Topical formulations and uses thereof

Abstract

Topical formulations are provided, including formulations suitable for ocular administration. [Solution] A formulation comprising polyoxyl lipids or fatty acids and polyalkoxylated alcohols, which contains mixed nanomicelles, is organic solvent-free, and does not contain any pharmaceutically active agents that have received regulatory approval for the specific treatment of ocular conditions.

Description

[Technical field]

[0001] The present disclosure relates to formulations for topical administration, such as ophthalmic formulations, and methods of using such formulations. Related to the field. [Background technology]

[0002] The information provided herein and the references cited herein will aid the reader in understanding. are provided solely for informational purposes and any of these references or information may not be used in whole or in part to This is not an admission that the invention is prior art.

[0003] U.S. Patent Application Nos. 2010 / 0310462 and 2009 / 0092665 are A drug delivery system for ophthalmic use, with nanomicelles containing vitamin E TPGS. This information is disclosed.

[0004] Travoprost contains HCO-40 and a prostaglandin analog as active ingredients. With preparations for glaucoma or ocular hypertension. d.nlm.nih.gov / dailymed / lookup.cfm?setid= See 338e7ff4-0d91-4208-a45d-bfa2be52334d The active ingredient is present at 0.004%. The formulation contains propylene glycol. It does not contain nanomicelles. HCO-40 is 0.5% for travoprost. It exists. On the World Wide Web at ema.europa.eu / docs / e n_GB / document_library / EPAR_-_Product_Inf See ormation / human / 000665 / WC500038389.pdf I want to be. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent Application No. 2010 / 0310462 [Patent Document 2] U.S. Patent Application No. 2009 / 0092665 Summary of the Invention [Problem to be solved by the invention]

[0006] The present disclosure relates to topical formulations, including formulations suitable for ocular administration. In embodiments, the formulations of the present disclosure comprise a polyoxyl lipid or a fatty acid, and / or The composition may include polyalkoxylated alcohols and may include nanomicelles. In certain embodiments, the formulations of the present disclosure may further comprise a polyoxyl lipid or a fatty acid, and / or or polyalkoxylated alcohols, and may include nanomicelles. And in embodiments, the formulations of the present disclosure are all in the absence of any pharma- ceutical active agent. i.e., any non-lipid, non-surfactant drug that has received regulatory approval for the treatment of an ocular condition. As used herein, the term "formulation" refers to a formulation in which the ingredients are or the component is a pharma- ceutical active agent, i.e., a compound that has regulatory approval for the treatment of an ophthalmic condition. It is intended to suggest that the compound may be combined with any non-lipid, non-surfactant active agent. isn't it. [Means for solving the problem]

[0007] In certain aspects and embodiments described herein, The formulations disclosed herein have certain surprising features and properties that could not have been predicted prior to the present disclosure. This may have advantages.

[0008] In some embodiments, the formulations of the present disclosure can be used at elevated temperatures, for example, temperatures greater than about 40 degrees Celsius. In some aspects and embodiments, the compositions described herein are surprisingly stable at high temperatures. The nanomicellar nature of some of the formulations described herein allows for improved distribution in ocular tissues. In certain aspects and embodiments, the formulations described herein are suitable for delivery to the anterior segment of the eye, as well as are particularly suitable for delivery to the posterior segment of the eye, or to the anterior and posterior segments of the eye.

[0009] Thus, in a first aspect, there is provided a composition comprising a polyoxyl lipid or a fatty acid, and a polyalkoxylated alcohol, and no active agent. In some embodiments, the formulation comprises nanomicelles. The lipid or fatty acid is polyoxyl castor oil. Xyl lipids or fatty acids are HCO-40, HCO-60, HCO-80, or HCO In some embodiments, the polyoxyethylene alkyl ether is one or more selected from the group consisting of aryl, aryloxy ... lipids or fatty acids (HCO-40, HCO-60, HCO-80, or HCO-10 0, etc.) is present in an amount of 1 to 6% by weight, or 2 to 6% by weight, Or 2 to 6% by weight, or 3 to 6% by weight, or 4 to 6% by weight, or 2 to 5 % by weight, or 3-5% by weight, or 3-5% by weight, or 2-6% by weight, or about 4% by weight, or more than 0.7% by weight, or more than 1% by weight, or more than 1.5% by weight; Or greater than 2% by weight, or greater than 3% by weight, or greater than 4% by weight. In some embodiments, the polyoxyl lipid is HCO-60. The polyoxyl lipid is HCO-80. In some embodiments, the polyoxyl lipid is HCO-100. In some embodiments, the formulation contains octoxynol-4 In some embodiments, the formulation comprises a polyalkoxylated alcohol having a molecular weight of: 0.002 to 4% by weight, or 0.005 to 3% by weight, or 0.005 ~2% by weight, or 0.005-1% by weight, or 0.005-0.5% by weight, if or 0.005 to 0.1% by weight, or 0.005 to 0.05% by weight, or 0.0 Polyalkoxylated alcohol present at 0.08 to 0.02% by weight, or about 0.01% by weight. Contains aryl (e.g., Octoxynol-40).

[0010] As used herein, the term "polyoxyl lipid or fatty acid" refers to a lipid or fat. It refers to monoesters and diesters of acids and polyoxyethylene diols. The hydroxyl lipid or fatty acid, as is generally understood in the art, is an oxyethyl group. Numbered according to the average polymer length in olefin units (e.g., 40, 60, 80, 100) The term "n≧40 polyoxyl lipid" refers to a polyoxyl lipid or It means that the fatty acid has an average oxyethylene polymer length of 40 units or more. Hydrogenated castor oil and castor oil are commercially available as polyoxyl lipids or fatty acids. These are typical lipids / fatty acids that are used, however, any lipid or fatty acid is contemplated in the present invention. It is understood that the fatty acids may be polyoxylated to provide the desired polyoxylated lipids or fatty acids. Examples of polyoxyl lipids or fatty acids include, but are not limited to, HCO -40, HCO-60, HCO-80, HCO-100, Polyoxyl 40 stearate , Polyoxyl 35 Castor Oil.

[0011] As used herein, the term "micelle" or "nanomicelle" refers to a surfactant molecule. A micelle is an aggregate (or assembly) of surfactants that is formed when the concentration of the surfactant exceeds the critical micelle concentration (CMC ) are formed only when the surface area of ​​the surfactant exceeds 100 nm. Surfactants are amphiphilic chemicals that act on surfaces This means that the surfactant contains both hydrophobic and hydrophilic groups. Micelles are spherical, cylindrical, or They can exist in different shapes, such as round, oval, and disk-shaped. The cells are mixed micelles. In some embodiments, the ophthalmic compositions of the present disclosure are transparent. The mixed micellar aqueous solution includes:

[0012] In a second aspect, provided is a method for preparing a composition comprising: and optionally an active agent. In some embodiments, the formulation is a nano In some embodiments, the polyoxyl lipid or fatty acid is a polyoxyl In some embodiments, the polyoxyl lipid or fatty acid is H. One or more of the following: CO-40, HCO-60, HCO-80, or HCO-100 In some embodiments, the polyoxyl lipid or fatty acid (HCO- Polyoxyl castor oil such as HCO-40, HCO-60, HCO-80, or HCO-100 ) is 0.5 to 2% by weight, 0.7 to 2% by weight, or 1 to 6% by weight of the formulation. or 2 to 6% by weight; or 2 to 6% by weight; or 3 to 6% by weight; or 4 to 6% by weight; or 2 to 5% by weight; or 3 to 5% by weight; or 3 to 5% by weight; if or about 2-6% by weight; or about 4% by weight; or more than 0.7% by weight; or more than 1% by weight, or greater than 1.5% by weight; or greater than 2% by weight; or greater than 3% by weight; or 4% by weight In some embodiments, the polyoxyl lipid is HCO-60. In some embodiments, the polyoxyl lipid is HCO-80. In some embodiments, the polyoxyl lipid is HCO-100. In some embodiments, the formulation further comprises a polyalkoxylated alcohol. In some embodiments, the polyalkoxylated alcohol is octoxynol-40. In an embodiment, the formulation contains 0.002 to 4% by weight of the formulation; or 0.005 to 3% by weight; or 0.005 to 2% by weight; or 0.005 to 1% by weight; or 0 .005 to 0.5% by weight; or 0.005 to 0.1% by weight; or 0.005 to 0 .05% by weight; or 0.008-0.02% by weight; or 0.01-0.1% by weight or 0.02 to 0.08% by weight; or 0.005 to 0.08% by weight; or about Polyalkoxylated alcohol (s) present at 0.05% by weight, or about 0.01% by weight Octoxynol-40, etc.

[0013] In a third aspect, provided is a composition comprising a polyoxyl lipid or a fatty acid, A formulation containing no active agent, wherein the polyoxyl lipid or fatty acid is 1% or more of the formulation. In a similar embodiment, a polyoxyl lipid or a lipid is provided. and an acid, but no active agent, wherein the polyoxyl lipid or fatty acid is In some embodiments, the formulation is a nanomicelle. In some embodiments, the polyoxyl lipid or fatty acid comprises polyoxyl hyaluronate. In some embodiments, the polyoxyl lipid or fatty acid is HCO- One or more selected from HCO-40, HCO-60, HCO-80, or HCO-100 In some embodiments, the polyoxyl lipid or fatty acid (HCO-60, Polyoxyl castor oil such as HCO-80 or HCO-100) is the 0. 5 to 2% by weight, or 0.7 to 2% by weight, or 1 to 6% by weight; or 2 to 6% by weight %; or 2 to 6% by weight; or 3 to 6% by weight; or 4 to 6% by weight; or 2 up to 5% by weight; or 3 to 5% by weight; or 3 to 5% by weight; or 2 to 6% by weight; or about 4% by weight; or greater than 1.5% by weight; or greater than 2% by weight; or greater than 3% by weight; In some embodiments, the polyoxyl lipid is present at or above 4% by weight. In some embodiments, the polyoxyl lipid is HCO-60. In some embodiments, the polyoxyl lipid is HCO-80. In some embodiments, the polyoxyl lipid is HCO-100. In some embodiments, the formulation further comprises a polyalkoxylated alcohol. In some embodiments, the polyalkoxylated alcohol is octoxynol-40. In an embodiment, the formulation contains 0.002 to 4% by weight of the formulation; or 0.005 to 3% by weight; or 0.005 to 2% by weight; or 0.005 to 1% by weight; or 0 .005 to 0.5% by weight; or 0.005 to 0.1% by weight; or 0.005 to 0 .05% by weight; or 0.008-0.02% by weight; or 0.01-0.1% by weight or 0.02 to 0.08% by weight; or 0.005 to 0.08% by weight; or about Polyalkoxylated alcohol (s) present at 0.05% by weight, or about 0.01% by weight Octoxynol-40, etc.

[0014] In a fourth aspect, provided is a lipid composition comprising a polyoxyl lipid or a fatty acid, but having no active In some embodiments, the formulation does not include an active agent, and the formulation comprises nanomicelles. The polyoxyl lipid or fatty acid is polyoxyl castor oil. For example, polyoxyl lipids or fatty acids are HCO-40, HCO-60, HCO-80, or HCO-100. , polyoxyl lipids or fatty acids (HCO-40, HCO-60, HCO-80, or Polyoxyl castor oils such as HCO-100, etc.) are present in an amount of 0.5 to 2% by weight of the formulation, or is 0.7 to 2% by weight, or 1 to 6% by weight; or 2 to 6% by weight; or 2 to 6% by weight; % by weight; or 3 to 6% by weight; or 4 to 6% by weight; or 2 to 5% by weight; or 3 to 5% by weight; or 3 to 5% by weight; or 2 to 6% by weight; or about 4% by weight; if or more than 0.7% by weight; or more than 1% by weight; or more than 1.5% by weight; or more than 2% by weight or greater than 3% by weight; or greater than 4% by weight. The polyoxyl lipid is HCO-40. In some embodiments, the polyoxyl lipid In some embodiments, the polyoxyl lipid is HCO-80. In some embodiments, the polyoxyl lipid is HCO-100. In some embodiments, the formulation further comprises a polyalkoxylated alcohol. In its formulation, the formulation contains a polyalkoxylated alcohol, which is Octoxynol-40. In some embodiments, the formulation further comprises 0.002 to 4 wt. %; or 0.005 to 3% by weight; or 0.005 to 2% by weight; or 0.00 5 to 1% by weight; or 0.005 to 0.5% by weight; or 0.005 to 0.1% by weight or 0.005 to 0.05% by weight; or 0.008 to 0.02% by weight; or is 0.01 to 0.1% by weight; or 0.02 to 0.08% by weight; or 0.005 to 0.08% by weight; or about 0.05% by weight, or about 0.01% by weight Contains glycoxylated alcohols (such as Octoxynol-40).

[0015] In a further aspect, provided is 1-5% HCO-40, HCO-60 , HCO-80, and HCO-100; Contains oxyl lipids and about 0.01% octoxynol-40, and contains no active drug. , a formulation.

[0016] In another aspect, provided is 1-5% HCO-40, HCO-60, H one or more polyoxygenates selected from the group consisting of HCO-80, and HCO-100 The formulation contains about 0.01% octoxynol-40 and no active drug. It is a drug.

[0017] In yet another aspect, provided is a 1-5% HCO-40, HCO-6 0, HCO-80, and HCO-100 lyoxyl lipids and about 0.01% octoxynol-40, and does not contain any active agent. Yes, it is a formulation.

[0018] In one aspect, provided is 1-5% HCO-40, HCO-60, HC O-80, and HCO-100 and about 0.01% octoxynol-40, without any active drug. It is.

[0019] In a further embodiment, provided is about 4% HCO-60 and about 0.01% Octoxynol-40 and no active drug.

[0020] In another aspect, provided is 0.7-1.5% HCO-40, HCO- one or more selected from the group consisting of HCO-60, HCO-80, and HCO-100 Polyoxyl lipid and about 0.05% octoxynol-40, and does not contain an active agent. No, it is a formulation.

[0021] In another aspect, provided is 0.7-1.5% HCO-40, HCO- one or more selected from the group consisting of HCO-60, HCO-80, and HCO-100 Polyoxyl lipid and about 0.05% octoxynol-40, and does not contain an active agent. No, it is a formulation.

[0022] In yet another aspect, provided is 0.7-1.5% HCO-40, H one selected from the group consisting of HCO-60, HCO-80, and HCO-100; and about 0.05% octoxynol-40; It is a formulation that does not contain.

[0023] In one aspect, provided is a 0.7-1.5% HCO-40, HCO-6 0, HCO-80, and HCO-100 0.05% octoxynol-40 and no active agent. Yes, it is a formulation.

[0024] In a further embodiment, provided is about 1% HCO-60 and about 0.05% Octoxynol-40 and no active drug.

[0025] In various embodiments of any of the aspects and embodiments described herein In this case, the formulation comprises nanomicelles.

[0026] In some of the aspects and embodiments described herein, the present invention The agent comprises a polyoxyl lipid or a fatty acid. In some embodiments, the agent comprises a polyoxyl lipid or a fatty acid. In some embodiments, the fatty acid or oil is polyoxyl castor oil. The silllipids or fatty acids are HCO-40, HCO-60, HCO-80, or HCO- 100. In some embodiments, the polyoxyl Lipids or fatty acids (polyoxygenates such as HCO-60, HCO-80, or HCO-100) Castor oil, etc.) is present in an amount of 0.5 to 2% by weight, or 0.7 to 2% by weight, or 1-6% by weight; or 2-6% by weight; or 2-6% by weight; or 3-6% by weight; Or 4 to 6% by weight; or 2 to 5% by weight; or 3 to 5% by weight; or 3 to 5 % by weight; or 2-6% by weight; or about 4% by weight; or more than 0.7% by weight; or More than 1% by weight; or more than 1.5% by weight; or more than 2% by weight; or more than 3% by weight; if In some embodiments, the polyoxyl lipid is present at or above 4% by weight. In some embodiments, the polyoxyl lipid is HCO-60. In some embodiments, the polyoxyl lipid is HCO-80. The polyoxyl lipid is HCO-100.

[0027] In some of the aspects and embodiments described herein, the present invention In some embodiments, the formulation comprises a polyalkoxylated alcohol. In some embodiments, the polyalkoxylated alcohol is Toxinol-40. In the case of the present preparation, the present preparation may contain 0.002 to 4% by weight or 0.005 to 3% by weight of the present preparation. or 0.005 to 2% by weight; or 0.005 to 1% by weight; or 0.005 to 0 .5% by weight; or 0.005-0.1% by weight; or 0.005-0.05% by weight or 0.008 to 0.02% by weight; or 0.01 to 0.1% by weight; or 0 .02 to 0.08% by weight; or 0.005 to 0.08% by weight; or about 0.05% by weight %, or about 0.01% by weight of polyalkoxylated alcohol (octoxylated -40, etc.

[0028] In certain aspects and embodiments disclosed herein, the formulations of the present disclosure may be Any pharmacologic active agent, i.e., any pharmacologic agent that has received regulatory approval for the treatment of an ocular condition. It is formulated in the absence of a non-lipid, non-surface active pharma- ceutical agent.

[0029] Exemplary active agents that are optionally excluded from the formulations of the present disclosure include calcineurin inhibitors. toxic agents, mTOR inhibitors, peptides, eicosanoids (e.g., prostacyclin and prostaglandins), anti-inflammatory drugs (NSAIDs, etc.), autonomic agents (e.g., beta-blockers withdrawal, alpha blockers, beta agonists, and alpha agonists), biologics, Gene therapy agents (e.g., viral vectors), anti-infective agents (e.g., antifungals, antibiotics, and antiviral agents), retinoids, RNAi, photosensitizers, steroids (e.g., estradiol, steroids, mixed drugs, immunomodulators, Chemotherapy, G protein-coupled receptor antagonists, receptor tyrosine kinase (RTK ) inhibitors, growth hormone inhibitors, integrin inhibitors, Sdf1 / CXCR4 pathway inhibitors , as well as nACh receptor antagonists, resolvins (resolvin-like compounds), lipokines, and selected from the group consisting of stimulants, neuroprotectins, maresins, and oxylipins. There may be one or more.

[0030] In some embodiments, active ingredients that are optionally excluded from the formulations of the present disclosure include , cyclosporine A, voclosporin, ascomycin, tacrolimus, pimecrolimus , an analog thereof, or a pharma- ceutically acceptable salt thereof. In one embodiment, the active agent is cyclosporine A. In one embodiment, the active agent is voclosporin.

[0031] In some embodiments, active ingredients that are optionally excluded from the formulations of the present disclosure include , sirolimus (rapamycin), temsirolimus, everolimus, and their analogs, is one or more selected from the group consisting of pharma- ceutically acceptable salts thereof. .

[0032] In certain aspects and embodiments disclosed herein, any of the formulations disclosed herein may be used. Optionally excluded active agents include resolvins or resolvin-like compounds. As used herein, a resolvin-like compound refers to a compound that has a similar structure and function to a resolvin. Resolvins and resolvin-like compounds include compounds having the formula A A compound, a compound of any one of formulas 1 to 49, a compound of any one of formulas I to IX, a lipo a cysteine ​​compound, an oxylipin compound, a prodrug of any of the foregoing, or a pharmaceutical In some embodiments, the compounds of the present disclosure include commercially available salts of any of the foregoing. Active agents optionally excluded from the formulation include any one of the compounds of formulas 1-115. The compound may be selected from the group consisting of:

[0033] In some embodiments of any of the aspects and embodiments disclosed herein, the Active agents that are optionally excluded from the disclosed formulations include compounds of formula I:

[0034] [ka] and pharma- ceutically acceptable salts thereof, The stereochemistry of the double bond between carbons qq' and rr' is cis or trans; The stereochemistry of the double bond between carbons ss' and tt' is cis or trans; Re and Rf are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, hexane, hexanediamine ... Heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl , alkoxycarbonyl, or silyl; E is isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, 3-methyl 2,2-dimethylpropoxy, or 1,1,2-trimethylpropoxy and the like branched alkoxy. Rh and Ri are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro selected from alkyl, aryl, or heteroaryl; R5 is one of the following i to iv: i) CH2CH(R6)CH2 (wherein R6 is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro ii) CH2C(R6R7)CH2( In the formula, R6 and R7 are each independently an alkyl, alkenyl, alkynyl, peroxy, fluoroalkyl, aryl, or fluoro, or R6 and R7 are iii) CH2OCH2 , CH2C(O)CH2, or CH2CH2, or iv) R5 is a carbocyclic ring, is selected from a monocyclic ring, an aryl ring, or a heteroaryl ring; and R8 and R9 are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro alkyl, alkoxy, aryl, or heteroaryl, or R R8 and R9 are joined together to form a carbocyclic or heterocyclic ring. can be done.

[0035] In certain embodiments, compounds of formula I are optionally excluded from the formulations of the present disclosure. is represented by formula II,

[0036] [ka] and pharma- ceutically acceptable salts thereof, The stereochemistry of the double bond between carbons qq' and rr' is cis or trans; The stereochemistry of the double bond between carbons ss' and tt' is cis or trans; and Re, Rf, R5, and E are as defined above.

[0037] In certain embodiments, the compounds of formula I or I are optionally excluded from the formulations of the present disclosure. The compound of I has the formula III,

[0038] [ka] and pharma- ceutically acceptable salts thereof, Re, Rf, and E are as defined above.

[0039] In some embodiments of any of the aspects disclosed herein, the formulations of the present disclosure Optionally excluded active agents are compounds of formula I, and R9 is hydrogen, E is branched alkoxy (such as isopropyl), and R 5 is CH2CH2CH2].

[0040] In some embodiments of any of the aspects disclosed herein, the formulations of the present disclosure The optionally excluded active agent is Compound 1001 or a pharma- ceutically acceptable salt thereof. do.

[0041] The term "acyl" is art-recognized and refers to a group represented by the general formula: It refers to a group represented by C(O)-, preferably alkylC(O)-.

[0042] The term "acylamino" is art-recognized and refers to a compound that is substituted with an acyl group. It refers to a substituted amino group, for example represented by the formula: hydrocarbylC(O)NH-. This can be done.

[0043] The term "acyloxy" is art-recognized and refers to a group having the general formula: Preferably, it refers to a group represented by alkylC(O)O—, preferably alkylC(O)O—.

[0044] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, Examples include Shi.

[0045] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group; It can be represented by the general formula: alkyl-O-alkyl.

[0046] The term "alkenyl," as used herein, refers to an alkyl group containing at least one double bond. Refers to an aliphatic group, including "unsubstituted alkenyl" and "substituted alkenyl" (the latter of which is An alkenyl group having substituents replacing hydrogen on one or more carbons of the alkenyl group. Such substituents are intended to include both aryl and non-aryl moieties. It may occur at one or more carbons that are included or not included in a double bond. Such substituents include, except where stability is prohibitive, aryl groups as discussed below. The term "alkyl" includes all of the above contemplated groups. For example, one or more of alkyl, kalium, Alkenyl groups with ruthenium, aryl, heterocyclyl, or heteroaryl groups Substitution of is contemplated.

[0047] The term "alkyl" refers to the radical of a saturated aliphatic group, including straight-chain alkyl groups, branched-chain alkyl groups, and the like. Cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl In a preferred embodiment, straight or branched chain alkyl groups are included. has 30 or less carbon atoms in its main chain (e.g., C1-C3 in the case of a straight chain) 0, C3 to C for branched chains 30 ), more preferably 20 or less. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, more preferably Preferably, it has 5, 6, or 7 carbons in the ring structure.

[0048] Also, the term "alkyl" (or "lower alkyl") is used herein in the specification, examples, and specific examples. As used throughout the claims, the terms "unsubstituted alkyl" and "substituted alkyl" ( The latter of these is a substitution that replaces a hydrogen on one or more carbons of the hydrocarbon backbone. It is intended to include both such substituents and alkyl moieties. Unless otherwise specified, examples of aryl groups include halogen, hydroxyl, carbonyl (carbonyl), and carboxyl, alkoxycarbonyl, formyl, or acyl, etc.), thiocarbonyl ( thioester, thioacetate, or thioformate), alkoxyl, phosphoryl , phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, Cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate , sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or The aromatic or heteroaromatic moiety may be mentioned. The skilled person will recognize that, where appropriate, It will be understood that the moieties substituted on the hydrocarbon chain can themselves be substituted. For example, the substituents of the substituted alkyl are amino, azido, imino, amido, phosphoryl ( phosphonates and phosphinates), sulfonyls (sulfates, sulfones amide, sulfamoyl, and sulfonate), as well as silyl groups, and Ethers, alkylthios, carbonyls (ketones, aldehydes, carboxylates, and -CF3, -CN, etc.) Exemplary substituted alkyls are described below. Cycloalkyl is an alkyl , alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, It may be further substituted with -CF3, -CN, etc.

[0049] The term “C x-y " is an acyl, acyloxy, alkyl, alkenyl, alkynyl, or or alkoxy, a cyclic alkyl group containing x to y carbon atoms in the chain. For example, the term "C x-y "Alkyl" means a substituted or unsubstituted saturated It refers to a monovalent hydrocarbon group, including straight-chain alkyl groups and branched-chain alkyl groups containing x to y carbon atoms in the chain. and haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. Alkyl groups are included. CO alkyl indicates hydrogen when the group is in a terminal position; When it is internal, it indicates a bond. 2-y alkenyl" and "C 2-y Alkini "Alkyl" is similar in length and possible substitution to the alkyl, described above, but each has at least Both refer to a substituted or unsubstituted unsaturated aliphatic group that contains one double or triple bond.

[0050] The term "alkylamino" as used herein refers to an aryl group that is linked to at least one alkyl group. Thus, it refers to a substituted amino group.

[0051] The term "alkylthio," as used herein, refers to a thio group substituted with an alkyl group. It refers to an ol group and can be represented by the general formula, alkylS-.

[0052] The term "alkynyl," as used herein, refers to an alkynyl group containing at least one triple bond. Refers to an aliphatic group, including "unsubstituted alkynyl" and "substituted alkynyl" (the latter of which is An alkynyl group having substituents replacing a hydrogen atom on one or more carbons of the alkynyl group. Such substituents are intended to include both aryl and non-aryl moieties. It may occur at one or more carbons that are included or not included in the triple bond. Such substituents also include those groups discussed above, unless stability is prohibitive. The term "alkyl" includes all of the above contemplated for alkyl groups. For example, one or more alkyl, Alkynyl by carbocyclyl, aryl, heterocyclyl, or heteroaryl groups Substitution of groups is contemplated.

[0053] The term "amide" as used herein refers to the following group:

[0054] [ka] [In the formula, each R 10 each independently represents a hydrogen or a hydrocarbyl group, or two R 10 Together with the N atom to which they are attached, they have 4 to 8 atoms in a ring structure. This refers to completing a heterocycle.

[0055] The terms "amine" and "amino" are art-recognized and refer to unsubstituted or unsubstituted alkyl groups. Both amines and substituted amines, as well as salts thereof, such as those of the formula:

[0056] [ka] [In the formula, each R 10 each independently represents a hydrogen or a hydrocarbyl group, or two R 10 Together with the N atom to which they are attached, they have 4 to 8 atoms in a ring structure. completing a heterocyclic ring.

[0057] The term "aminoalkyl," as used herein, refers to an alkyl group substituted with an amino group. Refers to the alkyl group.

[0058] The term "aralkyl," as used herein, refers to an aralkyl group substituted with an aryl group. Refers to the kill group.

[0059] The term "aryl," as used herein, refers to a substituted or unsubstituted alkyl group in which each atom of the ring is carbon. The ring is preferably a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also refers to a ring having two or more carbon atoms in adjacent rings. Two or more cyclic rings that are shared and at least one of the rings is aromatic Polycyclic ring systems are also included, for example, where the other cyclic ring is a cycloalkyl, cycloalkenyl, aryl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl; The aryl group may be benzene, naphthalene, phenanthrene, phenol, Examples thereof include aniline.

[0060] The term "carbamate" is art recognized and refers to the following group:

[0061] [ka] [In the formula, R 9 and R 10 are independently hydrogen or a hydrocarbyl group such as an alkyl group. or R 9 and R 10 together with the intervening atom(s) in a ring structure It refers to a heterocyclic ring having 4 to 8 atoms.

[0062] The terms "carbocycle", "carbocyclyl" and "carbocyclic" as used herein In the case of aryl, it refers to a substituted or unsubstituted non-aromatic ring in which each atom of the ring is carbon. The ring contains from 3 to 10 atoms, more preferably from 5 to 7 atoms.

[0063] The term "carbocyclylalkyl" as used herein refers to a ring substituted with a carbocyclic group. It refers to an alkyl group.

[0064] The term "carbonate" is art-recognized and refers to the group, -OCO- R 10 [In the formula, R 10 represents a hydrocarbyl group.

[0065] The term "carboxy," as used herein, refers to a group represented by the formula: -COH. Refers to...

[0066] The term "ester," as used herein, refers to the group, -C(O)OR 10 [In the formula, R 1 0 represents a hydrocarbyl group.

[0067] The term "ether" as used herein means a radical linked through an oxygen to another hydrocarbyl group. Thus, an ether substituent on a hydrocarbyl group refers to The ether may be symmetric or unsymmetric. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle. Ethers include those of the general formula: alkyl-O-aryl, and aryl-O-heterocycles. Also included are "alkoxyalkyl" groups, which can be represented by alkyl.

[0068] The terms "halo" and "halogen" as used herein mean halogen and These include fluoro, bromo, and iodo.

[0069] The terms "hetarylalkyl" and "heteroaralkyl" as used herein refer to a heteroaryl group. It refers to an alkyl group substituted with an aryl group.

[0070] The term "heteroalkyl" as used herein means an alkyl group consisting of carbon atoms and at least one heteroaryl. It refers to a saturated or unsaturated chain with heteroatoms (where the two heteroatoms are not adjacent).

[0071] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring structures. The ring structure preferably contains a 5- to 7-membered ring, more preferably a 5- to 6-membered ring, and these ring structures are At least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or contains two heteroatoms. The terms "heteroaryl" and "hetaryl" also include Two or more carbons are shared between adjacent rings, and at least one of the rings Polycyclic ring systems having two or more cyclic rings, one of which is heteroaromatic, are included, for example: The other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or hexane. Heteroaryl and / or heterocyclyl. Heteroaryl groups include , for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, Examples include pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0072] The term "heteroatom" as used herein refers to any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0073] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to substituted or unsubstituted heterocyclic rings. The term "aromatic ring structure" refers to a 3- to 10-membered ring, preferably a 3- to 7-membered ring, and these rings The structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably contains one or two heteroatoms. Also, the terms "heterocyclyl" and "heterocyclic " has two or more carbons in common between two adjacent rings, and Polycyclic ring systems having two or more cyclic rings, at least one of which is heterocyclic, such as For example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, , heteroaryl, and / or heterocyclyl. Examples of suitable amines include piperidine, piperazine, pyrrolidine, morpholine, lactones, and lactams. etc.

[0074] The term "heterocyclylalkyl" as used herein refers to a heterocyclic group substituted It refers to an alkyl group.

[0075] The term "hydrocarbyl" as used herein refers to a group that is bonded through a carbon atom. , does not have =O or =S substituents, typically has at least one carbon-hydrogen bond and primarily It refers to a group having a carbon backbone and optionally containing heteroatoms. For the purposes of this application, methyl, ethoxyethyl, 2-pyridyl, and trifluoro Groups such as methyl are considered hydrocarbyl, while acetyl (= on the carbon to which it is attached) O substituent) and ethoxy (attached through an oxygen rather than a carbon). Substituents are not considered to be hydrocarbyl. The hydrocarbyl groups are not limited to: but not aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, aryl quinyl, and combinations thereof.

[0076] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group. It refers to an alkyl group.

[0077] The term "lower" refers to acyl, acyloxy, alkyl, alkenyl, alkynyl, or When used in conjunction with chemical moieties such as alkoxy, there should be no more than 10, preferably no more than 6, in the substituent. "Lower alkyl" is intended to include groups in which up to 10 non-hydrogen atoms are present. It refers to an alkyl group containing 10 or fewer carbon atoms, preferably 6 or fewer carbon atoms. In embodiments, acyl, acyloxy, alkyl, aryl, etc. are as defined herein. The aryl, alkynyl, or alkoxy substituents, whether they occur alone or is hydroxyalkyl and aralkyl (where, for example, the carbon atom of the alkyl substituent (When counting the atoms in an aryl group, atoms in the aryl group are not counted) Even when they appear in combination, they are each represented by lower acyl, lower acyloxy, lower alkyl, lower aryl, lower aryloxy ... It is lower alkenyl, lower alkynyl, or lower alkoxy.

[0078] Additionally, the terms "polycyclyl," "polycyclic," and "polycyclic" refer to groups having 1 or more rings in adjacent rings. Two or more rings in which two or more atoms are shared (e.g., cycloalkyl, cycloa alkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl For example, these rings are "fused rings." Each of the rings of a polycyclic ring may be substituted. In certain embodiments, the polycyclic rings may be substituted or unsubstituted. Each ring contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0079] The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

[0080] The term "substituted" refers to a substituent replacing a hydrogen on one or more carbons of the backbone. "Substituted" or "substituted by" refers to a moiety having such a substitution. , subject to the permitted valences of the substituted atom and the substituent, and Compounds that do not spontaneously undergo transformations, e.g., by rearrangement, cyclization, elimination, etc., are also available. It will be understood that the term includes the implied condition that the information is provided in accordance with the principles of the present invention. When used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, Branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic, organic The permissible substituents can be one or more of any suitable organic compound. may be multiple and may be the same or different. For purposes of this disclosure In addition, heteroatoms such as nitrogen may be substituted with hydrogen and / or aryl groups to satisfy the valence of the heteroatom. The organic compounds described herein may have any permissible substituents. Substituents include, but are not limited to, aryl, aryloxy ... , any of the substituents described herein, such as halogen, hydroxyl, carbonyl ( carboxyl, alkoxycarbonyl, formyl, or acyl, etc.), thiocarbonyl (thioester, thioacetate, or thioformate), alkoxyl, phosphoryl aryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine , cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or may include aromatic or heteroaromatic moieties. It will be understood that the moieties substituted on the hydrocarbon chain can themselves be substituted. Unless specifically stated to be "unsubstituted," the meaning of any group in the chemical moieties herein is Reference is understood to include substituted variants, e.g., "aryl" groups or moieties. Reference to implicitly includes both substituted and non-substituted variants.

[0081] The term "sulfate" is art-recognized and refers to the -OSOH group, or a pharma- ceutically acceptable salt thereof.

[0082] The term "sulfonamide" is art recognized and has the general formula:

[0083] [ka] [In the formula, R 9 and R 10 each independently represents hydrogen or a hydrocarbyl such as an alkyl or R 9 and R 10 Together with the intervening atom(s), there are 4 to 5 carbon atoms in the ring structure. It refers to a group represented by the formula: [completing a heterocyclic ring having 8 atoms].

[0084] The term "sulfoxide" is art-recognized and refers to a -S(O)-R 1 0 The group [wherein, R 10 represents hydrocarbyl].

[0085] The term "sulfonate" is art-recognized and refers to a SOH group, refers to a pharma- ceutically acceptable salt thereof.

[0086] The term "sulfone" is art-recognized and refers to a -S(O)-R 10 The group [wherein, R 10 represents hydrocarbyl].

[0087] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group. Refers to the alkyl group.

[0088] The term "thioester" as used herein refers to -C(O)SR 10 Group or -S C(O)R 10 The group [wherein, R 10 represents hydrocarbyl].

[0089] The term "thioether" as used herein refers to a thioether in which an oxygen is replaced by a sulfur. It is equivalent to ether.

[0090] The term "urea" is art recognized and has the general formula:

[0091] [ka] [In the formula, R 9 and R 10 each independently represents hydrogen or a hydrocarbyl such as an alkyl or any R 9 The appearance of R 10 together with the intervening atom(s) , completing a heterocycle having 4 to 8 atoms in the ring structure.

[0092] A "protecting group" is a group that, when attached to a reactive functional group in a molecule, masks the reactivity of that functional group. Typically, a protecting group is a group of atoms that acts to protect, reduce, or prevent a desired reaction during synthesis. Examples of protecting groups are described in Greene and Wuts, Protective Groups in Organic Chemistry,3 rd Ed., 1999, John Wiley & Sons, NY and Harry son et al, Compendium of Synthetic Organi c Methods,Vols.1-8,1971-1996,John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to: However, formyl, acetyl, trifluoroacetyl, benzyl, tert-butoxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl Methylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES") , trityl group and substituted trityl group, allyloxycarbonyl, 9-fluorenylmethyl oxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") Representative hydroxyl protecting groups include, but are not limited to, , those in which the hydroxyl group is acylated (esterified) or alkylated, e.g., benzoyl Diethyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers ethers, such as ethylene glycol and propylene glycol derivatives, and allyl ethers. Examples include tel.

[0093] The present disclosure further provides methods for treating ophthalmic diseases or disorders, e.g., by topical administration of the formulations described herein. Relates to the treatment or prevention of harm.

[0094] The patient or subject to be treated by any of the disclosed compounds or methods may be a human or The subject may be a non-human animal. In certain embodiments, the present disclosure relates to a human patient in need of treatment. In one embodiment, the present disclosure provides a method for treating an ocular disease in a subject. In one embodiment, the present invention provides a method for treating an inflammatory eye disease in a human patient in need of treatment. In certain embodiments, the present disclosure provides, but is not limited to, dog, horse, cat, rabbit, Felines, gerbils, hamsters, rodents, birds, aquatic mammals, cattle, pigs, camelids, To treat eye diseases in animal patients in need of treatment, including rabbits and other zoological animals. This provides a method for

[0095] In some embodiments of the compositions and methods described herein, the active agent is When present, the composition may contain a combination of two or more different active ingredients. In the present invention, the active agent, when present, is a resolvin or a resolvin-like compound, a steroid, from the group consisting of corticosteroids, cyclosporine A, and voclosporin The composition may include two or more selected active agents. In some embodiments, the active agents are , if present, may include resolvin and cyclosporin A. In the present invention, the active agents, if present, may include resolvins and corticosteroids. In some embodiments, the active agent, if present, is cyclosporine A and In some embodiments, the active agent is In some cases, resolvins, cyclosporine A, and corticosteroids may be included. In this embodiment, the active agent, if present, may include two or more active agents. One of the active agents is an antibiotic, e.g., azithromycin, ciprofloxacin, orthopedic acid. Floxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin one or more antibiotics selected from the group consisting of levofloxacin, sirolimus, and levofloxacin In some embodiments, the active agent, when present, comprises two or more active agents. One of the active agents may be an antibiotic, e.g., azithromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, bevacizumab one or more antibiotics selected from the group consisting of cifloxacin, and levofloxacin The second such agent is a resorcinol agent, such as those described herein. Rubin (including but not limited to compound 1001). In the form, the active agent, if present, may include two or more active agents, One type of drug is an antiviral drug, such as ganciclovir, trifluridine, or acyclovir. consisting of cyclosporine, famciclovir, valacyclovir, penciclovir, and cidofovir In some embodiments, the active agent is one or more antiviral agents selected from the group consisting of: When present, the active agent may contain two or more active agents, one of which may be an antibiotic. Substances such as ganciclovir, trifluridine, acyclovir, famciclovir, One or more selected from the group consisting of lacyclovir, penciclovir, and cidofovir are multiple antiviral agents, and the second such active agent is Resolvins such as those listed in the literature (including but not limited to compound 1001) It is.

[0096] The term "treat" refers to treating a disease, disorder, and / or condition that may be predisposed to, but is not yet diagnosed. in cells, tissues, systems, animals, or humans who have not been diagnosed with it Preventing the onset of a disease, disorder, or condition; stabilizing a disease, disorder, or condition and / or to prevent the progression of a disease, disorder, or condition; alleviating one or more symptoms of a disease, disorder, and / or condition; This refers to bringing about a return of

[0097] As used herein, a therapeutic agent that "prevents" a disorder or condition is an agent that is effective in treating a statistical sample. in treated samples compared to untreated control samples. or reduce the occurrence of a condition, or Delaying the onset of or reducing the severity of one or more symptoms of a disorder or condition It refers to a compound that

[0098] As used herein, the terms "ocular disease," "ocular condition," "ocular disorder," and "ocular The condition can be vision threatening, can lead to eye discomfort and can affect your overall health. Refers to eye diseases / conditions that may be a precursor to health problems.

[0099] As used herein, the term "anterior segment disease" refers to diseases affecting the ocular surface, anterior chamber, iris, and ciliary body. The term refers to any disorder that affects the crystalline lens of the eye, as well as the cornea. It also consists of the lacrimal and meibomian glands and their interconnecting nerves.

[0100] As used herein, the terms "posterior ocular disease" and "disease of the rear of the eye" refer to diseases that affect the rear of the eye. Posterior ocular diseases refer to any disorder that affects the choroid or sclera, the vitreous, or the vitreous cavity. vascular and vascular endothelial cells that vascularize or innervate the retina, optic nerve, and posterior eye sites. It is a disease that primarily affects the posterior eye areas, such as the eyes and nerves.

[0101] Thus, in one aspect, what is provided is a method for producing a method for the treatment of a disease comprising administering to a subject the method of the present invention ... and administering topically any of the formulations of the present invention to treat or treat an ocular disease or condition. In some embodiments, the eye disease is an anterior segment disease. In embodiments, the ocular disease is a posterior segment disease. In some embodiments, the ocular disease is , Dry Eye Syndrome, Sjogren's Syndrome, Uveitis, Anterior Uveitis (Iritis), Pulse Retinitis, posterior uveitis, conjunctivitis, allergic conjunctivitis, keratitis, keratoconjunctivitis, vernal keratoconjunctivitis keratoconjunctivitis (VKC), atopic keratoconjunctivitis, systemic immune-mediated diseases such as cicatricial conjunctivitis and and other autoimmune disorders of the ocular surface, such as blepharitis, scleritis, age-related macular degeneration (AMD), and diabetes Diabetic retinopathy (DR), diabetic macular edema (DME), ocular neovascularization, age-related macular degeneration (AR) MD), proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV) retinitis, optic nerve One or more of the following are selected from the group consisting of optic nerve inflammation, retrobulbar optic neuritis, and macular pucker In one embodiment, the eye disease is dry eye. In one embodiment, the eye disease is age-related macular degeneration (AMD). In one embodiment, the eye disease is diabetic retinopathy. The formulations of any of the aspects or embodiments disclosed herein may be used as artificial tears. For example, these formulations can be used to moisten and lubricate the eye. The formulations provided herein may also, or alternatively, be used to moisten contact lenses and may be used to moisten the eye in the presence of contact lenses. In some cases, the formulations provided herein may be "over-the-counter" drugs, i.e., sold by health care providers. These drugs can be provided directly to consumers without the need for a prescription. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0102] Active Agent In accordance with various aspects and embodiments of the methods and compositions provided herein, the present disclosure The formulation may be administered with any pharma- ceutical active agent, i.e., a medicament having regulatory approval for the treatment of an ocular condition. The formulation is formulated in the absence of any non-lipid, non-surface active pharma- ceutical agent.

[0103] In some embodiments, activities that may be specifically excluded from various embodiments of the formulations of the present invention The drug may be any drug capable of affecting a biological process, particularly the treatment of an ocular condition. Activities contemplated for exclusion in the present invention Drug (the term active ingredient is used interchangeably herein with the term active pharmaceutical agent) Examples of substances that may be involved include drugs, hormones, cytokines, toxins, therapeutic agents, vitamins, etc. In some embodiments, the present invention is directed to a method for treating a pulmonary circulation disorder according to aspects and embodiments disclosed herein. The active agents contemplated for exclusion in the invention are those capable of treating or preventing a disease or condition. For example, in some embodiments, The active agent is capable of treating or preventing an ocular disease or condition, or is authorized for.

[0104] The compositions of the present disclosure are useful as topical agents for the delivery of a variety of active agents, including hydrophobic, water-insoluble drugs. The present disclosure can be used as a drug delivery platform for local administration or local injection. Active agents that can be enhanced in delivery by the composition but that may be excluded from the compositions of the present disclosure Agents include calcineurin inhibitors or mTOR inhibitors, peptides, and eicosanoids. (e.g., prostacyclin and prostaglandins), anti-inflammatory agents, autonomic agents (e.g., beta-blockers, alpha-blockers, beta-agonists, and alpha-agonists) drugs), biologics, gene therapy agents (e.g., viral vectors), anti-infectives (e.g., fungal, antibiotic, and antiviral agents), retinoids, RNAi, photosensitizers, steroids drugs (e.g., estrogen and its derivatives), mixed drugs, immunomodulators, chemotherapeutic agents, G protein-coupled receptor antagonists, receptor tyrosine kinase (RTK) inhibitors, Growth hormone inhibitors, integrin inhibitors, Sdf1 / CXCR4 pathway inhibitors, and Examples include nACh receptor antagonists, resolvins, lipoxins, and oxylipins. In some embodiments, the compositions of the present disclosure can enhance delivery. Active agents that may be excluded from the compositions of the present disclosure are corticosteroids and prednisolones. These are donisolone, hydrocortisone, triamcinolone, and budesonide. In embodiments of the present disclosure, delivery can be enhanced by the compositions of the present disclosure. Active ingredients that may be excluded from the composition are nonsteroidal anti-inflammatory drugs (NSAIDs), e.g. The drug may be a Cox-2 inhibitor such as celecoxib, ruboxistaurin, or nimesulide. In certain embodiments, the compositions of the present disclosure can enhance delivery, Active agents that may be excluded from the compositions of the present disclosure include, but are not limited to, anti-growth factor molecules. pegaptanib (Macugen), ranibizumab (Lucentis), and bevacizumab (Berkeley, VA, and other FDA-approved drugs) are not approved for use in patients with ovarian cancer. Vascular endothelial growth factor (VEGF) inhibitors such as ciprofloxacin (Avastin) are some of the In embodiments, delivery can be enhanced by the compositions of the present disclosure, Active agents that may be excluded from the composition include antibiotics, e.g., azithromycin, ciprofloxacin, Ofloxacin, Gatifloxacin, Levofloxacin, Moxifloxacin , besifloxacin, and levofloxacin In some embodiments, the compositions of the present disclosure enhance delivery of Active agents that may be present in the compositions of the present disclosure, but may be excluded, are antiviral agents, e.g., Ganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir, One or more antiviral drugs selected from the group consisting of penciclovir and cidofovir It is a drug.

[0105] In some embodiments, when the composition of the present disclosure comprises an active agent, the active agent is a Combinations may also be used, including but not limited to vascular endothelial growth factor (VEGF) and F) inhibitors and antagonists of platelet-derived growth factor (PDGF).

[0106] In some embodiments of any of the aspects and embodiments disclosed herein, the When the disclosed compositions comprise an active agent, the following active agents are preferred: calcineurin inhibitors, e.g. Cyclosporine A, voclosporin, ascomycin, tacrolimus, pimecrolimus, Their analogs, or pharma- ceutically acceptable salts thereof, etc. are excluded from the compositions of the present disclosure. It is possible.

[0107] In some embodiments of any of the aspects and embodiments disclosed herein, the When the disclosed compositions comprise an active agent, the active agent may be one of the following: mTOR inhibitors, e.g., sirolimus rapamycin, temsirolimus, everolimus, their analogs, or Acceptable salts thereof and the like may be excluded from the compositions of the present disclosure.

[0108] Resolvins, lipoxins, etc. In some aspects and embodiments described herein, the compositions of the present disclosure include an active agent When the agent is included, resolvins are excluded as active agents. In some embodiments, when the composition of the present disclosure includes an active agent, the compound of formula A is used as the active agent. Any one of the compounds of formulas 1 to 49 is excluded as an active agent, and any one of the compounds of formulas I to IX is excluded as an active agent. Any one of the compounds listed above is excluded as an active agent, and a lipoxin compound is selected as an active agent. and oxylipin compounds are excluded as active agents, and any of the foregoing are excluded as active agents. or a pharma- ceutically acceptable salt of any of the foregoing may be used as the active agent. are excluded.

[0109] When the composition of the present disclosure includes an active agent, the active agent and Compounds optionally excluded from use as a compound include those of formula A:

[0110] [ka] [In the formula, Each of W' and Y' is a bond or a ring containing up to 20 atoms or a linker independently selected from a chain of 20 atoms, provided that W' and Y' are may contain, independently, one or more nitrogen, oxygen, sulfur, or phosphorus atoms. and further stipulated that W' and Y' are independently hydrogen, alkyl, alkenyl, alkyl, alkoxy ... Nyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, a alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamide, cyano, oxo, thio, alkylthio, arylthio, Acylthio, alkylsulfonate, arylsulfonate, phosphoryl, or sulfo and further with the proviso that the alkyl group may contain one or more substituents independently selected from alkyl, aryl, Furthermore, W' and Y' are independently one or more fused carbocyclic, heterocyclic rings. , aryl, or heteroaryl rings, provided further that o' is 0 and V1 is

[0111] [ka] provided that, if Y' is connected to V1 via a carbon atom, V1 is,

[0112] [ka] where, when q' is 0 and V3 is a bond, n' is 0 or 1. otherwise n' is 1, V2 is a bond,

[0113] [ka] where: L' is -C(R 1003 )(R 1004 )-, where R 1003 and R 1004 Each of is independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoro, or selected from the group consisting of orthoalkyl, alkoxy, aryl, and heteroaryl; is R 1003 and R 1004 are connected together to form a carbocyclic or heterocyclic ring. V3 is formed.

[0114] [ka] then L' is additionally selected from W', and n' is 0 or 1; V3 is a combination or

[0115] [ka] where: Each R 1001 and R 1002 is independently for each occurrence hydrogen, alkyl, alkenyl, Aryl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxy, or haloaryl. b) wherein the alkyl or aryl-containing moiety is optionally selected from up to three and is substituted by independently selected substituents of R a’ and R b’ Each of is independently for each occurrence -OR' or -N(R ')2 or adjacent R a’ and Rb’ Together, they form a cis configuration. or an epoxide ring having a trans configuration, where each R' is independently a hydrogen atom. alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, silyl, Alkoxyacyl, aminoacyl, aminocarbonyl, alkoxycarbonyl, or is selected from the group consisting of Or V1 is

[0116] [ka] and V2 is

[0117] [ka] If R 1002 and R b’ are both hydrogen, X' is -CN, -C(NH)N(R")(R"), -C(S)-A', -C(S)R" , -C(O)-A', -C(O)-R", -C(O)-SR", -C(O)-NH-S( O)2-R”, -S(O)2-A', -S(O)2-R”, S(O)2N(R”)(R” ), -P(O)2-A', -PO(OR")-A', -Tetrazole, alkyl tetrazo A' is selected from -OR", -N(R")(R "), or -OM', Each R" is independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or a detectable labeling molecule, wherein any aryl The alkyl, aryl, or heteroaryl-containing moiety may optionally include up to three independently selected and M' is a cation; G' is hydrogen, halo, hydroxy, alkyl, aryl, arylalkyl, heteroaryl, alkyl, heteroaryl, alkyl, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamide, or a detectable label Recognition molecules, wherein any alkyl, aryl, or heteroaryl containing moiety is selected from the group consisting of: is optionally substituted with up to three independently selected substituents; o' is 0, 1, 2, 3, 4, or 5; p' is 0, 1, 2, 3, 4, or 5; q' is 0, 1, or 2, and o'+p'+q' is 1, 2, 3, 4, 5, or 6, Where: when V2 is a bond, then q' is 0 and V3 is a bond; V3

[0118] [ka] If o' is 0, V1 is

[0119] [ka] , p' is 1, and V2 is

[0120] [ka] and any acyclic double bonds may be in either the cis or trans configuration. or optionally replaced by a triple bond, Any one of the compounds

[0121] [ka] The part, if present, is optional:

[0122] [ka] or one of the compounds

[0123] [ka] The part, if present, is optional:

[0124] [ka] where Q' represents one or more substituents and each Q' is independently Specifically, halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetero Aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, a Alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, carbo xyl, alkoxycarbonyloxy, aryloxycarbonyloxy, or amino carbonyl].

[0125] In certain embodiments, V1 is

[0126] [ka] is selected from.

[0127] In certain embodiments, V2 is a bond,

[0128] [ka] is selected from.

[0129] In certain embodiments, when q' is 0 and V3 is a bond, n' is 0 or or 1, otherwise n' is 1.

[0130] In certain embodiments, p' is 0, 1, 2, 3, or 5.

[0131] In certain embodiments, q' is 0 or 1.

[0132] In certain embodiments, V1 is

[0133] [ka] Then, o' is 0 or 1, p' is 1 or 2, and o'+p' is 1 or 2, and V2 is

[0134] [ka] and V3 is a bond.

[0135] In certain embodiments, V1 is

[0136] [ka] Then o' is 3, 4, or 5, p' is 0, 1, or 2, and o'+p ' is 4 or 5 and V2 is a bond.

[0137] In certain embodiments, when V2 is a bond, o' is 0, 3, 4, or 5. where p' is 0, 1, 2, or 5, o'+p' is 4 or 5, and q' is 0. and V3 is a bond.

[0138] In certain embodiments, each of W' and Y' is independently a bond, or is alkenyl, alkynyl, aryl, chloro, iodo, bromo, fluoro, hydroxy , amino, or oxo. optionally substituted lower alkyl or heteroalkyl.

[0139] In certain embodiments, the compound of formula A is represented by formula 48, 48a, 48b, 48c, Or it is other than compound 48d.

[0140] In certain embodiments of formula A, o' is 2 and V1 is

[0141] [ka] , p' is 1, and V2 is

[0142] [ka] and q' is 1 and V3 is a bond, then R 1001 At least one occurrence of , other than hydrogen.

[0143] Compounds optionally excluded from use as active agents in the present disclosure include those of formula 1

[0144] [ka] [In the formula, Carbons a' and b' are connected by a double or triple bond, Carbons c' and d' are connected by a double or triple bond, Re, Rf, and Rg are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aryl, heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl), aminocarboxylate, carbonyl, alkoxycarbonyl, or silyl; Rh, Ri, and Rj are independently hydrogen, alkyl, alkenyl, alkynyl, peroxy, selected from fluoroalkyl, aryl, or heteroaryl; I is selected from -C(O)-E, -SO2-E, -PO(OR)-E, where E is Hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or arylamino, where R is hydrogen or alkyl; J, L, and H may be independently selected from a ring containing up to 20 atoms or a chain of up to 20 atoms. a linker selected independently from the group consisting of J, L, and H, may contain multiple nitrogen, oxygen, sulfur, or phosphorus atoms, and further provided that J , L, and H are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, hexane, Tetraaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryl Oxy, carboxy, amino, alkylamino, dialkylamino, acylamino, chlorine Boxamide, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylthio arylsulfonate, arylsulfonate, phosphoryl, and sulfonyl and further, J, L, and H may each independently be substituted with one or more substituents. or one or more fused carbocyclic, heterocyclic, aryl, or heteroaryl rings. provided that the linker J may contain a ring, and that the linker J is connected via a carbon atom to the adjacent C (R) provided that it is connected to an OR group, G is hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, aryl, hexane. Tetraaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryl Oxy, carboxy, amino, alkylamino, dialkylamino, acylamino, or is selected from carboxamides; or a pharma- ceutically acceptable salt thereof.

[0145] In certain embodiments, the pharma- ceutically acceptable salt of the compound has E being -OM. where M is ammonium, tetraalkylammonium, The cation is selected from ammonium, Na, K, Mg, and Zn.

[0146] In certain embodiments, when the composition of the present disclosure comprises an active agent, it is represented by Formula 2 Optionally excluded from such compositions are compounds of Formula 1, represented by:

[0147] [ka] [In the formula, E, Re, Rf, and Rg are as defined above.

[0148] In certain embodiments, when the composition of the present disclosure comprises an active agent, it is -OM. A pharma- ceutical acceptable salt of a compound formed by derivatizing E, where M is , ammonium, tetraalkylammonium, Na, K, Mg, and Zn. are optionally excluded from such compositions.

[0149] Exemplary compounds of formula 2 that are optionally excluded from such compositions include compound 2a: ,

[0150] [ka] Examples include:

[0151] In certain embodiments, when the composition of the present disclosure comprises an active agent, it is represented by Formula 3 Optionally excluded from such compositions are compounds of Formula 1, represented by:

[0152] [ka] [In the formula, E, Re, Rf, and Rg are as defined above.

[0153] In certain embodiments, when the composition of the present disclosure comprises an active agent, it is -OM. A pharma- ceutical acceptable salt of a compound formed by derivatizing E, where M is , ammonium, tetraalkylammonium, Na, K, Mg, and Zn. are optionally excluded from such compositions.

[0154] Exemplary compounds of formula 3 that are optionally excluded from such compositions include compound 3a: ,

[0155] [ka] and compound 3b,

[0156] [ka] Examples include:

[0157] Further exemplary compounds of Formula 1 that are optionally excluded from such compositions include the compounds Compound X,

[0158] [ka] and pharma- ceutically acceptable salts and esters thereof.

[0159] When the compositions of the present disclosure include an active agent, the use of such an active ingredient in such compositions is Other compounds that are optionally excluded for use include those of formula 4:

[0160] [ka] [In the formula, A is H or -OP4, P1, P2, and P4 are each independently a protecting group or a hydrogen atom; R1 and R2 are each independently a substituted or unsubstituted, branched or unbranched alkyl group. aryl, alkenyl, or alkynyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted substituted branched or unbranched alkylaryl groups, halogen atoms, hydrogen atoms; Z is -C(O)OR d , -C(O)NR c R c , -C(O)H, -C(NH)NR C R C , -C(S)H, -C(S)OR d , -C(S)NR C R C , -CN, preferably Cal It is a carboxylic acid, ester, amide, thioester, thiocarboxamide, or nitrile. , Each R a is, when present, hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, cyclohexyl, (C4- C11) cycloalkyl alkyl, (C5-C10) aryl, phenyl, (C6-C1 6) arylalkyl, benzyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocyclyl, Morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered heterocyclic arylalkyl, 5-10 membered heteroaryl, and 6-16 membered heteroarylalkyl are independently selected from Each R b If present, =O, -OR d , (C1-C3) haloalkyloxy, -OC F3, =S, -SR d , =NR d , =NOR d , -NR c R c , halogen, -CF3, - CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)R d , -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -S(O)NR c R c , -OS(O)R d , -OS(O)2R d , -OS(O)2OR d , -OS(O) 2NR c R c , -C(O)R d , -C(O)OR d , -C(O)NR c R c , -C(NH )NR c R c , -C(NR a )NR c R c , -C(NOH)R a , -C(NOH)NR c R c , -OC(O)R d , -OC(O)OR d , -OC(O)NR c R c , -OC(NH )NR c R c , -OC(NR a )NR c R c , -[NHC(O)] n R d , -[NR a C (O)] n R d , -[NHC(O)] n OR d , -[NR a C(O)] n OR d , [NH C(O)] n NR c R c , -[NR a C(O)] n NR c R c , -[NHC(NH)] n NR c R c and -[NR a C(NR a )] n NR c R c A suitable It is based on Each R c is, if present, independently a protecting group or R a or alternatively, 2 R c together with the nitrogen atom to which they are attached, form one or more additional Optionally, R a , or a suitable R b Group 1 Optionally substituted with one or more 5-8 membered heterocyclyl or heteroaromatic groups Form the reel, each n is independently an integer from 0 to 3; Each R d are independently a protecting group or R a is] or a pharma- ceutically acceptable salt thereof.

[0161] Exemplary compounds of formula 4 that are optionally excluded from such compositions include compound 4a: ,

[0162] [ka] compound 4b,

[0163] [ka] and pharma- ceutically acceptable salts and esters thereof.

[0164] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 5:

[0165] [ka] or a pharma- ceutically acceptable salt thereof, The stereochemistry of the bond between carbons ii' and jj' is cis or trans; P3 is a protecting group or a hydrogen atom, and P1, P2, R1, and Z are as defined above in Formula 4. .

[0166] In certain embodiments, the stereochemistry of the bond between carbons ii' and jj' is It is.

[0167] Exemplary compounds of formula 5 that are optionally excluded from such compositions include compound 5a: ,

[0168] [ka] compound 5b,

[0169] [ka] and pharma- ceutically acceptable salts and esters thereof.

[0170] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 6:

[0171] [ka] or a pharma- ceutically acceptable salt thereof, The stereochemistry of the bond between carbons gg' and hh' is cis or trans; Each X represents hydrogen or both X groups taken together form a three-membered ring. one substituted or unsubstituted methylene, oxygen atom, substituted or unsubstituted N atom, or represents a sulfur atom, and P1, P2, P3, R1, and Z are as defined above.

[0172] In certain embodiments, the stereochemistry of the bond between carbons gg' and hh' is It is.

[0173] Exemplary compounds of formula 6 that are optionally excluded from such compositions include compound 6a: ,

[0174] [ka] compound 6b,

[0175] [ka] and pharma- ceutically acceptable salts and esters thereof.

[0176] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 7:

[0177] [ka] or a pharma- ceutically acceptable salt thereof, Carbons e' and f' are connected by a double or triple bond, and carbon e' is If it is connected to carbon f' through a double bond, the stereochemistry can be cis or trans. the law of nature, Carbons g' and h' are connected by a double or triple bond, and carbon g' is If it is connected to carbon h' through a double bond, the stereochemistry can be cis or trans. the law of nature, m is 0 or 1; T' is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) aryl, Aryl, (C5-C14)aryl, (C6-C16)arylalkyl, 5-14 membered Heteroaryl, 6-16 membered heteroarylalkyl, or -CH=CHCH2CH3 and T is -(CH2) q -or-(CH2) q -O-, where q is an integer from 0 to 6. is a number, Z' is substituted by 1, 2, 3, 4, 5, or 6 identical or different halogen atoms. optionally substituted (C1-C6)alkylene, -(CH2) p -O-CH2-, TAHA-(CH2) m -S-CH2-, where p is an integer from 0 to 4; R 11 , R 12 , and R 13 are each independently substituted or unsubstituted, branched or or unbranched alkyl, alkenyl, or alkynyl groups, substituted or unsubstituted aryl groups; aryl groups, substituted or unsubstituted branched or unbranched alkylaryl groups, C 1-4 Alkoxy, halogen atoms, -CHR 14 , -CHR 14 R 14 , -CR 14 R 14 R 14 or a halogen atom, R 14 is independently selected for each occurrence from -CN, -NO2, or halogen; and P1, P2, P3, and Z are as defined above.

[0178] In certain embodiments, carbons e' and f' are connected by a cis double bond. It is being done.

[0179] In certain embodiments, carbons g' and h' are connected by a double bond. There are.

[0180] In certain embodiments, carbons e' and f' are connected by a cis double bond. where carbons g' and h' are connected by a double bond.

[0181] Exemplary compounds of formula 7 that are optionally excluded from such compositions include compound 7a: ,

[0182] [ka] compound 7b,

[0183] [ka] and pharma- ceutically acceptable salts and esters thereof.

[0184] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 8:

[0185] [ka] or a pharma- ceutically acceptable salt thereof, The stereochemistry of the bond between carbons i' and j' is cis or trans; m is 0 or 1; D' is CH3, -CH=CHCH2U, or -CH=CHCH2CH2A; U is a branched or unbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl , cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, aryl Aryl carbonyl, alkoxy carbonyl, aryloxy carbonyl, alkoxy carbonyl nyloxy, and aryloxycarbonyloxy groups, A is H or -OP4, P1, P2, P4, R1, R2, and Z are as defined above. .

[0186] In certain embodiments, the stereochemistry of the bond between carbon i' and carbon j' is cis. do.

[0187] Exemplary compounds of formula 8 that are optionally excluded from such compositions include compound 8a: ,

[0188] [ka] compound 8b,

[0189] [ka] compound 8c,

[0190] [ka] and pharma- ceutically acceptable salts and esters thereof.

[0191] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 9:

[0192] [ka] or a pharma- ceutically acceptable salt thereof, Carbons k' and l' are connected by a double or triple bond, and carbon k' is If it is connected to carbon l' through a double bond, the stereochemistry can be cis or trans. the law of nature, The stereochemistry of the double bond between carbon m' and carbon n' is cis or trans; m is 0 or 1; D is -CH3 or -CH=CHCH2CH3; P1, P2, P3, R1, X, and Z are as defined above.

[0193] In certain embodiments, the stereochemistry of the double bond between carbon m' and carbon n' is cis. It is.

[0194] In certain embodiments, carbons k' and l' are connected by a cis double bond. It is being done.

[0195] In certain embodiments, the stereochemistry of the double bond between carbon m' and carbon n' is cis. where carbons k' and l' are connected by a cis double bond.

[0196] Exemplary compounds of formula 9 that are optionally excluded from such compositions include compound 9a: ,

[0197] [ka] compound 9b,

[0198] [ka] and pharma- ceutically acceptable salts and esters thereof.

[0199] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 10:

[0200] [ka] or a pharma- ceutically acceptable salt thereof, P1, P2, P3, R1, and Z are as defined above; and Q represents one or more substituents and each Q', if present, is individually a halogen atom; or branched or unbranched, substituted or unsubstituted alkyl, alkenyl, aryl Quinyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl , arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy nyloxy, or aminocarbonyl group.

[0201] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 11:

[0202] [ka] or a pharma- ceutically acceptable salt thereof, P1, P2, P3, R1, and Z are as defined above.

[0203] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 12:

[0204] [ka] or a pharma- ceutically acceptable salt thereof, P1, P2, P3, Q, R1, and Z are as defined above.

[0205] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 13:

[0206] [ka] or a pharma- ceutically acceptable salt thereof, P1, P2, R1, R2, U, and Z are as defined above.

[0207] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 14:

[0208] [ka] or a pharma- ceutically acceptable salt thereof, P1, P2, R1, R2, Q, and Z are as defined above.

[0209] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 15:

[0210] [ka] or a pharma- ceutically acceptable salt thereof, P1, P2, and Z are as defined above.

[0211] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 16:

[0212] [ka] or a pharma- ceutically acceptable salt thereof, P1 and Z are as defined above.

[0213] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 17:

[0214] [ka] or a pharma- ceutically acceptable salt thereof, Carbons o' and p' may be joined by a single bond or a double bond (e.g., a cis or trans double bond). ), Carbons q' and r' may be single or double bonds (e.g., cis or trans double bonds). ), P1, P2, and Z are as defined above.

[0215] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 18:

[0216] [ka] or a pharma- ceutically acceptable salt thereof, The stereochemistry of the double bond between carbons s' and t' is cis or trans; The stereochemistry of the double bond between carbons u' and v' is cis or trans; and P1, P2, R1, R2, and Z are as defined above.

[0217] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 19:

[0218] [ka] or a pharma- ceutically acceptable salt thereof, Carbons w' and x' are connected by a single or double bond, Carbons y' and z' are connected by a single or double bond, and P1, P2, and Z are as defined above.

[0219] In certain embodiments of Formulas 4-19, each R b If present, =O, -OR d , (C1-C3) haloalkyloxy, -OCF3, =S, -SR d , =NR d , =N OR d , -NR c R c , halogen, -CF3, -CN, -NC, -OCN, -SCN, - NO, -NO2, =N2, -N3, -S(O)R d , -S(O)2R d , -S(O)2O R d , -S(O)NR c R c , -S(O)NR c R c , -OS(O)R d , -OS(O )2R d , -OS(O)2OR d , -OS(O)2NR c R c , -C(O)R d , -C( O)OR d , -C(O)NR c R c , -C(NH)NR c R c , -C(NR a )NR c R c , -C(NOH)R a , -C(NOH)NR c R c , -OC(O)R d , -OC(O) OR d , -OC(O)NR c R c , -OC(NH)NR c R c , -OC(NR a )NR c R c , -[NHC(O)] n R d , -[NR a C(O)] n R d , -[NHC(O)] n OR d , [NHC(O)] n NR c R c , -[NR a C(O)] n NR c R c , -[NH C(NH)] n NR c R c and -[NR a C(NR a )] n NR c R c Selected independently from It is a suitable group to be selected.

[0220] When the compositions of the present disclosure include an active agent, the use of such compounds as active agents may be Other compounds that are optionally excluded for use include those of formula 20:

[0221] [ka] The one of formula 21,

[0222] [ka] The one of formula 22,

[0223] [ka] The one of formula 23,

[0224] [ka] The one of formula 24,

[0225] [ka] The one of formula 25,

[0226] [ka] The one of formula 26,

[0227] [ka] The one of formula 27,

[0228] [ka] Or the one of formula 28,

[0229] [ka] or a pharma- ceutically acceptable salt thereof, each P is independently selected from H or a protecting group; and R is H, C 1-6 Alkyl (e.g., methyl, ethyl, glycerol), C 2-6 Al Kenyl, or C 2-6 alkynyl].

[0230] Exemplary compounds of formula 21 that are optionally excluded from such compositions include compound 2 1a,

[0231] [ka] and pharma- ceutically acceptable salts and esters thereof.

[0232] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 29:

[0233] [ka] and pharma- ceutically acceptable salts, hydrates and solvates thereof, D1-E1 and F1-G1 are independently cis or trans -C=C-, or - C≡C-, R 101 , R 102 , and R 103 are independently hydrogen, (C1-C4) straight or branched chain Branched alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) Alkoxy, -CHR 104 , -CHR 104 R 104 , and -CR 104 R 104 R 104 is selected from Each R 104 is independently selected from CN, -NO2, and a halogen; W1 is -R 105 , -OR 105 , -SR 105 , and -NR 105 R 105 Choose from Selected, Each R 105 are optionally substituted by one or more of the same or different R groups, Selectively substituted (C1-C6) alkyl, (C2-C6) alkenyl or (C2- C6) alkynyl, optionally substituted with one or more of the same or different R groups; (C5-C14)aryl, optionally substituted by one or more of the same or different R groups; optionally substituted phenyl, optionally with one or more of the same or different R groups; (C6-C16)arylalkyl substituted with one of the same or different R groups or 5-14 membered heteroaryl optionally substituted with multiple, same or different R groups 6-16 membered heteroarylalkyl optionally substituted with one or more of and a detectable label molecule, A1 is substituted by 1, 2, 3, 4, 5 or 6 identical or different halogen atoms. optionally substituted (C1-C6)alkylene, -(CH2) m -O-CH2-, O And-(CH2) m -S-CH2-, where m is an integer from 0 to 4; X1 is -(CH2) n- and - (CH2) n -O-, where n is 0 is an integer between 0 and 6, Y1 is hydrogen, the same or different R 100 Optionally substituted with one or more of the groups (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkoxy quinyl, same or different R 100 Optionally substituted with one or more of the groups (C5-C14) aryl, same or different R 100 One or more of the groups may be used optionally substituted phenyl, the same or different R 100 By one or more of the groups Optionally substituted (C6-C16)arylalkyl, the same or different R 100 5-14 membered heteroaryl optionally substituted with one or more groups, the same or is a different R 100 6-16 membered heterocyclic ring optionally substituted with one or more groups arylalkyl, and a detectable labeling molecule; Each R 100 are independently an electronegative group, ═O, -OR a1 , (C1-C3) haloalkyl Oxy, =S, -SR a1 , =NR a1 , =NONR a1 , -NR c1 R c1 ,halogen , -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3 , -S(O)R a1 , -S(O)2R a1 , -S(O)2OR a1 , -S(O)NR c 1 R c1 , -OS(O)R a1 , -OS(O)2Ra1 , -OS(O)2OR a1 , -O S(O)2NR c1 R c1 , -C(O)R a1 , -C(O)OR a1 , -C(O)NR c 1 R c1 , -C(NH)NR c1 R c1 , -OC(O)R a1 , -OC(O)OR a1 , -OC(O)NR c1 R c1 , -OC(NH)NR c1 R c1 , -NHC(O)R a1 , -NHC(O)OR a1 , -NHC(O)NR c1 R c1 and -NHC(NH)NR c 1 R c1 is selected from Each R a1 are independently hydrogen, (C1-C4) alkyl, (C2-C4) alkenyl, or or (C2-C4)alkynyl, and Each R c1 are independently a1 or alternatively, R c1 R c1 But it is binding together with the nitrogen atom at which it is bonded, to form a five- or six-membered ring.

[0234] In certain embodiments of formula 29, when X1-Y1 is -CH2CH3, R 101 , R 102 , or R 103 At least one of is other than hydrogen.

[0235] In certain embodiments, the compound of formula 29, as represented by formula 30:

[0236] [ka] and pharma- ceutically acceptable salts, hydrates and solvates thereof, D1-E1 and F1-G1 are independently cis or trans -C=C-, or - C≡C-, and R 101 , R 102 , R 103 , R 104 , W1, R 105 , A1, X1, n, Y1, R 100 , R a1 , and R c1 is as defined above], but from such a composition are optionally excluded from

[0237] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formulae 31-37:

[0238] [ka] and pharma- ceutically acceptable salts, hydrates and solvates thereof. [In the formula, R 106 is -OH, -OCH3, -OCH(CH3)2, or -NHCH2CH3 Yes, and R 107 teeth,

[0239] [ka] or

[0240] [ka] Examples include:

[0241] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 38:

[0242] [ka] [In the formula, Carbons aa' and bb' are connected by a double or triple bond, Carbons cc' and dd' are connected by a double or triple bond, Re, Rf, and Rg are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aryl, heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl), aminocarboxylate, carbonyl, alkoxycarbonyl, or silyl; E is hydroxyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, arylamino, or arylamino; Rh, Ri, and Rj are independently hydrogen, alkyl, alkenyl, alkynyl, peroxy, selected from fluoroalkyl, aryl, or heteroaryl; R4 is hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, aryl, selected from heteroaryl, fluoro, hydroxyl, alkoxy, aryloxy; R5 is one of the following i to iv: i) CH2CH(R6)CH2 (wherein R6 is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro ii) CH2C(R6R7)CH2( In the formula, R6 and R7 are each independently an alkyl, alkenyl, alkynyl, peroxy, fluoroalkyl, aryl, or fluoro, or R6 and R7 are iii) CH2OCH2 , CH2C(O)CH2, or CH2CH2, or iv) R5 is a carbocyclic ring, is selected from a monocyclic ring, an aryl ring, or a heteroaryl ring; and R8 and R9 are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro alkyl, alkoxy, aryl, or heteroaryl, or R 8 and R9, taken together, form a carbocyclic or heterocyclic ring. or a pharma- ceutically acceptable salt thereof.

[0243] In certain embodiments, R8 and R9 are hydrogen.

[0244] In certain embodiments, the compound is formed by derivatizing E to -OM. A pharma- ceutically acceptable salt of the compound, The cations are selected from the group consisting of tungsten, sodium, potassium, magnesium, and zinc. are optionally excluded from the composition.

[0245] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formulae 39-44:

[0246] [ka] and pharma- ceutically acceptable salts thereof, Re, Rf, E, Ri, R5, R8, and R9 are as defined above. can be done.

[0247] Exemplary compounds of formulas 39, 41, and 43 include:

[0248] [ka] and pharma- ceutically acceptable salts and esters thereof.

[0249] In certain embodiments, when the composition of the present disclosure comprises an active agent, it is -OM. A pharma- ceutical acceptable salt of a compound formed by derivatizing E, where M is , ammonium, tetraalkylammonium, Na, K, Mg, and Zn. [which is a cation that is present in the composition] are optionally excluded from such compositions. An example of the product is compound Z.

[0250] [ka]

[0251] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 46:

[0252] [ka] or a pharma- ceutically acceptable salt or prodrug thereof, each

[0253] [ka] independently represent a double bond or a triple bond; R 1 , R 2 , and R 3 are independently OR, OX 1 ,SR,SX 2 , N(R) 2. NHX 3 , NRC(O)R, NRC(O)N(R)2, C(O)OR, C(O)N( R), SO2R, NRSO2R, C(O)R, or SO2N(R), Each R is independently selected from hydrogen, or 0 to 4 nitrogen, oxygen, or sulfur. C having a heteroatom selected from the group consisting of 1-6 Aliphatic, 3-8 membered saturated, partially unsaturated, or aliphatic an optionally substituted group selected from the group consisting of aryl rings, The two R's in the formula, together with the nitrogen, form one to three nitrogen, oxygen, or sulfur atoms. 5-8 membered heterocyclyl or heteroaryl having heteroatoms independently selected from Forming a cyclic ring, each X 1 are independently a suitable hydroxyl protecting group; each X 2 is independently a suitable thiol protecting group, each X 3 is independently a suitable amino protecting group, and R 4 is NRC(O)R, NRC(O)N(R)2, C(O)OR, C(O)N(R)2 , SO2R, NRSO2R, C(O)R, or SO2N(R)2. .

[0254] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 47:

[0255] [ka] or a pharma- ceutically acceptable salt or prodrug thereof, The stereochemistry of the double bond between carbons kk' and ll' is cis or trans; The stereochemistry of the double bond between carbons mm' and nn' is cis or trans; The stereochemistry of the double bond between carbons oo' and pp' is cis or trans; Y' may consist of a bond, a ring containing up to 20 atoms, or a chain of up to 20 atoms. A linker of choice, provided that Y' is one or more of a nitrogen, oxygen, sulfur, or or phosphorus atom, and further provided that Y' is hydrogen, alkyl, alkoxy, nyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hyd. hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkyl alkylamino, acylamino, carboxamide, cyano, oxo, thio, alkylthio, a Arylthio, acylthio, alkylsulfonate, arylsulfonate, phosphoryl, or sulfonyl. and further provided that Y' is one or more fused carbocyclic, heterocyclic, aryl or aryl rings. provided that the aryl or heteroaryl ring may be Z' is -CN, -C(NH)N(R")(R"), -C(S)-A', -C(S)R" , -C(O)-A', -C(O)-R", -C(O)-SR", -C(O)-NH-S( O)2-R”, -S(O)2-A', -S(O)2-R”, S(O)2N(R”)(R” ), -P(O)2-A', -PO(OR")-A', -Tetrazole, alkyl tetrazo or -CHOH, where A' is selected from -OR", -N(R")(R"), or -OM'; Each R" is independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or a detectable labeling molecule, wherein any aryl The alkyl, aryl, or heteroaryl-containing moiety may optionally include up to three independently selected and M' is a cation.

[0256] In certain embodiments, the compound of formula 47 is represented by formula 48:

[0257] [ka] or pharma- ceutically acceptable salts and esters thereof, The stereochemistry of the double bond between carbons kk' and ll' is cis or trans; The stereochemistry of the double bond between carbons mm' and nn' is cis or trans; The stereochemistry of the double bond between carbons oo' and pp' is either cis or trans. It is expressed as:

[0258] In certain embodiments, the stereochemistry of the double bond between carbons kk′ and ll′ is: It's a trance.

[0259] In certain embodiments, the stereochemistry of the double bond between carbons mm' and nn' is: It's a trance.

[0260] In certain embodiments, the stereochemistry of the double bond between carbons oo' and pp' is It is Sith.

[0261] In certain embodiments, the stereochemistry of the double bond between carbons kk′ and ll′ is: The stereochemistry of the double bond between carbons mm' and nn' is trans; The stereochemistry of the double bond between carbons oo' and pp' is cis.

[0262] In certain embodiments, the compound of formula 47 is compound 48a,

[0263] [ka] compound 48b,

[0264] [ka] compound 48c,

[0265] [ka] or pharma- ceutically acceptable salts and esters thereof.

[0266] In certain embodiments, the compound of formula 47 has the formula 48d:

[0267] [ka] or pharma- ceutically acceptable salts and esters thereof, The stereochemistry of the double bond between carbons kk' and ll' is cis or trans; The stereochemistry of the double bond between carbons mm' and nn' is cis or trans; The stereochemistry of the double bond between carbons oo' and pp' is either cis or trans. It is expressed as:

[0268] In certain embodiments, the compound of formula 47 is represented by the formula 48, 48a, 48b, 48c , or other than compound 48d.

[0269] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include those of formula 49:

[0270] [ka] or a pharma- ceutically acceptable salt or prodrug thereof, Y' may consist of a bond, a ring containing up to 20 atoms, or a chain of up to 20 atoms. A linker of choice, provided that Y' is one or more of a nitrogen, oxygen, sulfur, or or phosphorus atom, and further provided that Y' is hydrogen, alkyl, alkoxy, nyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hyd. hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkyl alkylamino, acylamino, carboxamide, cyano, oxo, thio, alkylthio, a Arylthio, acylthio, alkylsulfonate, arylsulfonate, phosphoryl, or sulfonyl. and further provided that Y' is one or more fused carbocyclic, heterocyclic, aryl or aryl rings. provided that the aryl or heteroaryl ring may be Z' is -CN, -C(NH)N(R")(R"), -C(S)-A', -C(S)R" , -C(O)-A', -C(O)-R", -C(O)-SR", -C(O)-NH-S( O)2-R”, -S(O)2-A', -S(O)2-R”, S(O)2N(R”)(R” ), -P(O)2-A', -PO(OR")-A', -Tetrazole, alkyl tetrazo or -CHOH, where A' is selected from -OR", -N(R")(R"), or -OM'; Each R" is independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or a detectable labeling molecule, wherein any aryl The alkyl, aryl, or heteroaryl-containing moiety may optionally include up to three independently selected and M' is a cation, and R a’ and R b’ Each of is independently selected for each occurrence from -OR' , or adjacent R a’ and R b’ together form a cis or trans configuration wherein each R' is independently hydrogen, alkyl, alkenyl, Aryl, alkynyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl, amino a protecting group selected from the group consisting of aryl, aminocarbonyl, alkoxycarbonyl, and protecting groups; Some examples include:

[0271] Exemplary compounds of formula 49 include compound 49a,

[0272] [ka] compound 49b,

[0273] [ka] or pharma- ceutically acceptable salts and esters thereof.

[0274] The above compounds (e.g., compounds of formula A or formulas 1-49) are useful for treating inflammation or inflammatory diseases. Examples of such compounds are known to be useful in the treatment or prevention of Patents and Applications: U.S. Patent Application No. 2003 / 0191184, International Publication No. WO2004 / 014835, WO2004 / 078143, U.S. Pat. No. 6,670,396, U.S. Patent Application Nos. 2003 / 0236423, 2005 / 0228047, and 2006 / 0229046. This is disclosed in US Pat. Nos. 005 / 0238589 and 2005 / 0261255. These compounds are optionally excluded for use in the methods of the present disclosure.

[0275] Although delivery may be enhanced by the compositions of the present disclosure, the compositions of the present disclosure do not include Other compounds that can be obtained include those compounds of formula A or chemically analogous to any of the compounds of formulas 1-49 set forth above. The term "chemically similar variants" includes, but is not limited to, Replacement of various parts by known biosteres, but not by and the terminal group of one of the above compounds by the corresponding terminal group of any other of the above compounds. Replacement, modification of the configuration of any double bond in any compound, Replacement of a bond with a triple bond, and one or more of the bonds present in one of the above compounds. Replacement of multiple substituents with the corresponding substituents of any other compound is included.

[0276] When the compositions of the present disclosure include an active agent, the optional exclusions for use as the active agent include Suitable lipoxin compounds include those of formula 50:

[0277] [ka] [In the formula, X is R 301 , OR 301 , or S.R. 301 and R 301 teeth, (a) a hydrogen atom, (b) 1 to 8 carbon atoms, inclusive, which may be linear or branched. ) alkyl, (c) cycloalkyl of 3 to 10 carbon atoms, (d) aralkyl having 7 to 12 carbon atoms; (e) phenyl, (f) Substituted phenyl

[0278] [ka] (In the formula, Z i , Z ii , Z iii , Z iv , and Z v are each independently -NO2 , -CN, -C(=O)-R 301 , -SO3H, hydrogen atom, halogen, methyl, -OR x (where R x is 1 to 8 carbon atoms (inclusive) and may be linear or and hydroxyl, wherein Z i , Z ii , Z iii , Z iv , or Z v Either of the following is C(=O)-R 301 If Z i , Z ii , Z iii , Z iv , or Zv is another C(=O)-R 301 Replaced by not present) (g) a detectable labeling molecule, or (h) a straight or branched alkenyl of 2 to 8 carbon atoms (inclusive); Q1 is (C=O), SO2, or (CN), provided that when Q1 is CN , X does not exist, Q3 and Q4 are each independently O, S, or NH; R 302 and R 303 One of the groups is a hydrogen atom, and the other is (a) H, (b) 1 to 8 carbon atoms, inclusive, which may be linear or branched. ) alkyl, (c) cycloalkyl of 3 to 6 carbon atoms (inclusive); (d) a chain of 2 to 8 carbon atoms, inclusive, which may be linear or branched; ), or (e)R k Q2R l (Wherein, Q2 is -O- or -S-, where R k is a linear chain alkylene of 0 to 6 carbon atoms (inclusive), which may be branched or unbranched and R l The alkyl group may be linear or branched and may have 0 to 8 carbon atoms (both (including the terminal) alkyl, except that R l If is 0, R l is a hydrogen atom (subject to the condition that R 304 teeth, (a) H, (b) 1 to 6 carbon atoms (inclusive), which may be straight-chained or branched. is an alkyl group of R 305 teeth,

[0279] [ka] (In the formula, Z i , Z ii , Z iii , Z iv , and Z v is defined as above) the law of nature, R 306 teeth, (a) H, (b) a linear or branched alkyl group of 1 to 4 carbon atoms (inclusive); Here, Y 301 is a 2-4 carbon atom that can be -OH, methyl, -SH, straight or branched. alkyl of 1 to 4 carbon atoms (inclusive); alkoxy of 1 to 4 carbon atoms (inclusive); (CH) p (Z) q (In the formula, p+q=3, p=0 to 3, and q=0 to 3, and Z is cyano, nitro, or halogen; and T is O or S] or a pharma- ceutically acceptable salt thereof.

[0280] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Optionally excluded lipoxin compounds for use include those of formula 51, 52, 53, or There are 54 of them.

[0281] [ka] [In the formula, Each R 307 are independently selected from hydrogen and straight-chain, branched, selected from cyclic, saturated or unsaturated alkyl; R 308 , R 309 , R 310, R 319 , and R 320 is, independently, (a) hydrogen, (b) linear, branched, cyclic, saturated, or unsaturated alkyl groups having 1 to 20 carbon atoms; kill, (c) substituted alkyl having 1 to 20 carbon atoms, where alkyl is one or more a number of halo, hydroxy, lower alkoxy, aryloxy, amino, alkylamino, Dialkylamino, acylamino, arylamino, hydroxyamino, alkoxyamino No, alkylthio, arylthio, carboxy, carboxamide, carboalkoxy, a aryl, and heteroaryl; (d) substituted aryl or heteroaryl, where aryl or heteroaryl is One or more of alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaromatic groups substituted by a substituent selected from aryl, carboxyl, and carboxamide; (including (e)ZY(in the formula, Z is a linear, branched, cyclic, saturated, or unsaturated alkyl group having 1 to 20 carbon atoms. alkyl; substituted lower alkyl (wherein alkyl is selected from the group consisting of one or more of halo, hydroxy, Lower alkoxy, aryloxy, amino, alkylamino, dialkylamino, acyl Amino, arylamino, hydroxyamino, alkoxyamino, alkylthio, aryl Ruthio, carboxy, carboxamido, carboalkoxy, aryl, and heteroaryl aryl; and substituted aryl or aryl (wherein aryl or heteroaryl is selected from one or more of alkyl, Cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl, and substituted by a substituent selected from carboxamide; Y is hydrogen, alkyl, cycloalkyl, carboxyl, carboxamide, aryl, hexafluorophenyl, ... Heteroaryl, substituted aryl or heteroaryl (wherein aryl or heteroaryl The group may be one or more of alkyl, cycloalkyl, alkoxy, halo, aryl, Substituted by a substituent selected from heteroaryl, carboxyl, and carboxamide. is selected from) selected from) R 311 ~R 318 is, independently, (a) hydrogen, (b) Halo, (c) linear, branched, cyclic, saturated, or unsaturated alkoxy groups having 1 to 20 carbon atoms; kill, (d) substituted alkyl having 1 to 20 carbon atoms, where alkyl is one or more a number of halo, hydroxy, lower alkoxy, aryloxy, amino, alkylamino, Dialkylamino, acylamino, arylamino, hydroxyamino, alkoxyamino No, alkylthio, arylthio, carboxy, carboxamide, carboalkoxy, a aryl, and heteroaryl; (e) substituted aryl or heteroaryl, where aryl or heteroaryl is One or more of alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaromatic groups substituted by a substituent selected from aryl, carboxyl, and carboxamide; or R 308 ~R 320independently, along with the lipoxin backbone, a carbon-carbon double bond, a carbon -carbon triple bond or a bond forming a ring, or R 307 ~R 320 Any two of , 1 to 6 oxygen atoms, 1 to 6 nitrogen atoms, or 1 to 6 oxygen atoms and 1 to 6 and nitrogen atoms of the aryl group, which together with both of the aryl and nitrogen atoms form a ring containing 3 to 20 atoms. can be.

[0282] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Optionally excluded lipoxin compounds for use include those of formula 55:

[0283] [ka] [In the formula, R 401 teeth,

[0284] [ka] is selected from R 402 teeth,

[0285] [ka] is selected from X 10 is R 411 , OR 411 , or S.R. 411 and R 411 teeth, (a) a hydrogen atom, (b) 1 to 8 carbon atoms, inclusive, which may be linear or branched. ) alkyl, (c) cycloalkyl of 3 to 10 carbon atoms, (d) aralkyl having 7 to 12 carbon atoms; (e) phenyl, (f) Substituted phenyl

[0286] [ka] (In the formula, Z i , Z ii , Z iii , Z iv , and Z v are each independently -NO2 , -CN, -C(=O)-R 411 , -SO3H, hydrogen atom, halogen, methyl, -OR x (where R x is 1 to 8 carbon atoms (inclusive) and may be linear or and hydroxyl, wherein Z i , Z ii , Z iii , Z iv , or Z v Either of the following is C(=O)-R 411 If Z i , Z ii , Z iii , Z iv , or Z v is another C(=O)-R 411 Replaced by not present) (g) a detectable labeling molecule, or (h) a straight or branched alkenyl of 2 to 8 carbon atoms (inclusive); Q1 is (C=O), SO2, or (CN); Q3 is O, S, or NH; R 412 and R 413 One of the groups is a hydrogen atom, and the other is (a) H, (b) 1 to 8 carbon atoms, inclusive, which may be linear or branched. ) alkyl, (c) cycloalkyl of 3 to 6 carbon atoms (inclusive); (d) a chain of 2 to 8 carbon atoms, inclusive, which may be linear or branched; ), or (e)R 431 Q2R 432 (Wherein, Q2 is -O- or -S-, where R 43 1 is 0 to 6 carbon atoms (inclusive), which may be linear or branched R is an alkylene group. 431 may be linear or branched, 0 to 8 is selected from alkyl of 1 to 4 carbon atoms (inclusive); R 413a and R 413b are each independently (a) H, (b) 1 to 8 carbon atoms, inclusive, which may be linear or branched. ) alkyl, (c) cycloalkyl of 3 to 6 carbon atoms (inclusive); (d) a chain of 2 to 8 carbon atoms, inclusive, which may be linear or branched; ), or (e)R 431 Q2R 432 (In the formula, R 431 , Q2, and R 432 is defined above (As stated above) R 414 teeth, (a) H, (b) 1 to 6 carbon atoms (inclusive), which may be straight-chained or branched. is an alkyl group of R 415 teeth, (a) alkyl of 1 to 9 carbon atoms, which may be linear or branched; (b)-(CH2)-R i (where n = 0 to 4, R i teeth, (i) cycloalkyl of 3 to 10 carbon atoms (inclusive); (ii) phenyl, or (iii) Substituted phenyl

[0287] [ka] (In the formula, Z i ~Z v is as defined above), (c)R 431 Q2R 432 (In the formula, R 431 , Q2, and R 432 is defined above (As stated above) (d)-C(R iii )(R iv )-R i (In the formula, R iii and R iv are each independently (i) a hydrogen atom, (ii)(CH) p (Z) q (where Z, p, and q are as defined above. (is) (e) Straight or branched chains having 1 to 8 carbon atoms (inclusive) and 1 to 6 halogen atoms. haloalkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 38, 39, R 416 teeth, (a) H, (b) a straight or branched alkyl group having 1 to 4 carbon atoms (inclusive); (c) a halogen; Y 401 or Y 402is -OH, methyl, or -SH, and the other is (a) H, (b)(CH) p (Z) q (Wherein, p+q=3, p=0 to 3, and q=0 to 3. and each Z is independently cyano, nitro, or halogen; (c) a straight-chain or branched alkyl group having 2 to 4 carbon atoms (inclusive); or (d) alkoxy of 1 to 4 carbon atoms (inclusive); Or Y 401 and Y 402 Together, (a)=NH, or (b)=O, Y 403 or Y 404 is -OH, methyl, or -SH, and the other is (a) H, (b)(CH) p (Z) q wherein Z, p, and q are as defined above; (c) a straight-chain or branched alkyl group having 2 to 4 carbon atoms (inclusive); or (d) alkoxy of 1 to 4 carbon atoms (inclusive); Or Y 401 and Y 402 Together, (a)=NH, or (b)=O, Y 405 or Y 406 is -OH, methyl, or -SH, and the other is (a) H, (b)(CH) p (Z) q wherein Z, p, and q are as defined above; (c) a straight-chain or branched alkyl group having 2 to 4 carbon atoms (inclusive); or (d) alkoxy of 1 to 4 carbon atoms (inclusive); Or Y 401 and Y 402 Together, (a)=NH, or (b)=O, R 421 teeth, (a) H, or (b) alkyl of 1 to 8 carbon atoms; R 422 and R 423 are each independently (a) H, (b) hydroxyl or thiol, (c) methyl or halomethyl, (d) halogen, or (e) alkoxy of 1 to 3 carbon atoms; R 424 and R 425 are each independently (a) H, (b) hydroxyl or thiol, (c) methyl or halomethyl, (d) halogens, (e) alkoxy having 1 to 3 carbon atoms, or (f) a chain of 2 to 4 carbon atoms (inclusive), which may be linear or branched; ) alkyl or haloalkyl; R 426 teeth, (a) Substituted phenyl

[0288] [ka] (In the formula, Z i ~Z v is as defined above), (b) Substituted phenoxy

[0289] [ka] (In the formula, Zi ~Z v is as defined above), or (c)

[0290] [ka] (In the formula, Z i ~Z v is as defined above).

[0291] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Optionally excluded lipoxin compounds for use include those of formula 56:

[0292] [ka] [In the formula, E is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkyl amino, or -OM (where M is ammonium, tetraalkylammonium, etc. and a cation selected from sodium, potassium, magnesium, and zinc cations. On) and W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hyd. hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkyl acylamino, acylamino, carboxamide, or sulfonamide; R 501 ~R 503 Each of is independently hydrogen, alkyl, aryl, acyl, or is selected from alkoxyacyl; n is 0, 1, or 2; m is 1 or 2, and The two substituents on the phenyl ring are ortho, meta, or para.

[0293] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Optionally excluded lipoxin compounds for use include those of formula 57:

[0294] [ka] [In the formula, I is selected from -C(O)-E, -SO2-E, -PO(OR)-E, where E is , hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino No, or -OM (where M is ammonium, tetraalkylammonium, Na, is a cation selected from K, Mg, and Zn, and R is hydroxyl or or alkoxy, J' and K' are independently a chain of up to 20 atoms and a ring containing up to 20 atoms. provided that J' and K' are independently one or more and further providing that J' and and K' are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, Aryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy , carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamide Amido, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsulfur one or more selected from phenyl, arylsulfonate, phosphoryl, and sulfonyl; or more than one substituent, and further provided that J' and K' may also each include one or more substituents. or multiple condensed carbocyclic, heterocyclic, aryl, or heteroaryl rings; provided that the linkers J' and K' may contain a carbon atom or a C-heteroatom. adjacent via atomic bonds (wherein the heteroatom is oxygen, sulfur, phosphorus or nitrogen) provided that it is connected to a C(R)OR group, G is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, Iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, a amino, alkylamino, dialkylamino, acylamino, and carboxamide; Selected, Re, Rf, and Rg are independently hydrogen, alkyl, aryl, heteroaryl, a selected from acyl, silyl, alkoxyacyl, and aminoacyl; R 601 , R 602 , and R 603 are independently hydrogen, alkyl, aryl, and heteroaryl, with the proviso that R 601 , R 602 , and R 603 But and connected to linkers J' and K', R 604 and R 605 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aryl, heteroaryl, and fluoro, with the proviso that R 604 and R 605 but may be joined together to form a carbocyclic, heterocyclic, or aromatic ring. Furthermore, R 604 and R 605 is replaced by a bond to form a triple bond. [Provided that the

[0295] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use are described in International Application No. WO2006055965. , WO2007090162, and WO2008103753. The compounds of these applications are incorporated herein by reference. Examples of such compounds are shown in Table 1, and are represented by formulas 58 to 115. The compound was a long-chain omega-6 fatty acid, docosapentaenoic acid (DPAn-6) (compound 5 8-73), and docosatetraenoic acid (DTAn-6) (compounds 74-83), The omega-3 counterpart of DPAn-6, docosapentaenoic acid (DPAn-3) (compound 84 Further compounds include docosanoids 98-115, α-linolenic acid (GL A) (compounds 116-122), and stearidonic acid (SDA) (compounds 123-13 2).

[0296] [Table 1-1]

[0297] [Table 1-2]

[0298] [Table 1-3]

[0299] [Table 1-4]

[0300] [Table 1-5]

[0301] [Table 1-6]

[0302] [Table 1-7]

[0303] [Table 1-8]

[0304] [Table 1-9]

[0305] [Table 1-10]

[0306] [Table 1-11]

[0307] [Table 1-12]

[0308] [Table 1-13]

[0309] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other oxylipin compounds that are optionally excluded for use are shown in Table 1. Such compounds include, but are not limited to, analogs of the compounds: Analogues in which one or more double bonds are replaced by triple bonds, Similar compounds in which a number of carboxy groups have been derivatized to form esters, amides, or salts. The carbon bearing the hydroxyl may be (e.g., substituted or unsubstituted, branched or unbranched) branched alkyl, alkenyl, or alkynyl groups, substituted or unsubstituted aryl groups; Substituted or unsubstituted, branched or unbranched alkylaryl groups, halogen atoms Further derivatization to give tertiary alcohols (or their ethers, esters, etc.) or other derivatives), one or more hydroxyl groups are derivatized. or analogs of the aforementioned modifications, which have been substituted to form esters or protected alcohols. Analogs having any combination are included.

[0310] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Further oxylipin compounds that are optionally excluded for use include the following: docosapentaenoic acid Isolated docosanoid of dibenzofuranone (DPAn-6); monohydroxy, dihydroxy Hydroxy and trihydroxy derivatives; isolated docosanoids of docosapentaenoic acid (DP An-3); monohydroxy, dihydroxy, and trihydroxy derivatives of DPAn-3 docosapentaenoic acid (DTAn-6); or the monolayer of DTAn-6 These include monohydroxy, dihydroxy, and trihydroxy derivatives.

[0311] When the compositions of the present disclosure include an active agent, the use of such an active agent in such compositions is Other compounds that are optionally excluded for use include compounds of formula I:

[0312] [ka] and pharma- ceutically acceptable salts thereof, The stereochemistry of the double bond between carbons qq' and rr' is cis or trans; The stereochemistry of the double bond between carbons ss' and tt' is cis or trans; Re and Rf are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, hexane, hexanediamine ... Heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl , alkoxycarbonyl, or silyl, preferably hydrogen, acyl (e.g., alkoxy acyl, aminoacyl), aminocarbonyl, and alkoxycarbonyl, most preferred or hydrogen; E is isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, 3-methyl 2,2-dimethylpropoxy, or 1,1,2-trimethylpropoxy and branched alkoxy such as, preferably, isopropoxy; Rh and Ri are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro Alkyl, aryl, or heteroaryl, preferably hydrogen or alkyl, most preferably or hydrogen; R5 is one of the following i to iv: i) CH2CH(R6)CH2 (wherein R6 is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro ii) CH2C(R6R7)CH2( In the formula, R6 and R7 are each independently an alkyl, alkenyl, alkynyl, peroxy, fluoroalkyl, aryl, or fluoro, or R6 and R7 are iii) CH2OCH2 , CH2C(O)CH2, CH2, or CH2CH2, or iv) R5 is a carbocyclic ring. A ring having a formula (CH 2) Selected from 3, and R8 and R9 are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro alkyl, alkoxy, aryl, or heteroaryl, or R 8 and R9 are joined together to form a carbocyclic or heterocyclic ring, preferably is selected from hydrogen and alkyl, most preferably hydrogen.

[0313] For example, if a composition of the present disclosure includes an active agent, such composition may optionally exclude The active agent is a compound of formula Ia:

[0314] [ka] and pharma- ceutically acceptable salts thereof, Re and Rf are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, hexane, hexanediamine ... Heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl , alkoxycarbonyl, or silyl, preferably hydrogen, acyl (e.g., alkoxy acyl, aminoacyl), aminocarbonyl, and alkoxycarbonyl, most preferred or hydrogen; E is isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, 3-methyl 2,2-dimethylpropoxy, or 1,1,2-trimethylpropoxy and branched alkoxy such as, preferably, isopropoxy; Rh and Ri are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro Alkyl, aryl, or heteroaryl, preferably hydrogen or alkyl, most preferably or hydrogen; R5 is one of the following i to iv: i) CH2CH(R6)CH2 (wherein R6 is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro ii) CH2C(R6R7)CH2( In the formula, R6 and R7 are each independently an alkyl, alkenyl, alkynyl, peroxy, fluoroalkyl, aryl, or fluoro, or R6 and R7 are iii) CH2OCH2 , CH2C(O)CH2, CH2, or CH2CH2, or iv) R5 is a carbocyclic ring. A ring having a formula (CH 2) Selected from 3, and R8 and R9 are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro alkyl, alkoxy, aryl, or heteroaryl, or R 8 and R9 are joined together to form a carbocyclic or heterocyclic ring, preferably may be selected from hydrogen and alkyl, most preferably hydrogen.

[0315] In certain preferred embodiments of formula Ia, the carbon atom having -ORf and -ORe is The elementary stereochemistry is as shown in formula Ia'.

[0316] [ka]

[0317] In certain embodiments, the compound of formula I has formula II:

[0318] [ka] and pharma- ceutically acceptable salts thereof, The stereochemistry of the double bond between carbons qq' and rr' is cis or trans; The stereochemistry of the double bond between carbons ss' and tt' is cis or trans; Re, Rf, R5, and E are as defined above.

[0319] For example, if a composition of the present disclosure includes an active agent, such composition may optionally exclude The active agent is a compound of formula IIa:

[0320] [ka] and pharma- ceutically acceptable salts thereof, Re, Rf, R5, and E can be as defined above.

[0321] In certain embodiments, the compound of formula I or II has formula III,

[0322] [ka] and pharma- ceutically acceptable salts thereof, Re, Rf, and E are as defined above.

[0323] In certain embodiments of Formulas I-III, when E represents OR, wherein R is an alkyl group, preferably a lower alkyl group, which is branched at the position attached to the oxygen atom; are optionally excluded from such compositions. Exemplary such R moieties include , -CH(CH3)2(isopropyl), -CH(CH2CH3)2, -CH(CH3) (CH2CH3)(sec-butyl), and -C(CH3)3(tert-butyl) Some examples include:

[0324] Exemplary compounds of formulas I, II, and III include compound 1001,

[0325] [ka] and pharma- ceutically acceptable salts thereof.

[0326] In some embodiments, when the compositions of the present disclosure include an active agent, such compositions The active agents optionally excluded from are compounds of formula IV:

[0327] [ka] or a pharma- ceutically acceptable salt thereof, X is -C≡C-, -C(R 7 )=C(R 7 )-, -(cyclopropyl)-, -(cyclo -(butyl)-, -(cyclopentyl)-, and -(cyclohexyl)-; R 1 -OR a , -N(R a )-SO2-R c , and -N(R a )(R b ) where R a and R b Each of is independently H, C1-C6-alkyl, a R is selected from aryl, aralkyl, heteroaryl, and heteroaralkyl;c teeth, C1-C6-Alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl are selected from R 2 are -CH2-, -C(O)-, -SO2-, -PO(OR)-, and tetrazo are selected from R is selected from hydrogen and alkyl; R 3 is a carbocyclic ring, a heterocyclic ring, -(CH2) n -, CH2C(O)CH2, and - CH2-O-CH2, where n is an integer from 1 to 3, R 3 Any hydrogen atom in is optionally and independently selected from halo, (C1-C5)-alkyl, , perfluoroalkyl, aryl, heteroaryl, hydroxy, or O-(C1- C5)-alkyl; and R 3 Any two hydrogen atoms bonded to a common carbon atom in the together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring, R 4a and R 4b Each of the is independently hydrogen, halo, -OH, -O-(C1-C5 )-Alkyl, -O-Aryl, O-Heteroaryl, -OC(O)-(C1~C5) -Alkyl, -OC(O)-aryl, -OC(O)-heteroaryl, -OC( O)-O-(C1-C5)-alkyl, -OC(O)-O-aryl, -OC(O) -O-heteroaryl, and -OC(O)-N(R a )(R b ), wherein any alkyl, aryl, or heteroaryl may optionally be selected from up to three , halo, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, Carboxyl, ester, alkoxycarbonyl, acyl, thioester, thioacyl, thio independently selected from oether, amino, amido, acylamino, cyano, and nitro; is substituted by a substituent that is R 5a and R 5b each independently represents hydrogen, halo, (C1-C5)-alkyl, Perfluoroalkyl, aryl, and heteroaryl, preferably hydrogen, halo, and and (C1-C5)-alkyl; R 6 is -phenyl, -(C1-C5)-alkyl, -(C3-C7)-cycloalkyl , -C≡C-phenyl, -C≡C-(C3-C7)-cycloalkyl, -C≡C-(C1 -C5)-alkyl, and -O-phenyl, where phenyl is optionally up to three of the following: halo, (C1-C5)-alkyl, O-(C1-C5)-alkyl, Hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, thioester , thioacyl, thioether, amino, amido, acylamino, cyano, and nitro and is substituted by substituents independently selected from Also, R 6 if: a) X is -C(R 7 )=C(R 7 )- or -(cyclopropyl)-, and teeth b)R 4a and R 4b are each hydrogen or halo, or c)R 5a and R 5b If each of is a halo, or d) R 2is -CH2-, then additionally selected from -C≡CH; Each R 7 are independently selected from hydrogen and (C-C)-alkyl, or R 7 Two occurrences of may optionally be joined together with the carbons to which they are attached to form a five-membered ring or may form a six-membered ring, R 10a and R 10b Each of is independently hydrogen, (C1-C5)-alkyl, phenyl, Fluoroalkyl, O-(C1-C5)-alkyl, aryl, and heteroaryl or R 10a and R 10b and the carbon atom to which they are bonded. together form a carbocyclic or heterocyclic ring, and each double bond can be independently in the E or Z configuration.

[0328] In certain embodiments, R 1 When is -OM, M is ammonium, tetrahydrofuran, a cation selected from alkylammonium, Na, K, Mg, and Zn; It is optionally excluded from such compositions.

[0329] In certain embodiments, R2 and R1 together represent:

[0330] [ka] It is.

[0331] In certain embodiments, X is -C≡C-. X is -C(R 7 )=C(R 7 )-, -(cyclopropyl)-, -(cyclobutyl) -, -(cyclopentyl)-, or -(cyclohexyl)-. In this state, X is -C(R 7 )=C(R 7 In certain embodiments, , X is -C≡C-, -(cyclopropyl)-, -(cyclobutyl)-, -(cyclopentyl)-, In certain embodiments, X is -(cyclohexyl)-, -(cyclohexyl)-, or -(cyclohexyl)-. In certain embodiments, X is -C≡C- or -C(R 7 )=C(R 7 )-. X is -(cyclopropyl)-, -(cyclobutyl In certain embodiments, the aryl group is -(cyclopentyl)-, -(cyclohexyl)-, or -(cyclopentyl)-. In terms of form, R 4a The olefins and carbons having -(cyclopropyl)-, - on a (cyclobutyl)-, -(cyclopentyl)-, or -(cyclohexyl)- ring system are attached to adjacent carbons.

[0332] In certain embodiments, R 4b is hydrogen. In certain embodiments, , R 4b is halo, -OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, Heteraryl, -OC(O)-(C1~C5)-alkyl, -OC(O)-aryl , -OC(O)-heteroaryl, -OC(O)-O-(C1-C5)-alkyl, -OC(O)-O-aryl, -OC(O)-O-heteroaryl, or -OC (O)-N(R a )(R b ), where any alkyl, aryl, or heteroaryl group is Aryl is optionally selected from the group consisting of halo, (C1-C5)-alkyl, O-(C1- C5)-Alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, a Cyl, thioester, thioacyl, thioether, amino, amido, acylamino, cyano and nitro. In the embodiment, R 4b is fluoro. In certain embodiments, R 4b teeth , hydrogen, -OH, -O-(C1~C5)-alkyl, -O-aryl, O-heteroaryl -OC(O)-(C1~C5)-alkyl, -OC(O)-aryl, -OC (O)-heteroaryl, -OC(O)-O-(C1-C5)-alkyl, -OC( -OC(O)-O-aryl, -OC(O)-O-heteroaryl, or -OC(O)-N (R a )(R b ), where any alkyl, aryl, or heteroaryl is Optionally, up to three of the following: halo, (C1-C5)-alkyl, O-(C1-C5)-a alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, thio Ester, thioacyl, thioether, amino, amido, acylamino, cyano, and In certain embodiments, the aryl group is substituted with a substituent independently selected from nitro. For details, see R 4b -OH, -O-(C1-C5)-alkyl, O-aryl, O-hetero -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, O -C(O)-heteroaryl, and -OC(O)-N(R a )(R b ) are selected In certain embodiments, R 4b is hydrogen, halo, -OC(O)-O-(C 1-C5)-alkyl, -OC(O)-O-aryl, or -OC(O)-O-hetero wherein any alkyl, aryl, or heteroaryl is any Optionally, up to three of the following may be selected: halo, (C1-C5)-alkyl, O-(C1-C5)-alkyl Alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, thioester ester, thioacyl, thioether, amino, amido, acylamino, cyano, and nitrile In certain embodiments, each of the groups is substituted by a substituent independently selected from the group consisting of aryl, aryloxy ... is R 4b is selected from hydrogen, halo, -OH, or -O-(C1-C5)-alkyl; In certain embodiments, R 4b is -O-aryl, O-heteroaryl , -OC(O)-(C1-C5)-alkyl, -OC(O)-aryl, -OC( O)-heteroaryl, -OC(O)-O-(C1-C5)-alkyl, -OC(O )-O-aryl, -OC(O)-O-heteroaryl, or -OC(O)-N( R a )(R b ), where any alkyl, aryl, or heteroaryl is Optionally, up to three of halo, (C1-C5)-alkyl, O-(C1-C5)-alkanol, alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, thio ester, thioacyl, thioether, amino, amido, acylamino, cyano, and diacyl In certain embodiments, the aryl group is substituted with a substituent selected from the group consisting of aryl, aryl, aryl and aryl. R 4b -OH, -O-(C1-C5)-alkyl, -O-aryl, O-hetero -aryl, -OC(O)-(C1-C5)-alkyl, -OC(O)-aryl, -OC(O)-heteroaryl, -OC(O)-O-(C1-C5)-alkyl, - -OC(O)-O-aryl, -OC(O)-O-heteroaryl, and -OC( O)-N(R a )(R b ), where any alkyl, aryl, or hexafluoroalkyl group is selected from the group consisting of aryl, hexafluoroalkyl ... The heteroaryl is optionally selected from up to three halo, (C1-C5)-alkyl, O-(C 1-C5)-Alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl , acyl, thioester, thioacyl, thioether, amino, amide, acylamino, and substituted by substituents independently selected from cyano, cyclohexyl ... In the embodiment of the present invention, R 4b is selected from hydrogen or halo.

[0333] In certain embodiments, R 4b In certain embodiments, In this case, R 4b is in the (S) configuration.

[0334] In certain embodiments, R 4a is hydrogen. In certain embodiments, , R 4a is halo, -OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, Heteraryl, -OC(O)-(C1~C5)-alkyl, -OC(O)-aryl , -OC(O)-heteroaryl, -OC(O)-O-(C1-C5)-alkyl, -OC(O)-O-aryl, -OC(O)-O-heteroaryl, or -OC (O)-N(R a )(R b), where any alkyl, aryl, or heteroaryl group is Aryl is optionally selected from the group consisting of halo, (C1-C5)-alkyl, O-(C1- C5)-Alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, a Cyl, thioester, thioacyl, thioether, amino, amido, acylamino, cyano and nitro. In the embodiment, R 4a is fluoro. In certain embodiments, R 4a teeth , hydrogen, -OH, -O-(C1~C5)-alkyl, -O-aryl, O-heteroaryl -OC(O)-(C1~C5)-alkyl, -OC(O)-aryl, -OC (O)-heteroaryl, -OC(O)-O-(C1-C5)-alkyl, -OC( -OC(O)-O-aryl, -OC(O)-O-heteroaryl, or -OC(O)-N (R a )(R b ), where any alkyl, aryl, or heteroaryl is Optionally, up to three of the following: halo, (C1-C5)-alkyl, O-(C1-C5)-a alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, thio Ester, thioacyl, thioether, amino, amido, acylamino, cyano, and In certain embodiments, the aryl group is substituted with a substituent independently selected from nitro. For details, see R 4a -OH, -O-(C1-C5)-alkyl, O-aryl, O-hetero -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, O -C(O)-heteroaryl, and -OC(O)-N(R a )(R b) are selected In certain embodiments, R 4a is hydrogen, halo, -OC(O)-O-(C 1-C5)-alkyl, -OC(O)-O-aryl, or -OC(O)-O-hetero wherein any alkyl, aryl, or heteroaryl is any Optionally, up to three of the following may be selected: halo, (C1-C5)-alkyl, O-(C1-C5)-alkyl Alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, thioester ester, thioacyl, thioether, amino, amido, acylamino, cyano, and nitrile In certain embodiments, each of the groups is substituted by a substituent independently selected from the group consisting of aryl, aryloxy ... is R 4a is selected from hydrogen, halo, -OH, or -O-(C1-C5)-alkyl; In certain embodiments, R 4a is -O-aryl, O-heteroaryl , -OC(O)-(C1-C5)-alkyl, -OC(O)-aryl, -OC( O)-heteroaryl, -OC(O)-O-(C1-C5)-alkyl, -OC(O )-O-aryl, -OC(O)-O-heteroaryl, or -OC(O)-N( R a )(R b ), where any alkyl, aryl, or heteroaryl is Optionally, up to three of halo, (C1-C5)-alkyl, O-(C1-C5)-alkanol, alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, thio ester, thioacyl, thioether, amino, amido, acylamino, cyano, and diacyl In certain embodiments, the aryl group is substituted with a substituent selected from the group consisting of aryl, aryl, aryl and aryl. R 4a-OH, -O-(C1-C5)-alkyl, -O-aryl, O-hetero -aryl, -OC(O)-(C1-C5)-alkyl, -OC(O)-aryl, -OC(O)-heteroaryl, -OC(O)-O-(C1-C5)-alkyl, - -OC(O)-O-aryl, -OC(O)-O-heteroaryl, and -OC( O)-N(R a )(R b ), where any alkyl, aryl, or hexafluoroalkyl group is selected from the group consisting of aryl, hexafluoroalkyl ... The heteroaryl is optionally selected from up to three halo, (C1-C5)-alkyl, O-(C 1-C5)-Alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl , acyl, thioester, thioacyl, thioether, amino, amide, acylamino, and substituted by substituents independently selected from cyano, cyclohexyl ... In the embodiment of the present invention, R 4a is selected from hydrogen or halo.

[0335] In certain embodiments, R 4a is in the (S) configuration. In this case, R 4a is in the (R) configuration.

[0336] R 4a In certain embodiments, R 5a is hydrogen or (C1 -C5)-alkyl. 4a -OH, -O-(C1-C5)-alkyl , -O-aryl, O-heteroaryl, -OC(O)-(C1-C5)-alkyl, -OC(O)-aryl, -OC(O)-heteroaryl, -OC(O)-O-( C1-C5)-Alkyl, -OC(O)-O-Aryl, -OC(O)-O-Hetero Aryl, and -OC(O)-N(R a )(R b ) a particular implementation selected from In terms of form, R 5a is selected from hydrogen or (C1-C5)-alkyl. In certain embodiments, R 5a is fluoro. In certain embodiments, R 5a is selected from hydrogen and (C1-C5)-alkyl.

[0337] R 4b In certain embodiments, R 5b is hydrogen or (C1 -C5)-alkyl. 4b -OH, -O-(C1-C5)-alkyl , -O-aryl, O-heteroaryl, -OC(O)-(C1-C5)-alkyl, -OC(O)-aryl, -OC(O)-heteroaryl, -OC(O)-O-( C1-C5)-Alkyl, -OC(O)-O-Aryl, -OC(O)-O-Hetero Aryl, and -OC(O)-N(R a )(R b ) a particular implementation selected from In terms of form, R 5b is selected from hydrogen or (C1-C5)-alkyl. In certain embodiments, R 5b is fluoro. In certain embodiments, R 5b is selected from hydrogen and (C1-C5)-alkyl.

[0338] In certain embodiments, R 2 is -CH2-. In certain embodiments, R 2 is -C(O)-.

[0339] In certain embodiments, R a is selected from H and (C1-C6)-alkyl In certain embodiments, R a is an aryl, aralkyl, or heteroaryl group. and heteroaralkyl.

[0340] In certain embodiments, R b is selected from H and (C1-C6)-alkyl In certain embodiments, R b is an aryl, aralkyl, or heteroaryl group. and heteroaralkyl.

[0341] In certain embodiments, R c is C1-C6-alkyl, aryl, or hexafluorophenyl In certain embodiments, R c is aryl, aralkyl, heteroaryl, and heteroaralkyl.

[0342] R 3 Carbocyclic ring, heterocyclic ring, -(CH2) n - and CH2C(O)CH2 In certain selected embodiments, R 3 Any hydrogen atom in the and independently, halo, (C1-C5)-alkyl, perfluoroalkyl, aryl, heptyl substituted by aryl, hydroxy, or O-(C1-C5)-alkyl .R 3 In certain embodiments, R 3 Any of The hydrogen atoms are optionally and independently selected from halo, (C1-C5)-alkyl, perfluoro Substituted by alkyl, aryl, heteroaryl, or O-(C1-C5)-alkyl. In certain embodiments, R 3 is -(CH2) n - and -CH 2-O-CH2, where n is an integer from 1 to 3, and up to two R 3 In Hydrogen atoms are optionally and independently replaced by (C1-C5)-alkyl; In certain embodiments, R 3 is a carbocyclic ring, a heterocyclic ring, and a CH (O)CH2, where n is an integer from 1 to 3; R 3 Any hydrogen atom in is optionally and independently halo, (C1-C5)-alkyl, perfluoroalkyl , aryl, heteroaryl, hydroxy, or O-(C1-C5)-alkyl. and R 3 Any two hydrogen atoms bonded to a common carbon atom in Optionally, together with the carbon atom to which they are attached, a carbocyclic or heterocyclic ring Form.

[0343] In certain embodiments, R 10a is hydrogen. In certain embodiments, is R 10a is (C1-C5)-alkyl, perfluoroalkyl, O-(C1-C5 )-alkyl, aryl, and heteroaryl, or R 10a but, R 10b and together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. Forms a cyclic ring.

[0344] In certain embodiments, R 10b is hydrogen. In certain embodiments, is R 10bis (C1-C5)-alkyl, perfluoroalkyl, O-(C1-C5 )-alkyl, aryl, and heteroaryl, or R 10b but, R 10a and together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. Forms a cyclic ring.

[0345] In certain embodiments, R 1 -OR a In certain embodiments, is R 1 is -N(R a )-SO2-R c and -N(R a )(R b ) is selected. In certain embodiments, R 1 -N(R a )-SO2-R c A certain In an embodiment, R 1 -OR a and -N(R a )(R b ) is selected. In certain embodiments, R 1 -N(R a )(R b ) In certain embodiments In R 1 -OR a and -N(R a )-SO2-R c is selected from.

[0346] In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is (C1-C5)-alkyl or R 7 Two occurrences of, optionally, Together with the carbon to which they are attached, they may form a 5- or 6-membered ring.

[0347] In certain embodiments, X is -C≡C-, and R 4b is hydrogen.

[0348] In certain embodiments, X is -C≡C-, and R 4a is hydrogen.

[0349] In certain embodiments, X is -C≡C-, and R 4a is fluoro and R 5a is fluoro.

[0350] In certain embodiments, X is -C≡C-, and R 4b is fluoro and R 5b is fluoro.

[0351] In certain embodiments, X is -C≡C-, and R 4a and R 4b Each of them These are independently -OH, -O-(C1-C5)-alkyl, O-aryl, O-hetero Aryl, -OC(O)-(C1-C5)-alkyl, OC(O)-aryl, O- C(O)-heteroaryl, and -OC(O)-N(R a )(R b ) are selected from .

[0352] In certain embodiments, X is -C≡C-, and R 2 is -CH2-.

[0353] In certain embodiments, X is -(cyclopropyl)-, -(cyclobutyl) -, -(cyclopentyl)-, or -(cyclohexyl)-. In this embodiment, X is -(cyclopropyl)-.

[0354] In certain embodiments, X is -C(R 7 )=C(R 7 )-.

[0355] In certain embodiments, R a and R b each independently represents H and C 1-C6-alkyl; R c is C1-C6-alkyl, R 3 is -(C H2) n - and -CH2-O-CH2, where n is an integer from 1 to 3; , up to two, R 3 hydrogen atoms in the is replaced by R 4a and R 4b each independently represents hydrogen, halo, - OH, -O-(C1-C5)-alkyl, and R 10a and R 10b Noso Each of them is hydrogen.

[0356] In certain embodiments, each double bond is in the E configuration. In certain embodiments, each double bond is in the Z configuration. one double bond is in the E configuration and one double bond is in the Z configuration.

[0357] In certain embodiments, any combination of the foregoing is contemplated in the present invention. A person skilled in the art can easily identify the individual possible residues in the variable regions of the compounds disclosed herein. For example, R 1 , R 2 , R 3 , R 4a , R 4b , R 5a , R5b , R 6 , R 7 , R 10a , R 10b , R a , R b , R c , n, o and X are within the scope of the present disclosure. 4a Various specific examples are listed regarding Any of the embodiments may be combined with any of the various specific embodiments of X listed. It is possible.

[0358] In certain embodiments, compounds that are optionally excluded from such compositions are ,below:

[0359] [ka]

[0360] [ka]

[0361] [ka]

[0362] [ka] is selected from one of the following:

[0363] In some embodiments, when the compositions of the present disclosure include an active agent, such compositions The active agents optionally excluded from are compounds of formula V:

[0364] [ka] or a compound of formula VI,

[0365] [ka] or a pharma- ceutically acceptable salt of any of the foregoing, R 1 -OR a , -N(R a )-SO2-R c , and -N(R a )(R b ) where R a and R b Each of is independently H, C1-C6-alkyl, a R is selected from aryl, aralkyl, heteroaryl, and heteroaralkyl; c teeth, C1-C6-Alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl are selected from R 2 is selected from -C(O)-, -SO2-, -PO(OR)-, and tetrazole; R, R is selected from hydrogen and alkyl; R 3 is -(CH2) n - and -CH2-O-CH2, where n is 1 to 3, and optionally up to two, R 3 The hydrogen atoms in 1-C5)-alkyl or O-(C1-C5)-alkyl, R 5a and R 5b each independently represents hydrogen, (C1-C5)-alkyl, perfluoro fluoroalkyl, aryl, and heteroaryl, preferably hydrogen and (C1-C5 )-alkyl; R 6 -C≡CH, -phenyl, -(C1-C5)-alkyl, -(C3-C7)-cyclohexyl Chloroalkyl, -C≡C-phenyl, -C≡C-(C3-C7)-cycloalkyl, -C ≡C-(C1-C5)-alkyl, and -O-phenyl, The group may optionally contain up to three of the following: halo, (C1-C5)-alkyl, O-(C1-C5) -Alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, Thioester, thioacyl, thioether, amino, amide, acylamino, cyano, and nitro; R 8 and R 9 Each of is independently hydrogen, -(C1-C5)-alkyl, -aryl. -C(O)-(C1-C5)-alkyl, -C(O)-aryl , -C(O)-heteroaryl, -C(O)-O-(C1-C5)-alkyl, -C(O )-O-aryl, -C(O)-O-heteroaryl, and -C(O)-N(R a )( R b ), where any alkyl, aryl, or heteroaryl is selected from any Optionally, up to three of the following may be selected: halo, (C1-C5)-alkyl, O-(C1-C5)-alkyl Alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, thioester ester, thioacyl, thioether, amino, amido, acylamino, cyano, and nitrile substituted by substituents independently selected from b; R 10a and R 10b Each of is independently hydrogen, (C1-C5)-alkyl, phenyl, Fluoroalkyl, O-(C1-C5)-alkyl, aryl, and heteroaryl or R 10a and R10b together with the carbon atom to which they are attached form a carbocyclic ring or forms a heterocyclic ring, and Each double bond can independently be in the E or Z configuration.

[0366] In certain embodiments, R 1 When is -OM, M is ammonium, tetrahydrofuran, a cation selected from alkylammonium, Na, K, Mg, and Zn; It is optionally excluded from such compositions.

[0367] In certain embodiments, R 2 and R 1 Together,

[0368] [ka] It is.

[0369] In certain embodiments, R 2 is -C(O)-. In certain embodiments, For details, see R 1 -OR a where R a is hydrogen or C1-C6-alkyl In certain embodiments, R 3 Ha-(CH2) n - where n is 3 In certain embodiments, R 6 is -C≡CH. In certain embodiments, For details, see R 5a is hydrogen. In certain embodiments, R 5b is hydrogen. In certain embodiments, R 10a is hydrogen. In certain embodiments, R 10bis hydrogen. In certain embodiments, R 2 is -C(O)- and R 1 -OR a where R a is C1-C6-alkyl, R 3 Ha-(CH2) n where n is 3 and R 6 is -C≡CH, and R 5a is hydrogen, and R 5b is hydrogen, and R 10a is hydrogen and R 10b is hydrogen.

[0370] In certain embodiments, compounds that are optionally excluded from such compositions are ,below:

[0371] [ka] is selected from one of the following:

[0372] In some embodiments, when the compositions of the present disclosure include an active agent, such compositions The active agents optionally excluded from are compounds of formula VII:

[0373] [ka] and pharma- ceutically acceptable salts thereof, Re and Rf are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, hexane, hexanediamine ... Heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl , alkoxycarbonyl, or silyl; E is hydroxyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, arylamino, or arylamino; Rh and Ri are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro selected from alkyl, aryl, or heteroaryl; R5 is one of the following i to iv: i) CH2CH(R6)CH2 (wherein R6 is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro ii) CH2C(R6R7)CH2( In the formula, R6 and R7 are each independently an alkyl, alkenyl, alkynyl, peroxy, fluoroalkyl, aryl, or fluoro, or R6 and R7 are iii) CH2OCH2 , CH2C(O)CH2, or CH2CH2, or iv) R5 is a carbocyclic ring, is selected from a monocyclic ring, an aryl ring, or a heteroaryl ring; and R8 and R9 are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro alkyl, alkoxy, aryl, or heteroaryl, or R 8 and R9 are joined together to form a carbocyclic or heterocyclic ring; obtain.

[0374] In certain embodiments, the compound of formula VII has formula VIII:

[0375] [ka] and pharma- ceutically acceptable salts thereof, Re, Rf, R5, and E are as defined above.

[0376] In certain embodiments, the compound of formula VII or VIII has formula IX,

[0377] [ka] and pharma- ceutically acceptable salts thereof, Re, Rf, and E are as defined above.

[0378] eye disease In various aspects and embodiments, the formulations disclosed herein are useful for treating ophthalmic diseases or disorders. The present invention can be used to treat or prevent eye diseases. Diseases and disorders include anterior and posterior diseases. In certain embodiments, Exemplary eye diseases that can be treated with the formulations disclosed herein include: Some examples include:

[0379] Dry Eye Syndrome (DES, chronic dry eye, keratitis sicca, xerophthalmia, keratoconjunctivitis sicca) ) includes a variety of disorders that result in the loss or alteration of the composition of the natural tear film that maintains the ocular surface. In the absence of this tear film, vision is impaired and the patient is ill. Patients may suffer from severe eye discomfort. DES is caused by excessive evaporation of tears. This condition may be caused by a decrease in tear production in the lacrimal gland, which is where tears are produced. The exact cause of the condition is unknown, but it is thought to involve reduced tear production and damage to one or more components of the lacrimal apparatus. There is evidence supporting a link between vascular inflammation and DES. Currently available medications for DES include , leaving ample room for more effective and well-tolerated products.

[0380] DES may also be a symptom of the autoimmune disorder Sjögren's syndrome. In this disorder, the glands that produce tears and saliva are destroyed. This can result in dry mouth, reduced tearing, and This results in dry mucous membranes underneath and elsewhere.

[0381] Non-infectious uveitis is associated with significant visual morbidity and is TH1 / TH17-mediated It is a chronic inflammatory autoimmune disease that may lead to blindness. Blindness from uveitis usually does not result from a single inflammatory episode, but rather from recurrent episodes. It is caused by cumulative damage resulting from repeated inflammatory episodes, resulting in vision loss. Inflammatory sequelae include cystoid macular edema, cataracts, vitreous debris, glaucoma, and macular pathology (scarring). These may include one or more of the following: retinal detachment, optic neuropathy, and retinal detachment. .

[0382] Anterior uveitis (iritis) occurs in the front of the eye and is the most common form of uveitis. Peripheral uveitis is inflammation of the pars plana, a narrow area between the iris and the choroid. The condition occurs more frequently in young men and is usually not associated with another disorder. Posterior uveitis (chondritis) primarily affects the choroid, the posterior part of the uvea. When the retina is also involved, it is called chorioretinitis. Posterior uveitis is an autoimmune disease. It may occur in association with disease or secondary to a systemic infection. In glaucoma, inflammation can last for months to years and, despite treatment, may not result in permanent vision loss. Disability may result.

[0383] Uveitis can result in blurred vision, eye pain, and vision loss. It is estimated that approximately 10% of new cases in the United States are caused by uveitis. Approximately 300,000 people in Germany suffer from uveitis, the majority of whom You have peripheral uveitis. FDA-approved lenses to treat uveitis The only therapeutic class in the world is corticosteroids, which are used to treat hypertension, hyperglycemia, and Several side effects have been reported, including hypercholesterolemia and hypercalcemia, as well as intraocular glaucoma and cataract formation. It is being considered.

[0384] Conjunctivitis (epidemic conjunctivitis) is a type of infection that occurs when the inside of the eyelid is covered with conjunctiva, which is the exposed area of ​​the sclera, or white of the eye. Describes a group of conditions that cause swelling, itching, burning, and redness of the conjunctiva, the protective membrane that covers the eye area. This is to clarify.

[0385] Keratitis is an inflammation of the cornea (the clear front part of the eye). Keratitis can be caused by an infection (bacterial, Bacteria, viruses, parasites, etc.) or noninfectious agents (noninfectious agents ent) (e.g., certain types of autoimmune diseases are associated with a variety of non-infectious keratitis. This can be caused by the following:

[0386] Keratoconjunctivitis refers to inflammation of the cornea and conjunctiva.

[0387] Vernal keratoconjunctivitis (VKC) is characterized by firm, raised, cobblestone-like bumps on the upper eyelid. It is a recurrent inflammatory disease of the eye that can be caused by conjunctival swelling and thickening. The conjunctiva is the outermost membrane that covers the eyelids and exposed parts of the eye, excluding the cornea.

[0388] Atopic keratoconjunctivitis is the result of a condition called atopy, which is a condition that affects the immune system. is a genetic condition that causes a person to produce more antibodies than normal in response to a given allergen. do.

[0389] Systemic immune-mediated diseases, such as cicatricial conjunctivitis and other autoimmune disorders of the ocular surface, can occur acutely. Clinically heterogeneous, with rapid and chronic autoreactive mechanisms that can result in significant damage to the eye. It represents a group of conditions. When severe and affecting the conjunctival epithelium and substantia, scarring occurs. These conditions can result in significant mechanical changes as a result of fibrosis. The condition is generally rare but can cause serious pathology and visual impairment.

[0390] Blepharitis is a common condition that causes inflammation of the eyelids.

[0391] Scleritis is a severe inflammatory disease that affects the outer white membrane of the eye, known as the sclera. .

[0392] Age-related macular degeneration (AMD) is a progressive, age-related condition that causes a gradual loss of sharp central vision. AMD is a related disease. It affects the macula, which is located in the center of the retina. It occurs in two forms: wet and dry. Wet AMD occurs when the retina It occurs when abnormal blood vessels begin to grow under the macula. These new blood vessels They tend to be fragile and often leak blood and fluids. The macula is raised from its normal position at the back of the eye. Damage to the macula occurs rapidly. Dry AMD occurs when the light-sensitive cells in the macula slowly break down, leading to The central vision in the affected eye gradually becomes blurred.

[0393] Diabetes affects the eyes in several ways. Diabetic retinopathy (DR) is a condition that affects the back of the eye. It is a complication of diabetes caused by damage to the blood vessels of the light-sensing tissue of the eye (the retina). In the early stages, diabetic retinopathy may not cause any symptoms or may only cause mild vision problems. However, diabetic retinopathy may ultimately lead to blindness. Diabetic macular edema (DME) is caused by leakage of fluid from blood vessels in the macula. , retinal swelling in diabetes mellitus.

[0394] Ocular neovascularization is the abnormal or excessive formation of blood vessels in the eye. Ocular neovascularization is a common cause of diabetes. It has been shown in chronic retinopathy and age-related macular degeneration (AMD).

[0395] Proliferative vitreoretinopathy (PVR) is the formation of scar tissue inside the eye. , "proliferative" and "vitreoretinopathy" because the problem involves the vitreous and retina PVR scar tissue forms in the form of sheets on the retina, which then shrink. This noticeable shrinkage pulls the retina towards the center of the eye, causing it to become severely detached and distorted PVR can occur both anteriorly and posteriorly, folding the retina both anteriorly and circumferentially. It is possible.

[0396] Cytomegalovirus (CMV) is a herpesvirus-related virus that is present in almost all humans. Human immune systems are compromised by disease (HIV), organ or bone marrow transplants, or chemotherapy. When the immune system is suppressed, the CMV virus can cause damage to the eye and other parts of the body. CMV can cause injury and disease by causing damage to the retina. In about 30% of cases, the eye is affected, which is called CMV retinitis.

[0397] Optic neuritis occurs when the optic nerve becomes inflamed and the myelin sheath becomes damaged or destroyed. Nerve damage that occurs in the part of the optic nerve located at the back of the eye is called retrobulbar optic neuritis. , which is another term that is sometimes used for optic neuritis.

[0398] Also known as macular pucker, epiretinal membrane is a membrane-like scar that forms on the macula. Epiretinal membranes generally progress slowly and can cause blurring and distortion. As the condition progresses, pulling of the membrane over the macula causes swelling. This may cause problems.

[0399] In certain embodiments, the composition is used to treat, for example, graft rejection of a corneal allograft following transplantation. In inflammation, T-lymphocytes stimulate the rejection of foreign tissue. It is well known that immunization plays a crucial role in mediating rejection. Prevention is paramount to maintaining the health of the transplanted cornea. Rejection can occur when the cornea, e.g. It can occur in any layer, including the corneal epithelium, the corneal stroma, or the corneal endothelium. The function of the endothelium may be impaired after endothelial rejection. The endothelium absorbs water from the stroma. It acts as a pump to remove blood from the cornea and keep it compact. If the function of the layer is compromised, loss of orientation of collagen fibers can result, leading to corneal The transparency of the endothelium may be lost. Human endothelial cells are non-replicative, which results in a high incidence of rejection. The loss of donor cells in this condition is irreversible, leading to reduced graft function and survival. Therefore, the present invention is useful for either preventing or treating corneal transplant rejection in corneal transplant recipients. The goal of the present invention is also to minimize endothelial cell loss. It can be used to prevent rejection after transplantation.

[0400] Additional formulation ingredients The compositions of the present disclosure may also contain, but are not limited to, additives, adjuvants, buffers, Other components such as isotonicity agents, bioadhesive polymers, and preservatives may also be included. In any of the compositions of the present disclosure for topical administration, the mixture is formulated to a pH of about 5 to about 8. This pH range can be achieved by adding a buffer to the composition, as described in the Examples. In some embodiments, the composition of the formulation may be The pH range in the composition is about pH 6.6 to about pH 7.0. salts, borates, acetates, citrates, carbonates, and borate-polyol complexes. Any of the common buffer systems can be used to adjust pH and osmolality to appropriate physiological values ​​according to well-known techniques. It should be understood that the mixed micelle compositions of the present disclosure can be adjusted and buffered by using a buffered aqueous solution. It is stable in liquid, i.e., there is no instability between the buffer and any other components of the composition. No adverse interactions that would lead to uncertainty would occur.

[0401] Examples of isotonic agents include mannitol, sodium chloride, and xylitol. These isotonicity agents can be used to adjust the osmotic pressure of the composition. The osmolarity of the formulation is adjusted to be within the range of about 250 to about 350 mOsmol / kg. In a preferred embodiment, the osmotic pressure of the present preparation is about 280 to about 300 mOsmol / kg.

[0402] Additives such as sugar, glycerol, and other sugar alcohols may be included in the compositions of the present disclosure. Pharmaceutical additives are substances added to increase the potency or effectiveness of other ingredients in a composition. For example, the pharmaceutical additive may be a calcineurin inhibitor or an mTOR inhibitor. In order to improve the stability of the inhibitor, the viscosity of the composition may be adjusted to adjust the osmotic pressure of the composition. For other reasons, such as to reduce the risk of infection or to effect drug delivery, Non-limiting examples of pharmaceutical additives of the present disclosure include trehalose, mannose, and the like. Examples of sugars that may be used include saccharides such as saccharide, ... In some cases, the sugar may be incorporated into the composition prior to hydration of the thin film (i.e., In another embodiment, sugar may be incorporated into the composition during the hydration step. In one embodiment, the translucency of the present disclosure is An obvious mixed micellar aqueous solution includes an additive such as a sugar.

[0403] In certain embodiments, the compositions of the present disclosure contain one or more bioadhesive polymers. Bioadhesiveness also includes certain synthetic and biopolymers, as well as hydrophilic components. Bioadhesion refers to the ability of a polymer to adhere to biological tissue. It is a complex phenomenon that depends in part on the characteristics of the surrounding environment. Several factors: The presence of functional groups (--OH, COOH) that can form an anionic charge, the presence and strength of the anionic charge, and the polymer chain Sufficient elasticity to penetrate the mucus layer and high molecular weight contribute to the bioadhesive ability of the polymer. Bioadhesive systems have been shown to be effective in dentistry, orthopedics, and ophthalmology. However, in recent years, soft tissue-based In other areas such as oral replacement surgery and controlled release systems for the localized delivery of bioactive agents. Recently, there has been significant interest in the use of bioadhesive materials. , systems for release of drugs in the buccal or nasal cavity, and systems for enteral or rectal administration. A system for administration is provided.

[0404] In certain embodiments, the compositions of the present disclosure comprise at least one bioadhesive polymer. The bioadhesive polymer increases the viscosity of the composition, thereby increasing its residence time in the eye. The bioadhesive polymers of the present disclosure can increase the Carboxylic acid-based polymers such as pol® (carbomer), Noveon® Polycarbophil, methylcellulose, hydroxypropylcellulose, etc. Ceramics, including alkyl and hydroxyalkyl celluloses, carboxymethyl celluloses, Lurose derivatives, locust bean, xanthan, agarose Gums such as gum, karaya, guar, and polyvinyl alcohols, including but not limited to polyvinyl alcohols. Coal, Polyvinylpyrrolidone, Polyethylene glycol, Pluronic ) (poloxamer), tragacanth, and hyaluronic acid; sustained delivery of encapsulated drugs to the eye and phase transition polymers (e.g., alginate, carrageenan) to provide controlled delivery. (e.g., Eucheuma), mixtures of xanthan and locust bean gum, pectin Cellulose acetate phthalate, alkyl hydroxyalkyl cellulose and its derivatives , hydroxyalkylated polyacrylic acid and its derivatives, poloxamer and its derivatives The physical properties of these polymers vary depending on ionic strength, pH, etc. or regulated by changes in environmental factors such as temperature, either alone or in combination with other factors ( In one embodiment, one or more of the optional The bioadhesive polymers are present in an amount of about 0.01% to about 10% by weight / volume, preferably about 0. In some embodiments, the compositions of the present disclosure are present in an amount of from 0.1 to about 5% by weight / volume. Examples of the materials include PVP-K-30, PVP-K-90, HPMC, HEC, and polycarbonate. The composition further comprises at least one hydrophilic polymer excipient selected from the group consisting of rubofil. In embodiments, the polymer excipient is PVP-K-90, PVP-K-30, or In one embodiment, the polymer excipient is selected from PVP-K-9. 0 or PVP-K-30.

[0405] In certain embodiments, if a preservative is desired, the composition optionally contains EDTA. Benzyl alcohol with or without benzoyl chloride, chlorhexidine, Cos Many of them, including mocil® CQ, or Dowicil® 200 It may be preserved with any of the well-known preservatives. It may be desirable for the formulations disclosed herein to be free of any preservatives. In this regard, in some embodiments, the preservative is present in the formulation contained in the single-use container. In some cases this may be unnecessary or undesirable. In other embodiments, such as in certain embodiments, it may be advantageous to include a preservative. It may be the case.

[0406] The ophthalmic composition is administered topically to the eye as a biocompatible, clear, aqueous mixed micellar solution. The composition incorporates the drug into micelles that disperse in an aqueous medium, and and / or enclose.

[0407] Non-Limiting List of Exemplary Embodiments In addition to the aspects and embodiments described and provided elsewhere in this disclosure, the following A non-limiting list of specific embodiments is specifically contemplated. 1. A formulation comprising a polyoxyl lipid or fatty acid and a polyalkoxylated alcohol. So, Mixed nanomicelles, Contains no organic solvents Does not contain any pharma- tically active agent that has received regulatory approval for the specific treatment of an ocular condition. No, formulations. 2. The embodiment in which the polyoxyl lipid or fatty acid is present in an amount of 1% or more of the formulation. 2. The formulation according to embodiment 1. 3.1-5% HCO-40, HCO-60, HCO-80, and HCO-100 and about 0.01 to 0.1% of one or more polyoxyl lipids selected from the group consisting of: octoxynol-40. 4.1.5–4% HCO-40, HCO-60, HCO-80, and HCO-10 0 and about 0.01 to 0.1 % octoxynol-40. 5. Approximately 4% of HCO-40, HCO-60, HCO-80, and HCO-100 and about 0.01 to 0.1% of one or more polyoxyl lipids selected from the group consisting of 2. The formulation of embodiment 1, comprising: 6. Contains about 4% HCO-60 and about 0.01 to 0.1% Octoxynol-40 , the formulation described in embodiment 1. 7.1-5% HCO-40, HCO-60, HCO-80, and HCO-100 and about 0.01% octoyl glyceryl monophosphate (OCT) or 0.1% octoyl glyceryl monophosphate (OCT) 2. The formulation of embodiment 1, comprising Cinol-40. 8.1.5-4% HCO-40, HCO-60, HCO-80, and HCO-10 0 and about 0.01% octyldodecyl ester (OCT) ...). 2. The formulation of embodiment 1, comprising toxinol-40. 9.1.5-4% polyoxyl lipids or fatty acids and about 0.01% octoxynol 2. The formulation of embodiment 1, comprising: 10. Approximately 4% of HCO-40, HCO-60, HCO-80, and HCO-100 and about 0.01% octoyl glyceryl monophosphate (OCT) or 0.1% octoyl glyceryl monophosphate (OCT) 2. The formulation of embodiment 1, comprising Cinol-40. 11. A method comprising the steps of: The formulation described in Form 1. 12. The method according to claim 1, wherein the polyoxyl lipid or fatty acid is 0.5 to 6% by weight of the formulation. The formulation according to any of the embodiments. 13. The method according to any one of the preceding claims, wherein the polyoxyl lipid or fatty acid is 0.5 to 2% by weight of the formulation. The formulation according to any of the embodiments. 14. The method according to any one of the preceding claims, wherein the polyoxyl lipid or fatty acid is 0.5 to 3% by weight of the formulation. The formulation according to any of the embodiments. 15. The method according to any one of the preceding claims, wherein the polyoxyl lipid or fatty acid is 0.5 to 4% by weight of the formulation. The formulation according to any of the embodiments. 16. The method according to any one of the preceding claims, wherein the polyoxyl lipid or fatty acid is 0.5 to 5% by weight of the formulation. The formulation according to any of the embodiments. 17. The method of any preceding embodiment, wherein the polyoxyl lipid or fatty acid is 1 to 6% by weight of the formulation. 2. The formulation according to any one of the following forms: 18. The method of any preceding embodiment, wherein the polyoxyl lipid or fatty acid is 1 to 2% by weight of the formulation. 2. The formulation according to any one of the following forms: 19. The method of any preceding embodiment, wherein the polyoxyl lipid or fatty acid is 1 to 3% by weight of the formulation. 2. The formulation according to any one of the following forms: 20. The method according to any one of the preceding embodiments, wherein the polyoxyl lipid or fatty acid is 1 to 4% by weight of the formulation. 2. The formulation according to any one of the following forms: 21. The method according to any one of the preceding embodiments, wherein the polyoxyl lipid or fatty acid is 1 to 5% by weight of the formulation. 2. The formulation according to any one of the following forms: 22. The method according to any one of the preceding embodiments, wherein the polyoxyl lipid or fatty acid is 1 to 6% by weight of the formulation. 2. The formulation according to any one of the following forms: 23. The method according to any one of the preceding embodiments, wherein the polyoxyl lipid or fatty acid is 2 to 6% by weight of the formulation. 2. The formulation according to any one of the following forms: 24. The method according to any one of the preceding embodiments, wherein the polyoxyl lipid or fatty acid is 3 to 6% by weight of the formulation. 2. The formulation according to any one of the following forms: 25. The method according to any one of the preceding embodiments, wherein the polyoxyl lipid or fatty acid is 4 to 6% by weight of the formulation. 2. The formulation according to any one of the following forms: 26. The method according to any one of the preceding embodiments, wherein the polyoxyl lipid or fatty acid is 2 to 5% by weight of the formulation. 2. The formulation according to any one of the following forms: 27. The method according to any one of the preceding embodiments, wherein the polyoxyl lipid or fatty acid is 3 to 5% by weight of the formulation. 2. The formulation according to any one of the following forms: 28. The preceding embodiment, wherein the polyoxyl lipid or fatty acid is about 4% by weight of the formulation. The formulation according to any one of the preceding claims. 29. The method of any preceding claim, wherein the polyoxyl lipid or fatty acid is greater than about 0.7% by weight of the formulation. The formulation according to any of the embodiments. 30. The method of any preceding embodiment, wherein the polyoxyl lipid or fatty acid is greater than about 1% by weight of the formulation. 2. The formulation according to any one of the following forms: 31. The method of any preceding claim, wherein the polyoxyl lipid or fatty acid is greater than about 1.5% by weight of the formulation. The formulation according to any of the embodiments. 32. The method of any preceding embodiment, wherein the polyoxyl lipid or fatty acid is greater than about 2% by weight of the formulation. 2. The formulation according to any one of the following forms: 33. The method of any preceding embodiment, wherein the polyoxyl lipid or fatty acid is greater than about 3% by weight of the formulation. 2. The formulation according to any one of the following forms: 34. The polyalkoxylated alcohol, if present, comprises 0.002 to 4% by weight of the formulation. %. 35. The polyalkoxylated alcohol, if present, comprises 0.005 to 3% by weight of the formulation. %. 36. The polyalkoxylated alcohol, if present, comprises 0.005 to 2% by weight of the formulation. %. 37. The polyalkoxylated alcohol, if present, comprises 0.005 to 1% by weight of the formulation. %. 38. The polyalkoxylated alcohol, when present, is present in an amount of 0.005 to 0.5 % by weight. 39. The polyalkoxylated alcohol, when present, is present in an amount of 0.005 to 0.1 % by weight. 40. The polyalkoxylated alcohol, if present, is present in an amount of 0.005 to 0.0% of the formulation. The formulation of any of the preceding embodiments, wherein the formulation is 5% by weight. 41. The polyalkoxylated alcohol, when present, is present in an amount of 0.008 to 0.0 The formulation of any of the preceding embodiments, wherein the formulation is 2% by weight. 42. The polyalkoxylated alcohol, when present, is present at about 0.01% by weight of the formulation. The formulation of any of the preceding embodiments. 43. Any of the preceding embodiments, which does not include a resolvin or resolvin-like compound. The formulation described. 44. The formulation of any of the preceding embodiments, which does not contain a resolvin. 45. The method of any preceding embodiment, wherein the polyoxyl lipid or fatty acid is polyoxyl castor oil. 2. The formulation according to any one of the following forms: 46. ​​The polyoxyl lipid or fatty acid is HCO-60, HCO-80, or HCO The process according to any of the preceding embodiments, wherein the compound is one or more selected from the group consisting of: Agent. 47. Any of the preceding embodiments, wherein the polyoxyl lipid or fatty acid is HCO-60. The formulation according to any one of the preceding claims. 48. The polyalkoxylated alcohol, when present, is octoxynol-40. The formulation of any of the preceding embodiments. 49. Calcineurin inhibitors, mTOR inhibitors, peptides, eicosanoids (e.g. Prostacyclin and prostaglandins), anti-inflammatory drugs (NSAIDs, etc.), autonomic nervous system agonists (e.g., beta-blockers, alpha-blockers, beta-agonists, and alpha-agonists) agonists), biologics, gene therapy agents (e.g., viral vectors), anti-infective agents (e.g., (e.g., antifungals, antibiotics, and antivirals), retinoids, RNAi, photosensitizers, steroids (e.g., estrogens and their derivatives, and corticosteroids), mixed Drug combinations, immunomodulators, chemotherapeutic agents, G protein-coupled receptor antagonists, receptor-type Tyrosine kinase (RTK) inhibitors, growth hormone inhibitors, integrin inhibitors, Sdf 1 / CXCR4 pathway inhibitors, as well as nACh receptor antagonists, resolvins (also are selected from the group consisting of resolvin-like compounds, lipoxins, and oxylipins. , the formulation of any of the preceding embodiments, which does not contain any active agent. 50. Cyclosporine A, voclosporin, ascomycin, tacrolimus, pimeclorimin mus, their analogs, or pharma- ceutically acceptable salts thereof. , the formulation of any of the preceding embodiments, which does not contain any active agent. 51. The formulation of any of the preceding embodiments, which does not contain cyclosporine A. 52. The formulation of any of the preceding embodiments, which does not contain voclosporin. 53. Sirolimus (rapamycin), temsirolimus, everolimus, and their analogues; or a pharma- ceutically acceptable salt thereof. The formulation of any preceding embodiment, wherein the formulation does not have 54. A compound of formula A, a compound of any one of formulas 1 to 49, and formulas I to IX, a lipoxin compound a compound, an oxylipin compound, a prodrug of any of the foregoing, or a pharma- ceutically acceptable The formulation of any of the preceding embodiments does not contain any salt of the foregoing. . 55. A compound of formula A, a compound of any one of formulas 1 to 49, and formulas I to IX, a lipoxin compound a compound, an oxylipin compound, a prodrug of any of the foregoing, or a pharma- ceutically acceptable The formulation of any of the preceding embodiments does not contain any salt of the foregoing. . 56. Any of the preceding embodiments that does not contain a combination of two different active agents. The formulation described. 57. Resolvins or resolvin-like compounds, steroids (e.g., corticosteroids), Two or more active agents selected from the group consisting of closporin A, and voclosporin. The formulation of any of the preceding embodiments does not contain. 58. Any of the preceding embodiments that does not contain a resolvin and a corticosteroid. The formulation described in 59. Any of the preceding embodiments that does not contain cyclosporine A and corticosteroids. The formulation according to any one of the preceding claims. 60. Resolvin, cyclosporine A, and corticosteroid-free, preceding The formulation of any one of the embodiments. 61. A compound of formula I,

[0408] [ka] or a pharma- ceutically acceptable salt thereof, Re and Rf are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, hexane, hexanediamine ... Heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl , alkoxycarbonyl, or silyl; E is branched alkoxy; Rh and Ri are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro selected from alkyl, aryl, or heteroaryl; R5 is one of the following i to iv: i) CH2CH(R6)CH2 (wherein R6 is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro ii) CH2C(R6R7)CH2( In the formula, R6 and R7 are each independently an alkyl, alkenyl, alkynyl, peroxy, fluoroalkyl, aryl, or fluoro, or R6 and R7 are iii) CH2OCH2 , CH2C(O)CH2, or CH2CH2, or iv) R5 is a carbocyclic ring, is selected from a monocyclic ring, an aryl ring, or a heteroaryl ring; and R8 and R9 are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoro alkyl, alkoxy, aryl, or heteroaryl, or R R8 and R9 are joined together to form a carbocyclic or heterocyclic ring. The formulation of any preceding embodiment, wherein the 62. A compound of formula I, Re, Rf, Rh, Ri, R8, and R9 are hydrogen; E is branched alkoxy (such as isopropyl), and R5 is CH2CH2CH2. Formulation. 63. Any of the preceding embodiments, wherein the resolvin, if present, is a compound of formula I. The formulation described above. 64. Any of the preceding embodiments, wherein the resolvin, if present, is compound 1001. The formulation described above. 65. The formulation of any of the preceding embodiments, further comprising a preservative. 66. Benzyl alcohol with or without EDTA, benzalkonium chloride, chlorhexidine Xyzidine, Cosmocil® CQ, and Dowicil® 20 0. The method of claim 1, further comprising one or more preservatives selected from the group consisting of: Any of the formulations described above. 67. The formulation of any of the preceding embodiments, which does not contain a preservative. 68. Benzyl alcohol with or without EDTA, benzalkonium chloride, chlorhexidine Xyzidine, Cosmocil® CQ, or Dowicil® 20 The formulation of any of the preceding embodiments, wherein no. 69. A method for treating an eye disease comprising topically administering a formulation according to any of the preceding embodiments. or a method of treating or preventing an eye condition. 70. A method for treating an eye disease comprising topically administering a formulation according to any of the preceding embodiments. Or a method of treating or preventing an ocular condition, wherein the disease is a disease of the anterior segment of the eye. 71. A method for treating an eye disease comprising topically administering a formulation according to any of the preceding embodiments. Or a method of treating or preventing an ocular condition, wherein the disease is a disease of the posterior segment of the eye. 72. A method for treating an eye disease comprising topically administering a formulation according to any of the preceding embodiments. or a method for treating or preventing an ocular condition, the disease being dry eye syndrome, shavings, Glenn's syndrome, uveitis, anterior uveitis (iritis), chorioretinitis, posterior uveitis, Conjunctivitis, allergic conjunctivitis, keratitis, keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopic Keratoconjunctivitis, systemic immune-mediated diseases such as cicatricial conjunctivitis and other autoimmune disorders of the ocular surface Etc., blepharitis, scleritis, age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic Macular edema (DME), ocular neovascularization, age-related macular degeneration (ARMD), proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV) retinitis, optic neuritis, retrobulbar optic neuritis, and The method of claim 1, wherein the macular pucker is one or more selected from the group consisting of: 73. A method for treating an eye disease comprising topically administering a formulation according to any of the preceding embodiments. or a method for treating or preventing an ocular condition, wherein the disease is dry eye syndrome. Law. 74. A method for treating an eye disease comprising topically administering a formulation according to any of the preceding embodiments. or a method for treating or preventing an ocular condition, wherein the disease is allergic conjunctivitis; method. 75. A method for treating an eye disease comprising topically administering a formulation according to any of the preceding embodiments. or a method for treating or preventing an ocular condition, wherein the disease is age-related macular degeneration (AMD). That is, the method.

[0409] The following examples are provided to further illustrate aspects of the present disclosure. The examples are non-limiting and should not be construed as limiting any aspect of the disclosure. It's not good. EXAMPLES

[0410] Preparation of mixed nanomicelle formulations using dialysis method Mixed nanomicelle formulations of active compounds were prepared by dialysis with different ratios of polymer and drug. The experimental design software, JMP 9.0, is used to plan experiments and analyze results. Use precisely weighed amounts of two polymers, namely, polyoxyl hydrogenated castor oil - 60 (HCO-60) and octoxynol-40 (Oc-40), 300 μl Dissolve in propylene glycol in a volume of 1 liter. 80 micrograms containing the active compound. 100 liters of propylene glycol (or 80 mg of active compound in PG) was added to this polymer. Add the glycerol to the mer mixture and vortex to obtain a clear, homogenous solution. Make up to 500 microliters with propylene glycol. Vortex the solution. A volume of 500 microliters of distilled, deionized water was added to the mixture. The total volume is then adjusted to 1000 microliters (1 milliliter). The addition of water to the drug-polymer mixture should spontaneously generate micelles, thereby The pharma- ceutical active agents are encapsulated in the hydrophobic core of the mixed nanomicelles.

[0411] The mixture was transferred to a dialysis bag (molecular weight cutoff 1000) and diluted with 1 liter of distilled deionized water. Cover the beaker and its contents with aluminum foil. Protect from sunlight with a damp cloth and keep under slow, constant stirring at room temperature. Dialysis of the mixture was continued for 24 hours. The mixture was run for a period of time to remove the water-soluble organic solvent, propylene glycol. The water in the dialysis chamber is then cooled at predetermined time points: 1 hour, 2 hours, 4 hours, 6 hours, and 12 hours. At the end of dialysis (24 hours), the contents of the dialysis bag are Carefully transfer the mixture into a 15 ml centrifuge tube and subject the preparation to sonication in a water bath (0 min - 5 min). (Time range of 10 min). Bring to final volume with 2x phosphate buffered saline and adjust the pH of the formulation to 6. The resulting formulation is then mixed with 0.22 micrometer nylon 100 ml of 0.5±0.1% water to obtain a 0.5±0.1% aqueous solution. Filter to remove any extraneous particulate matter.

[0412] The prepared formulations were analyzed for encapsulation efficiency, loading efficiency, size, and polydispersity index of mixed nanomicelles. It is subjected to various tests such as:

[0413] Size and polydispersity index of mixed nanomicelles: The size and polydispersity index of the formulations were determined by Z The results were determined using an etasizer (Malvern Instruments, NJ). Briefly, approximately 1 mL of each formulation was transferred to a cuvette and placed in the instrument. A 100% ethanolamine sieving machine was used to determine the size of the mixed nanomicelles. The size results are summarized in Table 2.

[0414] Encapsulation Efficiency: To determine the encapsulation efficiency of the formulation, all the prepared formulations are subjected to encapsulation efficiency test. Briefly, the formulation was vortexed to homogenize and 1 mL was transferred to a fresh ( Transfer each formulation to a 1.5 mL eppendorf tube. Obtain a solid at the bottom of the dorf tube. Add this solid to 1 mL of organic solvent (diethyl ether) and distill. The drug is suspended in an organic solvent (e.g., diethyl ether) to form reverse micelles, releasing the drug into the external organic solvent. The organic solvent is evaporated overnight under high-speed vacuum. The resulting reverse micelles are Resuspended in propanol (taking into account the dilution factor) and further diluted to obtain the respective micelle preparations The concentration of the active compound encapsulated in the formulation is determined by HPLC. The encapsulation efficiency of the formulation is evaluated according to the following: Calculate according to the formula (where MNF = mixed nanomicelle formulation): Encapsulation efficiency = (Quantified amount of drug in MNF) ×100 Amount of drug added in MNF

[0415] Drug quantification by HPLC: in vitro analysis of active compounds, Shimadzu H PLC pump (Shimadzu, Shimadzu Scientific inst ruments, Columbia, MD), Alcott autosampler (model 7 18 AL), Shimadzu UV / visible light detector (Shimadzu, SPD-2 0A / 20AV, USA), and an ODS column (5 μm, 150 × 4.6 mm), and a Hewlett Packard HPLC integrator ( Hewlett Packard, Palo Alto, CA) was used for reversed-phase high-performance liquid chromatography. The separation was carried out by RP-HPLC. The mobile phase was methanol (MeOH ), water, and trifluoroacetic acid (TFA) (70:30:0.05%, v / v). The flow rate is set to 0.5 mL / min. The detection wavelength is set to 272 nm. The temperature of the tray is maintained at 4° C. Calibration curve for active compounds (0.5-5 μg / mL) is prepared by making appropriate dilutions from a stock solution in 2-propanol. An injection volume of 1.0 l is injected onto the HPLC column for analysis. All standards and prepared samples were Samples are stored at 4°C before and during analysis. EXAMPLES

[0416] Preparation of mixed nanomicelle formulations using ethyl acetate solvent evaporation method The mixed nanomicelle formulations encapsulating the active compounds were prepared by the solvent evaporation method in two steps: The preparation is carried out in the following steps: 1) Preparation of the base formulation and 2) Rehydration. In step 1, the active compound and HCO-60 and Octoxynol-40 were dissolved separately in 0.3 mL of ethyl acetate. These three solutions are mixed together in a 15 mL centrifuge tube. The resulting mixture is vortexed to obtain a homogeneous solution. The ethyl acetate solvent is removed by rapid reduction. The residue is then removed under high vacuum at room temperature overnight. The remaining organic solvent is then removed.

[0417] In step 2, the resulting thin film is vortexed. The rehydrated formulation is then rehydrated in 1 mL of double distilled water by diluting in 2x phosphate buffered saline. The mixture was then filtered through a 0.2 μm nylon filter membrane. The active compound is filtered to remove any unencapsulated drug agglomerates and other foreign particles. Encapsulation was achieved by disruption of the micelles as well as the addition of 1001 diluent (2-propanediol) as described below. After solubilization in ethanol, the activity is determined by RP-HPLC.

[0418] The prepared formulation was evaluated for encapsulation efficiency, loading efficiency, mixed nanomicelles, and the like according to the method described in Example 1. The particles are then subjected to various tests such as particle size and polydispersity index.

[0419] The weight percent of drug loaded in the MNF was determined according to the method for encapsulation efficiency. The size and polydispersity index of the formulations were determined using the Zetasis™ from Malvern, as described above. The results are summarized in Table 2 below. The appearance of the formulation was clear. The appearance of the formulation is transparent, the size is small, and the size distribution is narrow. The size distribution is narrow.

[0420] [Table 2] EXAMPLES

[0421] Preparation of mixed nanomicelle formulations using a melting method Weigh out 200 milligrams of hydrogenated castor oil-60 (HCO-60) (4% by weight) and mix for 10 minutes. Transfer the solution to a 30 mL round-bottom flask (RBF). Close the neck of the round-bottom flask with aluminum foil and place in a Parabolic Seal with film and transfer to a water bath set to 40°C. Leave the round-bottom flask in the water bath overnight. Place in the flask to liquefy / melt the HCO-60. The next day, add 10 microliters of Octoki Dilute Cinol-40 100-fold and equilibrate in a water bath at 40°C for 1 hour. Similarly, the active compound (as neat oil) was equilibrated in a water bath at 40°C for 1 hour. Add 50 μL of 100-fold diluted Octoxynol (0 Add 0.01% by weight of the active compound to the above mixture at 40° C. Add and stir at 40° C. To this mixture, add approximately 2 mL of distilled dehydrate equilibrated at 40° C. Slowly add deionized water and stir. Close the neck of the round-bottom flask with aluminum foil and Seal with film. Keep the solution for 40 minutes, protected from light (covered with aluminum foil). Stir overnight in a water bath set at 40°C. The next day, remove the 40°C solution from the water bath. Remove from the oven, cool to room temperature, and observe for transparency. Add 2 ml of phosphate buffer (2x ) is added to the solution prepared above (the phosphate buffer is prepared in advance and adjusted to pH 5.5). The volume of the formulation is adjusted to 5 mL with 2x phosphate buffered saline. The agent is filtered through a 0.2 μm nylon filter and stored at 4°C.

[0422] The prepared formulation was evaluated for encapsulation efficiency, loading efficiency, mixed nanomicelles, and the like according to the method described in Example 1. The particles are then subjected to various tests such as particle size and polydispersity index. EXAMPLES

[0423] Preparation of mixed nanomicelle formulations using a second melting method The preparation of MNF encapsulating active compounds (as neat oil) is divided into two steps: 0.4% of the active compound can be encapsulated in 3.0% by weight of HCO-40 or H An example of the development of MNF for CO-60 is described below. In step 1, 150m g of HCO-40 or HCO-60 was melted in a water bath at 40°C and the results were A clear, thick, viscous liquid is obtained. The molten polymer is then added to an activation bath at a temperature of 40°C. Add the mixture (approximately 20 mg) and mix to disperse evenly. Allow the mixture to warm to room temperature. The result was a pale yellow viscous liquid with HCO-40 and a waxy liquid with HCO-60. To obtain a solid of HCO-40, the mixture is then mixed with water to obtain a solid of HCO-40. Store at 4°C (in a refrigerator).

[0424] In step 2, the pellets and / or viscous liquid are incubated at room temperature under natural conditions. The pellets and / or viscous liquid are kept in a water bath at 40°C for a constant Resuspend in 2.0 mL of distilled water (temperature adjusted to 40°C) while stirring. This naturally produces a clear aqueous solution of 0.4% of the active compound MNF. The solution was allowed to warm to room temperature under natural conditions. The pH of the solution was adjusted to 5.5, and Octoxynol-40 was added. (0.01 wt%) and 2x phosphate buffer containing PVP-K-90 (1.2 wt%) The volume is increased with saline (pH 5.5). The formulation is passed through a 0.2 μm nylon filter. and filtering to remove any extraneous material, leaving a clear, homogeneous, aqueous solution containing the active substance. The formulation is obtained.

[0425] 1 Qualitative studies by 1 H NMR: determining the absence of free drug in the external aqueous environment A qualitative study was carried out to determine the identity of the proton nuclear magnetic resonance (NMR) spectroscopy of the The NMR was performed using a 400MHz rian NMR spectrometer. The solvent system was deuterated chloroform and Deuterium oxide is used to resuspend the formulation and undergo NMR studies.

[0426] Results: Compounds added to HCO-40 or HCO-60 at 40°C contained active compounds. At higher temperatures, the polymer-drug mixture becomes viscous and When allowed to return to room temperature under natural conditions, the HCO-60 mixture remains in a solid state. This waxy solid is then cooled to a temperature of 40°C. When the formulation is resuspended in distilled water, the MNF containing the active compound is naturally dissolved in water. Similar observations and results are obtained with the viscous liquid HCO-40. The viscosity of the mixture appears to be improved at lower temperatures (4°C). The material appears to stick to the walls of the container as a thick, viscous liquid. The viscosity appears to decrease and the mixture regains its fluidity.

[0427] The waxy solid produced by the mixture of HCO-60 and the active compound is the drug This is useful for protecting the drug from degradation by providing a surface blanket of inert gas. Another polymer (HCO-40) when used at up to approximately 3.0% by weight, At room temperature or low refrigeration conditions (4° C.), it did not produce a waxy solid.

[0428] Qualitative proton NMR studies demonstrated the resuspension of the formulation in aqueous phase (D2O). The mixed nanomicelles were spontaneously formed, and no free drug peak was evident in the aqueous solution. If the drug is not encapsulated in the core of the mixed nanomicelles, it can be encapsulated in a separate oil phase. On the other hand, if the same preparation is mixed with deuterated chloroform, the oil will float on the surface. When the drug was resuspended in an organic solvent such as hexane (CDCl3), a peak for the drug was observed along with a peak for the polymer. The corresponding distinct peaks are shown, which indicates that the drug is not encapsulated in the core of the micelles. When present in an organic solvent, it is indicated as being freely available.

[0429] Regarding the physical appearance of the mixture, the different phases, and the appearance of the final formulation at different temperatures The results obtained are summarized in Tables 3a to 3c.

[0430] [Table 3a]

[0431] [Table 3b]

[0432] [Table 3c]

[0433] Conclusion: These studies demonstrated that the polymer HCO-60 can be activated using the hot melt method. It has been shown that HCO-40 can be used to encapsulate compounds under the conditions of this study. does not produce a waxy solid even at the higher weight percent (3.0%). On the other hand, HCO-60 produces a waxy solid at 2.0 wt.%. is said to be an easy and rapid method that avoids the use of organic solvents in preparing MNF. It has unique advantages. Its preparation method is also easy and quick. The powdered solid is useful for preventing drug degradation and is blanketed with an inert gas. , which may help keep the drug in a waxy solid state at room temperature. MR studies have demonstrated that the drug is freely available even when resuspended in aqueous solution. However, when the same formulation is resuspended in the organic solvent, CDCl3, In this case, the drug peak was clearly observed, and this formation was attributed to the presence of the drug in the external organic solvent environment. The presence of is indicated. EXAMPLES

[0434] Preparation of mixed nanomicelle formulations MNF formulations of active drugs can be prepared by the solvent evaporation method in two steps: 1. Preparation of the base formulation and 2. rehydration. In step 1, the active agent, HCO-40, and octyl Toxinol-40 is dissolved separately in 0.5 mL aliquots of ethanol. These three solutions are mixed together in a round bottom flask. The resulting mixture The ethanol solvent was removed by speed vacuum evaporation overnight. to obtain a solid thin film.

[0435] In step 2, the resulting thin film was diluted with 2.0 mL of redistilled deionized water. The rehydrated formulation is then resuspended in 100 ml of water with stirring overnight. The volume was increased with 2x phosphate buffer solution (pH 6.8). The drug is filtered through a LON filter membrane to remove unencapsulated drug aggregates and other foreign particles. and are removed.

[0436] Using the combination of different polymer weight percentages used in the previous examples This results in aqueous MNF that encapsulates 0.2 wt. % of the active agent. These formulations are characterized by size, polydispersity index, and The results are shown in Table 4a and 4b. Summarised in 4b.

[0437] [Table 4a]

[0438] [Table 4b]

[0439] Water Method. The MNF formulation of the active agent was Prepare the solution by the method described above. Heat 1 mL of double-distilled, deionized water to 60 °C in a round-bottom flask. Continue to stir the heated water. Add HCO-40 to the heated water and keep stirring. Continue stirring until dissolved. Octoxynol-40 is then added to the mixture and dissolved. In a separate container, shake the phosphate, sodium chloride, and CsA by hand for a few minutes. Under stirring conditions, the phosphate / CsA / sodium chloride blend is mixed. is added to a solution of HCO-40 and octoxynol-40 to disperse the drug. Allow the mixture to cool to room temperature while stirring and check to see if the drug is completely dissolved. Prepare the K90 solution separately using the remaining 1 mL of double-distilled deionized water. PK 90 solution in a polymer / surfactant / drug / phosphate / sodium chloride solution Add water to final volume. The formulation is then passed through a 0.2 μm nylon membrane. The mixture is then filtered to remove drug agglomerates and other extraneous particles. EXAMPLES

[0440] Local tolerance of the formulation in rabbits Healthy young adult New Zealand albino rabbits (3-4 Kg) were cultured as described herein. It is used to study the local tolerability of the formulations to be administered, such as the formulations of Examples 1 to 5. A volume of saline (approximately 30 μL) was placed in one eye of the rabbit, and one drop of the formulation was placed in the other eye. Both eyes of each animal were examined by a veterinary ophthalmologist using a handheld slit lamp and indirect ophthalmoscope. Both the control and test eyes are examined for conjunctival hyperemia, swelling, and discharge. , aqueous humor flare, iris light reflex and involvement, corneal opacity Hack The results were evaluated using the Hackett / McDonald scoring system (see, e.g., Hackett, R .B.and McDonald,TOophthalmic Toxicolog y and Assessing Ocular Irritation.Dermat oxicology,5.sup.th Edition.Ed.FNMarzul li and HIMaibach.Washington,DC:Hemis phere Publishing Corporation.1996;299-30 5 and 557-566). In the fluorescein test, approximately one drop of 0.9 % Sodium Chloride, USP was applied to the end of the fluorescein-impregnated strip and then left Apply fluorescein-impregnated strips to the right and left eyes (one strip for each animal) After approximately 15 seconds of exposure, the fluorescein dye is dissolved in 0.9% sodium chloride. Each eye is then gently rinsed with cobalt blue USP. The eye is examined using a light source filtered through a ray. For the examination of the crystalline lens, the pupil is dilated. To achieve acceptable dilation, approximately one drop of a short-acting mydriatic solution is placed in each eye. After birth, the lens of each eye is examined using a slit lamp microscope.

[0441] The lens is observed with the aid of a slit lamp and is illuminated by direct and backlighting. Identify the location of the opacity. Arbitrarily identify the location of the lens opacity into the following regions of the lens, beginning with the anterior capsule: The lens is divided into the following parts: anterior subcapsular, anterior cortical, posterior cortical, posterior subcapsular, and posterior capsule. The presence of lens opacity is evaluated in a systematic way and scored as 0 (normal) or 1 (abnormal). Write it down and note its location. EXAMPLES

[0442] 0.05%, 0.2%, and 0.5% by weight in the mixed micelle formulations of the present disclosure Ocular tissue distribution of the formulation The time distribution and the effect of repeated administration of the (ophthalmic solution) of the present disclosure (for example, the formulations of Examples 1 to 5) and potential accumulation, sex differences, as well as potential melanin binding, after application to the eye. Zealand White (NZW) rabbits and Dutch Belted (Dutch Belted, DB) by determining the concentration of the active ingredient in the ocular tissues, tears, and blood of rabbits. evaluate.

[0443] NZW rabbits were used in single-dose (SD) and 7-day repeated-dose (RD) studies. DB rabbits are used in single dose studies). Animals are untreated (control). ) or topical ocular application in a single dose or daily for 7 days (in one or both eyes) , provided at 0.05%, 0.2%, or 0.5% by weight in the mixed micelle formulation. Blood and ocular tissue concentrations are assessed.

[0444] Drug concentrations are determined in tissues at the front of the eye (cornea, conjunctiva, sclera) and at the back of the eye (retina, optic nerve ) in the tissues around the eye, but is minimal in the center of the eye (aqueous and vitreous humors). This suggests that the drug may be transported by a mechanism other than passive transport through the eye. The high drug concentrations achieved make topical administration of the compositions of the present disclosure ideal for treating diseases of the posterior segment of the eye (e.g., glaucoma, This makes it practical for the treatment of retinal diseases involving the optic nerve, such as glaucoma and optic nerve disorders. The compositions of the present disclosure demonstrate extremely high concentrations of erythropoietin, particularly in target tissues such as the lacrimal gland. become. EXAMPLES

[0445] Use of mixed nanomicelle formulations to treat dry eye The mixed nanomicelle formulations according to Examples 1 to 5 were administered for a period of 1 month to 1 year or more. It is administered twice daily at a concentration of .05% to 0.2% to patients with dry eye. EXAMPLES

[0446] Use of mixed nanomicelle formulations to treat diabetic retinopathy The mixed nanomicelle formulations according to Examples 1 to 5 were administered for a period of 1 month to 1 year or more. It is administered twice daily at concentrations of 0.2% to 0.5% to patients with proliferative diabetic retinopathy. EXAMPLES

[0447] Tolerability and ocular tissue distribution of mixed nanomicelle formulations To evaluate the tolerability and ocular tissue distribution of the nanomicelle formulation of the active agent compared with placebo and saline. To test for saline (BSS), a study was performed in rabbits. Zealand White rabbits (2-3 kg) are used in this study. Study drugs were administered essentially as described herein. Prepare as described in the Examples section below to have 0.1% active agent. The table below shows the formulation composition of the formulation and placebo.

[0448] [Table 5]

[0449] One drop (approximately 35 μL) of study medication was applied to the right eye, four times per day, two hours apart, for five days. Apply one drop of BSS to the contralateral eye.

[0450] Tolerability parameters evaluated are: clinical examination, acclimation, study release, study release); vitality (daily); clinical observation (daily); Hackett t-McDonald visual irritation score (pre-dose baseline data for each rabbit, and before each dose on each day [before the first dose of the day] and 30 minutes after the last dose of the day. The data after 10 minutes, pre-dose baseline intraocular pressure (IOP) data for each rabbit, and The data from 30 minutes after the test on each night and the electroretinogram (ER G) Pre-dose (pre-study) baseline data, as well as data one hour after the last treatment, etc. and ocular histopathology at the time of euthanasia.

[0451] Cumulative mean Hackett-McDonald visual stimulation scores were calculated for the BSS-treated left Both the right and left cyclosporine-treated eyes were examined pre- and posttreatment. Both showed very minimal scores throughout the study, with a cumulative average inflammation score of less than 2. These clinical scores were observed in eyes treated with TA, placebo, and BSS. A represents mild conjunctival hyperemia (redness) and swelling. However, there was no significant difference between the groups. There were no significant differences in the cumulative mean Cett-McDonald visual stimulation scores. Topical administration of 0.1% CsA in HCO-40, HCO-40 placebo, and BSS These results suggest that there is no difference in inflammation between the two groups.

[0452] Changes in IOP in eyes treated with BSS, HCO-40, or active agent After 5 days of treatment with the test substance, no toxicological changes in retinal function were observed in the ERG. The anterior (conjunctiva / cornea / iris) or posterior (vitreous / No toxicological or inflammatory changes were observed histologically in the retina.

[0453] Selected ocular tissue samples (aqueous humor, vitreous humor, conjunctiva, cornea, iris-ciliary body, lens, retina) / choroid, and sclera) 1 hour after the last dose on the fifth day, with HCO-40 0. The right eyes (OD) of all two rabbits that received 1% active drug and the right eyes (OD) of all two rabbits that received BSS The left eye (OS) of these rabbits, as well as one rabbit that received placebo HCO-40, The OD of rabbit (No. 21) and the BSS of this rabbit were collected from the administered OS. These samples were analyzed for active drugs by liquid chromatography-tandem mass spectrometry (LC-MS). The internal standard is d4-active drug. Established analytical ranges are 0.100 to 100 ng / mL for whole blood and 0.100 to 100 ng / mL for aqueous humor. and 2.00-2000 ng / mL for vitreous humor. Analytical ranges are 0.125-30ng (low range) and 1.00-2500ng (high range). By correcting for the amount of tissue analyzed, the results of the solid tissue analysis were expressed in ng / g Convert to.

[0454] The concentrations of active drug in ocular tissues collected 1 hour after the last dose on Day 5 are shown in Table 6. In summary, after repeated administration of 0.1% active drug-HCO-40 formulation, The highest mean concentration of active drug in the eye was observed in the cornea (7805 ng / g). , conjunctiva (2125ng / g), sclera (720ng / g), iris-ciliary body (204ng / g ), and aqueous humor (134 ng / mL). The lowest concentration of active drug was in the lens (68 .6ng / g), retina / choroid (54ng / g), and vitreous humor (approximately 8ng / mL). The concentration of active agent in the BSS-treated contralateral eye was very low. , suggesting that systemic delivery of the drug is minimal.

[0455] The ocular tissue concentrations observed in this study for the 0.1% active drug formulation were generally Repeated administration of 0.2% 3H-cyclosporine A formulation of Lergan to rabbits (7 days, 1 day C after 2 times max (Acheampong AA, Shackl eton M,Tang-Liu D,Ding S,Stern ME,Decker R Distribution of cyclosporin A in ocu lar tissues after topical administration to albino rabbits and beagle dogs;Curre nt Eye Research 18(2);1999;pp91-103).

[0456] [Table 6] EXAMPLES

[0457] Tolerability and ocular tissue distribution of mixed nanomicelle formulations of active compounds The tolerability and ocular tissue distribution of two nanomicelle formulations of the active compound were compared with the corresponding placebo ( 7a and 7b) and physiological saline (BSS) were tested in rabbits. Healthy female New Zealand White rabbits (2–3 kg) were used for this study. One drop (approximately 35 μL) of study medication was administered into the right eye four times a day for 5 days, 2 h after the first administration. Apply 1 drop of BSS to the contralateral eye.

[0458] Tolerability parameters evaluated are: clinical examination, acclimation, study release, study release); vitality (daily); clinical observation (daily); Hackett t-McDonald visual irritation score (pre-dose baseline data for each rabbit, and before each dose on each day [before the first dose of the day] and 30 minutes after the last dose of the day. The data after 10 minutes, pre-dose baseline intraocular pressure (IOP) data for each rabbit, and The data from 30 minutes after the test on each night and the electroretinogram (ER G) Pre-dose (pre-study) baseline data, as well as data one hour after the last treatment, etc. and ocular histopathology at the time of euthanasia.

[0459] [Table 7a]

[0460] [Table 7b]

[0461] The cumulative Hackett-McDonald visual irritation scores were calculated for the BSS-treated left and right eyes, respectively. Both the right and test article-treated eyes were examined at both pre- and post-treatment. The Hackett- No significant differences in the cumulative mean McDonald visual arousal scores were observed. The visual stimulus was interpreted as minimal and transient in all groups.

[0462] [Table 8]

[0463] No changes in IOP were noted in eyes treated with BSS or test article. After short-term treatment, no toxicological changes in retinal function were observed in the ERGs. Histological findings in the anterior (conjunctiva / cornea / iris) or posterior (vitreous / retina) segments of the eye No toxicological or inflammatory changes were noted.

[0464] In the active drug treatment groups (0.15% in HCO-60 and 0.1% in HCO-40), two mice were Ocular fluids / tissues were collected from rabbits, one rabbit from each of the matched placebo groups. (aqueous humor, vitreous humor, conjunctiva, cornea, iris-ciliary body, lens, retina / choroid, and sclera) , and the active compounds were identified by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Warfarin-d5 and 5-HDA are assayed for The distribution of RX-10045 and its active metabolite, RX-10008, in For other ocular tissues (solid tissues), d5 and phenylacetic acid-d5 (PAA-d5) were used as compounds 1001 and R Used as an internal standard for X-10008. The analytical range for solid tissue is 0.125-100n g. By correcting for the amount of tissue analyzed, the results of solid tissue analysis can be expressed as ng / mL. Convert to g.

[0465] Only sporadic and relatively low concentrations of the Compound 1001 ester prodrug were detected in the sclera and cornea. Compound 1001 was not detected in most ocular tissues or was not detected in the assay. These data indicate that RX-10045 is a potent agonist and its active metabolite, R This suggests that it is rapidly hydrolyzed to X-10008.

[0466] A summary of tissue concentrations of the parent compound (RX-10008) is presented in Table 9. RX-1000 The highest concentration of 8 was identified in the cornea, followed by the iris-ciliary body, conjunctiva, and sclera. Relatively high concentrations of RX-10008 are also present in the aqueous humor. , retina / choroid and lens. It is identified in the vitreous humor.

[0467] [Table 9]

[0468] The invention illustratively described herein includes any compound not specifically disclosed herein. The terminology and expressions used may be used without limitation. are used as terms of description rather than as terms of In any case, the intention is to exclude the features shown and described, or equivalents of portions thereof. It is understood that various modifications may be made within the scope of the invention as claimed. Thus, the present invention has been specifically disclosed by preferred embodiments and optional features. However, modifications and variations of the concepts disclosed herein may be used by those skilled in the art. and such modifications and variations are defined by the appended claims. It is to be understood that this is considered to be within the scope of the present invention.

[0469] The articles, patents, and patent applications, and all other documents described or cited herein The contents of the printed and electronically available information are incorporated by reference in their entirety. Each of the above-mentioned embodiments is incorporated herein by reference in its entirety to the same extent as if specifically and individually indicated. Applicants hereby grant to the assignee a right to use, distribute, publicly perform, or publicly perform any and all intellectual property rights, including, but not limited to, any right to use, publicly perform, or publicly perform any and all intellectual property rights, including but not limited to ... The right to physically incorporate any and all materials and information into this application is reserved.

[0470] The invention illustratively described herein includes any compound not specifically disclosed herein. The term "comprises" may be used interchangeably with "includes" or "includes" in any embodiment. Are "comprising," "including," and "containing" expansive? Further, the terms and expressions used in this specification should be read without limitation. The expressions are used as terms of description and not as terms of limitation, and such terms and expressions Where used, the features shown and described or equivalents to portions thereof are excluded. It is not intended that the present invention be limited to the above-mentioned specific embodiments, and various modifications may be made within the scope of the invention as claimed. It will be understood that the present invention is thus embodied in preferred embodiments and optional features. Although generally disclosed, the modifications and variations of the invention incorporated therein are disclosed herein. It is understood that modifications and variations may be employed by those skilled in the art and that such modifications and variations are within the scope of the present invention. It should be understood that these are considered to be within the scope of the disclosure.

[0471] The invention has been described broadly and generically herein. Each of the narrower species and sub-species groupings herein also form part of this invention. includes a comprehensive description of the present invention, but excludes any object from the concept. The invention has a condition or negative limitation, which means that the excluded subject matter is specifically recited in this specification. It doesn't matter if you're there or not.

[0472] In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that and whereby the invention also relates to any individual member of the Markush group or It will be appreciated that subgroups of members may also be described.

[0473] Other embodiments are within the scope of the following claims.

Claims

1. 1. Use of an ophthalmic formulation in the manufacture of a medicament for treating dry eye syndrome, comprising: The formulation comprises 0.05-5% by weight of one or more polyoxyl lipids or fatty acids selected from the group consisting of HCO-40, HCO-60, HCO-80, HCO-100, polyoxyl 40 stearate, and polyoxyl 35 castor oil, and 0.01-0.1% by weight of octoxynol-40; The formulation comprises mixed nanomicelles, The formulation is free of organic solvents; and The formulation does not contain any pharma- ceutical active agent; A use wherein said medicament is used as a medicine without containing any pharma- ceutical active agent.

2. 2. The use of claim 1, wherein the formulation comprises 1-5% by weight of one or more polyoxyl lipids selected from the group consisting of HCO-40, HCO-60, HCO-80, and HCO-100, and 0.01-0.1% by weight of octoxynol-40.

3. 2. The use of claim 1, wherein the formulation comprises 0.7-1.5% by weight of one or more polyoxyl lipids selected from the group consisting of HCO-40, HCO-60, HCO-80, and HCO-100, and 0.05% by weight of octoxynol-40.

4. 2. The use according to claim 1, wherein the polyoxyl lipid or fatty acid is HCO-40.

5. The use of claim 1 , wherein the formulation further comprises an isotonicity agent, a bioadhesive polymer, a preservative, a buffer, and water.

6. The use according to claim 1, wherein the pH of the formulation is from 5 to 8.

7. The use according to claim 1, wherein the pH of the formulation is from 6.6 to 7.

8. 2. The use according to claim 1, wherein the formulation is stable at 40°C.

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