TW201039824A - Compositions and methods for treating ocular inflammation with lower risk of increased intraocular pressure - Google Patents

Abstract

A composition for treating or controlling an ocular disease or condition comprises a dissociated glucocorticoid receptor agonist (''DIGRA''), which disease or condition has an etiology, or results, in inflammation. The composition can optionally include an anti-inflammatory agent, an anti-infective agent, or both. The composition can be formulated for topical application, injection, or implantation in an affected eye to treat or control the ocular inflammatory disease or condition.

Description

201039824 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a composition and method for treating or controlling inflammation of the eye. In particular, the present invention relates to compositions comprising a dissociated glucocorticoid receptor. agonist ("DIGRA") and methods of using the compositions to treat or control ocular inflammation - such compositions and methods It can reduce the risk of increased intraocular pressure. [Prior Art] 〇 Many anterior and posterior ocular conditions are caused by inflammation. For example, several studies have confirmed or strongly indicated that such as corneal edema, anterior uveitis and posterior uveitis, pterygium, corneal disease, dry eye, conjunctivitis, allergy-induced exudation and laser-induced exudation, macular degeneration The underlying cause of diseases such as macular edema, diabetic retinopathy and age-related macular degeneration is inflammation. See, for example, I. Kim et al., Price 0/· c/zew., Vol. 276, No. 10, 7614 (2001); Α·Μ. Joussen et al., 乂 乂 'Vol. 18, 1450 (2004) ) SC Pflugfelder, Knowledge, Vol. 137, 337 (2004). In addition, a mediator of tumor necrosis factor-α ("TNF-α"), a pro-inflammatory cytokine, has been recently identified as a retinal ganglion cell ("RGC") death. TNF-a and TNF-a receptor-1 were up-regulated in a rat model of glaucoma. In vitro studies further confirmed that 'TNF-a-mediated RGC death and receptor-mediated caspase cascade and mitochondria-mediated cell death cascade caspase-dependent and caspase-independent Related to the activation of sexual components. G_ Tezei and X. Yang, heart ρί7 do e, volume 81, 2〇7 (2〇〇5). Moreover, 147399.doc 201039824 has found that the amount of TNF-a and its receptor is greater in the retinal portion of the glaucoma eye than in the control eyes of the age-matched normal donor. G Tael ^ Person, /nvai. ^, Vol. 42, No. 8 1787 (2001). Therefore, there is growing evidence that the underlying cause of glaucoma may be chronic inflammation. Failure to control injury-induced immune responses may result in autoimmune morbidity and may cause or maintain ocular neurodegeneration in many patients. Glucocorticoids ("GC", also referred to herein as corticosteroids) are commonly used to treat various ocular conditions with inflammatory or angiogenic components, such as macular edema, "wet" age-related macular degeneration, grapes Membrane inflammation and surgical complications. The therapeutic benefit of GC is due to the multi-directional regulation and mobilization of a variety of intracellular signaling pathways, primarily covering the steroid-nuclear receptor complex transrepresive effect on the elements that interfere with the transcription of the selected gene (tranSrepreSSive effect) ). Glucocorticoid therapy (independent of the route of administration) is usually accompanied by an increase in intraocular pressure ("I〇p") which can lead to glaucoma, presumably as one or more genes not associated with the indication being treated Side effects caused by activation. Some patients who have eyelids (: may not show any effect, while others who are classified as responders show a range of recorded IOP increases due to several risk factors, including age, primary opening Angle glaucoma ("p〇A(3") history and genetic predisposition. POAG is characterized by high IOP, which is caused by the outflow of aqueous fluid through the trabecular meshwork ("τΜ"). The tubal area adjacent to the inner wall of the Schlemm, s canal (juxtaeanaUcuiar regi〇n) 147399.doc 201039824 (JCT) is a possible site for blocking outflow under normal physiological conditions, so the structure of the jct is expected. And biochemical changes affect I〇p. The common feature of p〇AG and steroid-induced lunar eye is that extracellular matrix (ECM) and other substances ("plaques") accumulate in JCT to form a blockage • outflow path. And increase the abnormal aggregates of macromolecules of IOP. As with many other non-ocular cells and tissues, it has been confirmed experimentally and in clinical samples that TM is susceptible to GC induction. The effect of ECM changes. Myofibrillin is a protein that is usually detected in the tissues of the eye, and its constitutive expression is most evident in TM (both intracellular and extracellular). Muscle fibrin gene (MFOC) mutation The discovery of selected forms of P〇AG and adolescent open-angle lunar eyelets ultimately turns attention to the role of wild-type myofibrillin in eye health and disease. Apparent uniqueness and characteristics of in vitro and in situ TM cells _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Etiology. In addition to having an effect on the internal structure and function of TM cells (as assessed in organ culture materials), GC treatment can induce these cells to synthesize and secrete excess myofibrillin, ultimately resulting in protein deposition in ECM. On the outflow path' and thus increase I〇p. Pharmacological dose of dexamethasone ("DEX") causes myofibrillin expression in cultured tm cells from normal human donors Increases, as indicated by immunohistochemical analysis of myofibrillin mRNA or by soluble myofibrillin released into the culture medium. Whether these changes constitute musculin has direct effects in the pathophysiology of any form of glaucoma The basis of action, the drug-induced increase of the protein 147399.doc 201039824 can be considered as an alternative indicator of the risk of secondary glaucoma. The industry's non-steroidal GC receptor (GR) agonists are: when interested, due to The structure of the agonists and the specific conformation that occurs after binding to ^ /L σ main: the 'dissociation and transduction of the selected genes normally affected by GC may be partially dissociated. Molecules with these unique biochemical properties are generally used in clinical steroid (10) agonists with improved clinical safety properties. Human TM cells have been widely used as responses in vitro. Accordingly, there remains a need to provide improved pharmaceutical compounds, compositions, and methods for treating or managing ocular inflammatory diseases, conditions, or conditions compared to prior art glucocorticuses for treating or controlling the same disease, condition, or condition. Hormone compositions and methods reduce the risk of increased IOP. SUMMARY OF THE INVENTION As used herein, the term "control" also includes reducing, alleviating, ameliorating, and pre-ocular inflammatory diseases, inflammatory diseases, conditions, or conditions. The present invention provides compounds for treating or controlling a condition or disorder, A composition or method. The condition is caused by inflammation or causes inflammation. In one aspect, the compounds, compositions, methods of the invention may reduce the risk of increased I〇p compared to compositions and methods for treating or controlling the same disease, condition or disorder using prior art GC. In another aspect, the anterior segment of the ocular inflammatory disease, condition or condition comprises uveitis (including anterior uveitis, posterior uveitis, and uveitis), keratitis, conjunctivitis, keratoconjunctivitis (including Spring keratoconjunctivitis 147399.doc 201039824 (or "VKC") and atopic keratoconjunctivitis), corneal ulcer, corneal edema, sterile corneal infiltrate, anterior scleritis, scleritis, orbital inflammation, and Such as refractive keratectomy, cataract extraction, intraocular len ("IOL") implantation, laser-assisted in situ keratomileusis ("LASIK"), conductive angulation, valvuloplasty, Post-operative (or post-surgical) ocular inflammation, dry eye, macular degeneration, macular edema, diabetic retinopathy, age-related macular degeneration (including wet and dry), and glaucoma caused by operations such as radial keratotomy (including all types of glaucoma). In yet another aspect, the inflammatory diseases, conditions or conditions are caused by infections caused by bacteria, viruses, fungi or protozoa. In still another aspect, the compositions comprise at least one glucocorticosteroid mimetic for use in treating or controlling the disease, condition or disorder. In still another aspect, a pharmaceutical composition for treating or controlling an inflammatory disease, condition or disorder comprises at least one dissociated glucocorticoid receptor agonist (DIGRA), a prodrug thereof, or a pharmaceutically acceptable Salt or ester. In still another aspect, the pharmaceutical compositions of the present invention comprise an ophthalmic topical formulation; an injectable formulation; or an implantable formulation, system or device. In yet another aspect, the formulation, system or device is administered or provided to the anterior segment of the eye. In a recurrence, the formulation, system or device is administered or provided to the posterior segment of the eye. In another aspect, the increase in IOP is shown in vitro or in vivo. In still another aspect, the increase in IOP is caused by an increase in resistance experienced by fluid flow through the trabecular meshwork 147399.doc 201039824. In yet another aspect, the increased resistance is due to increased expression and accumulation of fibrin in the trabecular meshwork. In another aspect, the invention provides methods of treating or controlling an anterior segment of an inflammatory disease, condition or disorder. The method comprises administering to a diseased eye of an individual in need of such treatment or control a composition comprising DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof. Other features and advantages of the present invention will become apparent from the following description and claims. [Embodiment] The dissociated glucocorticoid receptor agonist ("dIGrA") used herein is capable of binding to a glucocorticoid receptor (a polypeptide thereof) and can produce different degrees of gene expression resistance after binding. Transactivated compound. Compounds that bind to a polypeptide are sometimes referred to herein as ligands. As used herein, "alkyl or alkyl group" means a straight-bonded or branched-chain saturated aliphatic hydrocarbon monovalent group which may be unsubstituted or substituted. The group may be partially or completely via a halogen atom (F, C1, Br or substituted. Non-limiting examples of alkyl include fluorenyl, ethyl, n-propyl, benzylethyl (isopropyl), n-butyl Base, n-pentyl, U-dimethylethyl (tri-butyl) and the like. It can be abbreviated as "Alk". The technique used herein is "alkenyl or alkenyl group". a linear or branched aliphatic hydrocarbon monovalent group containing at least one carbon-carbon double bond. This term is exemplified by groups such as vinyl, acryl, n-butenyl, isobutenyl, 3_ Mercapto-2-enyl, n-pentenyl, hept 147399.doc 201039824 Alkenyl, octenyl, decenyl and the like. The term "alkynyl or alkynyl group" as used herein means a linear or branched aliphatic hydrocarbon monovalent group of at least one carbon-carbon triple bond. This term is exemplified by groups such as ethynyl, propynyl, n-butanyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl and the like. The term "stretching base" as used herein. (alkylene or alkylene group)" means a linear or branched saturated aliphatic divalent hydrocarbon group having a specific number of carbon atoms. This term is exemplified by groups such as methylene, ethyl, Propyl propyl, n-butyl butyl and the like, and which may be additionally and equivalently referred to herein as "-(alkyl)-". "5" "alkenylene or alkenylene group" means a linear or branched saturated aliphatic divalent hydrocarbon group having a specific number of carbon atoms and at least one carbon-carbon double bond. This term is exemplified by groups such as vinyl, propylene, and n-butyl. Alkenyl and the like, and which may be additionally and equivalently referred to herein as "-(alkenyl)-". 〇, ^ The term "alkynylene or alkynylene group" means at least one carbon-carbon. a straight-chain or branched aliphatic divalent hydrocarbon group of a triple bond. The term is exemplified by groups such as ethynyl, propynyl, n-butynyl, 2-butenyl, 3-methyl-butynyl, n-th-pentynyl, heptyl, octyl, anthranyl and As such, and may be additionally and equivalently referred to herein as "-(alkynyl)-". As used herein, "aryl or aryl group" means having a single ring (eg, 'benzene' Aromatic carbocyclic ring of 5 to 14 carbon atoms of a plurality of fused rings (for example, naphthyl or anthracene 147399.doc 201039824) or a plurality of bridging rings (for example, biphenyl) Monoterpene or divalent group. Unless otherwise stated, the aryl ring may be attached at any suitable carbon atom which results in a stable structure and, if substituted, may be at any suitable carbon atom which will result in a stable structure. Replaced. Non-limiting examples of aryl groups include phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, fluorenyl, biphenyl, and the like. It may be abbreviated as "Ar" ° '", and the term "heteroaryl or heteroaryl group" means having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur in the ring (any of them) a stable aromatic 5 to 14 membered monocyclic or polycyclic monovalent or divalent group of a sulfur heteroatom which may be oxidized and optionally a nitrogen heteroatom optionally oxidized or quaternized, which may comprise one or more One fused ring or bridged ring, preferably a 5- to 7-membered single ring or a 7-membered to 1-membered bicyclic group. Unless otherwise stated, the heteroaryl ring may be attached at any suitable heteroatom or carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable hetero atom or carbon atom which results in a stable structure. . Non-limiting examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, Tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, diazinyl, pyridazinyl, azaindazinyl, fluorenyl, azaindole, diaza Mercapto, dihydroindenyl, dihydroazaindolyl, isodecyl, azaheterodecyl, benzofuranyl, furopyridinyl, furopyrimidinyl, furopyrazine , furo-pyridazinyl, dihydrobenzofuranyl, dihydrofuropyridinyl, dihydrofuropyrimidinyl, benzothienyl, thienopyrene 147399.doc -10- 201039824 Ο

Pyridyl, thienopyrimidinyl, thieno. Biazinyl, thienopyridazinyl, dihydro benzoxanthene, dihydro-sinter. Than the base, chlorin and sulfhydryl, carbazolyl, azacarbazolyl, diazazolyl, benzimidyl, imidazopyridyl, benzothiazolyl, thiazolopyridyl , thiazolopyrimidinyl, benzoxazolyl, benzoxazinyl, benzoxazinyl, oxazoloacridinyl, oxazolopyrimidinyl, benzoisoxazolyl, fluorenyl, benzo Dichloropyranyl, azabenzodihydromu, decyl, (tetra), dioxinyl, tetrahydroquinolyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroquinoxaline Polinyl porphyrin, azaindolyl, pyridazinyl, azaoxazinyl, quinazolinyl, azaquinazolinyl, quinoxalinyl, azaquinoxalinyl, acridinyl, Dihydroacridinyl, tetrahydroacridinyl, acridinyl, oxazolyl, acridinyl, phenazinyl, phenothiazine, and phenoxazinyl and the like. The term "heterocycle", "heterocyclic group, heterocyclic or "heterocyclic group" means having from 1 to 3 independently selected from the group consisting of nitrogen, oxygen and sulfur in at least one ring. A stable non-aromatic 5 to 14 member monocyclic or polycyclic premature or bivalent atom of an atom (any of which may be oxidized and optionally a nitrogen heteroatom oxidized or quaternized) The ring, which may comprise - or a plurality of fused or bridged rings, is preferably a 5 to 7 membered single ring or a 7 to 1 membered ring. The heterocyclic group used herein does not include a heterocycloalkyl group, a heterocycloalkenyl group and a heterocyclic alkynyl group. Unless otherwise stated, the heterocyclyl ring may be attached at any suitable heteroatom or carbon atom which results in a stable structure and, if substituted, may be at any suitable heteroatom or carbon atom which results in a stable structure. Replace. Non-limiting examples of heterocycles include . Billy Lynn, material. Base, „比(四)基,吼(四)基,六H定147399.doc • 11 - 201039824 基, 琳琳基, thiopental, hexahydropyramine, tetrahydrogen D, sulphur Base, tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl and the like. The term "cycloalkyl or cycloalkyl group" refers to a stable aliphatic saturated 3 to 15 members consisting only of carbon and hydrogen atoms. A monocyclic or polycyclic monovalent group which may comprise one or more fused or bridged rings, preferably a 5 to 7 membered monocyclic ring or a 7 to 10 membered bicyclic ring. Unless otherwise stated, the cycloalkyl ring can be attached at any carbon atom which results in a stable structure and, if substituted, can be substituted at any suitable carbon atom which results in a stable structure. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, norbornyl, adamantyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthalene), naphthyl, bis% [2.2.2]octyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methyl ring Octyl and the like. "Cycloalkenyl (cycl0alkenyl or cycl〇alkenyl gr〇up)" means a stable aliphatic 5 member to 15 members having at least one carbon-carbon double bond and consisting only of carbon and hydrogen atoms. A monovalent group, which may comprise one or more slightly ring or bridged rings, preferably a 5 member i 7 member single ring or 7 members to 1 member. Unless otherwise stated, the ring may be attached at any carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Exemplary cycloaliphatic groups include perpentyl, hexyl, cycloheptyl, cyclooctyl, cyclodecenyl, behenyl, decyl, 2-fluorenylcyclopentyl, 2 anthracenyl octenyl and the like. 147399.doc 201039824 _Xj^ The cycloalkynyl or cycloalkynyl group means a stable carbon with a carbon-carbon triple bond and consisting only of carbon and hydrogen atoms, and a member of 15 members with a single ring or more A cyclic monovalent group which may comprise one or more fused or bridged rings 'preferably from 8 to 1 G 贞 monocyclic ring or 12 to 15 membered bicyclic ring. Unless otherwise stated, the cycloalkynyl ring may be attached at any carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Illustrative cycloalkynyl Ο 匕 includes octyl acetyl, cyclo fluorenyl, cyclodecynyl, 2-methylcyclooctyl and the like. The term "carbocyclic" or "carbocyclic group" means a stable aliphatic 3 member to 15 membered monocyclic or polycyclic monovalent or divalent group consisting solely of carbon and hydrogen atoms, which may include -or more One fused ring or bridged ring, preferably 5 to 7 members! Ring or 7- to 10-membered two-ring ring. Unless otherwise stated, the anatomical ring may be attached at any carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which will result in a stable structure. The term encompasses cycloalkyl (including spiroalkyl), cycloalkyl, cyclodextrin, cycloalkenyl, cycloalkynyl, and cycloalkynyl and the like. The terms "heterocyclic alkyl", "heterocyclic base" and "heterocyclic fast radical" mean respectively a cycloalkyl, cycloalkenyl and cycloalkynyl group having at least one hetero atom in at least one ring. Glucocorticoid ("GC") is the most effective drug for the treatment of allergic and chronic inflammatory diseases or inflammation caused by infection. However, as noted above, long-term treatment with GC is often accompanied by many adverse side effects such as diabetes, osteoporosis, hypertension, glaucoma or cataracts. As with other physiological manifestations, 147399.doc -13· 201039824, these side effects are caused by the abnormal performance of the genes responsible for these diseases. According to the past ten years of research, the molecular basis of the eight-worker application of gc mediation of GC response gene expression can be deeply understood. GC exerts its genomic effect by binding to the cytoplasmic GC receptor ("GR"). Binding to (10) results in the translocation of the GC-GR complex to the nucleus where the GC_gr complex can regulate gene transcription by a positive (transactivation) or negative (transfer) regulatory pattern. There is increasing evidence that the beneficial and undesirable effects of GC treatment are the result of the degree of indiscriminate performance of the two mechanisms of action; in other words, the two mechanisms of action are performed with similar levels of efficacy. Although the most critical aspect of GC's role in chronic inflammatory diseases is not yet established, evidence suggests that inhibition of cytokine synthesis by GC may be particularly important. Inhibition of inflammatory diseases involves several cytokines (10) (interleukin-1β), IL_2, IL_3, Jiang_6, il u, τΝρ_α (tumor necrosis factor-a), GM-CSF (granulocyte. giant) by transsuppressive mechanism嗟 cell colony stimulating factor)) and chemokines that attract inflammatory cells to the site of inflammation (including il_8, RANTES, MCP-1 (monocyte chemotactic protein)), mCP 3, Mcp_ 4 MIP-la Transcription of cell_inflammatory protein_la) and eosinophilic factor (eotaxin). PJ Barnes, C/M, Volume C, (1998). On the other hand, there is persuasive evidence that the synthesis of ΙκΒ kinase, which is a protein that inhibits the nf_kB pro-inflammatory transcription factor, can be increased by gC. These pro-inflammatory transcription factors regulate the expression of genes encoding many inflammatory proteins (eg, cytokines, inflammatory enzymes, adhesion molecules, and inflammatory receptors) S_Wissink et al. 'Afo/·, Vol. 12, No. 3 354- 363 (1998) ; PJ Barnes and M. Karin, iVew sigh / / / I47399.doc • Η - 201039824

Md., vol. 336, l〇66_1077 (1997). Therefore, both the transduction and the transactivation function of G C for different genes can produce beneficial inflammation inhibitory effects. On the other hand, steroid-induced diabetes and glaucoma appear to be caused by the transcriptional activation of genes responsible for these diseases by GC. η _ Schacke et al.,..., vol. %, 23 43 (2 (four)). - Therefore, although some genes may have beneficial effects when activated by GC transduction, other genes may have undesirable side effects when they are activated by the same GC. Therefore, it is highly desirable to provide pharmaceutical compounds and compositions which produce different levels of transactivation and transsuppressive activity against Gc responsive genes to treat or control inflammatory diseases, conditions or conditions, particularly chronic inflammation. The present invention provides a compound, composition or method for treating or controlling an individual's ocular inflammatory disease, condition or condition (anterior segment and/or posterior segment). These inflammatory diseases, conditions or conditions are caused by inflammation or cause inflammation. In a particular aspect, the compositions and compositions of the present invention reduce the extent of at least one adverse side effect compared to compositions comprising at least one prior art glucocorticoid for treating or controlling the same disease, condition or disorder. . The ocular inflammation pathway begins with the triggering of the peanut dilute acid cascade. This cascade is triggered by mechanical stimuli (such as in the case of unavoidable trauma caused by surgery) or by chemical stimuli (such as foreign substances (for example, decomposition components of pathogenic microorganisms) or allergens). Prostaglandins are produced in most tissues by activating the arachidonic acid pathway. Phospholipids in damaged cell membranes produce arachidonic acid as a receptor for phospholipase A, while cyclooxygenase ("") and lipoxygenase act on arachidonic acid to produce pro-inflammatory prostaglandins and thrombus 147399.doc -15· 201039824 Burning and white blood cells. μ The pro-inflammatory compound recruits more immune cells (such as giant scorpion cells and axillary cells in the φ f) to the site of injury, which in turn produces a large number of other pro-inflammatory cytokines and further enlarges inflammation. Cataract surgery and artificial 曰d-yang ("IOL") implantation and glaucoma filtration microsurgery (small (four) removal surgery) is one of the common (four) surgical operations. These procedures usually squat, ^.. The mineral parts are accompanied by some inflammation after surgery. The use of anti-inflammatory agents after surgery can quickly eliminate this event to alleviate the risk of pain, discomfort, and visual defects in the patient, which reduces the risk of other complications, such as the onset of cystic macular edema. Thus, in one aspect, the invention provides a compound or composition for treating or controlling an inflammatory disease, condition or disorder in an eye of an individual, in which the inflammatory disease, condition or disorder is caused by bacteria or viruses. Caused by infection caused by 1 bacteria, protozoa or /, combination. In another aspect, the infection comprises an ocular infection. In the aspect, the anterior segment of the inflammatory disease, the disease (4) is caused by the physical trauma of the eye 4 surgery. 4. Inflammatory diseases, conditions or conditions in the anterior segment of the eye include: membranous inflammation (including, for example, iritis and iridocyclitis), keratitis, conjunctivitis, keratoconjunctivitis (including spring corneal inflammation) (or Atopic keratoconjunctivitis), corneal ulcer, keratotic edema, sputum corneal-run, scleritis, scleral outer layer I, ophthalmia, and post-operative (or post-surgical) ocular inflammation caused by the following operations : For example, refractive surgery, cataract extraction, intraocular lens ("i〇L") implantation, 1 assisted in situ keratomileusis ("(10)K"), conductive corneal ligament 147399.doc 16- 201039824 And radial keratotomy. In a further aspect, the compositions comprise at least one glucocorticosteroid mimetic for the treatment or control of such diseases, conditions or conditions. In yet another aspect, The degree of action of the at least one adverse field is determined in vivo or ex vivo. For example, by performing cell culture and measuring the amount of the biomarker associated with the side effect, the at least one adverse side effect is measured in vitro. Such biomarkers may include proteins (e.g., enzymes), lipids, sugars, and derivatives thereof that are involved in a biochemical cascade that causes undesirable side effects or are products of the biochemical cascade. Representative in vitro test methods Further disclosed in the following. In still another aspect, the at least one adverse side effect is selected from the group consisting of glaucoma, cataract, hypertension, hyperglycemia, hyperlipidemia (increased triglyceride content), and High cholesterol syndrome (increased cholesterol content). In a further embodiment, the degree of the at least one adverse side effect is determined after the composition is first administered to the individual and stored in the body for about one day. In one embodiment, the degree of the at least one adverse side effect is determined after the composition is first administered to the individual and stored in the subject for about 14 days. In yet another embodiment, the composition is first administered to the individual. And determining the extent of the at least one adverse side effect after about 30 days in the subject. Alternatively, the compound or composition is first administered to the individual and stored in the individual The extent of the at least one adverse side effect is determined after about 2, 3, 4, 5 or 6 months in the body. In another aspect, after about the same time, it is sufficient to produce 147399.doc -17 201039824 The dosage and frequency equivalent to the beneficial effects of the compositions of the invention are administered to the individual for the treatment or control of the at least one prior art glucocorticoid of the same disease, condition or disorder. In yet another aspect At least one prior art glucocorticoid is selected from the group consisting of: 21-acetoxypregnenolone, alclometasone, ageston, acinionide, qi Beclomethasone, betamethasone, budesonide, chloroprednisone, citrabetasol, clobetasone, clostronone (cl〇cort〇i〇ne), cloprenolol, corticosterone, cortisone, cortiVazol, deflazacort, dinad (desonide), desoximetasone, Dexamethasone, diflorasone, diflucortolone, diHuprednate, enoxolone, fluazacort, fluorone (flucloronide), flumethasone, flunisolide, nuocinoloneacetonide, fluocinonide, fluocortin butyl, fluocortolone, fluoride Fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, blessing Formocortal, 147399.doc -18- 201039824 hacinoneide, halobetasol propionate, halometasone, halopedone acetate, hydrogen He is hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone , medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, predica (prednicarbate), prednisolone, prednisolone 2,5-diethylammonate, sodium prednisone, prednisone, prednisone (prednisone) Prednival), prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone, triamcinolone benetonide, hexavinide Triamcinolone hexacetonide, a physiologically acceptable salt thereof, combinations thereof, and mixtures thereof. In one embodiment, the at least one prior art glucocorticoid is selected from the group consisting of: dexamethasone, prednisone, prednisolone, methylprednisolone, methotrexate, triamcinolone , loteprednol ethyl carbonate, physiologically acceptable salts thereof, combinations thereof, and mixtures thereof. In another embodiment, the at least one prior art glucocorticosteroid is accepted for ophthalmic use. In one aspect, the compounds, compositions, methods of the present invention reduce the risk of IOP increase compared to compositions and methods that use prior art GC to treat or control the same disease, condition or disorder. In another aspect, the anterior segment of the ocular inflammatory disease, condition or condition package 147399.doc -19- 201039824 includes uveitis (including anterior uveitis, posterior uveitis, and uveitis), cornea Inflammation, conjunctivitis, keratoconjunctivitis (including spring keratoconjunctivitis (or "VKC") and atopic keratoconjunctivitis), corneal ulcer, corneal edema, aseptic corneal infiltration, anterior scleritis, scleral inflammation, orbital inflammation, and by Refractive keratotomy, cataract extraction, intraocular lens ("IOL") implantation, laser assisted in situ keratomileusis ("LASIK"), conductive keratoplasty, radial keratotomy, etc. Caused by post-operative (or post-surgical) ocular inflammation, dry eye, macular degeneration, macular edema, diabetic retinopathy, age-related macular degeneration (including wet and dry), and glaucoma (including all types of glaucoma). In a further aspect, the inflammatory diseases, conditions or conditions are caused by infections caused by bacterial 'viruses, fungi or protozoa. In re-states, the compositions comprise at least one glucocorticosteroid mimetic for the treatment or control of such diseases, conditions or conditions. In a re-state, a pharmaceutical composition for treating or controlling an inflammatory disease, condition or disorder comprises at least a dissociated glucocorticoid receptor agonist ("DIGRA"), a prodrug thereof, or a pharmaceutically acceptable Accept the salt or ester. In a re-state, the pharmaceutical compositions of the present invention comprise an ophthalmic topical formulation; an injectable formulation; or an implantable formulation, system or device. The formulation, system or device is applied or provided in the anterior segment of the eye. In a recurrence, the formulation, system or device is administered or provided to the posterior segment of the eye. '147399.doc •20· 201039824 In another aspect, the increase in IOP is shown in vitro or in vivo. In still another aspect, the increase in enthalpy is caused by an increase in resistance experienced by fluid flow through the trabecular meshwork. In yet another aspect, the increased resistance is due to increased performance and accumulation of myofibrin in the trabecular meshwork. In another aspect, the invention provides a method of treating or controlling an anterior segment of an inflammatory disease, condition or disorder. The method comprises administering to a diseased eye of an individual in need of such treatment or control a composition comprising DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof. In still another aspect, the at least one DIGRA has the formula I,

Wherein Α and Q are independently selected from the group consisting of unsubstituted and substituted aryl and heteroaryl, unsubstituted and substituted cycloalkyl and heterocycloalkyl, unsubstituted and substituted cycloalkenyl And heterocyclic, unsubstituted and substituted anthracene cycloalkynyl and heterocycloalkynyl, and unsubstituted and substituted heterocyclic groups; R1

, Ci-C^, or CVC5, or ^^3) linear or branched alkyl, substituted (^-(:15 (or, cvq., or (^-Cs, or C!-C) a substituted or unsubstituted C3_C 5-cycloalkyl group, and a substituted c C6 or Cs-C5) cycloalkyl group; R3 is selected from the group consisting of -cs, or CVC3), straight or branched, and substituted C3 -Cl5 (or, c is selected from the group consisting of hydrogen, unsubstituted CrCb (or 'Cl-C1G, or Cl_c5, or branched alkyl, substituted (^-(:15(or, q-Cm) , or Cl_C5, or C1-C3) straight or with, ci-c1〇, or Cl-C5, or Cl_ 147399.doc -21 · 201039824 C3) straight or branched, unsubstituted or , c3_c6 or c3_C5)%·alkyl and miscible, substituted C3-Ci5 (or 'C3-C; 6 or C3-C5) cycloalkyl and heterocycloalkyl, aryl, heteroaryl and a heterocyclic group; B comprises a carbonyl group, an amine group, a divalent hydrocarbon or a heterohydrocarbon group; E is a hydroxyl group or an amine group; and the ruthenium is absent or contains a carbonyl group, -NH- or -NR,-, wherein R, Substituted or substituted (^-(:15 (or 'Cl_ClG, or Cl_C5, or Ci_C3) straight or branched alkyl' and wherein R1 and R2 are Forming an unsubstituted or substituted C:3-Ci5 cycloalkyl group. In one embodiment, B may comprise one or more unsaturated carbon-carbon bonds. In another embodiment, B may comprise an alkyl carbonyl group. , an alkyloxy group, a carbonyloxy group, an alkyloxycarbonylamino group, an alkylamino group, an alkenylcarbonyl group, an alkenyloxycarbonyl group, an alkenylcarbonyloxy group, An alkenyloxycarbonylamino group, an alkenylamino group, an alkynylcarbonyl group, an alkynyloxy group, an alkynylcarbonyloxy group, an alkynyloxycarbonylamino group, an alkynylamino group, Arylcarbonyloxy, aryloxycarbonyl or ureido. In yet another embodiment, A and Q are independently selected from the group consisting of: at least one halogen atom, cyano group, hydroxy group or Ci_Cig alkoxy group (or , CrC: 5 alkoxy, or alkoxy) substituted aryl and heteroaryl; ri, R 2 and R 3 are independently selected from unsubstituted and substituted C1-C5 alkyl (preferably 'c---: a group of 3 alkyl groups; 丨_C5 alkyl (or Ci_c3 alkyl); D-NH- or -NR,- group, wherein r, is C丨-Cs alkyl (preferably ' C丨- C3 alkyl); and e is a hydroxyl group. In still another embodiment, A comprises a dihydro benzofuranyl group substituted with a halogen atom; Q comprises a q-Cw alkyl substituted quinolinyl or isoquinolyl group. ; Rl 147399.doc -22· 201039824 and R2 are independently selected from the group consisting of unsubstituted and substituted Cl-C5 alkyl (preferably, CVC3 alkyl); b is Cl_CM alkyl; D-NH a group; E is a trans group; and R3 comprises a fully halogenated Ci_Ci decyl group (preferably, a fully halogenated Ci-Cs alkyl group; more preferably a 'fully halogenated Ci_c3 alkyl group). In yet another embodiment, A comprises a difluorobenzofuranyl group substituted by a fluorine atom, Q comprises a methyl substituted quinolyl or isoquinolyl group; Ri&R2 is independently selected from the group consisting of unsubstituted and substituted groups; b is Cj- C3 is a stretching group; D is a -NH_ group; e is a hydroxyl group; and R3 comprises a trifluoromethyl group. In another embodiment, the at least one DIGRA has Formula II or ΠΙ, R4

(Π) (IN) group, hydroxyl group, CrCioi 岑, η 1 〇 cyanide (flyer (^-(^ or ^-匸3) alkoxy, unsubstituted c] c10 (or Ci_C4Ci_d straight or branched Key alkyl, substituted 1 ίο (or CVCACVCd linear or branched alkyl, unsubstituted C3-C10 (or C3_Cd c ^5) cycloalkyl, and substituted (VC, (or ' C3- C6 or C3-C5) cycloalkyl. 147399.doc • 23. 201039824 In yet another embodiment, the at least one DIGRA has the formula Iv.

(IV), a method for preparing a compound of the formula I, n, m or 1 is disclosed, for example, in U.S. Patent No. M97,224, No. 6,9G3,215, No. 6, No. 581, The entire contents of these patents are incorporated herein by reference. Other methods for the preparation of such compounds can also be found in U.S. Patent Application Publication No. 2006/0116396, which is hereby incorporated by reference, in its entirety, in its entirety, in its entirety in Non-limiting examples of compounds having formula I include 5-[4_(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy_4_indolyl 2_three" Amylamino]- 2-methylquinoline, 5-[4_(5-fluoro-2,3-dihydrobenzofuran-7-ylhydroxy- 4-methyl-2-trifluoromethyl-pentyl Amino]mercaptoisoquinoline, 5 [4_(5fluoro_ 2,3-dihydrobenzopyrano-7-yl)_2-hydroxy_4_methyl_2_trifluoromethyl-pentylamine Isoindene-1(2Η)-_,5_[4_(5_fluoro-2,3_dihydrobenzopyrano-7.yl)-2-hydroxy-4-methyl-2-trifluoro Methyl-pentylamino]_2,6-dimethylquinin 5 [4-(5-Gas-2,3-indolylbenzofirthyl)-2-perylene-4-methyl _2_monofluoromethyl-pentylamino]_6_gas_2-methylquinone, 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2- Hydroxy-4-methyl_2_trifluorodecyl-pentylamino]isoindole 5-[4-(5-gas-2,3-mono-l-benzophenoxy-7-yl)-2 -trans)-4-methyl-2-pyridylamino-pentylamino]quinoline, 5-[4·(2,3-dihydro-5-fluoro-7-benzofuranyl)-2- Hydroxy-4-mercapto-2-trifluoromethyl-pentylamino]quinoline_2[1η]_ 147399.doc •24- 201039824 嗣,6-气- 5- [4-(5-气- ^-Two Rat Benzoquinone Crunch---Base -light base-heart methyl-2-trifluoromethyl-pentylamino]-2-mercaptoquinoline, 8-fluoro-, 5-[4-(5-fluoro-2,3-dichloro Benzo-51-pentan-7-yl)-2-trans--4-methyl-2-trimethylmethyl-pentylamino]-2-methyl-lin, 5-[4-(5-gas -2,3-diazophenyl hydrazone <1 fluran-7-yl)-2-hydroxy-4-mercapto-2-trifluoromethyl-pentylamino]-2-methylisoquinoline- L-[2h]-ketones, and their enantiomers. Other compounds useful as DIGRA and methods for preparing such compounds are disclosed in, for example, U.S. Patent Application Publication No. 2004/0029932, 2004/0162321, 2004/0224992, 2005/0059714, 2005/0176706, 2005/0203128, 2005/0234091, 2005/0282881, 2006/0014787, 2006/ The entire disclosures of all of these patents are hereby incorporated by reference herein in its entirety in its entirety in its entirety in the the the the the the the the the the the the Or an ophthalmic pharmaceutical composition that controls the infection of the anterior segment of the eye and its inflammatory sequelae. In one embodiment, the inflammatory sequelae of the ® include acute inflammation. In another embodiment, the inflammatory sequelae comprise chronic anterior segment inflammation. The ophthalmic pharmaceutical composition comprises DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof. In another aspect, the composition further comprises an anti-infective agent. In still another aspect, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. The concentration of DIGRA, its prodrug, or a pharmaceutically acceptable salt or pharmaceutically acceptable salt thereof in the ophthalmic composition may range from about 0.0001 mg/ml to about 1000 mg/ml (or 147399.doc -25-201039824 Optionally, from about 0.001 mg/ml to about 500 mg/mi, or from about 0.001 mg/ml to about 300 mg/ml, or from about 〇_〇〇i mg/ml to about 250 mg/ml, or from From about o.ooi mg/ml to about 1 mg/ml, or from about 0.001 mg/ml to about 50 mg/ml, or from about 〇.〇1 mg/mi to about 3 mg/ml, or From about 0.01 mg/ml to about 250 mg/ml, or from about o. oi mg/mi to about 100 mg/ml, or from about ι·ι mg/mi to about 1 mg/ml, or from about 〇.1 mg/ml to about 50 mg/ml). In one embodiment, the composition of the invention is in the form of a suspension, dispersion, gel or ointment. In another embodiment, the suspension or dispersion is based on an aqueous solution. For example, the compositions of the present invention may comprise a sterile saline solution. In yet another embodiment, micro- or nano-sized particles of 'DIGRA, or a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof, may be used as a physiologically acceptable surfactant (non-limiting examples are disclosed below) Coating, and then dispersing the coated particles in a liquid medium. The coating agent retains the particles in the suspension. This liquid medium can be selected to produce a sustained release suspension. For example, the liquid medium can be a liquid medium that is slightly soluble in the ocular environment in which the suspension is administered. Anti-infective agents suitable for the compositions of the present invention are selected from the group consisting of antibacterial agents, antiviral agents, antifungal agents, antiprotozoal agents, and combinations thereof. Non-limiting examples of biologically derived antibacterial agents include aglycosides (eg, 'amikacin, arampyCin, arbekacin, bambermycins, Butrosin, dibekacin, dihydrostreptomycin, forticin, eucalyptus 147399.doc • 26 - 201039824 (gentamicin), isopa Isepamicin, kanamycin, micronomicin, neomycin, neodecanoic acid neomycin, netilmicin, paromomycin ( Paromomycin, ribomycin, sisomicin, Spectinomycin, streptomycin, t〇bramycin, trospectomycin , amphetamine (amphenicol) (for example, azidofenicol, chloramphenicol, florfenicol, thiamphenicol), ansaphrine ( Ansamycins) (eg 'rifamide, rifampicin (r Ifampin), rifamycin sv, rifapentine, rifapentine, rifaximin, beta-endoamine (for example, carbacephems (eg, , carbonaceous cephalosporin (l〇racarbef), carbapenems (eg, biapenem, imipenem, meropenem, panipenem) ), cephalosporins (eg, cefaclor, cefadroxil, cefmandole, ceftrizine, cefazedone, Cefazolin, cefcapene pivoxil, cefclidin, cefdinir, cefditoren, cefepime, cephalosporin Cefetamet, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, cefretide 147399.doc - 27- 201039824 (ce for an ide), cefotaxin (cefotaxime) ), cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime proxetil ), cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten , ceftizoxime, ceftrixone, cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cefotaxime Cephalolycin), cephaloridine, cephalosporin, cephalothin, cephapirin sodium, cephradine, pivcefalexin, cephalosporin Nutrients (for example, cefbuperazone, cefmetazole, cefminox, cefotetan, cefxidin), monochosamines , aztreonam, carumonam, tigemonam, oxacephems, fi〇in〇xef, moxalactam ), penicillins (eg, amdinocillin, anidinocillin pivoxil, amoxicillin, ampicillin (ampicUlin), apalcillin (apalcillin), apocillin ( aSp〇xiciiiin), azidocillin, azcilin (azl〇cillin), bamcillin • 28·147399.doc 201039824 (bacampicillin), benzyl penicillin acid (benzylpenicillinic acid), benzyl penicillin sodium, slow Carbenicillin, carindacillin, clomiteccilin, cl oxacillin, cyclacillin, dicloxacillin, epicicilin, fen Fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin, methicillin sodium, Mezlocillin, nafcillin sodium, oxa β oxacillin, penamecillin, penehamate hydriodide, phenethylpenicillin G, benzyl Penicillin G (penicillin G benzathine), diphenylmethylamine penicillin G, penicillin G, penicillin G hydrabamine, penicillin G slant, procaine penicillin G (penicillin G procaine), penicillin N, Penicillin 0, penicillin V, benzathine penicillin V, baibamin penicillin V, penimepicycline, phenethicillin 〇w potassium, piperacillin, pivampicillin, Propicillin, quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin, ticarcillin , ritipenem, lincosamides (eg, clindamycin, lincomycin), macrolides (eg For example, azithromycin, carbomycin, 147399.doc -29- 201039824 clarithromycin, dihithromycin, erythromycin, vinegar stearin Erythromycin acistrate, erythromycin estolate, erythromycin glucoheptonate, erythromycin lactobionate, erythromycin propionate S, erythromycin hard Fatty acid S, josamycin, leucomycins, midecamycins, miokamycin, oleandomycin, pleiomycin (primycin), rokitamycin, rosaramicin, roxithromycin, spiramycin, treleandomycin, peptides (eg, Amphomycin, bacitracin, capreomycin, colistin, enduracidin, enviomycin, fusafungine Brevibacterium peptide S (gramicidin s), gramicidin (s), mikamycin, polymyxin, pristinamycin, ristocetin , teicoplanin, thiostrepton, tuberactinomycin, tyrocidine, tyrothricin, vancomycin, purple Viomycin, virginiamycin, Zinc bacitracin, tetracyclines (eg, 'apicycline', chlortetracycline (chl〇rtetracycline), cyclamate ( Clomocycline), demeclocycline, Dorsey 147399.doc •30- 201039824 doxycycline, guamecycline, lymecycline, meclocycline, methotrexate Methacycline, minocycline, oxytetracycline, penimepicycline, pipacycline, rolitetracycline, cyclin Sancycline), tetracycline Non-limiting examples of tetracycline)), cycloserine, mupirocin, and tuberin; anti-bacterial agents include 2,4-diaminopyrimidines (eg, Brodimoprim, tetroxoprim, trimethoprim, trimethoprim (eg, furaltadone, furazolium chloride) , stone 吱 吱 吱 ni (nifuradene), Shi Xiao 0 feir (nifuratel), stone Xiao Fu Lin (nifurfoline), Shi Xiaoying. Nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin, quinolone and analogues (eg, sinofloxacin) (cinoxacin), ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine, plus Gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, miloxacin, moxifloxacin, nadifloxacin, Nalidixic acid, norfloxacin, ofloxacin, oxolinic acid (oxolinic 147399.doc -31 - 201039824 acid), pazufloxacin, culture Flufloxacin (pefl〇xacin), *pipemidic acid, ° ratio of piromidic acid, rosoxacin, rufloxacin, sparfloxacin (sparHoxacin), temafloxacin, tolfloxacin (tosufloxacin), trovafloxacin, or the chemical name 7-[(3R)-3-aminohexahydro-1H-azhen-1-yl]-8-a-1-1-cyclopropyl- 6-fluoro-1,4-dihydro-4-oxo-3-quinoline citrate monohydrochloride fluoroquinacridone), oxime amines (eg, acesulfame methoxy oxime), benzyl Diazoline, chloramine B, nitroamine T, diamine T, n2-mercaptosulfonyldimethylpyrimidine, η4-β-ϋ-glucosylsulfonamide, mefenide, 4'-(A Amidoxime sulfonyl phenylamine (4'-(methylsulfamoyl) sulfanilanilide), noprylsulfamide, phthalylsulfacetamide Sitting (phthalylsulfathiazole), Liu Niu Ji is dense. (salazo sulfadimidine), succinylsulfathiazole, sulfabenzamide, sulfacetamide, and hydrazine chloride. Sulfium (pyruchlorpyridazine), sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine ), sulfadoxine, and reductive amine. Sitting (sulfaethidole), sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfamerazine, feldspar Amine to sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine, continued 147399.doc - 32-201039824 Amine sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, sulfamidochrysoidine, and aminoxime. Sulfamexole, sulfanilamide, 4-hydrazine salicylic acid, η4- cis-amine hydrazine, sulfanilylurea, Ν-p-aminobenzoic acid-3,4-di N-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine, sulfaphenazole, sulfaproxyline , sulfapyrazine, sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfamethoxazole Sulfaxlamide, sulfisomidine, suinsoxazole, stone wind (eg, acedapsone, acediasulfone, ammonia) Benzene sulfone sodium, dapsone, diathymosulfone, glucosulfone sodium, s〇lasulfone, amber benzene Succisulfone, sulfamic acid, p-sulfonamidobenzylamine, Sulfone sodium, thiazolsulfone, clofoctol, hexedine, methenamine, dehydrated hydrazine urotropine, horse Uroic acid ururotropine, methenamine mandelate, sirolimus salicylate, nitroxoline, taurolidine and xibom〇i ). In one embodiment, the composition of the invention comprises an anti-infective agent selected from the group consisting of: Sinora 147399.doc • 33- 201039824 star, ciprofloxacin, clinfloxacin, hexafloxacin, enoxa Sand star, fleroxacin, flumethacin, gatifloxacin, gepafloxacin, levofloxacin, lomefloxacin, mirofloxacin, moxifloxacin, nalfloxacin, naphthalene acid, norfloxacin , Ofloxacin, Oxalic acid, Pazufloxacin, Pefloxacin, Pipemidic acid, ° ratio of each of the rice acids, Sasolfloxacin, Fiprofloxacin, Sparfloxacin, Temasa Star, toloxacin, trovafloxacin, and the chemical name 7-[(3R)-3-aminohexahydro-1H-aero-l-yl]-8-chloro-1-cyclopropyl- Fluoroquinolone of 6-gas-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid monohydrochloride (in the family of compounds disclosed in U.S. Patent Nos. 5,3,85,900 and 5,447,926 One of these patents is incorporated herein by reference. Non-limiting examples of antiviral agents include Rifampin, Ribavirin, Pleconaryl, Cidofovir, Acyclovir, and squirting Pencyclovir, Gancyclovir, Valacyclovir, Famciclovir, Foscarnet, Vidarabine, Amantadine, Zanamivir, Oseltamivir, Resiquimod, anti-protease, PEGylated interferon (PegasysTM), anti-HIV protease (eg, lopinivir, Saquinivir, amprenavir, HIV fusion inhibitors, nucleotide HIV RT inhibitors (eg 'AZT, lamivudine, abacavir (Abacavir)) , non-nucleotide HIV RT inhibitors, Doconosol, interferon, butylated hydroxytoluene (BHT) and hypericin (Hypericin). 147399.doc -34· 201039824 Non-limiting examples of biologically derived antifungal agents include polyenes (eg, amphotericin B, candicidin, dermostatin, filipin) ), fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin, Nystatin, pecilocin, perimycin, azaserine, griseofulvin, oligomycin

(oligomycins), neomycin undecylenate, pyrrolnitrin, siccanin, tubercidin, and viridin. Non-limiting examples of synthetic antifungal agents include allylamines (eg, butenafine, naftifine, terbinafine), imidazoles (eg, bifonazole (eg, bifonazole) Bifonazole), butoconazole, chlordantoin, chlormidazole, fluconazole, clotrimazole, econazole, Enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanocon. sitting (lanoconazole), π m Miconazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole ), thiocarbamates (for example, tolciclate, tolindate, tolna 147399.doc -35- 201039824 ester (tolnaftate), triazoles (eg, fluorine) Fluconaz〇le, itoconazole, itaconic (saperconaz〇ie), terconazole, acr is ore in, amorolfine, biphenamine, bromosalicylchloranilide , buclosamide, calcium propionate, chlorphenesin, ciclopirox, cloxyquin, coparaffinate, diamthazole hydrochloride Dihydrochloride), exalamide, flucytosine, halethazole, hexetidine, loflucarban, nifuratel, angstrom Decomposition, propionic acid, pyrithione, salicylanilide, sodium propionate, suibentine, tenonitrozole, triacetin, benzyl sulfide Ujothion, undecylenic acid, and octyl propionate. Non-limiting examples of antiprotozoal agents include polymycin B sulfate, bacitracin zinc, neomycin sulfate (e.g., neosporin). Rice 11 sitting class (for example, clomimazole, miconazole, ketoconazole), aromatic diterpenoids (for example, propamidine isethionate, hydroxy Brolene ethanesulfonate, polyhexamidine ("ΡΗΜΒ"), chlorhexidine, pyrimethamine (Daraprim®), sulfadiazine, ya Folinic acid (leucovorin), clindamycin, and trimethoprim mouth bite - reductive amine A. "sit (trimethoprim- 147399.doc -36- 201039824 sulfamethoxazole) ° In one aspect, the anti-infective agent is selected from the group consisting of bacitracin zinc, chloramphenicol, ciprofloxacin hydrochloride, erythromycin, gatifloxacin, gentamicin sulfate, levofloxacin, mo Soxacin, ofloxacin, sodium sulfacetamide, polymyxin B, tobramycin sulfate, trifluridine, arabinoside, acyclovir, valaciclovir Luo early, foscarnet, ganciclovir, formivir (f〇rmivirsen), cidofovir, sex Mycin B, natamycin' fluconazole, itraconazole, ketoconazole, mikangjun, polymyxin B, neomycin sulfate, clotrimazole, hydroxyethyl% SiL propoxygen , polyhexamidine, chlorhexidine, ethylamine mouth bite, reductive amine biting, leucovorin (leucovorin | bow), clindamycin, trimethoprim diazepam _ reductive amine oxazole and combinations thereof . The concentration of the anti-infective agent in the ophthalmic composition may range from about 1 mg/ml to about 1 mg/mi (or alternatively, from about 1 pawl/... to About 500 mg/m b or from about 0 00 i mg/ml to about 3 〇〇 mg/nU, or from about 0.001 mg/ml to about 250 mg/ml, or from about o.ooi mg/ml to about 1 〇 〇mg/ml, or from about 0.001 mg/ml to about 50 mg/ml, or from about 〇.〇1 mg/ml to about 300 mg/ml, or from about 〇.〇1 mg/mi to about 250 mg /ml, or from about 0.01 mg/ml to about 1 mg/n^, or from about 1 mg/ml to about 100 mg/ml, or from about mgmg/mi to about 5 mg/ml ) within the scope. In another aspect, the composition of the present invention may further comprise a nonionic surfactant, such as a polysorbate (eg, polysorbate 8 (polyoxyethylene sorbitan monooleate), Polysorbate 6〇 (polyoxyethylene sorbitan monostearate), polysorbate 2〇 (polyoxyethylene sorbitol 147399.doc -37- 201039824 liver lauric acid vinegar), usually based on its commodity Tween® 80, Tween® 60, Tween® 20, poloxamer (p〇l〇xamer) (synthetic block polymers of ethylene oxide and propylene oxide, for example, they are known under the trade name Pluronic® For example; piuronic® F127 or Pluronic® F1 08), or p〇i〇xamines (a synthetic block polymer of propylene oxide and ethylene oxide attached to ethylenediamine, for example, Its trade name

Tetronic® is known; for example, Tetronic® 1508 or Tetronic® 908, etc.) 'Other nonionic surfactants' such as Brij®, Myrj® and having about 12 or more carbon atoms (for example, from about 2 to about 2) A long-chain aliphatic alcohol having a carbon chain of up to about 24 carbon atoms (i.e., oleyl alcohol, stearyl alcohol, myristyl alcohol, docosahexanol, etc.). These compounds are described in Martindale, 34th edition, page i411_1416 (Martindale, "Ding^

Compiete Drug Reference," SC Sweetman (ed.), Pharmaceutical Press, Lond〇n, 2〇〇5) and Remingt〇n, "Science and Practlce of Pharmacy", 21st Edition, page 29i, and Lippincott Williams & Wilkins, New York, 2006; the contents of these sections are incorporated by reference. The concentration of the nonionic surfactant (when present) in the sigma may be between about 〇·_weight. /. Up to about 5% by weight (or alternatively from about 1% to about 4% by weight, from about 1% to about 2% by weight, or from about 0.01% to about 1% by weight, 忐戍From about 0.01% by weight to about 重量5 by weight 0/〇). Further, the composition, adjuvant or other excipients and the like of the present invention may include, for example, a buffer, a diluent, and an additive. Can be used for application to the eye 147399.doc -38· 201039824 ❹

A pharmaceutically acceptable buffer. For the various (4), other agents can be used for the composition. For example, buffers, anti-money, co-solvents, oils, moisturizers, emollients, stabilizers or antioxidants can be prepared. Usable: miscellaneous preservatives include sodium bisulfite, sodium hydrogen sulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, tMmerosal, ethanol, p-aminobenzoic acid, Polyvinyl alcohol, phenolic alcohol and phenylethyl alcohol. Such agents may be present from about 0% by weight to about 5 weights per ounce (preferably, from about 〇_〇1% by weight to about 2% by weight. Suitable waters can be used; gluten buffers are carbonated) Sodium, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, etc., as approved by the US Food and Drug Administration ("fda") for the desired route of administration. Such reagents may be present in an amount between about 2 and about u. Thus, the buffer can be up to about 5% by weight of the total composition. Electrolytes such as, but not limited to, gasified sodium and potassium chloride may also be included in the formulation. In one aspect, the pH of the composition is between about 4 and about 丨1. Alternatively, the composition has a PH system of between about 5 and about 9, between about 6 and about 9, or between about 6.5 and about 8. In another aspect, the composition comprises a buffer in the range of one of the ranges. In another aspect, the composition has a pH of about 72. Alternatively, the composition has a pH of between about 7 and about 7.5. In yet another aspect, the composition has a pH of about 7.4. In still another aspect, the composition may also comprise a viscosity-adjusted design designed to facilitate administration of the composition to an individual or to enhance bioavailability in the individual. 147399.doc -39- 201039824. In yet another aspect, the present viscosity modifying compound can be selected such that the composition does not disperse from the county after being administered to the vitreous. Such compounds may enhance the viscosity of the composition, and include primary τ + Α ^ but are not limited to: monomeric poly-fermentation, for example, glycerol, propylene glycol, ethylene glycol; succinyl alcohol, for example, polyethyl b Glycols; various polymers of the cellulose family, such as 'hydroxypropyl methylcellulose ("HPMC"), sodium carboxymethyl cellulose "CMC" sodium, hydroxypropyl cellulose ("HPC" "); polysaccharides, for example, swimming nn and a sulphate and its salts, chondroitin sulfate and its salts, dextran (for example, glucosinolate J sugar 70), water-soluble protein, such as gelatin Ethylene polymer, for example, polyethylene glycol, polyethylene ... Povidone, carbomer (carb_s), for example, carbomer 934P, carbomer 941, turbid + captain Lower anti-m 940 or carbomer 974P; and acrylic polymer. Generally, it is desirable that the viscosity can be in the range of from about 1 to about 400 centipoise ("cps") or mPa.s. In still another aspect, the invention is directed to a composition for treating or controlling an inflammatory disease, condition or disorder of the ophthalmology (anterior segment and/or posterior segment) of umbilical & In one embodiment, the composition comprises: (4) at least one mGRA, a prodrug, or a pharmaceutically acceptable salt thereof or §|; and (8) different from the sputum, a prodrug, and a pharmaceutically acceptable Accept the salt or brewed anti-inflammatory agent. In another embodiment, the anti-inflammatory agent is not GC. In an ampoule, the anti-inflammatory agent comprises a compound that inhibits or blocks the cyclooxygenase inflammatory pathway, the lipid hydrase synthase pathway, or both. In the case of a sample, (4) the inflammatory agent comprises a compound which inhibits the production of prostaglandins, ginseng or white blood cells. In a re-state, the invention provides a composition for the treatment or management of an inflammatory disease, condition or disorder in the ophthalmology (pre-existing 147399.doc-40; 201039824 and/or posterior segment). In one embodiment, the composition comprises: (a) at least one DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof; (b) an anti-infective agent; and (c) different from the DIGRA, An anti-inflammatory agent for prodrugs, and pharmaceutically acceptable salts or esters thereof. The DIGRA, an anti-infective agent, and an anti-inflammatory agent other than the DIGRA, a prodrug thereof, and a pharmaceutically acceptable salt or ester thereof are present in an amount effective to treat or control the disease, condition or disorder. In one embodiment, the anti-inflammatory agent is selected from the group consisting of non-steroidal anti-inflammatory drugs ("NSAIDs"); peroxy-sulphide-enzyme-enriched receptor ("PPAR") ligands, such as PPARtx, ΡΡΑΪΙδ or PPARy ligand; combinations thereof; and mixtures thereof. Non-limiting examples of NS AIDs are: amino aryl formic acid derivatives (eg, enfenamic acid, etofenamate, flufenamic acid, ivericin) Isonixin), meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, torr Tolfenamic acid, aryl acetic acid derivatives (for example, aceclofenac, acemetacin, alclofenac, amfenac, D Amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, Etodolac, felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac, 0 bow | Meixin 147399.doc -41 - 201039824 (indomethacin), triphenyl. Sitting acid (isofezolac), Iraq Isoxepac, lonazolac, metiazinic acid, molybdenum, mofezolac, oxametacine, pirazolac , proglumetacin, sulindac, ° tiaramide, tolmetin, tropesin, zomepirac, aryl butyl Acid derivatives (for example, bumadizon, butibufen, fenbufen, xenbucin), aryl carbamates (eg, cyclochlorodecanoic acid) Clidanac), ketorolac, tinoridine, aryl propionic acid derivatives (eg, alminoprofen, benoxaprofen, bermoprofen) Bermoprofen), bucloxic acid, carprofen' fenoprofen, flonoxaprofen, flurbiprofen, ibuprofen, iso Ibuproxam, 0 indoprofen, ketoprofen, loxoprofen Loxoprofen), naproxen, oxaprozin, piketoprolen, pirprofen, pranoprofen, protizinic acid ), supprofen, tiaprofenic acid, ximoprofen, zaltoprofen, ratio. Sitting class (for example, difenamizole, epirizole), beta quinone ketone (for example, apazone, benzpiperylon, non Feprazone, mofebutazone, morpha 147399.doc -42- 201039824 (morazone), oxyphenbutazone, phenylbutazone, pipebuzone, Propyphenazone, ramifenazone, suxibuzone, thiazolinobutazone, salicylic acid derivatives (eg, acetaminosalol) ), aspirin, benorylate, bromosaligenin, acetaminophen, diflunisal, etersalate, fentan Fendosal, gentisic 〇acid, glycolic acid glycolate, imidazolium salicylate, acetoacetate, mesalamine, salicylic acid, Salicylic acid 1-naphthylamine, olsalazine, parsalmide, acetaminophen Acid phenyl, phenyl salicylate, salacetamide, salicylamine-acetic acid, salicyl sulfate, salicylate, sulfasalazine, 0 stopper Azinamide (for example, ampiroxicam, droxicam, isoxicam, lornoxicam, phoxixicam) , tenoxicam, ε-ethylhexanoic acid, S-(5'-adenosyl)-L-methionine, 3-amino-4-hydroxybutyric acid, Ami Amixetrine, bendazac, benzydamine, α-bisabolol, bucolome, difenpiramide, and diazepam. Sitting (ditazol), emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxacillin ( Oxaceprol), renitoline 147399.doc -43- 201039824 (paranyline), 0 perisoxal, proquazone, superoxide dismutase, tenidap ( Tenidap), zileuton, its physiologically acceptable salts, combinations thereof, and mixtures thereof. In certain embodiments, the anti-inflammatory agent other than the DIGRA, a prodrug thereof, and a pharmaceutically acceptable salt or ester thereof is selected from the group consisting of flurbiprofen, suloprofen, bromfenac, dichlorinated Phenolic acid, indomethacin, ketorolac, salts thereof, and combinations thereof. In another aspect of the invention, the anti-inflammatory agent is a PPAR binding molecule. In one embodiment, the PPAR binds to a molecular PPARa-, PPAR5- or PPARy-binding molecule. In another embodiment, the PPAR binding molecule is a PPARa, PPAR5 or ΡΡΑΙΙγ agonist. This PPAR ligand binds to and activates PPAR to regulate the expression of genes containing appropriate peroxisome proliferator response elements in its promoter region. PPARy agonists can be obtained by human macrophages (C-Y. Jiang et al, TVaiwre, vol. 391, 82-86 (1998)) and T lymphocytes (A.E.

Giorgini et al., //orm. MeiaZ?. Λα. ’Vol. 31, 1-4 (1999)) inhibits TNF-α and other inflammatory cytokine production. Recently, the natural ΡΡΑίΙ agonist 15-deoxy-Δ-12,14-prostaglandin J2 (or "15-deoxy-Δ-12,14-PG J2") has been shown to inhibit neovascularization in the rat cornea. And angiogenesis (X. Xin et al., J. 〇/. C/^m., Vol. 274: 9116-9121 (1999)). Spiegelman et al., U.S. Patent No. 6,242,196, discloses the use of gamma gamma agonists to inhibit ΡΡΑΙΙγ-responsive hyperproliferative cell proliferation; Spiegelman et al. disclose a number of synthetic PPARy agonists 147399.doc-44-201039824 and for diagnosis A method of ΡΡΑΙΙγ-responsive hyperproliferative cells. All documents mentioned herein are hereby incorporated by reference. PPAR behaves differently in diseased and normal cells. ΡΡΑΙΙγ is expressed differently in different tissues of the eye (e.g., the retina and the cornea, the choroidal capillary layer, the uvea, the conjunctival epidermis, and certain layers of the intraocular muscle) (see, e.g., U.S. Patent No. 6,316,465). ❹ Ο In one aspect, the PPAR// agonist used in the compositions or methods of the invention is a thiazolidinedione, a derivative thereof, or an analog thereof. Non-limiting examples of thiazolidinedione-based gamma gamma agonists include pioglitazone, troglitazone, ciglitazone, englitazone, rosiglitazone ) and its chemical derivatives. Other ρρΑΙΙγ agonists include clofibrate (ethyl 2-(4-phenoxy)-2-methylpropionate), chlorobeic acid (2-(4-chlorophenoxy)- 2-mercaptopropionic acid), GW 1929 (N-(2-phenylhydrazinophenyl)-0-{2-(methyl-2-° ratio dimethylamino)ethyl b-tyrosine ), GW 7M7 (2-{{4_{2_{{(cyclohexylamino)carbonyl hydrazine (4-cyclohexylbutyl)amino}ethyl} phenyl}thio}-2-methylpropionic acid) And wy 14643 ({{4_chloro-6-{(2,3-dimethylphenyl)aminopyridyl 2-pyridinyl}thio)

Acetic acid). GW 1929, GW 7647 and WY 14643 +Α π a / ,, , , τ, can be from (for example) Koma

Biotechnology Corporation (Seoul, K〇rea) purchased. In one embodiment, the ΡΡΑΚγ agonist is a non-limiting form of 15-deoxy-^ PPAR-α agonist, including fibrates, such as fenofibrate and 吉It is only 4 (gemfibrozil). A non-limiting example of a PPAR-delta agonist is GW5 〇 1 $, t 6 (available from Axxora LLC, San 147399.doc 45 201039824

Diego, California or EMD Biosciences, Inc., San Diego, California). The concentration of any of the foregoing additional active ingredients in the ophthalmic composition may range from about 0.0001 mg/ml to about 1000 mg/ml (or alternatively, from about 0.001 mg/ml to about 500 mg/ml, or from约〇·〇〇1 mg/ml to about 300 mg/ml, or from about o.ooi mg/mi to about 250 mg/ml, or from about 0.001 mg/ml to about 1 mg/ml, or from From about 0.001 mg/ml to about 50 mg/ml, or from about 0.01 mg/ml to about 300 mg/ml, or from about 0.01 mg/ml to about 250 mg/ml, or from about 〇·〇ι mg/mi To a range of about 1 mg/ml, or from about 0.1 mg/ml to about 1 mg/ml, or from about 0.1 mg/ml to about 50 mg/ml. In another aspect, the method for preparing a composition of the invention comprises combining: (a) at least one DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof; (b) pharmaceutically acceptable The carrier to be accepted; and (c) a substance selected from the group consisting of: (i) an anti-infective agent, (ii) an anti-inflammatory other than the DIGRA, its drug, and its pharmaceutically acceptable salt or vinegar. And; (丨丨丨) a combination thereof. In one embodiment, the carrier can be a sterile saline solution or a physiologically acceptable buffer. In another embodiment, the carrier comprises a hydrophobic medium, such as a pharmaceutically acceptable oil. In yet another embodiment, the carrier comprises an emulsion of a hydrophobic material and water. Physiologically acceptable buffers include, but are not limited to, phosphate buffered bites Tris-HCl buffer (containing hydrazine (hydroxymethyl) aminomethane and HCl). For example, a Tris-HCl buffer having a pH of 7.4 contains 3 g/Ι ((meth)methyl) and 0.76 g/Ι of HC1. In still another aspect, the buffer is 147399.doc • 46· 201039824 1 0X phosphate buffered saline ("PBS") or 5X PBS solution. It can be found that other buffers are also suitable for use in or suitable for certain environments, for example, based on buffers having a pKa of 7.5 at 25 ° C and a pH between about 6.8 and 8.2 (N) -{2-hydroxyethyl}hexahydropyrazine-'N'-{2-ethanesulfonic acid}); BES having a pKa of 7.1 at 25 ° C and a pH between about 6.4 and 7.8 ( N,N-bis{2-hydroxyethyl}2-aminoethanesulfonic acid); MOPS (3-{N-?) having a pH of 7.2 at 25 °C and a pH between about 6.5 and 7.9 Phytyl}propane sulfonic acid); butyl ugly 8 (> 1-叁{hydroxymethyl}-methyl-2-) having a pKa of 7.4 at 25 ° C and a ratio of between about 6.8 and 8.2. Aminoethane sulfonic acid); MOBS (4-{N-morpholinyl}butane sulfonic acid) having a pKa of 7.6 and a pH between about 6.9 and 8·3 at 25 ° C; at 25 ° DIPSO (3-(N,N-bis{2-hydroxyethyl}amino)-2-hydroxypropane) having a pKa of 7.52 and a pH between about 7 and 8.2 at C; having at 25 ° C 7.61 pKa& TAPSO (2-hydroxy-3{叁(hydroxyindenyl)decylamino}-1_propanesulfonic acid) having a pH between about 7 and 8.2; having a pKa of 8.4 at 25 °C And TAPS ({(2-hydroxy-1) at a pH between about 7.7 and 9.1 ,1-bis(hydroxyindenyl)ethyl)aminodipyridinium-propane sulfonate

Acid); TABS (N-indole (hydroxymethyl)indolyl-4-aminobutanesulfonic acid) having a pKa of 8.9 and a pH between about 8.2 and 9.6 at 25 ° C; (: AMPSO having a pKa of 9.0 and a pH between about 8.3 and 9.7 (N-(l,l-didecyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid) At 25: (: has a pKa of 9.5 and a pH of between about 8.6-10.0 CHES (2-cyclohexylamino)ethanesulfonic acid); at 25 ° C with a pKa of 9.6 CAPSO (3-(cyclohexylamino)-2-yl-1-propanesulfonic acid) at a pH between 8.9 and 10.3; or a pKa of 10_4 at 25 ° C and a pH between about 9.7-11.1 CAPS 147399.doc • 47- 201039824 (3-(cyclohexylamino)_ι_propane sulfonic acid). In certain embodiments, the compositions of the present invention are formulated to have an acidic pH (eg, from about 4 to about 6.8, Or alternatively, it is selected from a buffer of from about 5 to about 6.8. In these embodiments, the buffering ability of the composition is such that the composition rapidly reaches physiological pH after administration to a patient. It should be understood that The parts of each component or mixture in the following examples can be adjusted according to the appropriate environment.Example 1 Two mixtures j and hydrazine were prepared separately by mixing the ingredients listed in Table 1. 5 parts by weight Mix! with 2 parts (to The mixture is π-mixed for 15 minutes or longer. The pH of the combined mixture is adjusted to 6.2-6.4 using 1 ν NaOH or 1 N HCl solution to obtain the composition of the present invention. Component amount mixture I carbomer 934PNF 0.25 g Purified water 99.75 g Mixture II Propylene glycol 5 g EDTA 0.1 mg Compound of formula IV 50 g Example 2: Two mixtures and II were prepared separately by mixing the ingredients listed in Table 2. 5 parts by weight The mixture is mixed with a "part(by weight) mixture of workers for 15 minutes or longer. The pH of the mixture is adjusted to 6.2-6·4 using i N NaOH ii : (:1 solution to obtain the present invention) Composition 147399.doc •48· 201039824 Table 2 Ingredient mixture I Moxifloxacin 0-2 g Bisphenolic acid 0.3 g Carbomer 934P NF 0.25 g Purified water 99.25 g Mixture II Propylene glycol 5g EDTA 0.1 mg Compound of formula IV 50 g Ο U Example 3: Two mixtures I and II were separately prepared by mixing the ingredients listed in Table 3. Mix 5 parts by weight of mixture I with 20 parts by weight of mixture II 15 minutes or more Time using 1 N NaOH or 1 N HC1 solution of pH of the mixture was adjusted to 6.2-6.4 were combined to obtain a combined product of the present invention. Table 3 Ingredient Mixture I Gatifloxacin 0.2 g Cycloglitazone 0.2 g Carbomer 934PNF 0.25 g Purified water 99.35 g Mixture II Propylene glycol 3 g Triacetin 7 g Compound of formula II 50 g EDTA 0.1 mg 147399.doc • 49- 201039824 Example 4: Two mixtures I and II were prepared separately by mixing the ingredients listed in Table 4. Mix 5 parts by weight of mixture I with 20 parts by weight of mixture II for 15 minutes or longer. The pH of the combined mixture was adjusted to 6.2-7.5 using 1 N NaOH or 1 N HCl solution to obtain a composition of the present invention. Table 4 Ingredient Mixture I Tobramycin Sulfate 0.3 g Gemfibrozil 0.3 g Carbomer 934PNF 0.25 g Olive Oil 99.15 g Mixture II Propylene Glycol 7g Glycerin 3g Formula III Compound 50 g Cyclosporine A 5g HAP (30%) 0.5 mg alexidine 2HC1 1-2 ppm Note: "HAP" means hydroxyalkyl phosphonates, such as those known under the trade name Dequest®. Example 5: The ingredients listed in Table 5 were mixed together for at least 15 minutes. The pH of the mixture was adjusted to 6.2-7.5 using 1 N NaOH or 1 N HCl solution to obtain a composition of the present invention. 147399.doc -50- 201039824 Table 5 Ingredients (weight ° / & 〇 Pavia 嗣 1 HAP (30%) 0.05 glycerol 3 propylene glycol 3 compound IV 0.5 ty loxapol 0.25 BAK 10-100 ppm Pure water is added to 100 Note: “BAK” means benzalkonium chloride. Example 6: Mix the ingredients listed in Table 6 together for at least 15 minutes. Adjust the pH of the mixture with 1 N NaOH or 1 N HC1 solution. To 7-7.5 to obtain the composition of the present invention. Table 6 Component amount (% by weight) Pavitonone 1.5 HAP (30%) 0.05 Glycerol 3 Propylene glycol 3 Formula III compound 0.75 Tyloxapol 0.25 Alesidine 2HC1 1- 2 ppm pure water make up to 100 Example 7: Mix the ingredients listed in Table 7 together for at least 15 minutes. Adjust the pH of the mixture to 6.5-7.8 using 1 N NaOH or 1 N HCl solution to obtain the combination of the invention 147399.doc -51- 201039824 Table 7 Ingredient Quantity (% by weight) CMC (MV) 0.5 HAP (30%) 0.05 Glycerin 3 Propylene Glycol 3 Formula II Compound 0.75 Tylosapo (surfactant) 0.25 Alesidine 2HC1 1-2 ppm purified water to 100% Example 8: Will be listed in Table 8. The ingredients were mixed together for at least 15 minutes. The pH of the mixture was adjusted to 6.2-7.4 using 1 N NaOH or 1 N HCl solution to obtain the composition of the invention. Table 8 Component Amount (% by weight) CMC (MV) 0.5 HAP ( 30%) 0.05 Glycerol 3 Propylene glycol 3 Compound IV 0.75 Miconazole 0.2 15-Deoxy_Δ·12,14 Prostaglandin J2 0.3 Tyloxapol (surfactant) 0.25 Alesidine 2HC1 1-2 ppm Pure Water uptake to 100 Example 9: The ingredients listed in Table 9 were mixed together for at least 15 minutes. The pH of the mixture was adjusted to 6.2-6.8 using 1 N NaOH or 1 N HCl solution to obtain a composition of the invention. 147399.doc -52- 201039824 Table 9 Ingredient Amount (% by weight) CMC (MV) 0.5 HAP (30%) 0.05 Glycerol 3 Propylene Glycol 3 Compound of Formula IV 0.75 Bacillus Peptide 0.2 Flurbiprofen 0.2 Levofloxacin 0.3 Teroxabor ( Surfactant) 0.25 Alesidine 2HC1 1-2 ppm Purified water to 100. Example 10: Mix the ingredients listed in Table 10 together for at least 15 minutes. The pH of the mixture was adjusted to 6.2-6.8 using a 1 N NaOH or 1 N HCl solution to obtain a composition of the present invention. Table 10 Component (% by weight) Ο CMC (MV) 0.5 HAP (30%) 0.05 Glycerol 3 Propylene glycol 3 Compound III 0.75 Moxifloxacin 0.2 15-Deoxy-Δ-12,14-Prostaglandin J2 0.3 g of mold 0.2 Tyloxapol (surfactant) 0.25 Alesidine 2HC1 1-2 ppm Purified water to 100 147399.doc -53 201039824 Example 11 : The ingredients listed in Table 11 were mixed together for at least 15 minutes. The pH of the mixture 1 was adjusted to 6.2-7 using 1 N NaOH or 1 N HCl solution to obtain a composition of the present invention. Table 11 Ingredient amount ketorolac 0.4 g Compound of formula IV 0.2 g Carbomer 934PNF 0.25 g Propylene glycol 5 g EDTA 0.5 mg Purified water 98.65 g In another aspect, DIGRA, its prodrug, or its pharmaceutically acceptable The salt or ester is included in the formulation for topical administration or periocular injection into the anterior segment. Injectable formulations may preferably contain carriers which provide sustained release of the active ingredient (for example, longer than about 1 week, or longer than about 1, 2, 3, 4, 5 or 6 months). In certain embodiments, the sustained release formulation preferably comprises a carrier that is insoluble or only slightly soluble in the anterior segment of the eye. The carrier can be an oil based liquid, emulsion, gel or semi-solid. Non-limiting examples of oil-based liquids (4) sesame oil, peanut oil (pe_t. (1), olive oil, coconut oil, sesame oil, cottonseed oil, corn oil, sorghum oil, cod liver oil, arachis oil and liquid paraffin In another embodiment, the formulation further comprises a substance selected from the group consisting of: (1) an anti-infective agent; (1) a salt different from the prodrug thereof, and a pharmaceutically acceptable salt. ; ϋ (4) 147399.doc -54- 201039824 and (iii) its combination. In one embodiment, a compound or composition of the invention can be injected using a microlobule (e.g., '25-35 gauge) injection needle. Typically, a composition comprising (iv) RA, a prodrug thereof, or a pharmaceutically acceptable salt or vinegar thereof is administered to a patient in an amount from about 沁 to about (10) Μ. The concentration of this DIGRA, its prodrug, or the pharmaceutically acceptable salt or g is selected from the ranges disclosed above. In a further aspect, RA, a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof, is incorporated into an ophthalmic device comprising a biodegradable material, and the device is implanted in the anterior segment of the eye of the individual. For the long term (for example, longer than about!

Weeks or longer than about 1, 2, 3, 4, 5 or 6 months) treat or control anterior inflammatory diseases, conditions or conditions. The device can be implanted into the eye or periocular tissue of an individual by a physician skilled in the art. In a further aspect, a method of treating or controlling an ocular inflammatory disease, condition or disorder comprises: (a) providing a composition comprising DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt or vinegar thereof; b) administering to the individual an amount and frequency sufficient to treat or control the ocular disease, condition or disorder in the individual, wherein the method increases the IOP of the individual compared to the method of prior art GC. The risk is reduced. In one embodiment, the prior art Gc is dexamethasone. In another embodiment, the prior art GC is prednisolone acetate. In still another aspect, a method of treating or controlling inflammation of the anterior segment of the eye comprises: (a) providing a composition comprising DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof; and (b) The composition is administered or controlled to the individual in an amount and frequency of inflammation following the procedure, wherein the method reduces the risk of IOP elevation in the individual compared to the method of prior art 147399.doc-55-201039824 GC. In one embodiment, the prior art GC is dexamethasone. In another embodiment, the prior art GC is prednisolone acetate. In a further aspect, a method of treating or controlling an anterior segment of an inflammatory disease, condition or disorder comprises: (a) providing a composition comprising DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof; b) administering to the individual the composition in an amount and frequency sufficient to treat or control the eye disease, condition or disorder of the individual' wherein the method increases the IOP of the individual compared to the method using prior art GC The risk is reduced. In one embodiment, the prior art GC is dexamethasone. In another embodiment, the prior art is prednisolone acetate. In still another aspect, a method of treating or controlling inflammation of the anterior segment of the eye comprises: (a) providing a composition comprising DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof; and (b) The composition is administered or controlled to the individual in an amount and frequency of the post-operative inflammation, wherein the method reduces the risk of increased I〇p in the individual compared to the method of prior art GC. In one embodiment, the prior art GC is dexamethasone. In another embodiment, the prior art GC is prednisolone acetate. In still another aspect, a method of treating or controlling an anterior segment inflammatory disease, condition or disorder comprises: (a) providing a composition comprising: (1) DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt thereof Or an ester; (1) an anti-inflammatory agent different from the DIGRA, a prodrug thereof, and a pharmaceutically acceptable salt or ester thereof; and (iii) an anti-infective agent; and (b) an anterior segment disease sufficient to treat or control the individual The amount and frequency of the condition or condition is administered to the individual, and the method reduces the risk of increased 该ορ of the individual as compared to the method of prior art GC, 147399.doc • 56-201039824. In one embodiment, the prior art GC is dexamethasone. In another embodiment, the prior art GC is prednisolone acetate. In another aspect, a method of treating or controlling inflammation of the anterior segment of the eye comprises: (a) providing a composition comprising: (1) digrA, a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof; (ii) An anti-inflammatory agent different from the DIGra, its other drug, and a pharmaceutically acceptable salt or ester thereof; and (Hi) an anti-infective agent, and (b) to the individual in an amount and frequency sufficient to treat or control the post-operative inflammation The composition is administered wherein the method can reduce the risk of IOP increase in the individual compared to the method of prior art Gc. In one embodiment, the prior art GC is dexamethasone. In another embodiment, the prior art GC is prednisolone acetate. In certain embodiments, the DIGRA is selected from the ones disclosed above. In other embodiments, the anti-inflammatory agent is selected from the ones disclosed above. In some embodiments, the anti-inflammatory agent is selected from the group consisting of flurbipro, suloprofen, bromfenac, diclofenac, indomethacin, ketorolac, salts thereof, and combinations thereof. In another embodiment, the inflammation is chronic inflammation. In yet another embodiment, the inflammation will take at least two weeks to resolve if left untreated. In still another embodiment, the anterior segment inflammatory disease, condition or condition is caused by an ocular infection caused by a virus, a bacterium, a fungus or a protozoan. In another aspect, the composition of the invention is administered periocularly or in the anterior chamber. In the re-formation, the composition of the invention is implanted into the human ophthalmic implant system 147399.doc -57-201039824 or In the device, the implant system or device is surgically implanted into the tissue of the eye of the person or in the area in front of the adjacent eye to slowly release the active ingredient. A typical implant system or device suitable for use in the methods of the present invention comprises a biodegradable matrix in which the active ingredient or ingredients are filled or dispersed. Examples of lightness of ophthalmic implant systems or devices for the slow release of active ingredients are disclosed in U.S. Patent No. 5,378,475; 5,773, No. 19; No. 5,902,598; No. MG1,386; No. No. 6,726,918, the contents of which are incorporated herein by reference. In another aspect, 'the invention, the composition is one or two owed a week, one month, one year, one year, two times a year, four times a year, or It is administered at a suitable frequency for the treatment or control of anterior segment inflammatory diseases, conditions or conditions. Comparison of Glucocorticoids and DIGRA One of the most common undesirable effects of glucocorticoid therapy is steroid diabetes. The cause of this undesired condition is the gluconeogenesis in the liver, which is affected by the liver enzyme transcript. The liver enzymes are involved in the degradation of the protein f (the catabolism of glucocorticoids). Health and metabolism. The key enzyme in catabolism in the liver is glycosylamine transferase ("TAT"). The activity of this enzyme can be determined photometrically from the cell culture of the treated rat hepatoma cells. Therefore, the gluconeogenesis of the glucocorticoid can be compared to the digrA2 gluconeogenesis by measuring the activity of the enzyme. For example, in one procedure, the cells are treated with the test substance (DIGRA or glucocorticoid). After an hour, the TAT activity was measured. The TAT activity of the selected DIGRA and glucocorticoids was then compared. Other liver enzymes 147399.doc -58- 201039824 can be used instead of TAT', for example, serotonin pyruvate kinase, glucose luciferase or fructose-2,6-bisphosphatase. Alternatively, the amount of blood glucose in the animal model can be directly measured and individual individuals treated with glucocorticoids for the selected condition compared to those treated with DIGRA for the same condition. Another undesired result of glucocorticoid therapy is Gc-induced leucorrhea. The cataract potential of a compound or composition can be determined by quantifying the effect of a compound or composition on the potassium ion flux through a lens of a lens cell (e.g., a mammalian lens epithelial cell). This ion current can be determined, for example, by electrophysiology techniques or ion current imaging techniques (e.g., by using a fluorescent dye). An exemplary in vitro method for determining the cataract potential of a compound or composition is disclosed in U.S. Patent Application Publication No. 2004/0219512, which is incorporated herein by reference. Another undesired result of glucocorticoid therapy is hypertension. The blood pressure of similarly matched individuals treated with glucocorticoids for inflammatory conditions and D j G R A treatment can be directly measured and compared. A further undesired result of glucocorticoid therapy is an increase in individual IOP. The IOPs of similar matched individuals for pathological glucocorticoids and DIGRA treatment can be directly measured and compared. Test. Comparison of DIGRA with Formula IV and two corticosteroids and one NSAID in the treatment of anterior segment inflammation 1. Introduction to the inflammatory process in a multitude of causes' and characterized by complex cells and molecules involved in multiple components Events, all such components are not yet clear. Prostaglandins belong to these mediators and play an important role in some forms of ocular inflammation 147399.doc .59· 201039824. Puncture of the anterior chamber of the rabbit's eye causes an inflammatory response due to disruption of the blood-water barrier ("BAB"), which is at least to some extent regulated by prostaglandin E2 [see references 1-3]. Intraocular or topical administration of PGE2 destroys BAB. [Reference 4 below]. The treatment regimen used in this study was similar to the clinical NS AID (Ocufen) treatment regimen used by surgeons for patients prior to cataract surgery. We studied different doses of dissociated glucocorticoid receptor agonists ("BOL-303242-X", a compound of the above formula IV) with vehicle, dexamethasone, loteprednol and fluoride. The difference in the rabbit puncture model between the evaluation of the amount of aqueous biomarkers and the activity of the iris-ciliary body MPO was compared. 2. Method 2.1 Drugs and Materials 2.1.1 Test commodity BOL-3 03 242-X (0.1%, 0.5% and 1% topical formulation), batch number 2676-MLC-107, Bausch & Lomb Incorporated ("B& L") Rochester, USA. Vehicle (10 ° / PEG 3350; 1% Tween 80; phosphate buffer pH 7.00), batch number 2676-MLC-107, B&L Rochester, USA.

Visumetazone® (0.1% dexamethasone topical formulation), batch number T253, Visufarma, Rome, Italy.

Lotemax® (0.5% gastipol topical formulation), batch number 078061, B&L IOM, Macherio, Italy. Okefin® (0.03% flurbiprofen topical formulation), batch number E45324, Allergan, Westport, Ireland. 147399.doc -60- 201039824 2.2 Animal Species: Rabbit Variety. New Zealand Rabbit (Source: Morini (Reggi〇 Emila, Italy) Gender: Male Age at the start of the experiment: 10 weeks. Weight range at the beginning of the experiment: 2.0-2.4 Kg Total number of animals: 2 8 markers: Mark the ear with an alphanumeric code (ie, A1 means test commodity A and animal 1). Description: Rabbit is a standard non-female animal species used for pharmacodynamics studies. Based on the judgment of the investigators, the number of animals used in this study is the minimum amount required to properly implement such studies and is consistent with world regulatory guidelines. Oral Environmental Adaptation/Quarantine: After arrival, the veterinarian staff evaluates the overall health of the animal. & to the interval between the animal and the beginning of the experiment in order to adapt the animal to the laboratory environment and to observe the development of infectious diseases of these animals. Animal management: All animals are housed in a clean and sterilized state with a constant temperature (22 ± 1. 〇, humidity (relative, 30%) and in a dark-and-dark cycle (in the 8 〇〇 and 2 〇〇〇 periods) In the room. Randomly obtain commercially available food and tap water. Measure the body weight (absence) before the experiment (4). All animals have a weight distribution curve (four) points (1 (%)) to (4) body weight. 4 Rabbits were replaced with animals of the same age and of similar age and weight, 147399.doc •61 - 201039824 because three of them showed signs of ocular inflammation and one died on arrival. Animal welfare provided: according to the study All experiments conducted by the ARVO (Association for Research in Vision and Ophthalmology) guidelines for animals. There is no other test system that has been fully validated to replace the live animals used in this study. The maximum amount of information is obtained while minimizing the number of animals needed for this study. To the best of our knowledge, this study is not redundant or repetitive. The University of Catania's Institutional Animal Care and Use Committee (IACUC) reviews and approves and meets the acceptable standards for animal welfare care. 2.3 Experimental preparation 2.3.1 Study design and randomization Twenty-eight rabbits were randomly divided into 7 groups (4 animals/group) as shown in the following table.

Group rabbit treatment observation and measurement termination and analysis I 4 CTR 180, 120, 90 and 30 minutes before the first puncture and 50 μΐ at 15, 30, 90 minutes after the first puncture 180 180 and 5 minutes before the first puncture And the clinical observation and pupil diameter at 5 minutes before the first puncture. Puncture was performed at 0 and 2 hours. Terminate immediately after the second puncture. Aqueous water was collected for PGE2, protein, white blood cells, and ltb4 measurements. Iris-ciliary bodies were collected for MPO activity measurements. II 4 1% BOL III 4 0.5% BOL IV 4 0.1% BOL V 4 0.5% LE VI 4 0.1% Dex VII 4 0.03% F "—J CTR=media

BOL=BOL-303242-X LE=gyptonol ethyl carbonate; Dex=dexamethasone; F=flurbiprofen 147399.doc -62- 201039824 Randomly prepare each test commodity with letters from A to G Α = vehicle (10% PEG3350/1% Tween 80/PB pH 7.00) B = oufufen (flurbiprofen 〇 〇 3%) C = Visumetazone (dexamethasone 〇 · 1%) D = Lotemax (chloroform) Epoxyethyl carbonate 〇.5〇/〇) E=BOL-303242-X 0.1% (1 mg/g) F=BOL-303242-X 0.5% (5 mg/g) G=BOL-303242-X 1 % (10 mg/g) O 2.3.2 Preparation of reagents for MPO analysis 2.3.2.1 Carbonate buffer (5 mM; pH=6) Dissolve 3.9 g of NaH2P〇4 2H20 in a volumetric flask and make up with water to 500 ml. The pH was adjusted to pH = 6 with 3 N NaOH. 2.3.2.2 Cetyl-tridecyl-ammonium bromide (0.5 〇/〇) Dissolve 〇5 g of cetyl-tridecyl-ammonium bromide in 1 〇〇mi phosphate buffer . 2.3.2.3 O-dianisidine 2HC1 (0.0167%) / H2〇2 (0.0005%) solution ◎ This solution was newly prepared. 10 μl of H 2 〇 2 (30% by weight) was diluted to 1 ml with water (solution A). 7.5 mg of o-dianisidine 2HC1 was dissolved in 45 ml of phosphate buffer and 75 μL of solution A was added. 2_4 Experimental Protocol 2. 4.1 Animal Treatment and Sample Collection Each rabbit was placed in a restriction device and marked with an alphanumeric code. 180, 120, 90, and 30 minutes before the first puncture; then, at 15, 30, and 90 minutes after the first puncture, the formulations (50 μΐ) were dropped into the conjunctival sac of both eyes 147399.doc • 63 - 201039824. When the first puncture is performed, 5 mg/kg is given by intravenous injection.

Zoletil® (Virbac; 2.5 mg/kg of tiletamine HC1 and 2.5 mg/kg of zolazepam HC1) were anesthetized and administered 1 drop of local anesthetic to the eye ( Novesina®, Novartis). The anterior chamber puncture is performed with a 26 G needle attached to a tuberculin syringe; the needle is introduced into the anterior chamber via the cornea. Be careful not to damage the tissue. The animals were sacrificed with 0. 4 ml of Tanax® (Intervet International B.V.) 2 hours after the first puncture and a second puncture was performed. Take about 1 房 of aqueous humor during the second puncture. Immediately divide the water into 4 equal parts and _8 〇. (: Store until analysis. Then remove both eyes and carefully remove the iris-ciliary body, place in a polypropylene tube and store at -8 (TC until analysis). 2.4 · 2 pupil diameter measurements before the first puncture The diameter of the pupils of both eyes was measured with a Castroviej〇caliper for 1 800 minutes and 5 minutes and 5 minutes before the second puncture. 2 _ 4 · 3 clinical evaluation for the first time Clinical § parity was performed on both eyes by slit lamp (4179-T; Sbw, Italy) at 180 minutes and 5 minutes before puncture and 5 minutes before the second puncture. Clinical scores were assigned according to the following protocol: 〇 = normal 1 = iris and conjunctival vascular discrete expansion 2 = iris and conjunctival vascular moderate expansion 3 = strong iris congestion and redness in the anterior chamber 4 = strong iris congestion and redness in the anterior chamber with fibrinity 147399.doc -64 - 201039824 Exudate. 2.4.4 Prostaglandin £2 (卩0£2) Measurement We used the PGE2 immunoassay kit (R&D Systems; catalog number 1^ ug 004; lot number 240010) to quantify the room 0?2 in the water. Provided by the • set Diluted solution Dilute 11 μl or 16 μl of aqueous humor to 11 μL or 160 μl. Load 100 μl of sample and standard into a 96-well plate and record in a plate layout. The analysis procedure described in the sample was processed and the samples were calibrated and analyzed using a microplate reader (GDV, Italy; DV 990 B/V6) set at 450 nm (corrected at 540 nm). .5 Protein Measurements We used the Protein Quantification Kit (Fluka; catalog number 77371; lot number 1303 129) to determine the protein concentration in aqueous humor. Dilute 5 microliters of aqueous humor to 1 microliter with water. Twenty microliters of sample and standard were loaded into a 96-well plate and recorded in a plate layout. Samples were processed according to the analytical procedure described in the kit. A microplate reader (GDV, set at 670 nm) was used. Italy; DV 990 B/V6) Perform calibration and analyze the samples 2.4.6 White blood cell (PMN) measurement We used a blood cell counter (Improved Neubauer Chamber; Bright-line, Hausser Scientific) and Polyvar 2 microscope (Reichert- Jung) to determine white The number of cells. 2·4·7 Leukocyte three-dilute B4 (LTB4) measurement We used the LTB4 immunoassay kit (r&d Systems; catalog number 147399.doc -65-201039824 KGE006; batch number 243623) for quantitative determination LTB4 concentration in aqueous humor. Dilute 11 μl of aqueous humor to Π 0 μl using the calibration dilution solution provided in the kit. One hundred microliters of the sample and standard were loaded into a 96-well plate and recorded in a flat panel arrangement. The samples were processed according to the analytical procedure described in the kit. Calibration was performed and analyzed using a microplate reader (GDV, Italy; DV 990 B/V6) set to 45 0 nm (corrected at 540 nm). 2.4.8 Myeloperoxidase (MPO) measurement The activity of MPO was measured as previously described by Williams et al. [5]. The iris-ciliary body was carefully dried, weighed and immersed in 1 ml of cetyl-trimethyl-ammonium bromide solution. Subsequently, the samples were ultrasonicated for 10 seconds on ice by a supersonic homogenizer (HD 2070, Bandelin electronics), frozen-thawed 3 times, supersonic for 10 seconds and centrifuged at 14,000 g for 10 minutes. Remove cell debris. An aliquot of the supernatant (40-200 microliters) was diluted to 3 ml with o-dianisidine 2HC1/H202 solution. The absorbance change was continuously monitored by a spectrophotometer (UV/Vis Spectrometer Lambda EZ 201; Perkin Elmer) at 460 nm for 5 minutes. The linear slope (Δ/min) of each sample was measured and used to calculate the number of MPO units in the tissue according to the following formula: MPO unit (Δ/m111): -1?. ε · μΐ · mg where ε = 11.3 mM_1. Values are expressed in terms of the number of MPO units per gram of tissue. 2.5 Data analysis The pupil diameter, PGE2, protein, PMN and MPO were expressed as mean SEM. One-way ANOVA and 147399.doc -66- 201039824

Statistical analysis was performed on the Newman-Keuls post hoc test. Statistical analysis was performed with the Kruskal_WalHs and Dunri p〇st h〇c test in terms of % of the eye. In both cases, p < 〇 〇 5 is considered to be statistically significant. Use Prism 4 software (GraphPad Software) for analysis and plotting. 3 · Results 3 · 1 pupil diameter measurement The raw data are shown in Tables T-2 and T-3. No statistically significant differences were found between the CRT and all treatment groups. 3.2 Clinical evaluation The raw data are shown in Tables T-4 and T-5. Only 0.5% of the LE group showed a significant difference from CTR (p<〇.〇5). 3.3 months of adenosine E2 (PGE2) measurements The raw data are shown in Tables T-6 and T-7. There was a statistically significant difference between the treatment group of 0.03% F, 0.5% LE, 0.1% B0L, and 0.5% B0L and CTR (P < 0.05). 〇 ” w 3.4 Protein Measurement The original data is not shown in Tables T-8 and T-9. It has been found that the treatment group

There was a statistically significant difference between 0.03% F and 1% between B0L and CTR (p<0.001) and 0.5% between BOL and CTR (ρ<0·05). 3 · 5 white blood cell (ΡΜΝ) measurement The raw data are shown in Tables Τ-10 and Τ-11. All treatment groups were statistically significantly different from cTR (ρ < 0.001). 3.6 leukotriene B4 (LTB4) measurement 147399.doc -67- 201039824 All samples were limited by the quantitative analysis of this analysis (about 0. 2 ng / ml). 3.7 Myeloperoxidase (MPO) measurements The raw data are shown in Tables T-12 and T-13. It has been found that 'all treatment groups are present with CTR (for 0.03% F 'p<0_01; and for 0.1% Dex, 0.5% LE, 0.1% BOL, 0.5% BOL, and 1% BOL 'ρ<0·001)) Significant statistical differences. 4. Discussion The preliminary conclusions drawn from the data generated are: • BOL-303242-X is active in this model. • There is no significant difference between these concentrations of BOL-303242-X and NSAIDs versus steroid-positive controls. BOL-303242-X has no meaningful dose response and may be at maximum efficacy or maximum drug exposure at these doses. However, the results show that BOL-303242-X is equally effective as an anti-inflammatory drug with some of the commonly accepted prior art steroids or NS AIDs. Some other preliminary data (not shown) indicate that BOL-303242-X does not have some of the side effects of corticosteroids. 5. References 1. Eakins KE (1977). Prostaglandin and non prostaglandin-mediated breakdown of the blood-aqueous barrier. Exp. Eye Λα., Vol. 25, 483-498. 2. Neufeld AH, Sears ML (1973). The site of action of prostaglandin E2 on the disruption of the blood-aqueous barrier in the rabbit eye. Five λ: /?· five 'Vol. 17 '445-448 ° 147399. Doc-68-201039824 3. Unger WG, Cole DP, Hammond B (1975). Disruption of the blood-aqueous barrier following paracentesis in the rabbit. Exp. Eye Res. > Vol. 20, 255-270. 4. Stjernschantz J (1984). Autacoids and Neuropeptides. Sears, ML (ed.) Pharmacology of the Eye. Springer-\^1*1& Lu, New York, pp. 3 1 1-3 65. 5. Williams RN, Paterson CA, Eakins KE, Bhattacherjee

P (1983) Quantification of ocular inflammation: evaluation of polymorphonuclear leukocyte infiltration by measuring myeloperoxidase activity. Cwrr. and I., Vol. 2, 465-469 ° Table Tl: Rabbit weight rabbit ID and body weight measured before the start of the experiment (g) A1 M 2090 A2 M 2140 A3 M 2100 A4 M 2320 B1 M 2270 B2 M 2190 B3 M 2340 B4 M 2300 Cl M 2160 C2 M 2160 C3 M 2280 C4 M 2400 D1 M 2220 D2 M 2200 D3 M 2180 147399. Doc -69- 201039824 D4 Μ 2260 Ε1 Μ 2170 Ε2 Μ 2330 Ε3 Μ 2350 Ε4 Μ 2300 F1 Μ 2190 F2 Μ 2240 F3 Μ 2120 F4 Μ 2200 G1 Μ 2410 G2 Μ 2270 G3 Μ 2310 G4 Μ 2130 Average ± SD 2236.8 ± 89.2 Table T-2 raw data for pupil diameter at -180 minutes (basal), -5 minutes (5 minutes before the first puncture) and +115 minutes (5 minutes before the second puncture), and at +115 minutes The difference between the value and the value at _18〇 minutes. Treated rabbit ID Eye diameter 〇nm> T1 : -180 min T2 : -5 min T3 : +115 min Δ(Τ3-Τ1) CTR A1 DX 6.0 5.5 4.0 -2.0 SX 5.5 5.5 4.0 -1.5 A2 DX 6.0 6.5 4.5 -1.5 SX 6.0 6.5 5.0 -1.0 A3 DX 6.5 6.5 5.0 -1.5 SX 6.5 6.5 5.0 -1.5 A4 DX 6.0 6.5 5.0 -1.0 SX 6.0 6.5 5.0 -1.0 0.03% F B1 DX 5.0 6.0 4.0 -1.0 SX 5.0 6.0 3.5 -1.5 147399. Doc -70- 201039824

B2 DX 7.0 6.5 5.5 -1.5 sx 6.0 7.0 5.0 -1.0 B3 DX 6.0 6.5 4.5 -1.5 SX 6.0 6.5 6.0 0.0 B4 DX 5.5 6.0 5.5 0.0 SX 6.0 5.5 5.0 -1.0 0.1% Dex Cl DX 6.0 5.5 5.5 -0.5 SX 7.0 6.5 5.5 -1.5 C2 DX 5.5 6.5 6.0 0.5 SX 5.5 6.0 5.5 0.0 C3 DX 6.5 6.0 4.5 -2.0 SX 6.5 6.5 5.0 -1.5 C4 DX 6.5 7.0 6.0 -0.5 SX 7.0 7.5 6.5 -0.5 0.5% LE D1 DX 6.0 6.0 4.5 -1.5 SX 6.0 6.0 5.0 -1.0 D2 DX 6.5 6.5 5.5 -1.0 SX 6.5 6.5 5.5 -1.0 D3 DX 6.0 6.0 6.0 0.0 SX 6.5 6.5 6.0 -0.5 D4 DX 6.5 6.5 6.0 -0.5 SX 6.5 6.5 5.0 -1.5 0.1% BOL El DX 6.5 6.5 5.0 -1.5 SX 6.5 6.5 6.0 -0.5 E2 DX 6.5 7.0 5.0 -1.5 SX 6.5 7.0 6.0 -0.5 E3 DX 7.0 7.0 6.0 -1.0 SX 7.5 7.5 6.5 -1.0 E4 DX 7.0 6.5 5.5 -1.5 SX 7.0 7.0 5.5 -1.5 147399 .doc -71 - 201039824 0.5% F1 DX 8.0 8.0 6.5 -1.5 BOL SX 8.0 8.0 6.5 -1.5 F2 DX 7.0 7.0 6.5 -0.5 SX 7.0 7.0 6.0 -1.0 F3 DX 7.5 7.5 7.0 -0.5 SX 8.0 8.0 7.0 -1.0 F4 DX 7.0 7.0 6.0 -1.0 SX 7.5 7.0 6.5 -1.0 1%B0L G1 DX 6.0 6.0 5.5 -0.5 SX 6.5 6.5 5.0 -1.5 G2 DX 6.0 6.5 5.0 -1.0 SX 6.0 6.5 5.0 -1.0 G3 DX 6.5 7.0 5.5 -1.0 SX 6.5 7.0 5.0 -1.5 G4 DX 6.5 6.5 6.0 -0.5 SX 6.5 6.0 6.0 -0.5 Table T-3 at Τ3=+115 minutes (in the second puncture The difference between the value of the pupil diameter in the previous 5 minutes) and the value at Tl = -180 minutes (basis) (mean SEM). Treatment rabbit group ID mean (mm) △(T3-T1) SEM n CTR A -1.4 0.12 8 0.03% FB -0.9 0.22 8 0.1% Dex C -0.8 0.30 8 0.5% LE D -0.9 0.18 8 0.1% BOL E -1.1 0.16 8 0.5% BOL F -1.0 0.13 8 1%B0L G -0.9 0.15 8 147399.doc -72- 201039824 Table T-4 at -180 minutes (basis), -5 minutes (5 minutes before the first puncture) And raw data for clinical scores at +115 minutes (5 minutes before the second puncture).

Treatment Rabbit ID Eye Clinical Score -180 min -5 min +115 min CTR A1 DX 0 1 3 sx 0 1 3 A2 DX 0 0 2 SX 0 0 2 A3 DX 0 0 3 SX 0 0 3 A4 DX 0 0 3 SX 0 0 3 0.03% F B1 DX 0 0 2 SX 0 0 2 B2 DX 0 0 2 SX 0 0 2 B3 DX 0 0 2 SX 0 0 2 B4 DX 0 0 2 SX 0 0 2 0.1% Dex Cl DX 0 0 1 SX 0 0 1 C2 DX 0 0 1 SX 0 0 1 C3 DX 0 1 3 SX 0 1 3 C4 DX 0 0 1 SX 0 0 1 0.5% LE D1 DX 0 0 2 147399.doc -73- 201039824 SX 0 0 2 D2 DX 0 0 1 SX 0 0 1 D3 DX 0 0 1 SX 0 0 1 D4 DX 0 0 1 SX 0 0 1 0.1% BOL El DX 0 0 2 SX 0 0 2 E2 DX 0 0 2 SX 0 0 2 E3 DX 0 0 2 SX 0 0 2 E4 DX 0 0 3 SX 0 0 3 0.5% BOL FI DX 0 0 2 SX 0 0 2 F2 DX 0 0 1 SX 0 0 2 F3 DX 0 0 1 SX 0 0 1 F4 DX 0 0 2 SX 0 0 2 1%B0L G1 DX 0 0 2 SX 0 0 2 G2 DX 0 0 2 SX 0 0 2 G3 DX 0 0 2 SX 0 0 2 G4 DX 0 0 2 SX 0 0 2 147399.doc -74· 201039824 Table T-5 is a clinical evaluation expressed as the percentage of eyes at -180 minutes (basal), -5 minutes (5 minutes before the first puncture), and +115 minutes (5 minutes before the second puncture) Minute.

Treatment rabbit group ID N score (%) (eye) 0 1 2 3 4 [80 min CTR A 8 100 __ __ 0.03% FB 8 100 __ __ __ 0.1% Dex C 8 100 0.5% LE D 8 100 cap · __ __ 0.1% BOL E 8 100 __ __ __ 0.5% BOL F 8 100 __ a· _ 1% BOL G 8 100 -5 min CTR A 8 75 25 __ _ a 0.03% FB 8 100 __ __ __ 0.1% Dex C 8 75 25 一· __ 0.5% LE D 8 100 0.1% BOL E 8 100 __ _· __ 0.5% BOL F 8 100 __ • 1% BOL G 8 100 + 115 min CTR A 8 25 75 0.03% FB 8 __ __ 100 __ ___ 0.1% Dex C 8 __ 75 __ 25 __ 0.5% LE D 8 __ 75 25 _ _ _ _ 0.1% BOL E 8 __ 75 25 0.5% BOL F 8 __ 37.5 62.5 _ _ __ 1% BOL G 8 One _ _ 100 — __ 147399.doc -75- 201039824 Table T-6 Raw data of PGE2 in aqueous samples taken during the second puncture

Treatment sample pge2 (ng/ml) CTR 2-A1-DX 3.81 2-A1-SX 2.91 2-A2-DX 4.77 2-A2-SX 'n/a 2-A3-DX 1.46 2-A3-SX 3.00 2 -A4-DX 1.87 2-A4-SX 1.88 0.03% F 2-B1-DX 1.04 2-B1-SX 0.75 2-B2-DX 0.85 2-B2-SX 1.11 2-B3-DX 2.11 2-B3-SX 0.93 2-B4-DX 0.61 2-B4-SX 2.11 0.1% Dex 2-C1-DX 2.51 2-C1-SX N/A 2-C2-DX 2.32 2-C2-SX N/A 2-C3-DX 2.10 2 -C3-SX 3.03 2-C4-DX 2.32 2-C4-SX 1.30 0.5% LE 2-D1-DX 2n/d 2-D1-SX N/D 147399.doc -76- 201039824

2-D2-DX N/D 2-D2-SX 0.23 2-D3-DX N/D 2-D3-SX 0.68 2-D4-DX N/D 2-D4-SX 1.10 0.1% BOL 2-E1-DX 1.62 2-E1-SX 1.88 2-E2-DX 2.15 2-E2-SX 0.70 2-E3-DX 1.34 2-E3-SX 1.03 2-E4-DX N/D 2-E4-SX N/D 0.5% BOL 2-F1-DX 2.31 2-F1-SX 2.59 2-F2-DX N/D 2-F2-SX 0.53 2-F3-DX 0.75 2-F3-SX 0.80 2-F4-DX 1.62 2-F4-SX 1.09 1%B0L 2-G1-DX 0.50 2-G1-SX 1.87 2-G2-DX 1.71 2-G2-SX 4.04 2-G3-DX 1.11 2-G3-SX 3.78 2-G4-DX N/D 2-G4 -SX N/D ]N/A=Not available 147399.doc -77- 201039824 2n/d=Undetectable, subject to quantitative limit Table T-7 The amount of PGE2 in the aqueous sample taken during the second puncture ( Average soil SEM). Mean sample group (ng/ml) SEM n CTR A 2.815 0.449 7 0.03% FB 1.189 0.209 8 0.1% Dex C 2.263 0.232 6 0.5% LE D 0.672 0.250 3 0.1% BOL E 1.452 0.221 6 0.5% BOL F 1.384 0.306 7 1%B0L G 2.168 0.586 6 Table T-8 Raw data of the amount of protein in the aqueous sample taken during the second puncture. Treatment sample protein (mg/ml) CTR 2-A1-DX 50.24 2- A1-SX 53.51 2-A2-DX 28.73 2-A2-SX *N/A 2-A3-DX 40.09 2-A3-SX 30.84 2-A4-DX 41.79 2-A4-SX 30.35 0.03% F 2-B1- DX 20.78 2-B1-SX 28.80 2-B2-DX N/A 2-B2-SX 23.41 147399.doc -78- 201039824 2-B3-DX 20.21 2-B3-SX 17.53 2-B4-DX 15.12 2-B4 -SX 20.52 0.1% Dex 2-C1-DX 31.31 2-C1-SX N/A 2-C2-DX 31.81 2-C2-SX N/A 2-C3-DX 35.95 2-C3-SX 37.15 2-C4- DX 32.12 2-C4-SX 32.40 0.5% LE 2-D1-DX 36.14 2-D1-SX 39.10 2-D2-DX 34.69 2-D2-SX 26.10 2-D3-DX 26.30 2-D3-SX 28.16 2-D4 -DX 40.90 2-D4-SX 39.85 0.1% BOL 2-E1-DX 34.87 2-E1-SX 34.41 2-E2-DX 31.14 2-E2-SX 22.82 2-E3-DX 29.46 2-E3-SX 31.69 2- E4-DX 35.70 2-E4-SX 49.2 5

147399.doc -79· 201039824 0.5% BOL 2-F1-DX 33.98 2-F1-SX 33.65 2-F2-DX 19.99 2-F2-SX 27.11 2-F3-DX 19.72 2-F3-SX 36.35 2-F4- DX 27.71 2-F4-SX 32.24 1%B0L 2-G1-DX 20.99 2-G1-SX 21.48 2-G2-DX 15.11 2-G2-SX 20.28 2-G3-DX 20.94 2-G3-SX 21.89 2-G4 -DX 20.03 2-G4-SX 30.76 iN/A=The amount of protein in the aqueous sample taken at the second puncture of Table T-9 (mean SEM) was not available. Mean sample group SEM n (mg/ml) CTR A 39.364 3.754 7 0.03% FB 20.910 1.648 7 0.1% Dex C 33.457 1.001 6 0.5% LE D 33.905 2.190 8 0.1% BOL E 33.667 2.655 8 0.5% BOL F 28.844 2.249 8 1% BOL G 21.435 1.529 8 147399.doc -80- 201039824 Table Τ-10 Raw data of the amount of PMN in the aqueous sample taken during the second puncture

Treatment sample PMN (quantity / μΐ) CTR 2-A1-DX 90 2-A1-SX 80 2-A2-DX 70 2-A2-SX !ν/α 2-A3-DX 70 2-A3-SX 80 2 -A4-DX 50 2-A4-SX 40 0.03% F 2-B1-DX 50 2-B1-SX 40 2-B2-DX Ν/Α 2-B2-SX 20 2-B3-DX 10 2-B3- SX 40 2-B4-DX 30 2-B4-SX 20 0.1% Dex 2-C1-DX 20 2-C1-SX Ν/Α 2-C2-DX 20 2-C2-SX Ν/Α 2-C3-DX 50 2-C3-SX 40 2-C4-DX 20 2-C4-SX 30 0.5% LE 2-D1-DX Ν/Α 2-D1-SX Ν/Α 2-D2-DX 40 147399.doc -81 - 201039824 2-D2-SX 20 2-D3-DX 20 2-D3-SX 30 2-D4-DX 40 2-D4-SX 20 0.1% BOL 2-E1-DX N/A 2-E1-SX 20 2- E2-DX 40 2-E2-SX 50 2-E3-DX 20 2-E3-SX 20 2-E4-DX 20 2-E4-SX N/A 0.5% BOL 2-F1-DX 40 2-F1-SX 20 2-F2-DX 20 2-F2-SX 10 2-F3-DX 10 2-F3-SX 10 2-F4-DX 20 2-F4-SX 40 1% BOL 2-G1-DX 30 2-G1- SX 20 2-G2-DX 30 2-G2-SX 40 2-G3-DX 20 2-G3-SX 30 2-G4-DX 40 2-G4-SX 20 iN/A=Not available 147399.doc -82- 201039824 Table -11 The number of sputum in the aqueous sample taken during the second puncture (mean SEM). Mean sample group (quantity / μΐ) SEM η CTR A 68.571 6.701 7 0.03% FB 30.000 5.345 7 0.1% Dex C 30.000 5.164 6 0.5% LE D 28.333 4.014 6 0.1% BOL E 28.333 5.426 6 0.5% BOL F 21.250 4.407 8 1% BOL G 28.750 2.950 8

Table -12 shows the raw data of ΜΡΟ activity in iris-ciliary body samples taken after the second puncture. Treatment sample iris-ciliary body weight (mg) 1 volume (μΐ) 2 Δ/min ΜΡΟ unit / g CTR Al-DX 41.7 40 0.021 1.11 Al-SX 42.3 40 0.024 1.26 A2-DX 46.6 40 0.039 1.85 A2-SX 40.5 40 0.037 2.02 A3-DX 48.9 40 0.075 3.39 A3-SX 51.1 40 0.049 2.12 A4-DX 36.6 40 0.013 0.79 A4-SX 38.8 40 0.019 1.08 0.03% F Bl-DX 39.5 100 0.049 1.10 Bl-SX 42.7 100 0.082 1.70 B2 -DX 34.1 100 0.013 0.34 B2-SX 36.6 100 0.031 0.75 B3-DX 45.6 100 0.038 0.74 B3-SX 38.0 100 0.027 0.63 147399.doc -83- 201039824 B4-DX 40.1 100 0.033 0.73 B4-SX 42.6 100 0.061 1.27 0.1% Dex Cl-DX 36.4 100 0.029 0.71 Cl-SX 45.8 100 0.031 0.60 C2-DX 42.9 100 0.064 1.32 C2-SX 42.7 100 0.023 0.48 C3-DX 43.0 100 0.019 0.39 C3-SX 46.8 100 0.024 0.45 C4-DX 42.3 100 0.023 0.48 C4-SX 36.1 100 0.021 0.51 0.5% LE Dl-DX 38.9 200 0.026 0.30 Dl-SX 44.7 200 0.053 0.51 D2-DX 35.9 200 0.067 0.81 D2-SX 40.7 200 0.055 0.60 D3-DX 46.3 200 0.076 0.73 D3-SX 41.9 200 0.096 1.01 D4-DX 46.7 3n/a N/AN/A D4-SX 32.9 N/AN/AN/A 0.1% B OL El-DX 43.6 100 0.051 1.04 El-SX 37.2 100 0.042 1.00 E2-DX 32.6 100 0.042 1.14 E2-SX 37.4 100 0.045 1.06 E3-DX 36.2 100 0.050 1.22 E3-SX 45.1 100 0.031 0.61 E4-DX 30.4 100 0.036 1.05 E4-SX 42.3 100 0.031 0.65 0.5% BOL Fl-DX 45.8 100 0.044 0.85 Fl-SX 38.2 100 0.040 0.93 F2-DX 34.9 100 0.031 0.79 F2-SX 42.0 100 0.049 1.03 F3-DX 39.1 100 0.033 0.75 147399.doc •84 - 201039824 F3-SX 40.6 100 0.034 0.74 F4-DX 36.2 100 0.022 0.54 F4-SX 39.5 100 0.026 0.58 1% BOL G1-DX 32.4 100 0.024 0.66 G1-SX 43.1 100 0.033 0.68 G2-DX 30.6 100 0.017 0.49 G2-SX 39.9 100 0.018 0.40 G3-DX 41.3 100 0.016 0.34 G3-SX 44.9 100 0.052 1.02 G4-DX 36.6 100 0.013 0.31 G4-SX 36.9 100 0.018 0.43 〇1 volume = equal parts (microliter) of the supernatant diluted to 3 ml For analysis. 2A/min=average of linear slope recorded every 5 seconds for 5 minutes in a row 5N/A=not available Table T-13 MPO activity of iris-ciliary body sample collected after second puncture (mean soil SEM ). The mean value of the treatment sample group MPO unit / g SEM n CTR A 1.703 0.297 8 0.03% FB 0.906 0.151 8 0.1% Dex C 0.618 0.106 8 0.5% LE D 0.661 0.102 6 0.1% BOL E 0.971 0.079 8 0.5% BOL F 0.775 0.058 8 1% BOL G 0.542 0.083 8 ❹ Test 2: BOL-3 03 242-X inhibits IL-Ιβ-induced cytokine expression in human corneal epithelial cells 1. Background / Rationale: Cytokines associated with immune cells The content is a direct indication of the activity of such fine 147399.doc-85-201039824 cells in inflammatory conditions. A decrease in the levels of these cytokines indicates that the test compound has a positive therapeutic effect on inflammation. This study was designed to determine the effect of BOL-3 03242-X on IL-Ιβ-induced cytokine production in human corneal epithelial cells (“HCEC”). 2. Objective To determine the effect of bol-303242-X on IL-1 β-stimulated cytokine expression in primary human corneal epithelial cells using the 30-cytokine Luminex kit. Dexamethasone was used as a control. 3. Experimental Design Primary HCEC was seeded in 24-well plates. After 24 h, the cells were treated with vehicle, IL-Ιβ, Ι[-1β+dexamethasone, or IL-lp+BOL-303242-X in the base EpiLife medium for 18 h (Table T-14). Repeat twice for each treatment. The medium was collected and used to determine the cytokine content using the 30-cytokine Luminex kit. Cell viability was determined by alamarBlue assay (LP06013).

Group* Day 1 Day 2 • Treatment of cells with test reagents in basal EpiLife medium for 18 h Day 3 1 ^ cells without control (0.1% DMSO) Collection medium 2 10 ng/ml IL- in 24-well plates Ιβ was used in EpiLife medium 10 ng/ml IL-Ιβ+Ι nM dexamethasone Luminex score 4 (5x105/well, 10 ng/ml IL-Ιβ+ΙΟ nM dexamethasone; 5 in 0.5 ml medium 10 ng/ Ml IL-Ιβ+ΙΟΟ nM dexamethasone on cells 6) lOng/ml IL-Ιβ+Ι μΜ dexamethasone cell viability / 10 ng/ml IL-Ιβ+ΙΟ μΜ Dexamethasone analysis 8 10 ng/ml IL-13+1 nM BOL-303242-X 9 10 ng/ml IL-Ιβ+ΙΟ nM BOL-303242-X 10 10 ng/ml IL-13+100 nM BOL-303242-X 11 10 ng/ml IL- Ιβ+Ι μΜ BOL'303242-X 12 --- 10 ng/ml IL-Ιβ+ΙΟ μΜ BOL-303242-X *Each group was repeated three times in the well 147399.doc -86- 201039824 Dexamethasone: Batch number :016K14521 Parent MW : 392.46 Parent: Total MW ratio = 1.0 BOL-303242-X : Lot number: 6286 Parent MW : 462.48 Parent: Total MW ratio = 1.0 〇 4. Data analysis using median fluorescence intensity (MFI) is based on L The standard curve of each cytokine was determined by uminex to obtain the concentration (pg/ml) of each cytokine. Cytokine concentrations were determined using a linear range of standard curves for each cytokine. take

The average value of the test values was repeated twice for each sample. The data is expressed as the mean ± SD. Statistical analysis was performed using one-way ANOVA-Dunnett test' and corpse <0.05 was considered statistically significant. 5 · Results

Q No statistically significant effects of various treatments on cellular metabolic activity were observed (as measured by the alamarBlue assay). In this study, essentially six of the 30 cytokines tested were tested and detected. Among the 14 cytokines, 3 cytokines were stimulated by j 〇ng/ml IL-Ιβ (Table T-14). IL-Ιβ was excluded from the analysis because it was an irritant. IL-Ira was excluded because MFI was not within the standard range. Dexamethasone and BOL-303242-X significantly inhibited the cells stimulated by χ_1β by 147399.doc -87- 201039824, for 6 cytokines (IL-6, IL-7, MCP-1, TGF-α, TNF The potency of -α and VEGF was comparable, and significant inhibition of MCP-1, TGF-α and TNF-α was observed at 1 nM for IL-6 and at 10 nM (Table T-14 and Figure 1A- 1F). BOL-303242-X also significantly inhibited IL-Ιβ-stimulated G-CSF production, which was more potent than dexamethasone, and observed that 10 pg/ml of BOL-303242-X had significant inhibitory effect, but not A significant effect of dexamethasone on this cytokine was observed (Figure 2). BOL-3 03 242-X also significantly inhibited IL-Ιβ-stimulated cytokine production, which was less potent against cytokines (GM-CSF, IL-8, and RANTES) than dexamethasone. It was observed that 1 nM dexamethasone and 10 nM BOL-303242-X had significant inhibitory effects on GM-CSF. It was observed that 1 μΜ of dexamethasone had a significant inhibitory effect on RANTES, while no significant effect of BOL-3 03 242-X on this cytokine was observed (Fig. 3A-3C). 6. Summary of the efficacy of BOL-303242-X and dexamethasone in inhibiting IL-Ιβ-stimulated cytokine production in HCEC for IL-6, IL-7, TGF-a, TNF-ot, VGEF and MCP-1 quite. BOL-303242-X is more potent than dexamethasone in inhibiting IL-Ιβ-stimulated G-CSF production in HCEC. The efficacy of IL-Ιβ-stimulated GM-CSF, IL-8 and RANTES in HCEC was slightly worse than that of dexamethasone BOL-303242-X. 147399.doc -88 - 201039824 Table Τ-14 Dexamethasone and BOL-3 03242-X Inhibition of IL-1 β-stimulated cytokine production in primary human corneal epithelial cells detected by IL-Ιβ Rice pine (μΜ) inhibits inhibition by ΒΟί-303242-Χ(μΜ) cytokine* (10 ng/ml) 0.001 0.01 0.1 1 10 0.001 0.01 0.1 1 10 G-CSF XX GM-CSF XXXXXXXXX IL-la X IL- 6 XXXXXXXXXXX IL-7 XXX IL-8 XXXX IP-10 X MCP-1 XXXXXXXXX MIP-la ΜΙΡ-1β X RANTES XXX TGF-a XXXXXXXXX TNF-a XXXXXXX VEGF XXXXX :(*) EGF, eosinophilin, Chemokine CX3

(Fractalkine), IFNY, IL-10, IL-12p40, IL-12p70, IL-13, IL15, IL-17, IL-2, IL-4, IL-5, sCD40L were not detected. IL-1β was excluded from the analysis because it was an irritant. IL -1 ra was excluded because MFI was not within the standard range. Test 3: Myofibrillin expression in trabecular meshwork cells treated with dexamethasone or BOL-303242-X and release material and method of myofibrillin from these cells. TM cells and media All animal procedures are in accordance with ARVO (Visual and Institute of Ophthalmology Research) 147399.doc -89- 201039824 Resolution on animal care. The eye from the newly killed healthy rhesus monkey (Mflcaca/αίίβ) (obtained from Lonza (Walkersville, Maryland)) was transferred to C〇2 independent medium on ice and treated for about 40 hours after excision. . After removal of the iris, lens, and most of the ciliary body, the perforated occluded flap (0percula) (the anatomical feature of the monkey TM). Use a sharp pair of scissors to cut a TM and explant the subdivided tm fragments into a multi-well plate containing growth medium (described below) and

Cytodex-3 gelatin coated beads (Sigma Chemical Company, St. Louis,

Missouri) - cultivation. The beads attach to the explants within a few hours and provide additional substrate areas for cell migration. The proliferating TM cells migrate to the extra beads and "span" onto the tissue culture plastic to form colonies. After a few days, the original TM explants and beads were transferred to new wells to produce additional primary cultures. The subconfluent cell monolayers on tissue culture plastics were transferred from 12-well plates to 35 mm or 60 mm culture dishes using collagenase-dispase (Roche Applied Bioscience, Indianapolis, Indiana). Finally, the second or third generation subculture was harvested enzymatically as described above, and the cells were counted and refrigerated in liquid nitrogen. The medium for the initiation and expansion of TM culture (proliferation medium) is human endothelial serum-free medium ("HESFM"; !nVitrogen, Carlsbad California), which contains the following supplements: fetal calf jfe clear ("fbS"; ι〇 (v/v) ; Hyclone, Logan, Utah); endothelial cell growth supplement (25 pg/ml; BD Biosciences, San Jose, Calif〇rnia) · 'heparin (25 pg/ml; Sigma); Acid (3.2 μΜ; Sigma); fatty acid _ albumin complex (200 mg/L; Invitrogen); ascorbyl phosphate (〇 147399.doc -90- 201039824 mM ; Wako Pure Chemicals, Richmond, Virginia); Transfer protein (25 mg/L; Sigma); human fetuin (0.1 mg/ml; Sigma); glucose (1.5 g/L; Sigma); fructose (0.33 g/L; Sigma); cercosin (5) Pg/ml; Sigma); hydrocortisone (14 • nM; Sigma); and penicillin-streptomycin (InVitrogen) as an antibiotic additive. For each study, up to 9 strains of TM cells were tested individually and each strain was obtained from individual monkeys. The cells were thawed and seeded in a proliferation medium in a 12-well or 48-well cluster (Falcon, BD Biosciences; 150,000 and 30,000 cells/well, respectively). When the cells were 75% to 90% confluent, the proliferation medium was replaced with a 5:4 mixture of HESFM and Dulbecco's MEM, supplemented with 10% FBS, and added with bovine acid, ascorbic acid nitrate, as in the proliferative medium (above). Glutathione and antibiotics were added with 2.72 g/L glucose and 1.72 g/L fructose. At the time of confluence, the medium was changed to Dulbecco's MEM containing 10% FBS40, ascorbyl phosphate, antibiotics, 2.72 g/L glucose, and 1.72 g/L fructose. The cells were maintained as a stable confluent monolayer in this latter medium for 4 to 7 days prior to the start of the experimental treatment. Treatment of TM cells with DEX and BOL-3 03 242-X The response to DEX and BOL-3 03242-X was directly compared using TM cell strains from 9 different individual monkeys. In each study, cells in three identical sample wells (24-well tubes) were incubated with DEX (Sigma) and side-by-side with corresponding cell samples exposed to BOL-303242-X; drug concentration In the range of 3 nM to 300 nM. 147399.doc -91 - 201039824 The final DMSO concentration contained in all treatments including the medium for the vehicle control sample was 〇 1% (v/v) over the entire selected concentration range. The treatment lasted for 96 hours, in which the medium was replaced on the third day of treatment. Collect all final 48-hour conditioned medium ("CM") samples (0-5 ml), centrifuge briefly to remove particles, aliquot 'and store at _2 (rc^ until thawed for analysis. Cellular metabolic activity analysis first An improved version of the method described is used to evaluate cellular metabolic activity, an indicator of cell viability and cell viability. After collecting CM samples, the cells are in modified Hanks balanced salt containing Ca++ and Mg++. Solution) (short rinse in 'MHBSS)' and then add 〇.〇〇25〇/0 (w/v) resazurin (Sigma) stored in the MMHSS to the sample well. (37t, 5% C〇2, 95°/. humidity) for 90 minutes, then read fluorescence (excitation wavelength is 56〇nm, emission wavelength is 590 nm) (Victor 3V Multilabel Counter, Wallac' Turku, Finland). As a positive control for the reduction of metabolic reduction of resazurin cells, the vehicle-treated cells of the other well were treated with 0.06% nitrogen peroxide in MHVSS (Fisher, Atlanta, in each plate). Georgia) - pre-nurturing. Western Dot analysis combines undiluted CM with denatured 4x sample buffer containing 2% SDS' and loads the sample to 4_2〇% Tris_HC1 polyacrylamide gel (BioRad, Hercules, California) at equivalent protein content After electrophoresis, the protein was wet transferred to 〇2 mm nitrocellulose (BioRad) for 147399.doc -92-201039824. The filter was stored in Tris buffered saline plus 0.02% (v /v) 5% (w/v) skim milk powder (BioRad) blocked by Tween-20 ("TBST"; Tween-20 from Calbiochem, San Diego, California) and anti-recombinant human myofibrillin with goat The antibody (R&D Systems, Minneapolis, Minnesota) was incubated overnight in a 1:2000 dilution (from 200 pg/ml) in blocking buffer at 4 ° C. After washing in TBST, the filter was Horseradish peroxidase-conjugated mouse anti-goat IgG (H+L) (Pierce Biotechnology, Rockford, Illinois) in blocking buffer 1: 25,000 dilutions (from 0.8 mg/ml) in the chamber Cultivate together for 90 minutes. After washing in TBST, ink dots were generated in the SuperSignal® West Dura Extended Duration Substrate (Pierce) for chemiluminescence detection. Bands corresponding to myofibrillin were captured digitally and stored using a FluorChem imager (Alpha-Innotech, San Leandro, California) where all ink dots were subjected to equal exposure/capture time. The imager system software is then used to calculate the pixel density of the equal rectangular regions that are included in the strip. ^ Quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) Cultured TM prepared in 6-well tube after triplicate treatment with DEX, PA, BOL-303242-X or vehicle control medium Cells were lysed and total RNA was isolated using RNeasy Plus ' Mini Kit from Qiagen (Valencia, California) according to the manufacturer's instructions. After quantification of purified total RNA (Quant-iT RNA Analysis Kit 'Molecular Probes, Eugene, Oregon), this RNA was equally distributed to generate for 147399 using random primers (Affinity Script, Stratagene, La Jolla, California). .doc -93- 201039824 The first CDNA strand of each treated sample. Designing oligonucleotide-based myofibrillin primers based on the MYOC gene of the macaque, and using a fluorescent Taqman probe (Applied)

PCR amplification was performed by Biosystems, Foster City, California. Equal amounts of total RNA-equivalent mass (approximately 25 〇 1 〇〇〇 range) of the reaction cDNA were added to PCR Master Mix (Stratagene) and myofibrillin primer/Taqman probes. Amplification was carried out in a thermocycler (Mx3005P, Stratagene), wherein the initial denaturation step was extended at 95 Torr for 1 hour, followed by 40 cycles of 95 ° C for 1 5 seconds and 60 ° C for 1 min. Each experiment included a standard control (i.e., 'no reverse transcriptase or lack of template). The relative tether of myofibrillar mRNA abundance was determined using the difference in threshold cycle ("Ct") between vehicle control and drug treatment. Each sample was analyzed in triplicate in wells and the average of the corresponding values was taken to perform further quantitative analysis. The Mx3005P software was used to calculate the myofibrillar mRNA abundance, which is expressed as the ratio to the vehicle-treated sample. Data analysis and statistical method data were subjected to Box-Cox transformation to perform one-way or two-way analysis of variance (ANOVA) followed by Tukey-Kramer test using JMP software (SAS, Cary, N (mh Car〇Hna). The specific transformation is described in the legend. For each set of triplicate samples from each of the individual monkey TM cell strains tested, the Western blot densitometry (as a geometric mean) of the myofin detected in CM was plotted. Value) and the relative abundance of muscle fibrin mRNA 2 (as a geometric mean) as a function of drug concentration. P values less than 〇〇5 were considered statistically significant. Dose response curve data was used using methods similar to those previously described. Substituting the reparameterized four-parameter logistic equation 147399.doc •94·201039824 parameterized four-parameter logistic equation), and the equations can estimate the EC50 value of each drug treatment ± 95% confidence interval. Results In vitro properties of monkey TM cells Rhesus TM cells exhibited robust proliferation during initial explants and during early passage. The overall cell morphology and uniform cobblestone pattern monolayer were consistent with the TM cells from the young donors and cynomolgus monkeys reported in the prior art and were maintained in confluent subcultures for these studies. Effect of 〇DEX and BOL-303242-X on myofibrillin in monkey TM cells CM Myofibrillin is released into CM by rhesus monkey TM cells, and in the Western blotting method a single thick band - possibly fusion - Detected at the expected molecular weight (about 55 kDa) as previously observed in the CM of DEX treated human TM cells and the Western blotting method of monkey aqueous fluid. When exposed to increasing concentrations of BOL-3 03242-X or DEX, a higher density of immunoreactive bands can be seen only by visual inspection. However, it is important to note that DEX-induced myofibrillin performance is higher than BOL-303242-X at high doses, indicating that BOL-❹ 303242-X has partial agonistic activity on myofibrillin gene expression. Figure 3 shows the effect of DEX and BOL-3 03242-X on the amount of accumulated myofibrillin released into the CM during the second 48 hour treatment. Although both compounds increased the concentration of myofibrin in a dose-dependent manner, the amount of myofibrillin produced by BOL-303242-X and released into the medium at all doses studied was less than DEX. As shown in Figure 4 for a monkey TM cell strain, the full range of DEX treatments were statistically significant compared to the vehicle control (Figure 4, solid symbols). (Note: 100 nM is also commonly used to evaluate 147399.doc -95-201039824 in vitro steroid responsiveness 55, which corresponds to a local dose commonly used in clinical applications for DEX.) Within the dose range used, at 300 nM At the time of DEX, the maximum efficacy was achieved; for a strain of monkey scorpion cells tested, this concentration of DEX achieved a fibrin content of 1233% (about 11 times) higher than that of the control. Among the several strains tested, no dose-response curve of DEX was observed in the high concentration range with a significant plateau (Fig. 4). Although BOL-303242-X also increased myofibrillar accumulation in CM of monkey mites throughout the range of concentrations tested (Figure 4, open symbols), the maximum efficacy calculated for all 9 TM cell strains was DEX treatment. About 50% of the maximum efficacy observed afterwards (Table T-15). In fact, the dose response curve for BOL-303242-X showed significant signs of plateau after reaching a high dose concentration range, indicating that the compound has reached its maximum efficacy. Partial agonism of BOL-303242-X was further confirmed by statistically significant differences between DEX and BOL-3 03242-X at 3 nM, 10 nM, 100 nM and 300 nM (in Figure 4 by sword shape) Symbol representation). Regarding performance, DEX and BOL-3 03 242-X show EC5〇 of 14.58 nM and 20.96 nM, respectively (Table T-16). These differences were not statistically significant, with 95% confidence limits for their estimates overlapping (Table T-16). In the experiments lasting more than 3 months, the responses of 9 monkey TM isolates were similar and very reproducible; for DEX and BOL-3 03 242-X, the inter-assay variability of EC50 was 18.20% and 20.40%, respectively. Table T-16). These results indicate that BOL-303242-X, as a partial GC agonist, induces a significantly lower amount of fibrin to be released by the cultured monkey TM cells as compared to the model GC DEX. 147399.doc -96- 201039824 Table Τ-15 Partial agonism of BOL-303242-X compared to DEX. The estimated efficacy of myofibrillin expression in cultured monkey ticks was induced at 300 ηΜ. Compound Efficacy 95% confidence limit for iSE1 efficacy (weighted average; %) Coefficient of variation (%) DEX 100±6.09 BOL-303242-X 53.12±2.20 88.07-111.93 48.81-57.43 18.27 12.42 The efficacy shown is normalized to DEX ( 100%) - a weighted average of the experiments to calculate. The reciprocal of the variance of each strain was used for weighting.平均值 Take the average of the data from 9 experiments (one experiment per strain), which lasted more than 3 months. Table T-16 Comparison of the efficacy of DEX and BOL-303242-X on the expression of myofibrillin in cultured monkey tm cells. Data were compiled for two independent dose response studies using 9 monkey TM cell strains. Compound EC5〇±SE (nM)* ECS() 95% confidence limit coefficient of variation (%) DEX 14.58±2.65 10.21-20.83 18.20 BOL-303242-X 20.96±4·28 14.05-31.26 20.40 *The EC50 shown is The weighted average of the logarithm of the estimated EC50 for each TM cell strain in the study was calculated. The reciprocal of the variance of the estimate is used for weighting. The logarithm of the standard deviation (SE) of the estimate is converted back to the original scale using Taylor series expansion. Effect of DEX and BOL-303242-X on the expression of myofibrillin mRNA The effect of DEX and BOL-303242-X on the expression of myofibrillin mRNA in monkey TM was exemplified by the results shown in Figure 5; data from Figure 4 The same cell strain is depicted in (above). For the dose response of DEX and BOL-303242-X 147399.doc •97-201039824 (Figure 5), the expression pattern of myofibrillin mRNA is very similar to that of protein, and it is also shown with respect to protein content. Similar to statistical significance. The BOL-303242-X qRT-PCR data again showed partial agonistic properties of this agent, with significantly lower mRNA abundance values at all doses compared to DEX. At 300 nM, BOL-303242-X showed the greatest efficacy, with a maximum efficacy of about 67% of DEX (Figure 5). Regarding the estimated EC50 for all three drugs, there is an excellent generalized correlation between the myofibrillar value and the mRNA abundance value (see Tables T-16 and T-17). In fact, as shown by the previous table T-1 5 for myofibrillin, the average value of BOL-303242-X compared to DEXfl fibrin information (n=4 strains) was significant at 100 nM and 300 nM. Lower (Fig. 5; cells treated with DEX and BOL-3 03242-X are indicated by solid symbols and open symbols, respectively). Table T-17 Comparison of the efficacy of DEX and BOL-3 03 242-X on the expression of myofibrillin mRNA in cultured monkey TM cells. Data from two independent dose response studies were compiled and two monkey TM cell strains were used for each study. 95% confidence limit coefficient of variation for compound EC5〇±SE (nM)1 EC5〇 (%) DEX 14.66±1.27 12.37-17.38 8.68 BOL-303242-X 20.75±2.74 16.02-26.88 13.21 147399.doc -98 - 1 The EC5〇 was calculated as the weighted average of the logarithm of the estimated EC5〇 for each TM cell strain in the study. The reciprocal of the variance of the estimate is used for weighting. The logarithm of the standard error (SE) of the estimate is converted back to the original scale using Taylor series expansion. 201039824 Effect of drugs on cultured monkey TM cells in resazurin reduction assay As a result of exposure to different concentrations of DEX or BOL-303242-X, there is no correlation between fibrin expression and overall cellular metabolic status, and All drug treatments did not result in loss of cell viability compared to the vehicle control, as determined by measuring chemical reduction of resazurin at the end of the treatment period (results not shown). Thus, the results indicate that the observed increase or decrease in performance relative to control myofibrillin caused by either drug treatment regimen is not due to compromised functional cell integrity. In summary, the results presented herein indicate that BOL-303242-X exhibits complete agonistic properties as an anti-inflammatory agent and may have a more favorable therapeutic index than conventional GC when used to treat ocular diseases with inflammatory components. While the invention has been described with respect to the embodiments of the present invention, it will be understood by those skilled in the art The spirit and scope of the present invention. [Simple Description] ® Figure 1A-1F shows BOL-303242-X and dexamethasone 1-1-, IL-7, TGF-α, TNF stimulated by IL-Ιβ in human corneal epithelial cells (“HCEC”). -α, VGEF and MCP-1 effects, ρ < 0·05. Figure 2 shows the effect of BOL-3 03 242-X and dexamethasone on IL-Ιβ-stimulated G-CSF production in HCEC, ρ < 0.05. Figures 3A-3C show the effect of BOL-303242-X and dexamethasone on IL-Ιβ-stimulated GM-CSF, IL-8 and RANTES production in HCEC, ρ < 0.05. In each of the above figures, "*" indicates that compared with the control, and "* *" indicates that 147399.doc -99- 201039824 is compared with IL-Ιβ. Figure 4 shows a comparison of the effects of BOL-303242-X (SEGRA) and DEX on myofibrillin in CM of monkey TM cells. The myofibrillin band density of a single TM strain is provided in one study. *Ρ<〇·〇5, relative to vehicle control.卞 Ρ < 0.05, relative to the same dose of DEX. The hollow rod represents the vehicle to treat the cells. A two-way analysis of variance was performed on the log-transformed data, followed by a comparison. The data is expressed as the geometric mean SE of the Taylor series expansion estimate. Figure 5 shows representative quantitative real-time RT-PCR results from a single monkey sputum cell strain from a dose response study comparing the effects of BOL-303242-X and DEX on myofibrillin mRNA performance. *Ρ<0.05 vs. vehicle control (open cylinder). tP<〇.〇5, BOL-303242-X or ΡΑ relative to DEX, at the same test concentration. A two-way analysis of variance was performed on log-transformed data (SEGRA vs. DEX) or converted data (ΡΑ to DEX) up to 0.2, followed by comparison. The data is expressed in terms of the geometric mean value SE of the Taylor series expansion estimate. 147399.doc 100-

Claims (1)

201039824 VII. Scope of application: K A use of a dissociated glucocorticoid receptor agonist ("DIGRA") or its pharmaceutically acceptable salt for the treatment or control of ocular inflammatory diseases , a condition or a condition, wherein the digra is a formula I~ R2 R3 a^^^B/D\q (I) E 〇 is independently selected from the group consisting of unsubstituted and substituted aryl And heteroaryl, unsubstituted and substituted cycloalkyl and heterocycloalkyl, unsubstituted and substituted cycloalkenyl and heterocycloalkenyl, unsubstituted and substituted cycloalkynyl and heterocycloalkynyl, And unsubstituted and substituted heterocyclic groups; R1 and R2 are independently selected from the group consisting of hydrogen, unsubstituted RG-Cu straight chain or branched alkyl group, substituted c]_Ci5 straight chain or a branched alkyl group, an unsubstituted cycloalkyl group, and a substituted C3_Ci5 cycloalkyl group; R3 is selected from the group consisting of hydrogen, unsubstituted Ci_Cis straight chain or fluorene branched alkyl group, substituted ^/! 5 linear or branched alkyl, unsubstituted C3-Cu cycloalkyl and heterocycloalkyl, RC3_C _5 cycloalkyl and heterocycloalkyl Aryl, heteroaryl and heterocyclic groups; 8 comprising a carbonyl, an amine, a hydrocarbon or a heterohydrocarbyl group; an E-hydroxyl or an amine group; and £) not present or comprising a carbonyl group, -NH- or -NR, - wherein R, comprises unsubstituted or substituted c"Cls straight or branched alkyl; and wherein ... and rule 2 can form an unsubstituted or substituted CVCu cycloalkyl; wherein DIGRA, preceded The salt or vinegar received by the drug or its four drugs is present in an amount effective to treat or control the ocular inflammation, condition or condition of the ocular inflammation; wherein the composition induces an increased risk of ι〇ρ Lower than the risk of increasing I〇p by a composition using glucocorticoids, and wherein the lower risk arises from the reduction of trabecular meshwork in individuals receiving the composition for the treatment or control to produce myofibrillin. The use of the item, wherein the disease, condition or condition is selected from the group consisting of anterior uveitis, posterior uveitis, uveitis, keratitis, conjunctivitis, spring keratoconjunctivitis, atopic keratoconjunctivitis , keratorrhea ulcer, corneal edema, aseptic corneal infiltration 8 such as corneal infiltrate), anterior scleritis, scleritis, orbital inflammation, and in situ keratomileusis ("LASIK"), such as refractive keratectomy, cataract extraction, intraocular lens implantation, laser assisted "), postoperative ocular keratoplasty, or keratotomy, ocular inflammation, dry eye, macular degeneration, macular edema, diabetic retinopathy, wet age-related macular Degeneration, dry age-related macular degeneration and glaucoma. 3. The use of claim 2, wherein the DIGra has the formula I And wherein A and Q are independently selected from the group consisting of: an aryl group substituted with at least one halogen atom, a cyano group, a hydroxyl group or a Ci_Cig alkoxy group, and a heteroaryl group 'R, R2 and R3 are independently selected from unsubstituted And a group consisting of substituted alkyl groups; 8 series (: 1-(:5-alkyl); D----- or -NR,- group, wherein R. is C^C: 5 alkyl; Hydroxy. 147399.doc 0) 201039824 4. The use of claim 2, wherein the DIGRA has the formula i It comprises A comprising a dihydrobenzofuranyl group substituted by a fluorine atom; Q comprises an indenyl group or an isoindole group substituted by an fluorenyl group; and the caliper 2 is independently selected from an unsubstituted and substituted q-C5 alkyl group a group consisting of; BsCi_c3 alkyl; D-NH- group; E-hydroxy; and R3 comprising a tri-steryl group. Ο 5. The use of claim 4, where the 〇1 (3 feet eight has the formula 11 or 111 (II) (III) 9 wherein R4 and R5 are independent toast, and the ground is selected from the group consisting of hydrogen, halogen, cyano, thiol, C, Γ Li. Λ-院 oxy, unsubstituted Ci_ClG straight chain or branched The group 4 is substituted with a q-Cu straight or branched alkyl group, an unsubstituted C3_Ci〇 cycloalkyl group, and a substituted or substituted C3-C1Q cycloalkyl group. 6. If the request item 5 is used, i., the DIGRA has the formula IV 147399.doc (IV) 201039824 7. The use of claim 6, wherein the composition further comprises an anti-inflammatory agent selected from the group consisting of NSAIDs, PPAR agonists, combinations thereof, and mixtures thereof. 147399.doc -4-