US 20140364400A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0364400 A1 Gallois-Bernos (43) Pub. Date: Dec. 11, 2014

(54) FORTREATMENT OF OCULAR A63L/683 (2006.01) NFLAMMLATORY CONDITIONS A 6LX3/55.75 (2006.01) A63L/215 (2006.01) (71) Applicant: Johnson & Johnson Vision Care, Inc., (52) U.S. Cl. Jacksonville, FL (US) CPC ...... A6 IK3I/232 (2013.01); A61 K3I/55.75 (2013.01); A61 K3I/215 (2013.01); A61 K (72) Inventor: Annabelle Gallois-Bernos, Jacksonville, 3 1/683 (2013.01); A61 K9/0048 (2013.01) FL (US) USPC ...... 514/121; 514/549; 514/530: 514/529; 514f627 (21) Appl. No.: 14/466,137 (22) Filed: Aug. 22, 2014 (57) ABSTRACT Related U.S. Application Data The present invention relates to ophthalmic compositions and methods for the treatment of dry eye and other inflammatory (62) Division of application No. 13/495,052, filed on Jun. ocular conditions. In particular, the present invention relates 13, 2012, now Pat. No. 8,865,685. to a composition comprising an esterified anti-inflammatory (60) Provisional application No. 61/503,158, filed on Jun. lipid mediator, which is an of an anti-inflammatory lipid 30, 2011. mediator that is a reaction product of the anti-inflammatory lipid mediator and a polyol wherein the majority of the anti Publication Classification inflammatory lipid mediatoris present in an esterform. In this way, the compositions are substantially free of an acid form of (51) Int. C. the anti-inflammatory lipid mediators. This composition can A6 IK3I/232 (2006.01) be topically delivered to the ocular Surface via a preparation, A6 IK9/00 (2006.01) Solution, gel, ointment, and/or strip and/or a contact lens.

US 2014/0364400 A1 Dec. 11, 2014

0012. In a further embodiment, the present invention pro ing sterility include aseptic packaging and sterilization by vides a method of treating, preventing or mitigating inflam exposure to radiation, heat combinations thereof and the like. matory ocular conditions and/or dry-eye in an individual in 0021. As used herein, the term “individual' includes need thereof which comprises delivering to such individuals humans and vertebrates. ocular surface a therapeutically effective amount of a com 0022. As used herein, the term "agent” includes any com position comprising an anti-inflammatory lipid mediator. pound, composition, to be tested for efficacy in the methods 0013 These and other embodiments of the invention will disclosed herein. become apparent from the following description of the pres 0023. As used herein the term “ocular surface' includes ently preferred embodiments. The detailed description is the wet-surfaced and glandular epithelia of the cornea, con merely illustrative of the invention and does not limit the junctiva, lacrimal gland, accessory lacrimal glands, nasolac scope of the invention, which is defined by the claims and rimal duct and meibomian gland, and their apical and basal equivalents thereof. Variations and modifications of the matrices, puncta and adjacent or related structures, including invention may be effected without departing from the spirit the eyelids linked as a functional system by both continuity of and scope of the novel contents of the disclosure. epithelia, by innervation, and the endocrine and immune sys temS. DETAILED DESCRIPTION 0024. As used herein, the term “contact lens' refers to a structure that can be placed on the cornea of an individuals 0014 Provided are processes of making and using ocular eye. The contact lens may provide corrective, cosmetic, thera products containing esterified anti-inflammatory lipid media peutic benefit, including wound healing, delivery of drugs or tors, wherein the majority of the anti-inflammatory lipid neutraceuticals, diagnostic evaluation or monitoring, or UV mediator is present in an ester form. It has been discovered blocking and visible light orglare reduction, or a combination that the use of esterified anti-inflammatory lipid mediators, thereof. A contact lens can be of any appropriate material when the majority of the anti-inflammatory lipid mediator is known in the art, and can be a soft lens, a hard lens, or a hybrid present in the ester form, results in an ocular product that lens. greatly improves initial comfort upon contact with or admin 0025. As used herein, the term “silicone hydrogel contact istration to the ocular surface. Ocular products include, but lens' refers to a contact lens formed from a polymer compris are not limited to, preparations, solutions, gels, ointments, ing silicone containing and hydrophilic repeating units. emulsions, Strips, ophthalmic devices, and the like any which 0026. As used herein, the term “hydrogel' or “hydrogel can be administered to the ocular Surface, including the eye. material” refers to a hydrated crosslinked polymeric system 0015 With respect to terms used in this disclosure, the that contains water in an equilibrium state. Hydrogels gener following definitions are provided. ally contain at least about 15 wt % water, and in some embodi 0016 Reference to “anti-inflammatory lipid mediator ments at least about 20 wt % water at equilibrium. includes those molecules that play a role (directly or indi 0027 Conventional hydrogels are prepared from mono rectly) in the inhibition of cytokine production by epithelial meric mixtures predominantly containing hydrophilic mono cells or immune cells, in the inhibition of reactive oxygen mers, such as 2-hydroxyethyl methacrylate (“HEMA'), N-vi species (ROS) production by epithelial cells or immune cells, nyl pyrrolidone (“NVP), or vinyl acetate. U.S. Pat. Nos. in the control and/or inhibition of recruitment of white blood 4,495,313, 4,889,664, and 5,039459 disclose the formation of cells (reduction in leukocytes infiltration), and/or in the reso conventional hydrogels. lution of (promotion of uptake of dead cells). Suitable anti-inflammatory lipid mediators are generally 0028. As used herein, the term “silicone hydrogel” refers acid-based entities whose carboxylic groups of the hydrocar to a hydrogel obtained by copolymerization of at least one bon chain can be esterified. The majority of the anti-inflam silicone-containing monomer, macromer, prepolymer, with matory lipid mediator is present in the ester form. Anti-in at least one hydrophilic component. Examples of silicone flammatory lipid mediators can be reacted with hydroxyl hydrogels include balafilcon, acquafilcon, lotrafilcon, com groups of various entities as desired. The hydroxyl groups are filcon, galyfilcon, senofilcon, narafilcon, falcon II 3, asmofil delivered by polyols that can provide therapeutic benefits to con A, as well as silicone hydrogels as prepared in U.S. Pat. the eye, including osmoprotection, in conjunction with the No. 5,998,498, WO 03/22321, U.S. Pat. No. 6,087,415, U.S. Pat. No. 5,760,100, U.S. Pat. No. 5,776,999, U.S. Pat. No. esterified anti-inflammatory lipid mediators. 5,789,461, U.S. Pat. No. 5,849,811, U.S. Pat. No. 5.965.631. 0017. As used herein, the term “about refers to a range of U.S. Pat. No. 7,553,880, WO 2008/061992, and U.S. 2010/ +/-5% of the number that is being modified. For example, the 048847. These patents, as well as all other patents disclosed phrase “about 10” would include both 9.5 and 10.5. in this paragraph, are hereby incorporated by reference in 0018. As used herein, the use of “a” “an, and “the their entireties. includes the singular and plural. 0029 Hard contact lenses are made from polymers that 0019. As used herein, the term “ophthalmic composition' include but are not limited to polymers of poly(methyl)meth refers to a compound or mixture Suitable for administration to acrylate, silicon acrylates, fluoroacrylates, fluoroethers, poly the eye or ocular Surface. Ocular compositions include prepa , and polyimides, where the preparation of repre rations, Solutions, gels, ointments, emulsions, strips and the sentative examples may be found in JP 200010055, JP like. 6123860 and U.S. Pat. No. 4,330,383. Intraocular lenses of 0020. As used herein the term “sterile preparation' the invention can be formed using known materials. For includes any compound or mixture for direct administration example, the lenses may be made from a rigid material includ to any part of a mammalian body, including implantation, ing, without limitation, polymethyl methacrylate, polysty injection, administration as a drop, gel or wash, and the like, rene, polycarbonate, or the like, and combinations thereof. wherein the preparation is substantially free from undesired Additionally, flexible materials may be used including, with foreign matter just prior to administration. Methods for insur out limitation, hydrogels, silicone materials, acrylic materi

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(EPA), (DHA), and the like. An acid that contains oxygen) with a hydroxyl compound, such “omega-three fatty acid can comprise one or more omega as an alcohol. Esters are usually derived from an organic acid three fatty acids. in which at least one hydroxyl (-OH) group is replaced by an 0039. As used herein, the term “omega-six fatty acid —O-alkyl (alkoxy) group. Most commonly, esters are formed refers to one or more fatty acids that have a double bond 6 by condensing a carboxylic acid with an alcohol. In one or carbon atoms from their omega carbon atoms. For example, more embodiments, the esters of the present invention can be an omega-six fatty acid includes, but is not limited to linoleic naturally occurring, or can be formed by reaction of a fatty acid (LA). Other omega-six fatty acids include derivatives of acid with an alcohol. linolenic acid. A "derivative' of linoleic acid is a fatty acid 0048. As used herein, the term "amidoester refers to any that is made by a chemical modification performed upon chemical compound derived by reaction of an oxoacid with linoleic acid. Examples of omega-six fatty acids that are anamine. One or more embodiments provide that the reaction derivatives of linoleic acid include, but are not limited to, of a fatty acid with an amine provides an amidoester. Refer gamma linolenic acid (GLA), dihomogammalinolenic acid ence to the “ester form can include the amidoester in addi (DGLA), and the like. In some embodiments, the composi tion to the traditional ester. Reference to “reaction product tion comprises at least one non-inflammatory omega-six fatty means a resulting ester or amidoester that is formed by reac acid. A non-inflammatory omega-six fatty acid is an omega tion of an acid with an alcohol oramine, regardless of whether six fatty acid that does not promote or cause inflammation. In the ester or amidoester is naturally-occurring or synthesized. Some embodiments the inflammation is in the eye or affects If synthesized, the ester or amidoester can be prepared by the ocular surface. One of skill in the art can determine if a various esterification methods knownto one skilled in the art. fatty acid causes or promotes inflammation. If the fatty acid 0049. As used herein, the term “wax ester” refers to an causes or promotes inflammation, the fatty acid can be ester of a fatty acid and a long-chain alcohol. Wax esters excluded from the composition. include, without limitation, beeswax and carnauba wax. 0040. As used herein the term “linoleic acid” refers to Beeswax consists of Cao to C molecular species. Carnauba 9,12-octadecandienoic acid, which has a short hand designa wax constitutes from C to Cofatty acids esterified with Co tion of 18:2(n-6), which is number of carbons: number double to C. long-chain alcohols to provide a C to C molecular bonds (position). Throughout the specification linoleic acid is species. referred to as either linoleic acid or "LA'. 0050. As used herein, the term “alcohol” refers to any 0041. As used herein the term “arachidonic acid' refers to organic compound containing at least one hydroxyl func 5, 8, 11, 14 eicosatetraenoic acid, which has a short hand tional group (-OH) bound to a carbon atom, that is usually designation of 20:4(n-6) and a molecular weight of 304.5. bound to other carbon and hydrogenatoms; this includes, but Throughout the specification arachidonic acid is referred to as is not limited to, acyclic alcohols; cyclic alcohols; primary, either arachidonic acid or 'AA'. It should be noted that secondary, and tertiary alcohols; monohydric alcohols and arachidonic acid can yield pro-inflammatory . polyols. The alcohols of the present invention include poly It also should be noted that arachidonic acid can be involved hydric alcohols or polyols, which are alcohols that include at in enzymatic processes that result in beneficial anti-inflam least two hydroxyl functional groups and 4-10 carbon atoms matory lipid mediators such as lipoxins and an endocannab and in some embodiments 4-8 carbonatoms, and in others 5-8 inoid that is anandamide (arachidonoylethanolamine). carbon atoms. In other embodiments, alcohols include poly 0042. As used herein the term “alpha-linolenic acid ols that provide osmoprotection, including, but not limited to, refers to 9, 12, 15 octadecatrienoic acid, which has a short polyethylene glycol, polyvinyl alcohol, inositol, Sorbitol, hand designation of 18:3(n-3) and a molecular weight of xylitol, and erythritol. 278.4. Throughout the specification alpha-linolenic acid is 0051. As used herein, the term “' is an agent that referred to as either alpha-linolenic acid or “ALA’. is generated from the interaction between an omega-three 0043. As used herein the term “gamma-linolenic acid polyunsaturated fatty acid such as eicosapentaenoic acid refers to 9, 6, 12,-octadecatrienoic acid, which has a short (EPA) or docosahexaenoic acid (DHA), cyclooxygenase-II hand designation of 18:3(n-6) and a molecular weight of (COX-2) and an analgesic. Such as aspirin. of the E 278.4. Throughout the specification gamma-linolenic acid is series are derived from EPA, whereas resolvins of the D series referred to as either gamma-linolenic acid or "GLA'. are derived from DHA. Exemplary resolvins include resolvin 0044 As used herein the term “dihomogamma-linolenic E.1 (RVE1), resolvin E2 (RVE2), resolvin D1 (RVD1), resolvin acid' refers to 8, 11, 14 eicosatrienoic acid, which has a short D2 (RVD2), resolvin D3 (RVD3), resolvin D4 (RVD4), and hand designation of 20:3(n-6) and a molecular weight of combinations thereof 306.5. Throughout the specification eicosatrienoic acid is 0052. As used herein, the term “protectin' or “neuropro referred to as either eicosatrienoic acid or “DGLA'. tectin' is an agent, more particularly, a docosanoid (which is 0045. As used herein the term “eicosapentaenoic acid a signaling molecule made by oxygenation of 22-carbon refers to 5,8,11,14, 17-eicosapentaenoic acid, which has a essential fatty acids, especially DHA), that is derived from the short hand designation of 20:5(n-3) and a molecular weight polyunsaturated fatty acid docosahexaenoic acid (DHA). A of 302.5. Throughout the specification eicosapentaenoic acid “protectin' or “neuroprotectin' exerts potent anti-inflamma is referred to as either eicosapentaenoic acid or “EPA'. tory and anti-apoptotic bioactivity at nanomolar concentra 0046. As used herein the term “docosahexaenoic acid” tions in a variety of experimental models of brain and retinal refers to 4,7,10,13,16,19-docosahexaenoic acid, which has a diseases. An exemplary protectin includes protectin D1 short hand designation of 22:6(n-3) and a molecular weight (PD1). of 328.6. Throughout the specification docosahexaenoic acid 0053 As used herein, the term “lipoxin refers to a series is referred to as either docosahexaenoic acid or "DHA’. of anti-inflammatory lipid mediators that are synthesized by 0047. As used herein, the term “ester refers to any chemi the 5-lipoxygenase pathway. Lipoxins are short-lived, endog cal compound derived by reaction of an oxoacid (an organic enously produced, non-classic tetraene-containing US 2014/0364400 A1 Dec. 11, 2014 eicosanoids, whose appearance in inflammation signals the formed as part of the natural biochemical process of degrad resolution of inflammation. Lipoxins are also derived enzy ing and eliminating compounds. matically from arachidonic acid, an omega-six fatty acid. 0059. As used herein, the term “metabolically stable ana Exemplary lipoxins include lipoxin A4 (LXA), lipoxin B4 log refers to a compound that is a structural derivative of a (LXB4), and combinations thereof. parent compound (sometimes differing from the parent com 0054 As used herein, the term “” refers to pound by a single element), or is a compound with similar one of a number of hormone-like Substances that participate properties to the parent compound. The analog is not easily in a wide range of body functions such as the contraction and degraded, and, thus, is metabolically stable. relaxation of Smooth muscle, the dilation and constriction of 0060. As used herein the term “CD11b+ infiltration blood vessels, control of blood pressure, and modulation of includes the increase in CD11b cells present in the center inflammation. Prostaglandins are derived from omega-three and periphery of the cornea following dry eye induction. and omega-six fatty acids acid. There are three main types of prostaglandins: Prostaglandin E1 (PGE1) and prostaglandin 0061. As used herein the term “IL-1C. or TNF-C. expres E3 (PGE3), which have anti-inflammatory properties, and sion' includes measuring RNA transcripts of IL-1C. and prostaglandin E2 (PGE2), which promotes inflammation. TNF-C. by quantitative real-time Polymerase Chain Reaction. PGE1, derived from dihomo-gamma-linolenic acid, is a 0062. As used herein the term “inflammatory cytokines' potent vasodilator agent that increases peripheral blood flow, includes, without limitation, IL-1C. and TNF-C. inhibits aggregation, and has many other biological 0063 Turning to the details of the disclosure, provided are effects such as bronchodilation, and mediation of inflamma processes of making and using ocular products containing tion. PGE1 is important for lacrimal and salivary gland secre esterified anti-inflammatory lipid mediators, wherein the tion and for T cell function. PGE2, derived from arachidonic majority of the anti-inflammatory lipid mediator is present in acid, is released by blood vessel walls in response to infection an ester form. One or more embodiments provide that the or inflammation and acts on the brain to induce fever, PGE2 compositions are Substantially free of fatty acids. That is, in has also been used extensively as an oxytocic agent. PGE3, is such embodiments, the ocular products contain 10% by formed via the cyclooxygenase (COX) metabolism of eicosa weight or less (or 8%, or 6%, or 5%, or 4%, or 3%, or 2%, or pentaenoic acid. It is known that PGE3 lowers intraocular even 1%) of the acid form of the anti-inflammatory lipid pressure. mediator. In a further embodiment, the ocular products con 0055 As used herein, the term “retinoic acid refers to a tain 1% by weight or less (or 0.8%, or 0.6%, or 0.5%, or 0.4%, metabolite of Vitamin A (retinol) that mediates the functions or 0.3%, or 0.2%, or even 0.1%, or 0.05%, or 0.025%, or of Vitamin A required for growth and development. Retinoic 0.01%) of the acid form of the anti-inflammatory lipid media acids have been shown to have strong anti-inflammatory tor. The esterified anti-inflammatory lipid mediators are properties, in addition to their function as sebostaticums. (see esters of an acid anti-inflammatory lipid mediator. The esters Plewig. G. et al., Archives of Dermatological Research, Vol. may be formed by reacting the anti-inflammatory lipid 270, No. 1, 89-94). Retinoic acids can include, without limi mediator with at least one polyol having a carbon chain length tation, 13-cis-retinoic acid. of four to ten. Desirable anti-inflammatory lipid mediators 0056. As used herein, the term “endocannabinoid’ refers include omega-three and/or omega-six fatty acids, resolvins to a class of organic compounds found produced within the or a metabolically stable analog, protectins or a metabolically body that activate cannabinoid receptors. Endogenous can stable analog, lipoxins or a metabolically stable analog, pros nabinoids ("endocannabinoids'), when present in tissues at taglandins or a metabolically stable analog, retinoic acids, elevated concentrations, provide anti-inflammatory and anal endocannabinoids, and phospholipids. Inflammation is a gesic effects. Endocannabinoids serve as intercellular lipid component of dry eye. There is a need to deliver active can messengers, signaling molecules that are released from one didates, known to mitigate inflammation, informs that are not cell and activating the cannabinoid receptors present on other associated with initial discomfort (acute ocular discomfort) nearby cells; they use retrograde signaling. Endocannab upon administration to the eye, while providing long-term inoids are lipophilic molecules that are not very soluble in benefits to the eye. water. Endocannabinoids can include, without limitation, 0064 One or more embodiments provide that the ester is anandamide (arachidonoylethanolamine) and 2-arachi provided in a therapeutically effective amount. That is, the donoylglycerol. ester is present in an amount Sufficient to provide a beneficial 0057. As used herein, the term “phospholipid refers to effect to the ocular area, including but not limited to the ocular any of various phosphorous-containing lipids that are com surface, the back of the eye, tear formation and stability. A posed mainly of fatty acids, a phosphate group, and a simple therapeutically effective amount of ester can deliver an appro organic molecule Such as choline. Preferably, the phospho priate amount of anti-inflammatory lipid mediator that lipids contain residues of one or more fatty acids that are imparts a benefit to the ocular environment. omega-3 fatty acids, along with, as desired, omega-6 fatty 0065. In the free fatty acid formulations (for example, acids. Phospholipids are amphipathic in nature; that is, the alpha-linolenic acid emulsions) of the prior art (e.g., those polar end of a phospholipid is soluble in water (hydrophilic) compositions disclosed in U.S. Patent Application Pub. and aqueous solutions, while, the fatty acid end is soluble in 20070265341 (Dana et al.)), discomfort upon instillation to fats (hydrophobic). In an aqueous environment, phospholip the eye has been found. A change in the concentration of ids combine to form a two-layer structure (lipid bilayer) with surfactants (mostly Tween-80, from 2.5% to 0.25%) or the the hydrophobic ends in the middle and the hydrophilic ends use of additional Surfactant(s) (Such as the amphoteric exposed to the aqueous environment. Such lipid bilayers are monateric Surfactant) did not result in improved comfort upon the structural basis of cell membranes. instillation. The current invention seeks to avoid or remedy 0058 As used herein, the term “metabolite' refers to a the discomfort issue by making the essential fatty acid non compound that is the product of metabolism. A metabolite is ionic, i.e., using the esterified counterpart of the molecule. US 2014/0364400 A1 Dec. 11, 2014

0066 Anti-inflammatory lipid mediators, such as polyun 0072. Once in the ocular environment and/or incorporated saturated fatty acids, resolvins or a metabolically stable ana into the lipid layer or cell membrane lipid bilayer to carry-on log, protectins or a metabolically stable analog, lipoxins or a their tear film stabilization effect and/or anti-inflammatory metabolically stable analog, prostaglandins or a metaboli effect. cally stable analog, retinoic acids, endocannabinoids, and 0073. The ranges of n, X and R can fall within the follow phospholipids are desirable ingredients of ocular products for ing ranges: n: 2-5; X: 2-7: R: ophthalmologically compatible use in treating Such ocular conditions as inflammation, dry leaving group included, but not limited to: eye and/or dryness symptoms, and meibomian gland dys 10074 -(CH2), CH, where y is 0.1 or above. In some function. It has been discovered that the use of esterified embodiments y is between 0 and 5,or even 0 and 3, with anti-inflammatory lipid mediators, when the majority of the y=1 being preferred. anti-inflammatory lipid mediator is present in the ester form, 0075 Specifically, without limitation, the esterified anti inflammatory lipid mediator comprises an esterified omega results in an ocular product that greatly improves initial com three fatty acid, wherein the omega-three fatty acid is selected fort upon contact with or administration to the ocular Surface. from the group consisting of alpha-linolenic acid, Steari Generally, the esterified anti-inflammatory lipid mediator is a donic acid, eicosatetraenoic acid, eicosapentaenoic acid, reaction product of an acid anti-inflammatory lipid mediator docohexaenoic acid, docosapentaenoic acid (DPA), tetra and an alcohol or an amine. cosapentaenoic acid, and tetracosahexaenoic acid (Nisinic 0067 Such esterified anti-inflammatory lipid mediators acid), derivatives, metabolites, and mixtures thereof. Upon may also be useful in a rewetting drop, in Some instances esterification, the majority of the esterified anti-inflammatory unpreserved, or may be associated with a contact lens, such as lipid mediator is present in the ester form of the omega-three a silicone hydrogel, whereby the lens may be treated with a fatty acid. mixture of the esterified anti-inflammatory lipid mediators. 0076 Specially, esterified omega-three fatty acids can be The esterified anti-inflammatory lipid mediators can be incor selected from the following non-limiting examples: ethyl porated into the contact lens using various methods, for linolenate (alpha-linolenic acid ethyl ester (ALA-EE); steari example, incorporation can occur during the lens extraction donic acid ethyl ester and Stearidonic acid propyl ester, eico or hydration process or a combination thereof satetraenoic acid ethyl ester and eicosatetraenoic acid propyl 0068. Such a characteristic is not offered by previous uses ester, eicosapentaenoic acid ethyl ester and eicosapentaenoic offatty acids and/or fatty acid oils. The esterified anti-inflam acid propyl ester, and docohexaenoic acid ethyl ester and matory lipid mediators can be combined with an aqueous docohexaenoic acid propyl ester. delivery system—for desired ophthalmic compositions. 0077. The anti-inflammatory lipid mediator is reacted with a polyol having a carbon chain length of four to ten 0069 Esterified anti-inflammatory lipid mediators, when carbons to form the desired ester form of the anti-inflamma the majority of the anti-inflammatory lipid mediator is tory lipid mediator. present in the ester form, have the advantage of targeting the 0078. The inflammatory lipid mediator and polyol are inflammatory component of the dry eye disease (which per reacted under ester forming conditions. Suitable catalysts are petuates dry eye disease) and are less likely to cause initial known in the art and include acids, bases, carbodiimide, and discomfort at a wider concentration range. Upon contact with the like. The esterification and amidation reactions can take and uptake to the cells of the ocular surface, and without place at room temperature (typically in the range of about intending to be bound by theory, it is thought that esterified 19-25° C.) without much need to go higher and ambient anti-inflammatory lipid mediators, such as esterified polyun pressure, temperatures can be brought to higher ranges (about saturated fatty acids, esterified resolvins or a metabolically 25° C. to 80°C.) in order to accelerate the time to reaction stable analog, esterified protectins or a metabolically stable completion. analog, esterified lipoxins or a metabolically stable analog, (0079 Alternatively, the fatty acids may be esterified with esterified prostaglandins or a metabolically stable analog, polyethylene glycol or polyvinyl alcohol to generate omega esterified retinoic acids, endocannabinoids, and phospholip fatty acid ethoxylates and alkoxylates. Moreover, mixtures of ids, undergo hydrolysis and return to their acidic anti-inflam homologous molecules as well as amides and other functional matory lipid mediator state along with the alcohol that was derivatives may be desirable. For example, the esterified anti used in forming the ester. inflammatory lipid mediator can be the reaction product of a 0070 Turning to the esters of polyunsaturated fatty acids fatty acid and an amine to form an amidoester. Such as omega-three and omega-six fatty acids, the reaction of 0080 Omega-three fatty acids may also be reacted with carboxylic acids and alcohols or acetates will produce esters. the following molecules/alcohols: inositol, sorbitol, xylitol, In general terms, the following fatty acid derivatives such as and erythritol. The advantage of using Such ester forms/con esters (Ia) and other functionalities such as amides (Ib) are jugated materials is that upon hydrolysis and release of the desirable for their stability and improved initial eye comfort: omega-three fatty acid material, the Small solutefalcohol released in the process will provide osmoprotection and thus additional benefit, notably in dry eye subjects and/or contact lens wearers. This is because inositol, sorbitol, xylitol and CH-CH-CH=CH-(CH2—CH=CH), (CH) erythritol are osmoprotecting agents, and are well tolerated in —CO. NH-R (Ib) tissues in general. I0081. In the case of polyols, such as inositol, several of the 0071. Such derivatives are then expected to be converted hydroxyl groups may be esterified to the omega-three fatty back to their original fatty acid structure (II): acid (e.g. alpha linolenic acid) to improve efficiency in terms of the amount of the omega-three fatty acid material that can be delivered to the tissue per each molecule. The number of US 2014/0364400 A1 Dec. 11, 2014

fatty acid molecules per inositol molecule will affect the include, without limitation, saline solutions, other buffered solubility of the material or allow adjusting the hydrophobic Solutions, and deionized water. The preferred aqueous solu ity of the material for specific applications/control the rate of tion is saline solution containing salts including, without delivery from the medical device. limitation, Sodium chloride, sodium borate, sodium phos 0082 It should be noted that an esterified anti-inflamma phate, sodium hydrogenphosphate, Sodium dihydrogenphos tory lipid mediator does not take the form of naturally occur phate, or the corresponding potassium salts of the same. ring oils including Sunflower oil, Sesame oil, castor oil, lin These ingredients are generally combined to form buffered seed oil, and the like. It should be further noted that the Solutions that include an acid and its conjugate base, so that esterified anti-inflammatory lipid mediators of the present addition of acids and bases cause only a relatively small invention are not wax esters as they are formed from alcohols change in pH. The buffered solutions may additionally having short carbon chains (five to 10 carbon atoms, and in include 2-(N-morpholino)ethanesulfonic acid (MES), Some embodiments 5-8 carbon atoms). , 2.2-bis(hydroxymethyl)-2,2'2"-nitrilotri 0083 Mixtures may include omega-three and omega-six ethanol, n-tris(hydroxymethyl)methyl-2-aminoethane fatty acid esters at desired ratios. In one or more embodiments Sulfonic acid, citric acid, Sodium citrate, Sodium carbonate, it is desirable to provide a composition which will, upon Sodium bicarbonate, acetic acid, sodium acetate, and the like hydrolysis of the ester, provide a balance of omega-three fatty and combinations thereof Preferably, the solution is aborate acid: omega-six fatty acid in the eye to about 1:1. In other buffered or phosphate buffered saline solution. embodiments it is desirable to provide ophthalmic composi I0089. To form the packaging solution, at least one surfac tions which have ratios of the omega-three fatty acid: omega tant or emulsifier along with any additional ingredients are six fatty acid upon hydrolysis, in the range of about 10: about combined with the water-based solution, stirred, and dis 1 to no less than about 1: about 1 and from about 5:1 to about solved or dispersed. The pH of the solution preferably is 1:1, from about 4:1 to about 1:1, from about 3:1 to about adjusted to about 6.2 to about 7.5. The lens to be stored in the 1:1, from about 2:1 to about 1:1, about 1:1, about 2:1, about packaging solution of the invention is immersed in the solu 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, tion and the Solution and lens placed in the package in which about 9:1, or about 10:1. The ratio is based on the total amount the lens is to be stored. Alternatively, the solution may be of each class of omega fatty acids. placed into the package and the lens then placed into the 0084. Mixing of the ophthalmic compositions can be done Solution. Typically, the package is then sealed by any conve under aseptic conditions, or under ambient conditions and nient method, Such as by heat sealing, and undergoes a Suit then sterilized. Temperature can range widely and the reac able sterilization procedure. tions may be performed under ambient conditions of tem perature and pressure. 0090. The surfactants suitable for use in the invention are 0085. In addition to the usefulness of esterified anti-in of any suitable molecular weight, preferably about 200 to flammatory lipid mediators as ingredients in ophthalmic about 1,000,000, more preferably about 1000 to about compositions, including re-wetting drops, multipurpose solu 18,000. Useful surfactants have a hydrophile-lipophile bal tions, cleaning and storing Solutions and in contact lenses ance (“HLB) of about 10 to about 30, preferably about 15 to themselves. Such materials are also candidates for their inclu about 25, more preferably about 15 to about 23. sion in lens packing Solution. Lenses may be packaged with 0091 Any of the known surfactants fitting the aforemen esterified anti-inflammatory lipid mediators in formulations tioned criteria may be used provided that the surfactant is and/or emulsions or may be hydrated in Such materials as compatible, in terms of solubility, in the solution with which dissolved in appropriate solvent(s), followed by equilibration it is used. Thus, suitable surfactants include, without limita of the lens in packing Solution. tion, cationic, ionic, non-ionic Surfactants, and combinations I0086. Other ophthalmic compositions include lens care thereof. However, the use of a lens packaging solution con Solutions such as multipurpose Solutions, preparations, gels, taining cationic and ionic Surfactants may cause eye irritation. ointments, emulsions, and ophthalmic products such as Therefore, preferably the surfactant is a non-ionic surfactant. strips, inserts or punctal plugs or any product coming into 0092 Suitable non-ionic surfactants include, without contact with the ocular surface. limitation, polyethylene glycol esters of fatty acids, Such as 0087. In one embodiment, the esterified anti-inflamma polysorbate 20, 60 or 80, all available as TWEENR surfac tory lipid mediators are provided in an aqueous delivery sys tants, alkanolamides, amine oxides, ethoxylated alcohols and tem. Aqueous delivery systems are water based systems, acids, and Surfactants having one or more poly(oxyalkylene) which can be instilled directly in the eye, or may be used to chains. Such as poloxamine Surfactants (a Surface-active condition, store, or clean ophthalmic devices which are agent that removes lipid and environmental debris from the placed in the ocular environment. Examples of aqueous deliv lenses; polyalkoxylated block polymers of ethylene diamine) ery systems can include one or more of the following: packing or poloxamer Surfactants (any of a series of nonionic Surfac Solutions, storing solutions, cleaning and care solutions, mul tants of the polyoxypropylene-polyoxyethylene copolymer tipurpose solutions, conditioning solution and ophthalmic type, used as Surfactants, emulsifiers, stabilizers, and food drops. The aqueous delivery systems may also include known additives), and the like, and combinations thereof. Preferably, components, such as one or more of emulsifiers, chelant the Surfactant is a polysorbate or poloxamer Surfactant. agents, or stabilizers, Surfactants, wetting agents, antioxi Poloxamer surfactants are commercially available under the dants, tonicity adjusting agents, preservatives, combinations name PLURONIC200 that are polyoxyethylene polyox thereof, and the like. ypropylene non-ionic Surfactants having polyoxyethyl 0088. The packaging solution may be any water-based hydrophilic group ends that make up about 10 to about 80 Solution including that which is used for the storage of contact percent by weight of the molecule. Although any of the PLU lenses. The esterified anti-inflammatory lipid mediators are RONICR) surfactants are preferred, particularly preferred for dispersed in the packaging Solution. Typical Solutions use in the invention is PLURONIC(R) 127, which is about 70 US 2014/0364400 A1 Dec. 11, 2014 percent by weight ethylene oxide and has a molecular weight embodiments, the present invention comprises ophthalmic of about 12,000 to about 15,0000. compositions comprising at least one esterified omega-six 0093. The surfactant may be combined with any known fatty acid and at least one esterified omega-three fatty acid. active and carrier components useful for lens packaging Solu 0099. It is a benefit of the present invention that the esteri tion or for a rewetting drop. Suitable active ingredients for fied anti-inflammatory lipid mediators are hydrolytically lens packaging solutions include, without limitation, antibac stable at neutral pH, and do not hydrolyze during storage in terial agents, anti-dryness agents, such as polyvinyl alcohol, the pH neutral ophthalmic composition and sterile prepara polyvinylpyrrolidone, and dextran, tonicity agents, and the tions of the present invention. This means that the ophthalmic like, and combinations thereof Solutions and sterile preparations do not cause stinging when 0094 Suitable wetting agents, along with viscosity instilled in the eye. Upon contact with the cellular membranes enhancers include, without limitation: methyl gluceth-20 and/or transport into the cells of the ocular surface, and with (sold under the trade name, for example, Glucam E20), car out intending to be bound by theory, it is thought that esteri boxymethylcellulose, dextran 70, gelatin, hydroxymethylcel fied anti-inflammatory lipid mediators. Such as esterified lulose, hydroxypropyl methylcellulose, hydroxypropylethyl polyunsaturated fatty acids, esterified resolvins or a metaboli cellulose, hydroxypropyl cellulose, methylcellulose, PEG, cally stable analog, esterified protectins or a metabolically propylene glycol, polyvinyl alcohol (PVA), polyvinylpyrroli stable analog, esterified lipoxins or a metabolically stable done (PVP), Carbomer, polymethylvinylethermaleic anhy analog, esterified prostaglandins or a metabolically stable dride, hyaluronic acid, Xanthan gum, and polyacrylicacid. analog, esterified retinoic acids, endocannabinoids, and phos 0.095 Suitable antioxidants used in this invention include, pholipids, undergo hydrolysis and return to their acidic anti without limitation, hindered phenols, catechols, tocopherols, inflammatory lipid mediator state along with the alcohol that carotenoids, hyaluronic acid, lutein, or any species that can was used in forming the ester. Scavenge free radicals. Antioxidants are molecular species 0100. The amounts of the esterified anti-inflammatory that inhibit oxidative damage of other chemicals through lipid mediator can be stated as a percentage of the total com redox chemical reactions. These reactions typically transfer position or as a percentage of the Solution used in a processing electrons for a molecule species to an oxidant molecule. step Such as a lens hydration step (part of the lens making These can include free radicals, which can cause chain reac process that can result in the incorporation of the material into tions. In simplest terms, antioxidants are reducing agents. the device). The percentage of esterified anti-inflammatory Examples of antioxidants include, without limitation: Vita lipid mediator can be determined by any method, but can, for min E, Vitamin C, beta caroteine (which is converted to Vita example, be determined by dividing the weight of the anti min A), and peroxidases, and other agents which can inhibit inflammatory lipid mediator by the total weight of the oph the formation of free radicals, e.g., chelants, EDTA, diethyl thalmic composition or device. The percentage of any com ene triamine pentaacetic acid (DTPA), N, N-bis(carboxym ponent of the ophthalmic composition can be determined in a ethylglycine (NTA), and the like. similar manner. 0096. In some embodiments, Vitamin E is added to a solu 0101 The amount of esterified anti-inflammatory lipid tion comprising the esterified antiinflammatory lipid media mediator which may be present in the ophthalmic composi tOr tions or devices of the present invention include from about 0097. In another embodiment the composition of the 0.025 weight % to 5.0 weight% based upon all the compo present invention is incorporated into an ophthalmic device nents in the ophthalmiccomposition. When the ophthalmic Such as a contact lens or, more particularly, a silicone hydro composition is a rewetting drop, the esterified anti-inflamma gel contact lens. In this embodiment the esterified anti-in tory lipid mediator is present in an amount from about 0.025 flammatory lipid mediators, wherein the majority of the anti weight% to 0.5 weight% based upon all of the components inflammatory lipid mediator is present in the ester form, may in the composition, and the acid content can be no more than be incorporated into the lens in a number of ways, including 0.1 weight% (or 0.075, or 0.05, or 0.025, or even 0.01 weight but not limited to incorporating into the reaction mixture from %). When the ophthalmic composition is incorporated onto a which the lens is polymerized, contacting the lens with a contact lens, the esterified anti-inflammatory lipid mediatoris Solution comprising the esterified anti-inflammatory lipid present in an amount from 0.025 weight% to 5.0 weight % mediators either before during or after packaging. For based upon all of the components in the composition, and the example the esterified anti-inflammatory lipid mediators may acid content can be no more than 1 weight% (or 0.75, or 0.5, be included in the extraction, hydration or storage Solution or 0.25, or even 0.1 weight%). during the manufacture of the lens or may be included in a 0102. In some embodiments, the invention is directed to solution which is contacted with the contact lens by the lens the topical application of a composition comprising an esteri wearer. In one embodiment the solution swells the lens, fied anti-inflammatory lipid mediator (e.g., esterified ALA) which allows for enhanced uptake of the esterified anti-in as an effective therapeutic strategy to decrease ocular Surface flammatory lipid mediators. In embodiments where the inflammation. As discussed herein the inflammation of the esterified anti-inflammatory lipid mediator is incorporated ocular Surface can be seen in, for example, dry eye syndrome into the reaction mixture, the esterified anti-inflammatory and other inflammatory ocular conditions including, but not lipid mediator may be added to the reaction mixture as a limited to, both anterior segment/front of the eye conditions separate component, or may be pre-reacted with the alcohol and back of the eye conditions (e.g., meibomian gland dys group on at least one of the reactive components. function, blepharitis, atopic keratoconjunctivitis, contact lens 0098. In some embodiments, the present invention com related dry eye, Sjögren's syndrome, uveitis, macular degen prises ophthalmic compositions comprising at least one eration, and a wide range of other conditions). esterified omega-three fatty acid. In some embodiments, the (0103. In another embodiment, the invention is directed to present invention comprises ophthalmic compositions com the topical application of a composition comprising an esteri prising at least one esterified omega-six fatty acid. In some fied anti-inflammatory lipid mediator (e.g., esterified ALA) US 2014/0364400 A1 Dec. 11, 2014

as an effective strategy to improve tear film function or tear endocannabinoid, a phospholipid that comprises the film stability. Without intending to be bound by theory, it is residue of at least one omega-3 fatty acid, and mixtures thought that the esterified anti-inflammatory lipid mediator thereof, and improves the interaction between the lens and the tear film the composition is Suitable for administration to the eye or and/or the lids. ocular environment, is Substantially free from an acid. 0104. The present invention can also be administered to an 2. The composition of claim 1, wherein the ester is present individual that has been identified in need thereof of a com in a therapeutically effective amount. position described herein. The individual can be in need 3. The composition of claim 1, wherein the composition is thereof, if the individual has been identified as suffering or substantially free of fatty acids. having the condition of dry eye syndrome or one of the other 4. The composition of claim 1, wherein the composition inflammatory ocular conditions identified above. One in skill comprises 10% by weight or less of the acid form of the in the art would know how to identify the individual in need of anti-inflammatory lipid mediator. a treatment for dry eye syndrome. 5. The composition of claim 4, wherein the composition 0105. The present invention can also be administered to an comprises 5% by weight or less of the acid form of the individual to mitigate at least one sign and/or symptom of dry anti-inflammatory lipid mediator. eye, or to provide osmoprotection to an individual in need 6. The composition of claim 5, wherein the composition thereof. comprises 1% by weight or less of the acid form of the 0106 Without intending to be bound by theory, it is anti-inflammatory lipid mediator. thought that when the anti-inflammatory lipid mediator com 7. The composition of claim 1, wherein the ester is present position is loaded onto a contact lens for delivery to the eye in an amount in the range of about 0.01% to 5.0% by weight, during contact lens wear, by virtue of its anti-inflammatory based on the total composition. properties and the benefit provided to the tear film, the anti 8. The composition of claim 7, wherein the ester is present inflammatory lipid mediator can be held on to the eye via the in an amount in the range of about 0.025% to 0.5% by weight, contact lens long enough to be delivered efficiently to the eye based on the total composition. in order provide relief to individuals suffering from dry eye or 9. (canceled) other inflammatory ocular conditions. 10. The composition of claim 1, wherein the anti-inflam 0107 Reference throughout this specification to “one matory lipid mediator is a prostaglandin selected from the embodiment.'"certain embodiments.”“one or more embodi group consisting of prostaglandin E1 (PGE1), prostaglandin ments.”“further embodiment,” or “an embodiment’ means E3 (PGE3), or a metabolically stable analog, and combina that a particular feature, structure, material, or characteristic tions thereof. described in connection with the embodiment is included in at 11. The composition of claim 1, wherein the anti-inflam least one embodiment of the invention. Thus, the appearances matory lipid mediator is a resolvin selected from the group of the phrases such as “in one or more embodiments.”in consisting of resolvin E1 (RVE1), resolvin E2 (RVE2), certain embodiments.”“in one embodiment” or “in an resolvin D1 (RVD1), resolvin D2 (RVD2), resolvin D3 embodiment in various places throughout this specification (RVD3), resolvin D4 (RVD4), or a metabolically stable ana are not necessarily referring to the same embodiment of the log, and combinations thereof. invention. Furthermore, the particular features, structures, 12. The composition of claim 1, wherein the anti-inflam materials, or characteristics may be combined in any Suitable matory lipid mediator is a lipoxin selected from the group manner in one or more embodiments. consisting of lipoxin A4 (LXA).lipoxin B4 (LXB4), or a 0108. Although the invention herein has been described metabolically stable analog, and combinations thereof. with reference to particular embodiments, it is to be under 13. The composition of claim 1, wherein the anti-inflam stood that these embodiments are merely illustrative of the matory lipid mediator comprises protectin D1 (PD1) or a principles and applications of the present invention. It will be metabolically stable analog. apparent to those skilled in the art that various modifications 14. The composition of claim 1, wherein the anti-inflam and variations can be made to the method and apparatus of the matory lipid mediator comprises 13-cis-retinoic acid. present invention without departing from the spirit and scope 15. The composition of claim 5, wherein the anti-inflam of the invention. Thus, it is intended that the present invention matory lipid mediator comprises anandamide. include modifications and variations that are within the scope 16. The composition of claim 1, wherein the anti-inflam of the appended claims and their equivalents. matory lipid mediator comprises at least one omega-three fatty acid selected from the group consisting of alpha-lino 1. An ophthalmic composition for treatment of ocular con lenic acid, Stearidonic acid, eicosatetraenoic acid, eicosapen ditions, the ophthalmic composition comprising taenoic acid, docohexaenoic acid (DHA), docosapentaenoic an ester of an anti-inflammatory lipid mediator that is a acid (DPA), tetracosapentaenoic acid, and tetracosa reaction product of the anti-inflammatory lipid mediator hexaenoic acid (Nisinic acid), derivatives, metabolites, and and a polyol having a chain length of four to ten carbons; mixtures thereof. and 17-20. (canceled) an aqueous delivery system; 21. The composition of claim 1, wherein the aqueous deliv wherein the ester is selected from the group consisting of ery system comprises one or more of the following: a Surfac esterified resolvin or its metabolically stable analog, an tant, an emulsifier, a wetting agent, a chelant, and an antioxi esterified protectin or its metabolically stable analog, an dant. esterified lipoxin or its metabolically stable analog, an 22. The composition of claim 1, wherein the aqueous deliv esterified prostaglandin or its metabolically stable ana ery system comprises one or more ingredients selected from log, an esterified retinoic acid, metabolites thereof, an the group consisting of polysorbate 80TM, TyloxapolTM, US 2014/0364400 A1 Dec. 11, 2014

methylgluceth-20, Vitamin E, diethylenetriaminepentaacetic 34. The method of claim 31 wherein the delivery step acid, boric acid, sodium borate, and Sodium chloride. comprises positioning a contact lens on the ocular Surface, 23. The composition of claim 1, wherein the polyol is wherein the contact lens was soaked or hydrated in the com selected from the group consisting of polyethylene glycol, position. polyvinyl alcohol, inositol, sorbitol, xylitol, erythritol, and 35. A method of relieving dry-eye symptoms comprising combinations thereof. administering a therapeutically effective amount of the com 24.-28. (canceled) position of claim 1 to relieve at least one eye of a patient 29. A sterile preparation, Solution, gel, ointment, emulsion, Suffering from said symptoms. rewetting drop or strip for administration to the eye or a contact lens comprising the composition of claim 1. 36. A method of mitigating dry eye symptoms comprising 30. A method of preparing an ophthalmic composition for administering a therapeutically effective amount of the com treatment of ocular conditions, the method comprising pro position of claim 1 to at least one eye of a patient Suffering viding the composition of claim 1 and forming the oph from said symptoms. thalmic composition. 37. A method of treating an eye condition comprising 31. A method of preventing inflammatory ocular condi delivering, from an ophthalmic device, a therapeutically tions, dry-eye, or both in an individual in need thereof which effective amount composition of claim 1 to at least one eye comprises delivering a therapeutically effective amount of a Suffering in need of therapy for dry eye, meibomian gland composition according to claim 1 to the individual’s ocular dysfunction, blepharitis, atopic keratoconjunctivitis, contact Surface. lens-related dry eye, Sjögren's syndrome, uveitis, macular 32. The method of claim 31 wherein the concentration of degeneration, and combinations thereof. the ester in the composition is in the range of 0.025 weight% 38. The method of claim37, wherein the ophthalmic device to 5.0 weight%. is a contact lens. 33. The method of claim 31 wherein the delivery step comprises administering eye drops comprising the composi 39.-45. (canceled) tion of claim 1.