, or in some cases, is no longer detectable using standard diagnostic techniques.

[0033] The term "treat" or "treatment" refers to the treatment or care of a disease or medical condition (such as dry eye or eye disease associated with inflammation) in a patient, such as a mammal (particularly a human or animal), including ameliorating the disease or condition, i.e., eliminating or reversing the disease or condition in the patient, and inhibiting the disease or condition, i.e., slowing or arresting the progression of the disease or condition in the patient, or alleviating one or more symptoms of the disease or condition in the patient. The term encompasses prophylactic treatment of a disease or condition to prevent or reduce the risk of acquiring or developing a particular disease or condition, or to prevent or reduce the risk of recurrence.

[0034] As used herein, "dosage unit" refers to a physically discrete unit suitable as a unitary dosage for a particular patient to be treated. Each unit may contain a predetermined amount of active compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the present invention are determined by (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved; (b) the inherent limitations of the technology for formulating such active compounds.

[0035] The terms "subject," "individual," or "patient" typically include humans, but may also include other animals, such as, for example, other primates, rodents, dogs, cats, horses, sheep, pigs, etc. Preferred embodiments of the present invention

[0036] Preferably, the composition comprises an adiponectin peptide mimetic, a solubilizing agent generally recognized as safe selected from polypropylene glycol, glycerol, PEG400 and propylene glycol, and a surfactant generally recognized as safe selected from Tween 80, tyloxapol, poloxamer, PEG40 hydrogenated castor oil, PEG 35 castor oil and PEG40 sterate and acetate buffer, with an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0037] As used herein, all percentages of all composition components refer to weight percent. Preferably, 0.01% to 2% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 A composition comprising (SEQ ID NO:1), 1% to 2% propylene glycol, 0.08% to 0.12% tyloxapol or poloxamer, 0.02% to 0.20% acetic acid, and 0.05% to 0.5% sodium acetate, wherein the composition has an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5.

[0038] Preferably, 0.02% to 1.0% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 21.20%-1.90% propylene glycol, 0.10% tyloxapol or poloxamer, 0.04%-0.20% acetic acid, and 0.08%-0.42% sodium acetate, wherein the composition has an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5.

[0039] Preferably, 1.0% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.77% propylene glycol, 0.10% tyloxapol, 0.14% acetic acid, and 0.08% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0040] Preferably, 0.5% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.58% propylene glycol, 0.10% tyloxapol, 0.09% acetic acid and 0.24% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0041] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.57% propylene glycol, 0.10% tyloxapol, 0.09% acetic acid, and 0.24% sodium acetate, having a pH of 260-330 mOsm / kg and a pH of 4.5-5.5.

[0042] Preferably, 0.5% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2, 1.43% propylene glycol, 0.10% tyloxapol, 0.04% acetic acid and 0.34% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0043] Preferably, 0.5% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.44% propylene glycol, 0.10% tyloxapol, 0.04% acetic acid and 0.34% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0044] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.72% propylene glycol, 0.10% poloxamer 188, 0.11% acetic acid and 0.09% sodium acetate, having an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5.

[0045] Preferably, 0.50% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.73% propylene glycol, 0.10% poloxamer 188, 0.11% acetic acid and 0.09% sodium acetate, having an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5.

[0046] Preferably, 0.25% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.74% propylene glycol, 0.10% poloxamer 188, 0.11% acetic acid and 0.09% sodium acetate, having an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5.

[0047] Preferably, 0.50% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.55% propylene glycol, 0.10% poloxamer 188, 0.10% acetic acid and 0.24% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0048] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.55% propylene glycol, 0.10% poloxamer 188, 0.10% acetic acid and 0.24% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0049] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 A preferred composition is 1.40% propylene glycol, 0.20% poloxamer 188, 0.19% acetic acid, and 0.30% sodium acetate, with an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0050] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.38% propylene glycol, 0.10% tyloxapol, 0.19% acetic acid, and 0.30% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0051] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2, 1.25% propylene glycol, 0.10% tyloxapol, 0.17% acetic acid, and 0.41% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0052] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.54% propylene glycol, 0.10% tyloxapol, 0.19% acetic acid, and 0.14% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0053] Preferably, 0.80% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.54% propylene glycol, 0.10% tyloxapol, 0.19% acetic acid and 0.14% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0054] Preferably, 0.50% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.55% propylene glycol, 0.10% tyloxapol, 0.19% acetic acid and 0.14% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0055] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.5% propylene glycol, 0.10% tyloxapol, 0.19% acetic acid and 0.14% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0056] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.86% propylene glycol, 0.10% tyloxapol, 0.13% acetic acid, and 0.10% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0057] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.67% propylene glycol, 0.10% tyloxapol, 0.15% acetic acid, and 0.11% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0058] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.62% propylene glycol, 0.10% tyloxapol, 0.17% acetic acid, and 0.13% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0059] Preferably, 0.5% to 1% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.43% to 1.55% propylene glycol, 0.10% poloxamer 188, 0.04% to 0.10% acetic acid and 0.24% to 0.34% sodium acetate, having an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5.

[0060] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2, 1.55% propylene glycol, 0.10% poloxamer 188, 0.10% acetic acid, 0.24% sodium acetate, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0061] Preferably, 0.5% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.43% propylene glycol, 0.10% poloxamer 188, 0.04% acetic acid, 0.24, having an osmolality between 260 and 330 mOsm / kg and a pH between 4.5 and 5.5.

[0062] Preferably, 0.4% to 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 0.193% to 0.20% propylene glycol, 0.09 to 0.10% tyloxapol, 0.014% to 0.07% acetic acid, 0.06% to 0.138% sodium acetate, 0.09% boric acid, and 3.127% to 3.66% mannitol.

[0063] Preferably, 0.401% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 0.193% propylene glycol, 0.097% tyloxapol, 0.014% acetic acid, 0.138% sodium acetate, 0.09% boric acid, and 3.65% mannitol.

[0064] Preferably, 1.00% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 0.20% propylene glycol, 0.10% tyloxapol, 0.07% acetic acid, 0.06% sodium acetate, 0.09% boric acid, and 3.66% mannitol.

[0065] Preferably, the method of treating a disease in a patient comprises administering to the patient a composition comprising a solubilizing agent generally recognized as safe, the adiponectin peptide mimetic being selected from polypropylene glycol, glycerol, PEG 400, a surfactant generally recognized as safe, the surfactant being propylene glycol being selected from Tween 80, tyloxapol, poloxamer, PEG 40 hydrogenated castor oil, PEG 35 castor oil, and PEG 40 stearate, and an acetate buffer, the composition having an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5.

[0066] Preferably, the method for treating a disease in a patient comprises administering to the patient 0.1% to 2% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1% to 2% propylene glycol, 0.08% to 0.12% tyloxapol or poloxamer, 0.02% to 0.20% acetic acid, and 0.05% to 0.5% sodium acetate, wherein the composition has an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5 to a patient.

[0067] Preferably, the method for treating a disease in a patient comprises administering to the patient 0.20% to 1.0% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.20%-1.90% propylene glycol, 0.10% tyloxapol or poloxamer, 0.04%-0.20% acetic acid, and 0.08% to 0.42% sodium acetate, wherein the composition has an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5 to a patient.

[0068] Preferably, the method for treating a disease in a patient comprises administering to the patient 0.20% to 1.0% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2a composition comprising 1.20% to 1.90% propylene glycol, 0.10% tyloxapol or poloxamer, 0.04% to 0.20% acetic acid, and 0.08% to 0.42% sodium acetate, wherein the composition has an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.5 to a patient. Preparation of the Compounds of the Composition of the Invention

[0069] The peptidomimetic compounds of the present invention may be natural, recombinant or synthetic peptides. They may be chemically synthesized, for example using solid phase synthesis methods. Furthermore, the peptide transduction domains added to the peptides of the present invention may be natural or synthetic peptides, prepared by isolation from natural sources or synthesized.

[0070] The peptides of the present invention can be synthesized de novo using peptide synthesis methods. In such methods, a peptide chain is prepared by a series of coupling reactions in which the constituent amino acids are added to a growing peptide chain in a desired order. The use of various N-protecting groups includes, for example, carbobenzyloxy or t-butyloxycarbonyl groups, and various coupling reagents include, for example, dicyclohexylcarbodiimide or carbonyldiimidazole. Various active esters, such as esters of N-hydroxyphthalimide or N-hydroxysuccinimide, and various cleavage reagents, such as trifluoroacetic acid (TFA), HCl in dioxane, tris-(trifluoroacetate)boron, and cyanogen bromide, are used, but reactions in solution with isolation and purification of intermediates are methods well known to those skilled in the art. The reactions may be carried out with the peptide in solution or attached to a solid support. In solid-phase methods, the peptide is released from the solid support after completion of synthesis.

[0071] In some embodiments, peptide synthesis can follow the Merrifield solid phase procedure, see, e.g., Merrifield, J. Am. Chem. Soc., 1963, 85, 2149-54. Additional information regarding solid phase synthesis procedures can be found, for example, in Solid Phase Peptide Synthesis: A Practical Approach by E. Atherton and RC Sheppard (Oxford University Press, 1989), Solid Phase Peptide Synthesis, by JM Stewart and JD Young, (2nd ed., Pierce Chemical Company, Rockford, 1984), and in FF Nold, ed. (Interscience Publishers, New York, 1969) and BW Erickson and R. Merrifield in The Proteins Vol.2, pp.255 et seq., Edited by Neurath and Hill, (Academic Press, New York, 1976). Peptide synthesis may follow synthetic techniques such as those described in Fields et al., Introduction to Peptide Synthesis, Current Protocols in Molecular Biology (Chapter 11, Unit 11.15; John Wiley and Sons, 2008) and Amblard et al. (2006, Molecular Biotechnology,33:239-254).

[0072] The synthesis of peptides by solution methods is described, for example, in The Proteins, Vol. 11, edited by Neurath et al. (3rd ed., Academic Press 1976). Other general references on the synthesis of peptides include Peptide Synthesis Protocols edited by M.W. Pennington and Ben M. Dunn (Humana Press 1994), Principles of Peptide Synthesis, Miklos Bodanszky (2nd ed., Springer-Verlag, 1993), and Chemical Approaches to the Synthesis of Peptides and Proteins, Paul Lloyd-Williams, F. Albericio, E. Giralt (CRC Press 1997), and Synthetic Peptides, A User's Guide edited by G. Grant (Oxford University Press, 2002).

[0073] The nucleic acid encoding the desired peptide can be operably linked to one or more regulatory regions. Regulatory regions include promoters, polyadenylation signals, translation initiation signals (Kozak regions), stop codons, peptide cleavage sites, and enhancers. The regulatory sequences used must function in the cells of the vertebrate to which they are administered. The selection of an appropriate regulatory region or regions is a routine matter within the level of one skilled in the art.

[0074] The compounds of the present invention may be prepared by either chemical synthesis or recombinant DNA technology, and may be purified using known techniques, such as preparative HPLC, FPLC, affinity chromatography, and other chromatographic methods.The isolated compounds may then be evaluated for biological activity according to the methods described herein, as well as by any method known to those skilled in the art. Ocular diseases suitable for treatment with adiponectin peptidomimetic compounds

[0075] The adiponectin peptidomimetic compounds described herein are used to treat ocular diseases or disorders, including ocular diseases associated with dry eye or inflammation.

[0076] Dry eye disease or keratoconjunctivitis sicca (KCS) can be caused by or include a variety of conditions, including Sjögren's syndrome, cicatricial pemphigoid, congenital dacryoadenitis, blepharitis, lacrimal gland ablation, age-related lacrimal gland deficiency, dacryoadenitis (e.g., Triple A or Allgrove syndrome, and Riley-Day syndrome), lacrimal gland infiltration (e.g., sarcoidosis, lymphoma, and AIDS), lacrimal duct obstruction, meibomian gland disorders, pterygium, chronic inflammation of the conjunctiva, reflex block, herpes zoster, ocular allergies, autoimmune diseases, chronic graft-versus-host disease, and natural aging. process, diabetes, long-term contact lens wear, dry environment, excessive computer screen use, surgery with corneal incision or corneal nerve removal (e.g. cataract) surgery, refractive surgery, retinal surgery, eye oncology treatment, drug therapy, reduced blinking (reduced blink rate), impaired eyelid opening or eyelid / globe dynamics, pregnancy, polycystic ovary syndrome, acne rosacea, lupus, scleroderma, sarcoidosis, Stevens-Johnson syndrome, Parkinson's disease, thyroid disease, cosmetic surgery, smoking, radiation therapy, vitamin A deficiency and menopause.

[0077] Dry eye can also be caused by nutritional disorders, deficiencies, pharmacological side effects, skin diseases around the eyelids, ocular stress and glandular and tissue destruction, environmental exposure to smog, smoke, excessively dry air, airborne particulates, autoimmune diseases, and other immunodeficiency disorders. In dry eye, the ocular surface epithelium undergoes squamous metaplasia with loss of goblet cells, mucin deficiency, and keratinization. These changes result in tear film instability, leading to the clinical manifestations of dry eye syndrome.

[0078] Symptoms of dry eye include stinging, burning, scratching sensation in the eye, dryness or grittiness of the eye, stringy mucus in or around the eye, increased eye irritation, eye fatigue, sensitivity to light (photophobia), redness of the eye, excessive tearing, blurred vision episodes, foreign body sensation in the eye, soreness or pain around or in the eye, inability to cry when emotionally stressed, decreased tolerance of activities requiring sustained visual attention, and any combination thereof. Symptoms of dry eye can be quantified, for example, using the Ocular Surface Disease Index (OSDI) questionnaire. The OSDI questionnaire lists 12 symptoms and grades, each on a scale of 1 to 4. Clinical signs of dry eye can be assessed, for example, by impression cytology (e.g., ocular surface staining), measuring tear break-up time (TBUT), performing the Schirmer test, phenol red thread tear test, and analyzing tear components (e.g., tear protein or tear film osmolality). Increased osmolarity (hyperosmolarity) can lead to decreased tear film regulation, increased damage to the ocular surface, and in some cases increased ocular inflammation.

[0079] Eye diseases associated with inflammation include, but are not limited to, uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal neovascularization, lymphangiogenesis, uveitis, pterygium, retinitis, choroiditis, acute multifocal placoid pigment epitheliopathy, Behcet's disease, post-operative corneal wound healing, conditions caused by lasers, conditions caused by photodynamic therapy, wet and dry age-related macular degeneration (ARMD), conditions affecting the posterior segment, maculopathy, retinal degeneration, non-exudative age-related macular degeneration, exudative age-related macular degeneration Degeneration, Choroidal Neovascularization, Diabetic Retinopathy (Proliferative), Retinopathy of Prematurity (ROP), Acute Macular Neuroretinopathy, Central Serous Chorioretinopathy, Cystoid Macular Edema, and Diabetic Macular Edema, Birdshot, Lyme Retinopathy, Tuberculosis, Toxoplasmosis), Middle Uveitis (Pars Planitis), Multifocal Choroiditis, Multifocal Evanescent White Dot Syndrome (Meteor), Ocular Sarcoidosis, Posterior Scleritis, Spinal Choroiditis, Subretinal Fibrosis and Uveitis Syndrome, Vogt-Koyanagi and Harada Syndrome, Retinal Artery Occlusion, Central Retinal Vein Occlusion, Cystoid Macula, Disseminated Intravascular Coagulation, Branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal artery microaneurysms, Coats disease, parafoveal telangiectasia, hemiretinal vein occlusion, papillophlebitis, central retinal artery occlusion, retinal artery occlusion, retinal artery occlusion (CAD), frost branch vasculitis, sickle cell retinopathy and other hemoglobinopathies, vascular streaks, familial exudative vitreoretinopathy, Eales disease, sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, radiation conditions with photodynamic therapy, photocoagulation, hemiretinal vein occlusion, and bone marrow transplant retinopathy, proliferative vitreoretinopathy, epiretinal membrane, proliferative diabetic retinal plexus. Membranosis, ocular histoplasmosis, ocular toxicosis, presumed ocular histoplasmosis (PONS), endophthalmitis, toxoplasmosis, retinal disease associated with HIV infection, choroidal disease, uveitis associated with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal disease, ocular syphilis, tuberculous ophthalmopathy, diffuse unilateral subacute neuroretinitis, myopathies, retinitis pigmentosa, systemic diseases with congenital retinal quiescence, congenital blindness, cone dystrophies, Stargardt disease, Flavimaculatus disease, Best disease, pattern dystrophy of the retinal pigment epithelium, X-linked retinoschisis,These include Sorsby's fundus dystrophy, benign concentric maculopathy, Vietti's crystalline dystrophy, pseudoxanthoma, retinal detachment, macular hole, giant retinal breaks, retinal diseases associated with tumors, congenital hypertrophy of the retinal pigment epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastases, combined retinal and retinal pigment epithelial hamartoma, tumors of the fundus retina, retinal astrocytoma, intraocular lymphoid tumors, other diseases affecting the posterior segment of the eye, punctate inner choroidopathy, acute posterior multifocal spotty pigment epitheliopathy, myopic retinal degeneration, acute retinal pigment epitheliitis, postoperative corneal inflammation, corneal transplant blepharitis, MGD, glaucoma, ocular hypertension, branch occlusion, retinal diseases, Best's vitreous macular degeneration, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and other degenerative diseases of either the photoreceptor cells or the retinal pigment epithelium (RPE).

[0080] Symptoms or clinical signs of ocular diseases associated with inflammation include, but are not limited to, an unstable tear film, chronic hyperosmotic stress, evaporative tear loss, reduced lubrication, and other tear deficiencies, which lead to an increased proinflammatory response in the eye, inflammation, and any combination thereof. Pharmaceutical Compositions

[0081] Adiponectin peptidomimetic compounds can be used and formulated in any of a number of pharmaceutical compositions, including those described in the United States Pharmacopeia (USP), including The Pharmacological Basis of Therapeutics by Goodman and Gilman, 10th Edition, McGraw Hill, 2001, Katzung, Ed., Basic and Clinical Pharmacology, McGraw-Hill / Appleton&Lange, 8th Edition, Sep. 21, 2000, Physician's Desk Reference (Thomson Publishing; and / or The Merck Manual of Diagnosis and Therapy, 18th Edition, 2006, Beers and Berkow, Eds., Merck Publishing Group; or, for animals, The Merck Veterinary Manual, 9th Edition, Kahn, Ed., Merck Publishing Group, 2005.

[0082] The ophthalmic pharmaceutical composition may also include one or more excipients or other substances, such as preservatives, antioxidants, pH adjusting agents, buffers, gelling agents, thickening agents, surfactants, solubilizers, lubricants, salts, cosolvents, diluents, carriers, adjuvants, oils, moisturizers, emollients, stabilizers, emulsifiers, and / or dispersing agents. Other agents may be used in the composition for various purposes. By way of example, an injectable composition may include various excipients or other substances, such as preservatives, antioxidants, pH adjusting agents, buffers, salts, emulsifiers, and / or dispersing agents.

[0083] Non-limiting examples of preservatives, such as water soluble preservatives, include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, ethyl alcohol, methylparaben, polyvinyl alcohol, benzyl alcohol, and phenylethyl alcohol.

[0084] Examples of ophthalmically acceptable antioxidants include, but are not limited to, sodium bisulfite, sodium thiosulfate, acetylcysteine, cysteine, thioglycerol, sodium sulfite, acetone sodium bisulfite, dithioerythritol, dithiothreitol, thiourea, and erythorbic acid.

[0085] Useful examples of ophthalmically acceptable pH adjusting agents, such as acids, bases and / or buffers, include, but are not limited to, acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, sulfuric acid, and hydrochloric acid, bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, trishydroxymethylalanomethane, triethanolamine, and / or buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride or amino acids. Such acids, bases and / or buffers may be included in an amount sufficient to adjust the pH of the composition to an ophthalmically acceptable range.

[0086] The compositions can be formulated for topical ophthalmic application in the form of, for example, solutions, ointments, creams, lotions, eye ointments, and, most preferably, eye drops or eye gels, containing suitable conventional additives including, for example, preservatives, solvents to aid drug penetration, and emollients in ointments and creams. Ophthalmic vehicles include, but are not limited to, saline, water polyethers such as polyethylene glycol, polyvinyls such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropylmethylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, polysaccharides such as vegetable fats such as peanut oil and dextran, and glycosaminoglycans such as sodium hyaluronate and salts such as sodium chloride and potassium chloride.

[0087] Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose, tyloxapol, poloxomer 188, poloxomer 407, Tween 80, PEG 40, hydrogenated castor oil, PEG 35 castor oil, PEG 40 stearate, and the like, and combinations thereof. The amount of surfactant is typically between about 0.0001% (wt) and about 10% (wt), between about 0.001% (wt) and about 10% (wt), between about 0.01% (wt) and about 10% (wt), between about 0.05% (wt) and about 10% (wt), between about 0.075% (wt) and about 10% (wt), between about 0.1% (wt) and about 10% (wt), between about 1.0% and about 90% (wt), and the like. ), between about 10% and about 90% (wt), between about 1% and about 20% (wt), between about 5% and about 20% (wt), between about 10% (wt) and about 20% (wt), between about 0.05% (wt) and about 15% (wt), between about 0.05% (wt) and about 14% (wt), between about 0.05% (wt) and about 13% (wt), between about 0.05%(wt) and about 12%(wt), between about 0.05%(wt) and about 11%(wt), between about 0.05%(wt) and about 10%(wt), between about 0.05%(wt) and about 9%(wt), between about 0.05%(wt) and about 8%(wt), between about 0.05%(wt) and about 7%(wt), between about 0.05%(wt) and about 10 ... The preferred liquid compositions are between about 0.05% (wt) and about 6% (wt), between about 0.05% (wt) and about 5% (wt), between about 0.05% (wt) and about 4% (wt), between about 0.05% (wt) and about 3% (wt), between about 0.05% (wt) and about 2% (wt), and preferably between about 0.05% (wt) and about 0.1% (wt). Dispersions may be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these compositions may contain a preservative to prevent the growth of microorganisms.

[0088] Pharmaceutical compositions containing the compounds of the present invention may be in a form suitable for topical use, for example, an oily suspension, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be prepared encapsulated in microcapsules, for example, by coacervation techniques or interfacial polymerization, for example, by hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. Alternatively, the compounds may be formulated for injection into the eye, such as intravitreal injection, subconjunctival injection, and injection into the anterior chamber of the eye. In other examples, the compounds may be in a form suitable for use in implantation, for example, encapsulated in microcapsules. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th Edition, Osol, A. Ed. (1980). The composition may be an ophthalmic depot composition, such as for subconjunctival administration. The adiponectin peptide mimetics may be embedded in a biocompatible pharma- ceutically acceptable polymer or lipid encapsulant. The depot composition may be adapted to release all or substantially all of the active agent over an extended period of time. If present, the polymer or lipid matrix may be adapted to degrade sufficiently to be transported away from the site of administration after release of all or substantially all of the active agent. The depot composition may be a liquid composition comprising a pharma- cetically acceptable polymer and a dissolved or dispersed active agent, and upon injection, the polymer forms a depot at the injection site, for example by gelling or precipitating. The composition may comprise a solid article that can be inserted into a suitable location in the eye, such as between the eyelid and the conjunctival sac, and the article releases the active agent. Solid articles suitable for implantation in the eye in such a manner generally comprise a polymer and may be bioerodible or non-bioerodible.

[0089] Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention or a pharma- ceutical acceptable salt thereof as an active ingredient with a conventional ophthalmologically acceptable pharmaceutical excipient and preparing a unit dose suitable for ocular use.Suitable excipients include, but are not limited to, propylene glycol, glycerol, PEG400, and polypropylene glycol, and combinations thereof. The amount of excipient is typically between about 0.0001% (wt) and about 90% (wt), between about 0.001% (wt) and about 90% (wt), between about 0.01% (wt) and about 90% (wt), between about 0.1% (wt) and about 90% (wt), between about 1.0% and about 90% (wt), between about 10% (wt) and about 90% (wt), between about 1% and about 20% (wt), between about 5% and about 20% (wt), between about 10% (wt) and about 20% (wt), between about 1% (wt) and about 15% (wt), between about 1% (wt) and about 14% (wt), between about 1% (wt) and about 13% (wt), between about 1% (wt) and about 15 ... (wt) and about 12% (wt), between about 1% (wt) and about 11% (wt), between about 1% (wt) and about 10% (wt), between about 1% (wt) and about 9% (wt), between about 1% (wt) and about 8% (wt), between about 1% (wt) and about 7% (wt), between about 1% (wt) and about 6% (wt), between about 1% (wt) and about 5% (wt), between about 1% (wt) and about 4% (wt), between about 1% (wt) and about 3% (wt), between about 1% (wt) and about 2% (wt), and preferably between about 1.5% (wt) and about 10% (wt) in the liquid composition.

[0090] Alternatively, the active compound can be applied to the eye via liposomes. Additionally, the active compound can be infused into the tear film via a pump-catheter system. In some embodiments, the active compound is contained within a membrane, such as, but not limited to, a continuous or selective release device, such as those used in the pilocarpine (Ocusert™) system (Alza Corp., Palo Alto, Calif.). In some embodiments, the active compound is contained within, carried by, or attached to a contact lens that is placed on the eye. In other embodiments, the active compound is contained within a swab or sponge that can be applied to the ocular surface. In another embodiment, the active compound is contained within a liquid spray that can be applied to the ocular surface. In another embodiment, the active compound is injected directly into lacrimal tissue or the ocular surface.

[0091] When the pharmaceutical composition for treating dry eye is used as an eye drop, it is provided in any dosage form such as an eye drop, for example, an aqueous eye drop solution, an aqueous eye drop solution, a viscous eye drop solution, a solubilized eye drop solution, or a non-aqueous eye drop solution and a non-aqueous suspension eye drop solution used in non-aqueous eye drops. Among these, an eye drop solution is preferred.

[0092] When the pharmaceutical composition for treating dry eye is prepared as an eye drop, it is advantageous to contain various additives that are commonly used in eye drops, so long as they do not adversely affect the object of the present invention. Examples of such additives include buffers, isotonicity agents, preservatives, solubilizers (stabilizers), pH adjusters, osmotic pressure adjusters, thickeners, and chelating agents.

[0093] The buffer solution may be selected from the group including, but not limited to, phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer (e.g., sodium acetate) and amino acids. The tonicity agent may be selected from the group including, but not limited to, sugars such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin, polyethylene glycol and polypropylene glycol, and salts such as sodium chloride. The preservative may be selected from the group including, but not limited to, benzalkonium chloride, benzethonium chloride, alkyl paraoxybenzoates such as methyl paraoxybenzoate and ethyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid and its salts, thimerosal and chlorobutanol. The solubilizer (stabilizer) may be selected from the group including, but not limited to, cyclodextrin and its derivatives, water-soluble polymers such as polyvinylpyrrolidone, and surfactants such as polyethylene glycol, polypropylene glycol polysorbate 80 (trade name: Tween 80). The pH adjuster can be selected from the group including, but not limited to, hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide and ammonium hydroxide.The thickener can be selected from the group including, but not limited to, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose and carboxymethyl cellulose and their salts.The chelating agent can be selected from the group including, but not limited to, sodium edetate, sodium citrate and condensed sodium phosphate.

[0094] For ophthalmic applications, it is preferred to prepare the solution using saline as the primary vehicle. The pH of such eye drops is preferably maintained between 4.5 and 8.0, about 5 to 7.5, preferably 6 to 7, using an appropriate buffer system, with a neutral pH being preferred, but not essential. Examples of acids include acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, hydrochloric acid, etc., and examples of bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, THAM (trishydroxymethylaminomethane), etc. Salts and buffers include citrate / dextrose, sodium bicarbonate, ammonium chloride, and mixtures of the aforementioned acids and bases.

[0095] The osmolarity of the aqueous ophthalmic composition is generally about 200 to about 400 milliosmoles (mOsM), more preferably 260 to 340 mOsM. The osmolarity may be adjusted by using an appropriate amount of a physiologically and ophthalmologically acceptable ionic or non-ionic agent. Sodium chloride is a preferred ionic agent, and the amount of sodium chloride ranges from about 0.01% to about 1% (w / v), preferably about 0.05% to about 0.45% (w / v). Equal amounts of one or more salts composed of cations, such as potassium, ammonium, and anions, such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate, sodium bisulfate, ammonium sulfate, may be used in addition to or instead of sodium chloride to achieve an osmolarity within the above range. Additionally, non-ionic agents, such as mannitol, dextrose, sorbitol, glucose, etc., may also be used to adjust the osmolarity.

[0096] Tonicity adjusters may be added as necessary or convenient. They may include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster. Various buffers and means for adjusting pH may be used, so long as the resulting preparation is ophthalmically acceptable. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Ophthalmically acceptable antioxidants for use in the present invention include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

[0097] When the pharmaceutical composition for treating dry eye is formulated into an ophthalmic ointment, a base compound must be present. The base of the ophthalmic ointment may be selected from the group including, but not limited to, purified lanolin, VASELINE® Plastibase, liquid paraffin and polyethylene glycol.

[0098] The composition may also contain conventional pharma- ceutically acceptable preservatives, stabilizers and surfactants.Preferred preservatives that can be used in the pharmaceutical composition of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.Preferred surfactants are, for example, Tween 80.Similarly, various preferred vehicles can be used in the ophthalmic preparation of the present invention.These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose cyclodextrin and purified water.

[0099] Adiponectin peptidomimetic compounds may be formulated into lipid-based nanocarriers, such as solid lipid nanoparticles, nanostructured lipid carriers, lipid drug complexes, coated liposomes, and the like.

[0100] It is conveniently packaged in a suitable manner. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic materials and generally contain about 0.5 to about 15 ml of solution. One package may contain one or more unit doses. Particularly preservative-free solutions are often formulated in non-reclosable containers containing up to about 10, preferably up to about 5 unit doses, with a typical unit dose being 1 to about 8 drops, preferably 1 to about 3 drops. The volume of one drop is usually about 20-35 μl.

[0101] The composition may be in the form of a sterile solution or suspension. The solution or suspension may be for topical or injectable application. It may be a sterile injectable composition, for example, a liquid or suspension composition. In some embodiments, it may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic intraocularly or intravitreally acceptable diluent or solvent. Buffers, preservatives, antioxidants, and the like may also be incorporated as necessary. Method of administration

[0102] The compositions provided herein can be administered to the eye. In some embodiments, the compositions can be applied to the eyelid portion of the eye, such as the upper eyelid, the outer portion of the lower eyelid, the inner and outer eyelid, and / or the ocular surface of the eye. In some cases, the compositions can be administered to the conjunctival sac of the affected eye. In some embodiments, the compositions are administered locally by intravitreal injection, subconjunctival injection, conjunctival injection, intramuscular injection, subcutaneous injection, intravenous injection, intracameral injection, or implantation into the subject's eye. In some cases, administration includes intravitreal depot implantation or other ophthalmic drug delivery methods described, for example, in Edelhauser et al., Invest Ophthalmol Vis Sci, 2010, 51(11), 5403-5420. The eye includes, but is not limited to, tissues, glands, blood vessels, lens, muscles, nerves, or other structures in or around the eye, such as within the ocular tissues, the ocular surface, the chamber, the eyelid, the nasolacrimal duct, the meibomian gland, and the lacrimal gland.

[0103] The compositions may be formulated for ophthalmic use, for example in the form of a solution, ointment, cream, lotion, eye ointment, and most preferably eye drops or eye gel, and may contain suitable conventional additives, such as preservatives, solvents to aid in drug penetration, and emollients for ointments and creams. Such topical compositions may contain compatible conventional carriers, such as cream or ointment bases, and ethanol or oleyl alcohol for lotions.

[0104] The composition may be administered to the patient's eye by any suitable means, but is preferably administered as a liquid or gel suspension in the form of drops, sprays, or gels. In one embodiment, the composition is in the form of drops and is dropped onto the ocular surface. In another embodiment, the formulation is contained within a swab or sponge that can be applied to the ocular surface. In another embodiment, the formulation is contained within a liquid spray or ointment that can be applied to the ocular surface. In another embodiment, the formulation is injected directly into the eye, such as the lacrimal tissue or the ocular surface. In a further embodiment, the composition is first applied to a fingertip or other applicator, and then applied or rubbed directly onto the eyelid margin or orbit. Alternatively, the adiponectin peptidomimetic compound may be applied to the eye via a colloidal dosage form, such as nanoparticles, nanomicelles, liposomes, and microemulsions. Additionally, the composition may be infused into the tear film via a pump-catheter system. Another embodiment includes the adiponectin peptidomimetic compound contained within a continuous or selective release device, such as a membrane. As a further embodiment, the adiponectin peptidomimetic compound may be contained within, carried by, or attached to a contact lens or other compatible controlled release material that is placed on or around the eye.

[0105] In some embodiments, the compositions are administered topically, intraocularly, intracamerally, intraorbitally, periocularly, intravitreally, subconjunctivally, intraconjunctivally, intramuscularly, subcutaneously, intravenously, intracamerally, or via other routes in or around the eye. Non-limiting delivery routes of the therapeutic compositions described herein include aqueous solutions, oil-based solutions, such as ointments, colloidal carriers, such as micelles, emulsions, liposomes, nanoparticles, solid embodiments, such as collagen-based shields and / or particles, as well as medicated timed plugs, medicated canalicular plugs, contact lenses, implants, inserts.

[0106] The suitability of a particular route of administration will depend in part on the pharmaceutical composition, its components, the disorder being treated, and the subject requiring treatment. Administration

[0107] The dosage of the therapeutic agent administered to a subject will vary depending on a wide range of factors. For example, it may be necessary to provide a substantially higher dose to a human than to a smaller animal. The dosage will depend on the size, age, sex, weight, medical history and condition of the subject, and will also depend on the nature of the dry eye disease being treated, the use of other therapies, the potency of the substance being administered, and the frequency of administration. Those skilled in the art will be able to determine the appropriate dosage depending on these and other factors. For example, if the therapeutic agent is available as an eye drop solution to treat dry eye in a subject in need thereof, the aqueous eye drop solution may contain the therapeutic agent in an amount of about 0.001% (wt) to 30% (wt), e.g., about 0.001% (wt), about 0.005% (wt), about 0.01% (wt), about 0.02% (wt), about 0.03% (wt), about 0.005 ... 04%(wt), approx. 0.05%(wt), approx. 0.06%(wt), approx. 0.07%(wt), approx. 0.08%(wt), approx. 0.09%(wt), approx. 0.1%(w t), approx. 0.2%(wt), approx. 0.3%(wt), approx. 0.4%(wt), approx. 0.5%(wt), approx. 0.6%(wt), approx. 0.7%(wt), approx. 0.8%(w t), about 0.9% (wt), about 1% (wt), about 2% (wt), about 3% (wt), about 4% (wt), about 5% (wt), about 6% (wt), about 7% (wt), about 8% (wt), about 9% (wt), about 10% (wt), about 11% (wt), about 12% (wt), about 13% (wt), about 14% (wt), about 15% (wt), about 16% (wt), about 17% (wt), about 18% (wt), about 19% (wt), about 20% (wt), about 21% (wt), about 22% (wt), about 23% (wt), about 24% (wt), about 25% (wt), about 26% (wt), about 27% (wt), about 28% (wt), about 29% (wt), about or 30% (wt).In some embodiments, the therapeutic agent may be present in an amount ranging from about 0.001% (wt) to about 30% (wt), from about 0.005% (wt) to about 30% (wt), from about 0.01% (wt) to about 0.01% (wt), from about 30% (wt), from about 0.1% (wt) to about 30% (wt), from about 1% (wt) to about 30% (wt), from about 10 ... (wt) to about 30% (wt), about 20% (wt) to about 30% (wt), about 10% (wt) to about 20% (wt), about 0.001% (wt) to about 10% (wt), about 0.001% (wt) to about 1% (wt), about 0.001% (wt) to about 0.1% (wt), 0.01% (wt) to about 0.1% (wt), etc. When administered, the therapeutic agent may be given once a day, or in multiple daily doses, such as twice a day, three times a day, and four times a day. In some embodiments, the therapeutic agent may be administered once a day, every other day, or less frequently. The therapeutic agent may be administered when the subject has one or more symptoms of dry eye or ocular disease. In some cases, the therapeutic agent may be administered in a dose of 1-5 drops or more, e.g., 1 drop, 2 drops, 3 drops, 4 drops, 5 drops or more. When administered, the composition may be given once a day, or in multiple daily doses, such as twice a day, three times a day, four times a day, five times a day or more. In some embodiments, the therapeutic agent may be administered less frequently than once a day. For example, the therapeutic agent may be administered every week, every two weeks, every three weeks, every four weeks, every six weeks, every seven weeks, every eight weeks, or less frequently. In some embodiments, the therapeutic agent may be administered according to the severity of symptoms experienced by the subject.

[0108] The effective amount of the adiponectin peptide mimetic compound depends on the age, sex, and weight of the patient, the current medical condition of the patient, and the nature of the dry eye disease being treated. Those skilled in the art may determine the appropriate dosage depending on these and other factors. For example, when the pharmaceutical composition is used as an eye drop to treat dry eye in a subject in need thereof, the aqueous solution eye drop desirably contains the adiponectin peptide mimetic compound in an amount of about 0.0001% (wt) to 90%, for example, about 0.0001% (wt), about 0.0005% (wt), about 0.001% (wt), about 0.005% (wt), about 0.01% (wt), Approx. 0.02%(wt), approx. 0.03%(wt), approx. 0.04%(wt), approx. 0.05%(wt), approx. 0.06%(wt), approx. 0.07%(wt), approx. 0.08%(wt), approx. 0.09%(w t), about 0.1% (wt), about 0.2% (wt), about 0.3% (wt), about 0.4% (wt), about 0.5% (wt), about 0.6% (wt), about 0.7% (wt), about 0.8% (wt), about 0.9% (wt), approximately 1% (wt), approximately 2% (wt), approximately 3% (wt), approximately 4% (wt), approximately 5% (wt), approximately 6% (wt), approximately 7% (wt), approximately 8% (wt), approximately 9% (wt), approximately 10% (wt), approximately 11% (wt), approximately 12% ( approximately 13% (wt), approximately 14% (wt), approximately 15% (wt), approximately 16% (wt), approximately 17% (wt), approximately 18% (wt), approximately 19% (wt), approximately 20% (wt), approximately 21% (wt), approximately 22% (wt), approximately 23% (wt), Approximately 24% (wt), approximately 25% (wt), approximately 26% (wt), approximately 27% (wt), approximately 28% (wt), approximately 29% (wt), approximately), approximately 30% (wt), approximately 31% (wt), approximately 33% (wt), approximately 33% (wt), approximately 34% (wt), Approximately 35% (wt), approximately 36% (wt), approximately 37% (wt), approximately 38% (wt), approximately 39% (wt), approximately 40% (wt), approximately 41% (wt), approximately 42% (wt), approximately 43% (wt), approximately 44% (wt), approximately 45% (wt), approximately 46% (wt), about 47% (wt), about 48% (wt), about 49% (wt), about 50% (wt), about 51% (wt), about 52% (wt), about 53% (wt), about 54% (wt), about 55% (wt), about 56% (wt), about 57% (wt) ), about 58% (wt), about 59% (wt), about 60% (wt), about 61% (wt), about 62% (wt), about 63% (wt), about 64% (wt), about 66% (wt), about 66% (wt), about 67% (wt), about 68% (wt), about 6 The amount of glycerol present in the composition may be about 9% (wt), about 70% (wt), about 71% (wt), about 72% (wt), about 73% (wt), about 74% (wt), about 75% (wt), about 76% (wt), about 77% (wt), about 78% (wt), about 79% (wt), about 80% (wt), about 81% (wt), about 82% (wt), about 83% (wt), about 84% (wt), about 85% (wt), about 86% (wt), about 87% (wt), about 88% (wt), about 89% (wt), about, or about 90% (wt). In some embodiments, the adiponectin peptidomimetic compound is in an amount ranging from about 0.0001% (wt) to about 90% (wt), e.g., from about 0.0001% (wt) to about 90% (wt), from about 0.001% (wt) to about 90% (wt), from about 0.005% (wt) to about 90% (wt), from about 0.01% (wt) to about 90% (wt), from about 0.1%(wt) to about 90%(wt), about 1%(wt) to about 90%(wt), about 10%(wt) to about 90%(wt), about 20%(wt) to about 90%(wt), about 30%(wt) to about 90%(wt), about 40%(wt) to about 90%(wt), about 50%(wt) to about 90%(wt), about 60%(wt) to about 90%(wt), about 70%(wt) to about 90%(wt), about 80%(wt) to about 90%(wt), about 10%(wt) to about 50%(wt), about 10%(wt) to about 40%(wt), about 10%(wt) to about 30%(wt), about 1 The range may be from 0% (wt) to about 20% (wt), from about 0.0001% (wt) to about 10% (wt), from 0.0001% (wt) to about 1% (wt), from 0.0001% (wt) to about 0.1% (wt), from 0.0001% (wt) to about 0.01% (wt), from 0.0001% (wt) to about 0.001% (wt), from about 0.001% (wt) to about 10% (wt), from about 0.001% (wt) to about 1% (wt), from about 0.001% (wt) to about 0.1% (wt), from 0.01% (wt) to about 0.1% (wt), from 0.01% (wt) to about 1% (wt), and the like. When administered, the composition may be given once a day, or in multiple daily doses, such as twice a day, three times a day, and four times a day. In some embodiments, the composition is administered once a day, every other day, or less frequently. The composition can be administered when the subject has one or more symptoms of dry eye or eye disease. In some cases, the composition is given in doses of 1-5 drops or more, e.g., 1 drop, 2 drops, 3 drops, 4 drops, 5 drops, or more.

[0109] When the pharmaceutical composition is used as an eye ointment, the eye ointment desirably contains the adiponectin peptidomimetic compound in an amount of about 0.0001% (wt) to 90% (wt), for example, about 0.0001% (wt), about 0.0001% (wt), 0.0005% (wt), about 0.001% (wt), about 0.005% (wt), about 0.01% (wt), about 0.02% (wt ), approx. 0.03% (wt), approx. 0.04% (wt), approx. 0.05% (wt), approx. 0.06% (wt), approx. 0.07% (wt), approx. 0.08% (wt), approx. 0.09% (wt), approx. 0 .1% (wt), about 0.2% (wt), about 0.3% (wt), about 0.4% (wt), about 0.5% (wt), about 0.6% (wt), about 0.7% (wt), about 0.8% (wt), about 0.9% (wt), approximately 1% (wt), approximately 2% (wt), approximately 3% (wt), approximately 4% (wt), approximately 5% (wt), approximately 6% (wt), approximately 7% (wt), approximately 8% (wt), approximately 9% (wt), approximately 10% (wt), approximately 11% (wt), approximately 12% ( 13% (wt), 14% (wt), 15% (wt), 16% (wt), 17% (wt), 18% (wt), 19% (wt), 20% (wt), 21% (wt), 22% (wt), 23% (wt) , about 24% (wt), about 25% (wt), about 26% (wt), about 27% (wt), about 28% (wt), about 29% (wt), about 30% (wt), about 31% (wt), about 33% (wt), about 33% (wt), about 34% (wt), about 3 5% (wt), approximately 36% (wt), approximately 37% (wt), approximately 38% (wt), approximately 39% (wt), approximately 40% (wt), approximately 41% (wt), approximately 42% (wt), approximately 43% (wt), approximately 44% (wt), approximately 45% (wt), approximately 46% (w t), about 47% (wt), about 48% (wt), about 49% (wt), about 50% (wt), about 51% (wt), about 52% (wt), about 53% (wt), about 54% (wt), about 55% (wt), about 56% (wt), about 57% (wt), Approximately 58% (wt), approximately 59% (wt), approximately 60% (wt), approximately 61% (wt), approximately 62% (wt), approximately 63% (wt), approximately 64% (wt), approximately 66% (wt), approximately 66% (wt), approximately 67% (wt), approximately 68% (wt), approximately 69 %(wt), about 70%(wt), about 71%(wt), about 72%(wt), about 73%(wt), about 74%(wt), about 75%(wt), about 76%(wt), about 77%(wt), about 78%(wt), about 79%(wt), about 80%(wt), about 81%(wt), about 82%(wt), about 83%(wt), about 84%(wt), about 85%(wt), about 86%(wt), about 87%(wt), about 88%(wt), about 89%(wt), about, or 90%(wt). In some embodiments, the adiponectin peptidomimetic compound is in an amount ranging from 0.0001% (wt) to about 90% (wt), e.g., from about 0.0001% (wt) to about 90% (wt), from about 0.001% (wt) to about 0.001% (wt) 90% (wt), from about 0.005% (wt) to about 90% (wt), from about 0.01% (wt) to about 90% (wt), from about 0.1%(wt) to about 90%(wt), about 1%(wt) to about 90%(wt), about 10%(wt) to about 90%(wt), about 20%(wt) to about 90%(wt), about 30%(wt) to about 90%(wt), about 40%(wt) to about 90%(wt), about 50%(wt) to about 90%(wt), about 60%(wt) to about 90%(wt), about 70%(wt) to about 90%(wt), about 80%(wt) to about 90%(wt), about 10%(wt) to about 50%(wt), about 10%(wt) to about 40%(wt), about 10%(wt) to about 30%(wt), about 10 %(wt) to about 20%(wt), about 0.0001%(wt) to about 10%(wt), 0.0001%(wt) to about 1%(wt), 0.0001%(wt) to about 0.1%(wt), 0.0001%(wt) to about 0.01%(wt), 0.0001%(wt) to about 0.001%(wt), about 0.001%(wt) to about 10%(wt), about 0.001%(wt) to about 1%(wt), about 0.001%(wt) to about 0.1%(wt), 0.01%(wt) to about 0.1%(wt), 0.01%(wt) to about 1%(wt), etc. When administered, the composition may be given once a day, or in multiple daily doses, such as twice a day, three times a day, four times a day, five times a day or more. In some embodiments, the composition is administered less frequently than once a day. For example, the composition can be administered weekly, every two weeks, every three weeks, every four weeks, every six weeks, every seven weeks, every eight weeks, or less frequently. In some embodiments, the composition is administered according to the severity of symptoms experienced by the subject.

[0110] For adiponectin peptidomimetics administered locally, e.g., as eye drops or ointment, or for intraorbital or periocular injection, exemplary doses range from about 0.001 to about 100 mg, e.g., from about 0.1 to about 10 mg, applied, e.g., once a day, twice a day, or more frequently. For ADP355 administered locally, e.g., as eye drops or ointment, or for intraorbital or periocular injection, exemplary doses may be from about 0.01 mg / ml to about 200 mg / ml.

[0111] Having shown that there is variability in dosing, it is believed that one skilled in the art can determine appropriate dosing by administering relatively small amounts and monitoring the patient for therapeutic effects. If necessary, the dose may be gradually increased until the desired results are obtained. Generally, treatment is initiated with a smaller dose, which may be less than the optimal dose of the therapeutic agent. Thereafter, the dose may be increased in small increments until the optimal effect is obtained under the circumstances. If necessary, the total daily dose may be divided and administered in portions during the day.

[0112] The pharmaceutical composition may be packaged or prepared in unit dosage form. In such form, the composition is subdivided into unit doses containing appropriate amounts of active ingredients, for example, according to the dose of therapeutic agent. The unit dosage form may be a packaged preparation containing a discrete amount of the preparation. The composition may also contain other compatible therapeutic agents, if necessary.

[0113] The present invention provides a method for treating and / or ameliorating dry eye or inflammation-related eye disease in a subject in need thereof. The course of treatment is best determined individually, depending on the specific characteristics of the subject. The treatment may be administered to the subject daily, twice daily, three times daily, every other day, every other week, weekly, monthly, or on any applicable basis that is therapeutically effective. The treatment may be administered alone or in combination with at least one other therapeutic agent, for example, targeting the same eye disorder or associated symptoms. The additional agent may be administered at the same time as the adiponectin peptidomimetic compound, at a different time, or on a completely different treatment schedule (e.g., the adiponectin peptidomimetic compound may be administered daily while the additional agent is weekly). Combination with therapeutic drugs

[0114] In some embodiments, the methods provided herein include co-administration of an adiponectin peptidomimetic compound with one or more additional therapeutic agents. The term "co-administration" refers to administration of a first amount of an adiponectin peptidomimetic compound or a pharma- ceutically acceptable salt thereof, and a second amount of at least one other therapeutic agent, such as another therapeutic agent for treating an ocular disease, or a therapeutic agent for addressing an associated condition, such as inflammation. In some examples, the adiponectin peptidomimetic compound and the other therapeutic agent are administered simultaneously or essentially simultaneously. The adiponectin peptidomimetic compound and the other therapeutic agent may be in a single pharmaceutical composition or in multiple pharmaceutical compositions. In other examples, the adiponectin peptidomimetic compound and the other therapeutic agent are administered sequentially. In sequential administration, the adiponectin peptidomimetic compound and the other therapeutic agent are administered within a time sufficient to achieve a desired therapeutic effect. For example, the period between each administration that can result in a desired therapeutic effect may range from several minutes to several hours, and may be determined taking into account the properties of each compound, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile. Concomitant administration includes simultaneous administration using separate compositions or a single pharmaceutical composition, and sequential administration in either order, preferably during a period during which both (or all) active agents exert their biological activity simultaneously.

[0115] In some embodiments, the one or more additional therapeutic agents include punctual plugs, topical steroids topical tetracyclines, topical nonsteroidal anti-inflammatory drugs (NSAIDS such as topical diclofenac and topical ketorolac), IL-1 antagonists, other inflammatory pathway antagonists or inhibitors, angiogenesis inhibitory peptides, angiogenesis inhibitory steroids, VEGF or FGF modulators / inhibitors, glucocorticosteroids, leukotriene modulators, antihistamines, cytokine modulators / inhibitors, growth factor modulators / inhibitors, T-cell inhibitors, oral or topical pilocarpine, vitamin A, tretinoin (e.g., all trans retinoic acid), doxycycline, cyclosporine A (e.g., RESTASIS® (Allergan), azithromycin, mucin stimulants (e.g., Diquafasol (Inspire These include 15-(S)-HETE (Alcon), rebamipide (Otsuka) and ecabet (ISTA), hormonal agents and lacrimal gland stimulants (e.g., androgenic tears (Allergan)) and tear substitutes (e.g., artificial tears). In some cases, the compositions described herein are administered in combination with progesterone, synthetic progestogens, medroxyprogesterone acetate, norethindrone, norethindrone acetate, megestrol acetate, 17-α-hydroxyprogesterone caproate, norgestrel, and derivatives thereof. Additional therapeutic agents include liffitigrass, EBI-005 (Ele ven Biotherapeutics), anakinra (Amgen), MIM-D3 (Mimitogen Pharmaceuticals), rebamipide (Otsuka Pharmaceuticals), tofacitinib (Pfizer), dexamethasone phosphate (EyeGate Pharmaceuticals), RGN-259 (RegeneRx), KPI-121 (loteprednol etabonate, Kala Pharmaceuticals), bromfenac (ISTA Pharmaceuticals), and diquafosol tetrasodium (Merck and Co., Inc.), hydroxychloroquine (Sanofi-Aventis), rebamipide (Acucela Inc.), CF101 (Can-Fite BioPharma), rephytograss (Shire), EBI-005 (Eleven Biotherapeutics), cyclosporine (haporine-S, DH Bio Co., Ltd.), rimexolone (Alcon Research), ecabet sodium (Bausch & Lomb Incorporated), rituximab (IDEC Pharmaceuticals), tocilizumab (Hoffman-La Roche Ltd.), skQI (Mitotech, SA), cis-UCA (Herantis Pharma PLC), LME636 (Alcon Research), AGN-223575 (Allergan), ISV-101 (InSite Vision), OTX-DP (Ocular Therapeutix, Inc.), rivoglitazone (Santen Pharmaceutical Co.), mapracorat (Bausch & Lomb Incorporated), resolvin (Resolvyx), tasocitinib / tofacitinib (Pfizer), RU-101 (R-Tech Ueno, Ltd.), DNase (Genentech, Inc.), voclosporin (Lux Biosciences), P-321 (Pari on Sciences), ACCS (Stemnion, Inc.), AGN-23241 1 (Allergan), and those described in Ridder and Karsolia, Clinical Optometry, 2015, 2015(7), 91-102, etc.

[0116] Lifitigras is a small molecule that inhibits lymphocyte function-associated antigen-1 (LFA-1), an integrin, a cell surface protein found on white blood cells. Lifitigras can bind to LFA-1 and block its interaction with its cognate ligand, intercellular adhesion molecule-1 (ICAM-1). This mechanism downregulates inflammation mediated by T lymphocytes.

[0117] Combination of an adiponectin peptidomimetic compound with another therapeutic agent may result in enhanced efficacy in the treatment of ocular diseases. Administration of the active agents individually, sequentially, simultaneously, in combination, or on a completely different schedule compared to the individual administration of either active agent may result in greater anti-inflammatory activity and improved clinical efficacy. Clinical studies in animal models show both improved efficacy and enhanced anti-inflammatory activity (data not shown). Synergistic effects may also be observed. Synergistic effects may allow for reduced dosage of the active agent when administered individually, sequentially, simultaneously, in combination, or on a completely different schedule compared to the dosage of either active agent. Reduced dosages may help reduce any side effects that may appear. Thus, in combination therapy, an effective amount of the additional (second) therapeutic agent and an effective amount of the adiponectin peptidomimetic compound are effective to reduce the symptoms / effects of ocular diseases.

[0118] Those skilled in the art of medicine can best determine the appropriate dose of the additional therapeutic agent by considering the patient's condition, the recommended dose, the severity of the disease, and the effectiveness of administering the adiponectin peptidomimetic compound in combination with the therapeutic agent. Synergistic effects may also result from administering the adiponectin peptidomimetic compound in combination with the therapeutic agent. Methods for determining efficacy of treatment

[0119] Various methods can be carried out to evaluate the therapeutic response of a subject to the compositions provided herein.In some examples, assays, tests or measurements can be carried out to determine whether the methods described herein alleviate at least one symptom or clinical sign of eye disease related to dry eye or inflammation.Detailed descriptions of the methods for measuring or evaluating the symptoms or clinical signs of dry eye or eye disease provided herein can be found, for example, in Pult et al., Eye (Lond), 2011, 25(4), 502-510; Bhatnagar et al., Int J Opthalmol, 2015, 8(1), 174-81; Messmer, Dtsch Arztebl Int, 2015, 112(5), 71-82.

[0120] Changes in tear secretion can be assessed by the Schirmer test, the phenol red thread tear test (PRTT), and other methods that determine the rate and volume of tear production. Changes in tear clearance can be assessed by fluorescein clearance tests and fluorometry. Ocular surface damage and corneal epithelial defects can be assessed with vital stains such as fluorescein, rose bengal, and lissamine green. Ocular surface cytology can be analyzed by impression cytology, brush cytology, flow cytometry, and confocal microscopy. Tear film stability can be ascertained by analyzing tear break-up time using the tear film stability time analysis system (TSAS), wavefront aberrometry, laser scanning microscopy, functional visual acuity, and tear film interferometry. Changes in tear volume can be assessed by tear meniscus measurements. Changes in the lipid layer to the tear film can be assessed by tear film interferometry, meibometry, and meibography. Evaluation of tear evaporation can be performed with an evaporometer, closed chamber, or ventilated chamber. Improvement in tear film chemistry can be assessed by tear osmolality, freezing point depression, vapor pressure osmometry, and electrical conductivity (Ocusense). Biochemical analysis of tear composition may include mucin and lipid analysis. Improvement in the ocular surface can be visualized by observing irregular morphology or staining of the corneal or conjunctival epithelium using dyes (e.g., fluorescein, lissamine green, rose bengal) compared to baseline.

[0121] Alleviation of at least one symptom or clinical sign of an ocular disease, such as dry eye and inflammatory ocular diseases, can be determined by comparing the severity of the symptom or clinical sign after treatment with the severity of the same symptom or clinical sample before treatment. A decrease in the severity of the symptom or clinical sign after treatment indicates improvement or alleviation. Example 1

[0122] The excipient was prepared by dissolving propylene glycol (1.77 g) and tyloxapol (0.1 g) in 97 mL of 35 mM acetic acid / sodium acetate buffer, pH 4.3-4.5, by mixing until homogeneous. Peptide D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 (API, also referred to herein as ALY688 or ALY-688) (1.0 g) was added to the vehicle and mixed until dissolved. The pH was adjusted with a small amount of acetic acid or sodium hydroxide. The composition was sterile filtered.

[0123] The composition of Example 1 provided stability of the active pharmaceutical ingredient and minimal irritation potential. The solubility of the peptide was significantly increased. At a concentration of 12 mg / g acetate buffer, a clear solution was obtained with a pH of 4.5.

[0124] Similar to Example 1, the following formulations were prepared (all percentages are by weight): Formulation 1 API 1.00% Propylene glycol 1.72% Poloxamer 188 0.10% Acetic acid 0.11% Sodium acetate 0.09% Water 96.97% Total 100.00% Formulation 2 API 0.51% Propylene glycol 1.73% Poloxamer 188 0.10% Acetic acid 0.11% Sodium acetate 0.09% Water 97.47% Total 100.00% Formulation 3 API 0.25% Propylene glycol 1.74% Poloxamer 188 0.10% Acetic acid 0.11% Sodium acetate 0.09% Water 97.71% Total 100.00% Formulation 4 API 0.50% Propylene glycol 1.55% Poloxamer 188 0.10% Acetic acid 0.10% Sodium acetate 0.24% Water 97.51% Total 100.00% Formulation 5 API 1.00% Propylene glycol 1.55% Poloxamer 188 0.10% Acetic acid 0.10% Sodium acetate 0.24% Water 97.01% Total 100.00% Formulation 6 API 0.50% Propylene glycol 1.58% Poloxamer 188 0.10% Acetic acid 0.09% Sodium acetate 0.24% Water 97.99% Total 100.00% Formulation 7 API 1.00% Propylene glycol 1.57% Poloxamer 188 0.10% Acetic acid 0.09% Sodium acetate 0.24% Water 97.00% Total 100.00% Formulation 8 API 0.50% Propylene glycol 1.43% Poloxamer 188 0.10% Acetic acid % Sodium acetate 0.34% Water 97.59% Total 100.00% Formulation 9 API 0.50% Propylene glycol 1.44% Poloxamer 188 0.10% Acetic acid 0.04% Sodium acetate 0.34% Water 97.58% Total 100.00% Formulation 10 API 1.00% Propylene glycol 1.40% Poloxamer 188 0.20% Acetic acid 0.19% Sodium acetate 0.30% Water 96.92% Total 100.00% Formulation 11 API 1.00% Propylene glycol 1.38% Poloxamer 188 0.10% Acetic acid 0.19% Sodium acetate 0.30% Water 96.90% Total 100.00% Formulation 12 API 1.00% Propylene glycol 1.25% Poloxamer 188 0.10% Acetic acid 0.17% Sodium acetate 0.41% Water 97.05% Total 100.00% Formulation 13 API 1.00% Propylene glycol 1.54% Poloxamer 188 0.10% Acetic acid 0.19% Sodium acetate 0.14% Water 97.03% Total 100.00% Formulation 14 API 0.80% Propylene glycol 1.54% Poloxamer 188 0.10% Acetic acid 0.19% Sodium acetate 0.14% Water 97.23% Total 100.00% Formulation 15 API 0.50% Propylene glycol 1.55% Poloxamer 188 0.10% Acetic acid 0.19% Sodium acetate 0.14% Water 97.52% Total 100.00% Formulation 16 API 0.50% Propylene glycol 1.55% Poloxamer 188 0.10% Acetic acid 0.19% Sodium acetate 0.14% Water 97.52% Total 100.00% Formulation 17 API 1.00% Propylene glycol 1.53% Poloxamer 188 0.10% Acetic acid 0.19% Sodium acetate 0.14% Water 97.04% Total 100.00% Formulation 18 API 1.00% Propylene glycol 1.86% Poloxamer 188 0.10% Acetic acid 0.13% Sodium acetate 0.10% Water 96.82% Total 100.00% Formulation 19 API 1.00% Propylene glycol 1.67% Poloxamer 188 0.10% Acetic acid 0.15% Sodium acetate 0.11% Water 96.96% Total 100.00% Prescription 20 API 1.00% Propylene glycol 1.62% Poloxamer 188 0.10% Acetic acid 0.17% Sodium acetate 0.13% Water 96.98% Total 100.00% Example 2

[0125] A stock solution containing 200 mM boric acid and 400 mM mannitol was prepared and stirred for 2 h to form the boric acid / mannitol complex. A buffer solution (50 mL) was prepared by mixing 46.25 g of 20 mM acetic acid / sodium acetate buffer with 3.75 g of the boric acid / mannitol stock solution to bring the pH of the buffer to 4.3-4.5. An excipient (50 mL) was then prepared by mixing 48.29 g of the above buffer with tyloxapol (0.05 g), propylene glycol (0.10 g) and additional mannitol (1.58 g) for osmolality. Peptide D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 (0.5 g) was added to the vehicle and mixed until in solution. If necessary, the pH was adjusted with a small amount of acetic acid or sodium hydroxide. The entire composition was sterile filtered.

[0126] Following the above procedure, the following compositions were prepared: Prescription 21 API 0.401% Propylene glycol 0.193% Tyloxapol 0.097% Acetic acid 0.014% Sodium acetate 0.138% Boric Acid 0.090% Mannitol 3.65% Total 100%

[0127] Following a similar procedure, the following compositions can be prepared: Prescription 22 API 0.4% Propylene glycol 0.193% Tyloxapol 0.097% Acetic acid 0.015% Sodium acetate 0.228% Boric Acid 0.090% Mannitol 3.53% Total 100%

[0128] Following a similar procedure, the following compositions can be prepared: Prescription 23 API 0.1% Propylene glycol 0.193% Tyloxapol 0.097% Acetic acid 0.0065% Sodium acetate 0.25% Boric Acid 0.090% Mannitol 3.6% Total 100%

[0129] More generally, eye drop compositions can be prepared according to the following table. [Table 1] Example 3: Irritation test

[0130] Irritation studies in rabbits were performed with formulations 13, 14, 15, 16, 17, 18, 19, 20, and 21 and placebo. The formulations were found to be well tolerated by the test subjects. Example 4: Effect of ALY688 on atropine-induced dry eye in rabbits

[0131] The objective of this study was to evaluate the efficacy of a topical ALY688 ophthalmic composition according to Formula 22 in Example 2 in an atropine-induced dry eye model in rabbits. Experimental design

[0132] Corneal fluorescein staining, tear break-up time, and clinical assessment of tear volume were measured at five time points during the 14-day treatment period. Pre-treatment anterior segment slit-lamp examinations with corneal fluorescein staining, tear volume (TV), and tear break-up time (TBUT) assessments were performed. Animals were assigned to treatment groups such that mean baseline TV and TBUT values ​​were approximately equal across groups.

[0133] The study groups were assigned as follows: Group 1: Atropine + ALY688 0.4% ophthalmic TID (n=6) Group 2: Atropine + vehicle ophthalmic TID (n=6) Group 3: Atropine only (n=4)

[0134] Test article administration began on day 1.

[0135] Atropine eye drops (TID) were started on day 0.

[0136] Dry eye assessments were performed on days 1, 3, 7, 10, and 13.

[0137] Dosing and procedures were timed so that the interval between dosing and evaluation was consistent for all animals and the procedures did not interfere with each other. method

[0138] Assessors were masked to treatment group for all assessments.

[0139] Examination: Slit-lamp examination of the anterior segment was performed at baseline and on day 13 and included conjunctival injection, swelling and drainage, corneal opacity, pannus, anterior chamber cells and flare, iris, light reflex, and lens using the McDonald-Shattuck scoring system.

[0140] Tear Breakdown Time (TBUT): TBUT was measured after instilling 6 μL of 2% sodium fluorescein solution in sterile saline onto the lower eyelid. After manually blinking, the time until a black spot or streak appeared on the cornea under cobalt-filter illumination was recorded. This procedure was performed three consecutive times, and the average of the three readings was used.

[0141] Corneal epithelial staining: Corneal staining was assessed immediately after TBUT measurement after rinsing excess fluorescein. Fluorescein uptake was graded in five separate areas of the cornea using a grading scale of 0 to 3 (maximum score: 15) according to the NEI / Industry Grading System. A total staining score was calculated for each eye.

[0142] Tear Volume (TV): Using Schirmer Tear Test Strips (Intervet, Inc., Summit, NJ), tear volume was measured by placing the strip on the lower phonics for 60 seconds and recording the mm distance of the wetted area. result

[0143] Ophthalmic Examination: There were no abnormal findings at baseline or Day 13 related to test article administration based on anterior slit lamp examination.

[0144] Corneal staining results are shown in relation to Figure 1. Data are the mean ± SEM of n=12 (ALY-688 and vehicle), or n=8 (atropine only) eyes in each group. No corneal fluorescein staining was observed in any animals at baseline. Staining was lower in the ALY688 group than in the vehicle control group at all assessment time points during the treatment period. At days 1, 3, and 10, this difference was statistically significant (p<0.05). The ALY688 group was statistically significantly higher than the vehicle group at all days after baseline (two-sample, two-tailed t-test) at day 7 (p=0.01), day 10 (p<0.001), and day 13 (p=0.001).

[0145] Tear break-up time (TBUT) results are shown in relation to Figure 2. Data are mean ± SEM of n=12 (ALY-688 and vehicle), or n=8 (atropine only) per group. TBUT decreased in all groups within 1 day of atropine treatment, but to a lesser extent in the ALY-688 group (32% decrease on day 1 vs. 50% decrease in the vehicle group). By day 7, the vehicle group continued to decrease, while the ALY-688 group returned to baseline TBUT levels. ALY688 maintained normal TBUT levels throughout the remainder of the study, with statistically significantly higher TBUT compared to vehicle on days 7, 10, and 13 (p<0.01). The ALY688 group was statistically significantly higher than the vehicle group on all days after baseline (two-sample, two-tailed t-test) at day 7 (p=0.01), day 10 (p<0.001), and day 13 (p=0.001).

[0146] Tear volume (TV) results are shown in relation to Figure 3. Data are mean ± SEM for n=12 (ALY-688 and vehicle) or n=8 (atropine only) per group. TV was significantly reduced after atropine administration, but the ALY688 group was consistently higher than the vehicle control group at all time points. This difference was statistically significant only on day 13 (p<0.01). Variation in TV during the experiment was due to differences in the time of measurement compared to the previous atropine administration, with TV measurements on days 1, 3, and 13 taken 1.25 hours after atropine administration, and measurements on days 7 and 10 taken 20 and 3.25 hours after atropine administration, respectively. The ALL688 group was statistically significantly higher (p=0.01) than the vehicle group on day 13, with borderline significant differences (p=0.08) on days 1 and 7 (two-sample, two-tailed t-test). conclusion

[0147] Overall, using a pooled analysis at all post-baseline time points, ALY688 demonstrated statistically significant improvements (p<0.005) compared to vehicle for each parameter (Figures 4A-4C). Atropine administration induced the following characteristics of dry eye: decreased tear volume and tear breakup time, and increased corneal fluorescein staining. The timing of atropine administration may affect the severity of symptoms. Topical ALY688 reduced all parameters of dry eye evaluated. · Statistically significant improvements in tear volume, tear breakup time, and corneal fluorescein staining following ALY688 versus vehicle control were observed at multiple time points. This study demonstrated that ALY688 eye drops was highly effective in reducing the symptoms of dry eye in an atropine-induced disease model in New Zealand White rabbits. Effects were observed as early as 2 days after initiation of ALY688 treatment.

[0148] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood that those skilled in the art can practice certain changes and modifications within the scope of the appended claims.Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

1. A composition comprising a therapeutically effective amount of a 1 kDa to 2 kDa peptide, a solubilizing agent generally recognized as safe, one or more surfactants generally recognized as safe, and buffering agents generally recognized as safe, optionally including boric acid and optionally mannitol, wherein the composition has an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.

5.

2. A composition comprising a therapeutically effective amount of a 1 kDa to 2 kDa adiponectin peptide mimetic, a solubilizing agent generally recognized as safe, one or more surfactants generally recognized as safe, and a buffering agent generally recognized as safe, optionally boric acid and optionally mannitol, wherein the composition has an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.

5.

3. The composition of claim 2, comprising an adiponectin peptide mimetic as a solubilizing agent generally recognized as safe selected from polypropylene glycol, glycerol, PEG 400 and propylene glycol, a surfactant generally recognized as safe selected from Tween 80, tyloxapol, poloxamer, PEG 40 hydrogenated castor oil, PEG 35 castor oil and PEG 40 stearate, and optionally boric acid and optionally mannitol as an acetate buffer, wherein the osmolality of the composition is between 260 and 330 mOsm / kg and the pH is between 4.5 and 5.

5.

4. D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 4. The composition of claim 3, comprising: 1% to 2% propylene glycol; 0.08% to 0.12% tyloxapol or poloxamer; 0.02% to 0.20% acetic acid; and 0.05% to 0.5% sodium acetate, wherein the composition has an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.

5.

5. D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 5. The composition of claim 4, comprising: 1.20% to 1.90% propylene glycol; 0.10% tyloxapol or poloxamer; 0.04% to 0.20% acetic acid; and 0.08% to 0.42% sodium acetate, wherein the composition has an osmolality of 260 to 330 mOsm / kg and a pH of 4.5 to 5.

5.

6. Weight is 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.77% propylene glycol, 0.10% tyloxapol, 0.14% acetic acid, and 0.08% sodium acetate; 0.5%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.58% propylene glycol, 0.10% tyloxapol, 0.09% acetic acid, and 0.24% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.57% propylene glycol, 0.10% tyloxapol, 0.09% acetic acid, and 0.24% sodium acetate; 0.5%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.43% propylene glycol, 0.10% tyloxapol, 0.04% acetic acid, and 0.34% sodium acetate; 0.5%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.44% propylene glycol, 0.10% tyloxapol, 0.04% acetic acid, and 0.34% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.72% propylene glycol, 0.10% poloxamer 188, 0.11% acetic acid, and 0.09% sodium acetate; 0.51%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.73% propylene glycol, 0.10% poloxamer 188, 0.11% acetic acid, and 0.09% sodium acetate, 0.25%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.74% propylene glycol, 0.10% poloxamer 188, 0.11% acetic acid, and 0.09% sodium acetate; 0.50%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.55% propylene glycol, 0.10% poloxamer 188, 0.10% acetic acid, and 0.24% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.55% propylene glycol, 0.10% poloxamer 188, 0.10% acetic acid, and 0.24% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.40% propylene glycol, 0.20% poloxamer 188, 0.19% acetic acid, and 0.30% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.38% propylene glycol, 0.10% tyloxapol, 0.19% acetic acid, and 0.30% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.25% propylene glycol, 0.10% tyloxapol, 0.17% acetic acid, and 0.41% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.54% propylene glycol, 0.10% tyloxapol, 0.19% acetic acid, and 0.14% sodium acetate; 0.80%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.54% propylene glycol, 0.10% tyloxapol, 0.19% acetic acid, and 0.14% sodium acetate; 0.50%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.55% propylene glycol, 0.10% tyloxapol, 0.19% acetic acid, and 0.14% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.53% propylene glycol, 0.10% tyloxapol, 0.19% acetic acid, and 0.14% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.86% propylene glycol, 0.10% tyloxapol, 0.13% acetic acid, and 0.10% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.67% propylene glycol, 0.10% tyloxapol, 0.15% acetic acid, and 0.11% sodium acetate; 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 , 1.62% propylene glycol, 0.10% tyloxapol, 0.17% acetic acid, and 0.13% sodium acetate; The composition according to claim 5, characterized in that the osmotic pressure of each of the compositions is 260 to 330 mOsm / kg and the pH is 4.5 to 5.

5.

7. Weight is 1.00%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 4. The composition of claim 3, comprising: 0.20% propylene glycol; 0.10% tyloxapol; 0.07% acetic acid; 0.06% sodium acetate; 0.09% boric acid; and 3.66% mannitol, wherein the composition has an osmolality of 260-330 mOsm / kg and a pH of 4.5-5.

5.

8. Weight is 0.401%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 4. The composition of claim 3, comprising: 0.193% propylene glycol; 0.097% tyloxapol; 0.014% acetic acid; 0.138% sodium acetate; 0.09% boric acid; and 3.65% mannitol, wherein the composition has an osmolality of 260-330 mOsm / kg and a pH of 4.5-5.

5.

9. Weight is 0.4%D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 4. The composition of claim 3, comprising: 0.193% propylene glycol; 0.097% tyloxapol; 0.015% acetic acid; 0.228% sodium acetate; 0.09% boric acid; and 3.53% mannitol, wherein the composition has an osmolality of 260-330 mOsm / kg and a pH of 4.5-5.

5.

10. Weight is 0.1% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 4. The composition of claim 3, comprising: 0.193% propylene glycol; 0.097% tyloxapol; 0.0065% acetic acid; 0.25% sodium acetate; 0.09% boric acid; and 3.6% mannitol, wherein the composition has an osmolality of 260-330 mOsm / kg and a pH of 4.5-5.

5.

11. 1. A method of treating a disease in a patient, comprising: A method of treatment comprising administering to a patient a composition comprising a therapeutically effective amount of a 1 kDa to 2 kDa peptide, a solubilizing agent generally recognized as safe, one or more surfactants generally recognized as safe, and buffering agents generally recognized as safe, optionally including boric acid and optionally mannitol, wherein the composition has an osmolality of 260-330 mOsm / kg and a pH of 4.5-5.

5.

12. The method of claim 11, characterized in that the composition comprises a therapeutically effective amount of a 1 kDa to 2 kDa adiponectin peptide mimetic, a solubilizing agent generally recognized as safe, one or more surfactants generally recognized as safe, and buffering agents generally recognized as safe, optionally including boric acid and optionally mannitol, wherein the osmolality of the composition is between 260 and 330 mOsm / kg and the pH is between 4.5 and 5.

5.

13. Weight is 0.01% to 2% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 13. The method of claim 12, wherein the composition comprises: 1% to 2% propylene glycol; 0.08% to 0.12% tyloxapol or poloxamer; 0.02% to 0.20% acetic acid; and 0.05% to 0.5% sodium acetate, wherein the composition has an osmolality of between 260 and 330 mOsm / kg and a pH of between 4.5 and 5.

5.

14. Weight is 0.20% to 1.0% D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 14. The method of claim 13, wherein the composition comprises: 1.20%-1.90% propylene glycol; 0.10% tyloxapol or poloxamer; 0.04%-0.20% acetic acid; and 0.08%-0.42% sodium acetate, wherein the composition has an osmolality of 270-280 mOsm / kg or is adjusted to an osmolality of 270-280 mOsm / kg.

15. The method of claim 14, wherein the disease is an inflammation-related eye disease.

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