WO2024154047A1

WO2024154047A1 - Compositions and/or methods for prevention and/or treatment of dry eye disorders

Info

Publication number: WO2024154047A1
Application number: PCT/IB2024/050403
Authority: WO
Inventors: Judith Louise Flanagan
Original assignee: Brien Holden Vision Institute Limited
Priority date: 2023-01-18
Filing date: 2024-01-16
Publication date: 2024-07-25

Abstract

The present invention relates generally to compositions, particularly ophthalmic compositions, comprising a lipase inhibitor in combination with a cannabinoid receptor modulator, and methods of using the compositions for the prevention and/or treatment of an ocular disease or ocular disorder, such as dry eye disorders, and associated symptoms thereof.

Description

COMPOSITIONS AND/OR METHODS FOR PREVENTION AND/OR TREATMENT OF DRY EYE DISORDERS

FIELD

[0001] This application claims priority to U.S. Provisional Application No. 63/439,773, filed January 18, 2023. The entire contents of this priority application are herein incorporated by reference in its entirety.

FIELD

[0002] The present invention relates generally to compositions, particularly to ophthalmic compositions, and methods of using the same for the prevention and/or treatment of an ocular disease or ocular disorder, such as dry eye disorders, and associated symptoms thereof.

SUMMARY

Ocular diseases or disorders, such as dry eye disorder, are chronic conditions that affect between sixteen million and forty-nine million patients. Currently available products, such as artificial tears, corticosteroids, and antibiotic eye drops, fail to effectively relieve symptoms of these conditions. The disclosure herein describes ophthalmic compositions, and methods of using the same, that can be delivered topically to the surface of the eye, for example, transdermally to the surface of an eye, such as via topical application to the peri-ocular region of the eye, to alleviate signs and symptoms of ocular diseases, including dry eye disease. The ophthalmic compositions described herein comprise a fatty acid ester, such as glycerol monolaurate (GML), which may act as a permeation enhancer to assist in delivery of the compositions transdermally to the surface of the eye and as a bacterial lipase inhibitor while reestablishing equilibrium or homeostasis of the ocular microbiome. The ophthalmic compositions described herein further comprise a CB1 receptor modulator, such as quercetin, or a combination of a CB1 receptor modulator and a CB2 receptor modulator, such as betacaryophyllene, which target ocular endocannabinoid signaling pathways to provide symptomatic relief and protective benefits to the treated eye. Accordingly, the ophthalmic compositions described herein can provide symptomatic relief to the treated eye of the subject. Additionally, the ophthalmic compositions described herein can address the underlying causes of certain ocular diseases, such as via maintenance of the ocular microbiome, or via modulation of the ocular endocannabinoid receptor system. BRIEF DESCRIPTION OF THE DRAWINGS

[0003] The accompanying drawings and figures facilitate an understanding of the various embodiments of this invention.

[0004] FIG. 1A illustrates a sample chromatogram of the quercetin lower limit of quantitation (LLOQ).

[0005] FIG. IB illustrates a sample chromatogram of the quercetin-d3 (internal standard) LLOQ.

[0006] FIG. 2A illustrates a sample chromatogram of the quercetin upper limit of quantitation (ULOQ).

[0007] FIG. 2B illustrates a sample chromatogram of the quercetin-d3 (internal standard) ULOQ.

[0008] FIG. 3 illustrates a sample chromatogram of the beta-caryophyllene LLOQ.

[0009] FIG. 4 illustrates a sample chromatogram of the beta-caryophyllene ULOQ.

DETAILED DESCRIPTION

[0010] This disclosure relates to compositions, particularly to ophthalmic compositions, and methods of using the same for preventing and/or treating an ocular disease or ocular disorder, such as dry eye disorders, and associated symptoms thereof. In particular, this disclosure relates to the transdermal application of the compositions disclosed herein for preventing and/or treating an ocular disease or ocular disorder, such as dry eye disorders, and associated symptoms thereof.

[0011] The terms “administer,” “administering,” or “administration”, as used herein, refer to the act of delivering, or causing to be delivered, a compound, a pharmaceutical composition, or an ophthalmic composition, as disclosed herein, to the body of a subject, such as the eye of a subject, by a method described herein or otherwise known in the art. Administering a compound, a pharmaceutical composition, or an ophthalmic composition, includes prescribing a compound, a pharmaceutical composition, or an ophthalmic composition, to be delivered into the body of a patient. Exemplary forms of administration include topical and/or transdermal dosage forms, including ointments, gels, lotion, creams, jellies, powders, patches, sprays, or eye drops. Exemplary means of administration include placing the compound, pharmaceutical composition, or ophthalmic composition, onto the peri-ocular surface of the eye of a subject. The compound, pharmaceutical composition, or ophthalmic composition may be further incorporated into an ointment, gel, or cream for transdermal drug delivery. [0012] The term “anti-microbial effect”, as used herein, refers to the killing or inhibiting the growth of microorganisms such as bacteria. An administered agent has an anti-microbial effect if the agent exhibits bactericidal or bacteriostatic effects on microorganisms. When there is a minimal anti -microbial effect, the bactericidal or bacteriostatic effects are low, such that microorganisms, particularly commensal bacteria of an eye, are capable of growth. For example, an agent administered to a subject’s eye that provides no more than a 5-10% reduction of the total number of bacteria and maintains the ability of commensal bacteria of the subject’s eye to still grow is considered to be an agent that provides a minimal anti-microbial effect. For example, rather than inhibiting growth or killing all bacteria, an agent that provides a minimal anti-microbial effect targets bacterial virulence factors or mechanisms of virulence while maintaining the ability of commensal bacteria of an eye to grow.

[0013] The term “CB 1 receptor modulator”, as used herein, refers to a substance that binds to and regulates the activity of a CB1 chemical receptor. The CB1 receptor modulator can act on different parts of the CB 1 receptor and regulate activity in a positive, negative, or neutral manner. For example, the CB1 receptor modulator may be a CB1 receptor agonist, such as a CB1 receptor full agonist or a CB1 receptor partial agonist, a CB1 receptor antagonist, a CB1 receptor inverse agonist, or a CB1 receptor allosteric modulator. For example, a CB1 receptor modulator may be a flavonoid, such as quercetin.

[0014] The term “CB2 receptor modulator”, as used herein, refers to a substance that binds to and regulates the activity of a CB2 chemical receptor. The CB2 receptor modulator can act on different parts of the CB2 receptor and regulate activity in a positive, negative, or neutral manner. For example, the CB2 receptor modulator may be a CB2 receptor agonist, such as a CB2 receptor full agonist or a CB2 receptor partial agonist, a CB2 receptor antagonist, a CB2 receptor inverse agonist, or a CB2 receptor allosteric modulator. For example, the CB2 receptor modulator may be a terpene, such as beta-caryophyllene.

[0015] The term “diffusion cell system”, as used herein, refers to an in-line flow through cell diffusion system used for permeation tissue studies. The in-line cells have a continuous flow that mimics in-vivo blood flow across a membrane and may be used to evaluate compound uptake into the membrane, finite or infinite dose permeation, steady state flux, and/or the skin permeation coefficient of compounds. Sample membranes used in these cell diffusion cell systems may originate from human donor tissue such as human cadaver skin.

[0016] The terms “ocular disease” or “ocular disorder”, as used herein, include, but is not limited to, dry eye disorder, meibomian gland dysfunction (MGD), contact lens discomfort, ocular microbiome dysbiosis, inflammation in an eye, dry eye symptoms associated with Sjogren’s syndrome, elevated lipase production in an eye, elevated neuropathic pain in an eye, depressed wound healing in an eye, depressed lacrimal gland function, a poor score according to the Ocular Surface Disease Index (OSDI) in an eye, and/or a low level of meibum quality gland expressibility in an eye.

[0017] The term “ocular microbiome”, as used herein, refers to an eye’s bacterial community commonly present on the surface of the eye or in the eye of a subject. The ocular microbiome may include one or more microbiota in the bacterial community. For example, the ocular microbiome may include commensal and pathogenic microorganisms including bacteria, fungi, or viruses. Commensal bacteria offer a protective role by acting on the host’s immune system to induce protective responses that prevent colonization and invasion by pathogens. Proliferation of certain microbes can lead to the microbiome dysbiosis and lead to dry eye and dry eye symptoms. The Shannon Diversity Index can be used to determine the microbiota present in the ocular microbiome. The Shannon Diversity Index is a method of measuring the diversity of microbiota species by assessing the abundance of amplicon sequence variants to determine the presence of individual bacteria from each species. A healthy ocular microbiome will have more diversity in species and greater total number of bacterial species, while the ocular microbiomes of ocular diseases display a reduction in diversity and a lower number of total bacterial species. For example, in dry eye, the following microbiota may be less abundant: Corynebacterium, Ottowia, Flavobacterium, Veillonella, Rothia, and Microbacterium, Pseudomonas, Firmicutes. In dry eye the following microbiota may be more abundant: Proteobacteria, Actinobacteria and Bacterioidetes.

[0018] The term “pea-sized amount”, as used herein, refers to a practical measurement unit for topical medications. For example, in certain embodiments, a pea-sized amount is measured as the amount of topical medication that is the size of a green pea, where the size is 5-25 mm. In certain embodiments, the amount of topical medication is a pea size of 10 mm. In certain embodiments, a pea-sized amount of topical medication is in a range of 0.1-0.5 grams. In certain embodiments, a pea-sized amount of topical medication is 0.25 grams.

[0019] The term “peri-ocular”, as used herein, refers to the region of the eye that includes the lower and upper eyelids, eyefolds, and eyelid margins of an eye. The peri-ocular region of the eye can be used as a route for drug delivery to target the surface of the eye, such as for transdermal drug delivery to target the surface of the eye. The peri-ocular region can be used as a route to the meibomian glands located in the eyelids. The meibomian glands can also be used as a route for drug delivery to target the surface of the eye. [0020] The term “permeation enhancer”, as used herein, refers to a substance that increases the permeability of the subject’s outermost layer of skin, the stratum corneum. Permeation enhancers can be used to deliver a compound, a pharmaceutical composition, or an ophthalmic composition, as disclosed herein, to target sites, for example target tissue sites, such as an ocular surface of a subject’s eye, or for example target cellular sites, such as a CB1 receptor and/or a CB2 receptor. For example, a permeation enhancer may be a fatty acid ester, such as glycerol monolaurate (GML). Permeation enhancers may also be surfactants or emulsifiers.

[0021] The terms “preventing” or “prevention”, as used herein, refer to administering to a subject a therapeutically effective amount of an active, such that the signs and/or symptoms of a condition (e.g. dry eye) are averted, delayed, or significantly reduced in frequency in the subject, relative to a subject who does not receive the composition. Prevention does not require that the condition or symptoms are permanently avoided. In addition, the term “prevention” is used in its clinical sense to mean inhibit a disease, condition or disorder from occurring, rather than in an absolute sense of making it impossible for the disease, condition or disorder to ever occur in a given subject. Hence, inhibition of progression to disease, disorder or reduced new disease or disorder amounts to “prevention” within the meaning of this specification, even if there is pre-existing disease or disorder.

[0022] As used herein, the term “subject” to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, dogs, rabbits, and/or rodents; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. The subject can be a patient, for example, a patient having an ocular disease or disorder, or one or more symptoms of the same, such as a human patient. [0023] The terms “therapeutically effective amount” or “effective amount”, as used herein, refer to an amount of an active that results in an improvement or remediation of the symptoms of a disease or condition.

[0024] The terms “treating” or “treatment”, as used herein, refer to administering to a subject a therapeutically effective amount of an active such that the subject has an improvement in the condition to be treated (e.g. dry eye). Treatment may prevent worsening of the condition, improve the condition, but may not provide a complete cure for the condition. Efficacy of treatment may be determined by clinical assessment including the Ocular Surface Disease Index (OSDI), meibum quality, meibomian gland expressibility, and blepharitis. Ophthalmic Compositions

[0025] In one aspect, provided herein is an ophthalmic composition comprising a lipase inhibitor and a CB1 receptor modulator. In certain embodiments, the ophthalmic composition comprising a lipase inhibitor and a CB 1 receptor modulator, as disclosed herein, is for treatment of an ocular disease or ocular disorder, such as transdermal treatment of the ocular disease or ocular disorder. In certain embodiments, the ophthalmic composition disclosed herein is for treatment of a dry eye disorder, such as transdermal treatment of the dry eye disorder. In certain embodiments, the ophthalmic composition comprising a lipase inhibitor and a CB1 receptor modulator, as disclosed herein, is a transdermal, ophthalmic composition.

[0026] In another aspect, provided herein is an ophthalmic composition comprising a lipase inhibitor and a CB2 receptor modulator. In certain embodiments, the ophthalmic composition comprising a lipase inhibitor and a CB2 receptor modulator, as disclosed herein, is for treatment of an ocular disease or ocular disorder, such as transdermal treatment of the ocular disease or ocular disorder. In certain embodiments, the ophthalmic composition disclosed herein is for treatment of a dry eye disorder, such as transdermal treatment of the dry eye disorder. In certain embodiments, the ophthalmic composition comprising a lipase inhibitor and a CB2 receptor modulator, as disclosed herein, is a transdermal, ophthalmic composition.

[0027] In another aspect, provided herein is an ophthalmic composition comprising a lipase inhibitor, a CB1 receptor modulator, and a CB2 receptor modulator. In certain embodiments, the ophthalmic composition comprising a lipase inhibitor, a CB1 receptor modulator, and a CB2 receptor modulator, as disclosed herein, is for treatment of an ocular disease or ocular disorder, such as transdermal treatment of the ocular disease or ocular disorder. In certain embodiments, the ophthalmic composition disclosed herein is for treatment of a dry eye disorder, such as transdermal treatment of the dry eye disorder. In certain embodiments, the ophthalmic composition comprising a lipase inhibitor, a CB1 receptor modulator, and a CB2 receptor modulator, as disclosed herein, is a transdermal, ophthalmic composition.

[0028] In certain embodiments, the lipase inhibitor is glycerol monolaurate (GML), myrtenol, Intsia palembanica extracts, or Brazilin. In certain embodiments, the lipase inhibitor is present in the ophthalmic composition disclosed herein at a concentration in the range of 0.1- 5.0 wt.%. For example, in certain embodiments, the lipase inhibitor is present in the ophthalmic composition disclosed herein at a concentration of 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0 wt. %. In certain embodiments, the lipase inhibitor is present in the ophthalmic composition disclosed herein at a concentration of 1.0 wt. %. In certain embodiments, the lipase inhibitor present in the ophthalmic composition disclosed herein is a fatty acid ester, such as glycerol monolaurate (GML). In certain embodiments, GML is present in the ophthalmic composition at a concentration of 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5 wt. %. In certain embodiments, GML is present in the ophthalmic composition at a concentration of 1.0 wt. %. In certain embodiments, GML is present in the ophthalmic composition at a concentration which maintains the ocular microbiome. For example, in certain embodiments, the composition includes GML at a concentration of 1.0 wt. %, wherein said concentration maintains the ocular microbiome of a subject’s eye. In certain embodiments, GML is present in the ophthalmic composition at a concentration below that which imparts minimal anti -microbial activity when applied to the ocular surface. In certain embodiments, the lipase inhibitor enhances transdermal permeation of the composition.

[0029] In certain embodiments, the composition as disclosed herein further comprises a permeation enhancer. In certain embodiments, the permeation enhancer is glycerol monolaurate (GML), an essential oil, tea tree oil, peppermint oil, eucalyptus oil, Chenopodium, ylang-ylang, L-menthol, oleic acid, sorbitan monooleate, methyl laurate, ethylene vinyl acetate, glycerol monooleate, lauryl acetate, lauryl lactate, myristyl acetate, a sulphoxide, an azone, a pyrrolidone, an alcohol, an alkanol, a glycol, a fatty acid ester, or a fatty alcohol. In certain embodiments, the permeation enhancer is present in the ophthalmic composition disclosed herein at a concentration in the range of 0.1-5.0 wt.%. For example, in certain embodiments, the permeation enhancer is present in the ophthalmic composition disclosed herein at a concentration of 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0 wt. %. In certain embodiments, the permeation enhancer is present in the ophthalmic composition disclosed herein at a concentration of 1.0 wt. %. In certain embodiments, the permeation enhancer present in the ophthalmic composition disclosed herein is a fatty acid ester, such as glycerol monolaurate (GML). For example, in certain embodiments, the permeation enhancer is GML and is present in the ophthalmic composition at a concentration of 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5 wt. %. In certain embodiments, GML is present in the ophthalmic composition at a concentration of 1.0 wt. %. In certain embodiments, GML is present in the ophthalmic composition at a concentration that maintains the ocular microbiome. For example, the composition includes GML at a concentration of 1.0 wt. %, wherein said concentration maintains the ocular microbiome of a subject’s eye. In certain embodiments, GML is present in the ophthalmic composition at a concentration below that which imparts minimal antimicrobial activity when applied to the ocular surface.

[0030] In certain embodiments, the CB1 receptor modulator is a CB1 receptor selective modulator. In certain embodiments, the CB1 receptor modulator is a CB1 receptor agonist, such as a CB1 receptor full agonist or a CB1 receptor partial agonist, a CB1 receptor positive allosteric modulator, a CB1 receptor antagonist, or a CB1 receptor inhibitor.

[0031] In certain embodiments, the CB1 receptor modulator is a naturally occurring modulator. In certain embodiments, the CB1 receptor modulator is a non-naturally occurring modulator. In certain embodiments, the CB1 receptor modulator is anandamide, methanandamide, N-Arachidonyl dopamine, 2-Arachidonylglycerol, 2-Arachidonyl glyceryl ether, cannabinol, cannabipiperidiethanone, epicatechin gallate, gallocatechol, kava, levonantradol, tetrahydrocannabinol (THC), tetrahydrocannabiphorol (THCP), hexahydrocannabinol, yangonin, dronabinol, oleamide, kavain, pregnenolone, otenabant, ibipinabant, taranabant, guineensine, chelerythrine, or a flavonoid. In certain embodiments, the CB1 receptor modulator is a flavonoid, such as quercetin. In certain embodiments, quercetin is naturally present in acerola, alfalfa, almonds, apricot, apples, apricot, amaranth leaves, annual saw-thistle, arrowhead, artichoke, arugula, asparagus, avocado, Banaba, basil, bay berries, bay leaves, beans, beets, berries, blackberries, blood orange, blueberry, brassica vegetables, Brazil nuts, breadfruit, broadband, broccoli, brussel sprouts, cabbage, cantaloupe, capers, carob, carrots, cashews, cassava, celeriac, chamomile, chard, chia, chives, corn, cowpeas, cranberry, cress, crowberries, cucumber, currants, dill, dock, drumstick leaves, eggplant, elderberries, fennel leaves, figs, garlic, goji berries, gooseberries, gourd, grapes, grapefruit, green peppers, guava, hartwort, hazelnut, honey dew melon, jabuticaba, juniper, jujube, kale, kiwi, kohlrabi, leeks, lemon, lettuce, licorice root, ligon berry, lima beans, lime, milk, mulberries, mushrooms, mustard greens, nalta jute, nectarines, olive leaves, onions, oregano, pako fern malacca, parsley, papaya peach, pears, peas, pecans, peppermint, peppers, perilla leaves, pinenuts, pistachio, pitanga, pomegranate, potatoes, plum, prickly pear, pumpkin, propolis, purslane, Queen Anne’s lace, quince, radicchio, radishes, raisins, raspberry, red leaf lettuce, red onion, red wine, rowan berry, rosemary, soursop, spinach, squash, star apple, strawberry, sweet potato, tangerine, tarragon, taro, green tea, black tea, thyme, tofu, tomatoes, turmeric, turnip, vinegar, walnuts, watercress, watermelon, yams, yardlong bean, moringa oleifera, mandarin orange, spearmint, red-silk cotton, eucalyptus, maqui berry, thumys munbyanus, or coleus aromaticus. [0032] In certain embodiments, the CB1 receptor modulator is present in the ophthalmic composition disclosed herein at a concentration of 0.02 to 5.0 wt. %. For example, in certain embodiments, the CB1 receptor modulator is present in the ophthalmic composition disclosed herein at a concentration of 0.02, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0 wt. %. In certain embodiments, the CB1 receptor modulator is present in the ophthalmic composition disclosed herein at a concentration of 0.5 wt. %. In certain embodiments, the CB1 receptor modulator present in the ophthalmic composition disclosed herein is a flavonoid, such as quercetin. In certain embodiments, quercetin is present in the ophthalmic composition at a concentration of 0.02, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0 wt. %. In certain embodiments, quercetin is present in the ophthalmic composition at a concentration of 0.5 wt. %.

[0033] In certain embodiments, the CB2 receptor modulator is a CB2 receptor selective modulator. In certain embodiments, the CB2 receptor modulator is a CB2 receptor agonist, such as a CB2 receptor full agonist or a CB2 receptor partial agonist, a CB2 receptor positive allosteric modulator, a CB2 receptor antagonist, or a CB2 receptor inhibitor.

[0034] In certain embodiments, the CB2 receptor modulator is a naturally occurring modulator. In certain embodiments, the CB2 receptor modulator is a non-naturally occurring modulator. In certain embodiments, the CB2 receptor modulator is L-759633, L-759656, JWH-015, L-768242, SR144528, Dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide, Dodeca-2E,4E-dienoic acid isobutylamide (DDI), minocycline, or a terpene. In certain embodiments, the CB2 receptor modulator is a terpene, such as beta-caryophyllene. In certain embodiments, beta-caryophyllene is naturally present in Acmella oleracea, Thymelaeaceae, black pepper oil, Cananga oil, cedarwood oil, cinnamon bark oil, clove oil, grapefruit oil, lemongrass oil, lemon balm oil, niaouli oil, palmarosa oil, patchouli oil, or ylang ylang oil.

[0035] In certain embodiments, the CB2 receptor modulator is present in the ophthalmic composition disclosed herein at a concentration of 0.01 to 5.0 wt. %. For example, in certain embodiments, the CB2 receptor modulator is present in the ophthalmic composition disclosed herein at a concentration of 0.01, 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0 wt. %. In certain embodiments, the CB2 receptor modulator is present in the ophthalmic composition disclosed herein at a concentration of 0.1 wt. %. In certain embodiments, the CB2 receptor modulator is present in the ophthalmic composition disclosed herein at a concentration of 1.0 wt. %. In certain embodiments, the CB2 receptor modulator present in the ophthalmic composition disclosed herein is a terpene, such as beta-caryophyllene. In certain embodiments, beta-caryophyllene is present in the ophthalmic composition at a concentration of 0.01, 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0 wt. %. In certain embodiments, beta-caryophyllene is present in the ophthalmic composition at a concentration of 0.1 wt. %. In certain embodiments, beta-caryophyllene is present in the ophthalmic composition at a concentration of 1.0 wt. %.

[0036] In certain embodiments, the ophthalmic composition as disclosed herein further comprises an additional formulation component, said additional formulation component comprising petrolatum, one or more essential oils, wax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, propylene glycol monocaprylate, C12-C15 alkyl benzoate, one or more moisturizers, or one or more herbs, or combinations thereof. For example, in certain embodiments, the essential oils are eucalyptus oil, camphor oil, lavender oil, fennel oil, thyme, mint oil, aloe, rosemary, seabuck, myrrh, eyebright, chamomile, amia, marigold, echinacea, calendula, tea tree, tea bush, chocolate berry (aronia), ginkgo, ginseng, blueberry, elderberry, anise, jojoba, ylang ylang, castor oil, peppermint oil, abies koreana oil, soy bean, sesame oil, olive oil, almond oil, wheat germ oil, corn oil, canola oil, or sunflower oil. For example, in certain embodiments, the moisturizer is dexpanthenol. For example, in certain embodiments, the herb is hypericum perforatum.

[0037] In certain embodiments, the ophthalmic composition as disclosed herein further comprises an additional formulation component, said additional formulation component comprising petrolatum, beeswax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, or propylene glycol monocaprylate, or combinations thereof.

[0038] In certain embodiments, the composition as disclosed herein is a semisolid preparation, a solution, an emulsion, a suspension, or a colloid. In certain embodiments, the composition as disclosed herein is an ointment, a cream, a gel, a lotion, a spray, or an eye drop. In certain embodiments, the composition as disclosed herein is for use as a topical treatment released from an ophthalmic device such as a contact lens. For example, the composition as disclosed herein may be formulated into contact lens blister packs. In certain embodiments, the composition as disclosed herein is a delayed-release composition. In certain embodiments, the composition provided herein is for use as a transdermal treatment of dry eye disorders. In certain embodiments, the composition provided herein is a transdermal ophthalmic composition that provides benefits over direct administration to the ocular surface. For example, formulation of compositions for direct administration to the ocular surface results in a potential reduction of bioavailability of the topically applied drug due to drainage loss, tear turnover, and blinking. Approximately 80% to 90% of an instilled eye drop is lost from the tear film within the first minutes of instillation and only 20% of instilled dose is retained. An aqueous solution delivered to the surface of the eye provides a pulse drug permeation post drop instillation, followed by a rapid reduction in concentration of available agent roughly following first order kinetics. Emulsions, suspensions and ointments are often associated with ocular irritation, redness, inflammation, and blurred vision. In contrast, a transdermal peri-ocular ointment based delivery system prolongs contact time, maximizes delivery efficacy and reduces the potential for ocular irritation and blurred vision. In certain embodiments, formulation of the CB 1 receptor modulator, quercetin, and the CB2 receptor modulator, betacaryophyllene, as a transdermal ointment for peri-ocular delivery, improves delivery to the ocular surface.

Methods of Treating

[0039] Ocular diseases or ocular disorders in a subject, such as dry eye disorder, may manifest in a variety ways. Ocular disease or disorder may manifest, at least in part, in the lacrimal (tear) glands of said subject. Ocular diseases or ocular disorders, such as dry eye disorder, may be caused by or associated with meibomian gland dysfunction (MGD), may be caused by or associated with contact lens discomfort, and/or may be caused by or associated with ocular microbiome dysbiosis. In some embodiments, the ocular disease or ocular disorder, such as dry eye disorder, may be a symptom of another underlying condition (e.g., Sjogren’s syndrome).

[0040] Without being bound to a particular theory, in certain embodiments, dry eye is caused by a similar mechanism of action as toxic shock e.g., the mucosal environment open to the outside environment in which Staphylococcus aureus as an opportunistic pathogen (and others) can take control of the bacterial community and exude exotoxins and superantigens. The presence of opportunistic pathogens, such as in the case of dry eye, can lead to destabilization of the tear film and take control over the microbiome of the ocular surface, resulting in ocular microbiome dysbiosis. The destabilization of the ocular microbiome can cause dry eye disorder and inflammation of the eye.

[0041] In one aspect, provided herein is a method for treating an ocular disease or ocular disorder in a subject, comprising administering an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye. In certain embodiments, the subject has an ocular disease or ocular disorder. In certain embodiments, the ocular disease or ocular disorder is a dry eye disorder, meibomian gland dysfunction (MGD), contact lens discomfort, ocular microbiome dysbiosis, inflammation in an eye, dry eye symptoms associated with Sjogren’s syndrome, elevated lipase production in an eye, elevated neuropathic pain in an eye, depressed would healing of the ocular surface, depressed lacrimal gland function, a poor score according to the Ocular Surface Disease Index (OSDI) in an eye, and/or a low level of meibum quality gland expressibility in an eye. For example, in certain embodiments, the ocular disease or ocular disorder is dry eye disorder. In certain embodiments, the ocular disease or ocular disorder is meibomian gland dysfunction (MGD). In certain embodiments, the ophthalmic composition as disclosed herein is topically administered, such as transdermally administered, on the peri-ocular surface of a subject’s eye.

[0042] In another aspect, provided herein is a method for treating contact lens discomfort in an eye of a subject, comprising administering, such as topically administering, an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0043] In another aspect, provided herein is a method for mitigating ocular microbiome dysbiosis in an eye of a subject, comprising administering, such as topically administering, an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0044] In another aspect, provided herein is a method for reducing inflammation in an eye of a subject, comprising administering, such as topically administering, an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0045] In another aspect, provided herein is a method for reducing lipase production in an eye of a subject, comprising administering, such as topically administering, an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0046] In another aspect, provided herein is a method for reducing neuropathic pain in an eye of a subject, comprising administering, such as topically administering, an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0047] In another aspect, provided herein is a method for increasing wound healing in an eye of a subject, comprising administering, such as topically administering, an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0048] In another aspect, provided herein is a method for providing neuroprotective effects in an eye of a subject, comprising administering, such as topically administering, an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0049] In another aspect, provided herein is a method for improving the Ocular Surface Disease Index (OSDI) in an eye of a subject, comprising administering, such as topically administering, an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye. [0050] In another aspect, provided herein is a method for improving the meibum quality gland expressibility in an eye of a subject, comprising administering, such as topically administering, an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0051] In another aspect, provided herein is a method of transdermally delivering a CB1 receptor modulator to an ocular surface, comprising administering an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0052] In another aspect, provided herein is a method of transdermally delivering a CB2 receptor modulator to an ocular surface, comprising administering an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0053] In another aspect, provided herein is a method of transdermally delivering a CB1 receptor modulator and a CB2 receptor modulator to an ocular surface, comprising administering an ophthalmic composition as disclosed herein on the peri-ocular surface of a subject’s eye.

[0054] In certain embodiments, the methods provided herein comprise administering the ophthalmic composition as disclosed herein once daily. In certain embodiments, the methods provided herein comprise administering the ophthalmic composition as disclosed herein twice daily. In certain embodiments, the methods provided herein comprise administering the ophthalmic composition as disclosed herein once in the morning and once in the evening.

[0055] In certain embodiments, the methods provided herein comprise topically administering the ophthalmic composition disclosed herein to the peri-ocular surface of the subject’s eye. In certain embodiments, the methods provided herein comprise topically administering the ophthalmic composition disclosed herein to the meibomian glands via the peri-ocular surface of the claims.

[0056] In certain embodiments, the methods provided herein comprise topically administering one pea-sized amount of the ophthalmic composition disclosed herein to the periocular surface of the subject’s eye. In certain embodiments, the methods provided herein comprise topically administering two pea-sized amounts of the ophthalmic composition disclosed herein to the peri-ocular surface of the subject’s eye.

[0057] In certain embodiments, the methods provided herein maintain the ocular microbiome of the subject’s eye. In certain embodiments, the methods provided herein improve the ocular microbiome of the subject’s eye. For example, the Shannon Diversity Index is used to identify and quantify the microbiota present in the ocular microbiome. A healthy ocular microbiome comprises different microbiota compared with an ocular microbiome of an ocular disease, such as dry eye disorder. In certain embodiments, the methods reestablish the equilibrium of the ocular microbiome. In certain embodiments, the methods alter the microbiota of the ocular microbiome to that of a healthy eye. In certain embodiments, the methods further comprise measuring or determining the diversity of microbiota in said subject’s eye prior to the administration step. In certain embodiments, the methods provided herein are exclusive of providing an anti-microbial effect, or provide minimal anti -microbial effect to the subject’s eye. For example, the Shannon Diversity index is used to identify and quantify the microbiota present in the ocular microbiome. In certain embodiments, the methods provide no reduction in the microbiota in the eye. In certain embodiments, the methods provide a reduction of 5-10% in microbiota in the eye.

[0058] In certain embodiments, the methods provided herein reduce inflammation of the subject’s eye. In certain embodiments, the methods provided herein reduce inflammation of the subject’s eye by reducing production of inflammatory mediators or interfering with inflammatory mediators thereby preventing inflammatory effects. For example, in certain embodiments, the inflammatory mediators include inducible nitric oxide synthase (iNOS), interleukin 1 beta (IL-ip), interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF-a), nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), cyclooxygenase 1 and 2 (COX- 1 and COX-2) or peroxisome proliferator-activated receptors alpha (PPAR-a). For example, the inflammatory mediators are measured using a standard capture ELISA sandwich assay. Corneal staining may also be used to measure and assess inflammation. In certain embodiments, the methods decrease the levels of inflammatory mediators by 1.5 to 2-fold. In certain embodiments, the methods further comprise measuring or determining the level of inflammation in said subject’s eye prior to the administration step.

[0059] In certain embodiments, the methods provided herein reduce neuropathic pain of the subject’s eye. For example, ocular neuropathic pain can be measured using the Ocular Pain Assessment Survey (OPAS), a multi-dimensional survey that assesses eye pain intensity within the past 24 hours and two weeks, non-eye pain intensity, quality of life assessment, aggravating factors, and associated factors, using numerical rating scales (0-10). In certain embodiments, the methods provided herein improve the numerical ratings in one or more portions of the survey. In certain embodiments, the methods further comprise measuring or determining the level of neuropathic pain in said subject’s eye prior to the administration step.

[0060] In certain embodiments, the methods provided herein increase wound healing of the subject’s eye. For example, corneal wound healing is measured using corneal sodium fluorescein staining for visualization of damaged epithelial cells. Corneal erosion or superficial punctate keratitis is graded according to the loss of corneal integrity on a scale of 0 to 4 as determined by the fluorescein staining, with grade 0 being an absence of any loss of corneal integrity, grade 1 being 1-15% loss of corneal involvement, grade 2 being 16-30% loss of corneal involvement, grade 3 being 31-45% loss of corneal involvement; and grade 4 being 46% of great involvement. In certain embodiments, the methods provide a clinically significant staining grade is greater than 2 for the corneal erosion or superficial punctate keratitis. A statistically significant reduction in mean total corneal sodium fluorescein is reported as being clinically significant. In certain embodiments, the methods further comprise measuring or determining the level of wound healing in said subject’s eye prior to the administration step.

[0061] In certain embodiments, the methods provided herein increase lacrimal gland function in the subject’s eye. For example, lacrimal gland function can be measured by tear break-up time (TBUT). A normal TBUT is considered 10-35 seconds, which is the amount of time for the first dry spot to appear on the cornea after a complete blink. In certain embodiments, the methods provided herein re-establish a normal TBUT. In certain embodiments, the methods further comprise measuring or determining the level of lacrimal gland function in said subject’s eye prior to the administration step. In certain embodiments, the methods provided herein reduce lipase production in the subject’s eye. For example, in certain embodiments, the methods may reduce lipase production by 10-90%. For example, in certain embodiments, the methods may reduce lipase production by 25-90%, 25-75%, 35-65%, 50-75%, 50-90%, or 75-90%. In certain embodiments, the methods further comprise measuring or determining the level of lipase production in said subject’s eye prior to the administration step. In certain embodiments, the methods provided herein provide neuroprotective effects to the subject’s treated eye. For example, neuroprotective effects can be measured by tear break-up time (TBUT). A normal TBUT is considered 10-35 seconds, which is the amount of time for the first dry spot to appear on the cornea after a complete blink. In certain embodiments, the methods provided herein re-establish a normal TBUT. In certain embodiments, the methods further comprise measuring or determining the neuroprotective effect in said subject’s eye prior to the administration step.

[0062] In certain embodiments, the methods provided herein improve the Ocular Surface Disease Index (OSDI), a subjective questionnaire that assesses dry eye disease on a scale of 0- 100, of the subject’s treated eye. For example, mild dry eye disease is classified as a score of 13-22 out of 100 on the OSDI scale, moderate dry eye disease is classified as a score of 23-32, and severe dry eye disease is classified as a score >33. Improvements in a subject’s dry eye disease will lower the OSDI score. In certain embodiments, the methods improve an OSDI score by 4.5 to 7.3 units for mild or moderate symptoms. In certain embodiments, the methods improve the OSDI score by 7.3 to 13.4 units for severe symptoms. In certain embodiments, the methods further comprise measuring or determining an OSDI in said subject’s eye prior to the administration step.

[0063] In certain embodiments, the methods provided herein improve meibum quality gland expressibility. For example, the meibum scale of gland expressibility is 0 to 3. In certain embodiments, improvements in a subject’s dry eye disease will be at least an increase of 1 or more in gland expressibility. In certain embodiments, the methods further comprise measuring or determining the meibum quality gland expressibility in said subject’s eye prior to the administration step.

[0064] In certain embodiments, the methods provided herein modulate TRPV1 receptors on the ocular surface of the subject’s treated eye. For example, in certain embodiments, the TRPV1 receptors are inhibited by activation of CB1 receptors. In certain embodiments, modulation of the TRPV1 receptors reduces neuropathic pain in the eye. In certain embodiments, modulation of the TRPV 1 receptors improves one or more portions of the OP AS. In certain embodiments, the methods further comprise measuring or determining the activity of a TRPV1 receptor in said subject’s eye prior to the administration step. In certain embodiments, the methods provided herein modulate 5-HT1A receptors on the ocular surface of the subject’s treated eye. For example, TRPV1 and 5-HT1A receptor modulation is measured by extracting total RNA from eye samples and measuring RNA and protein levels for the receptors. In certain embodiments, the methods provided herein increase modulation of the receptors by a statistically and clinically significant amount. In certain embodiments, the methods further comprise measuring or determining the activity of a 5-HT1A receptor in said subject’s eye prior to the administration step.

[0065] In certain embodiments, the methods provided herein reduce capsaicin-evoked corneal pain responses of the treated eye. For example, capsaicin-evoked pain can be measured using the Ocular Pain Assessment Survey (OPAS), a multi-dimensional survey that assesses eye pain intensity within the past 24 hours and two weeks, non-eye pain intensity, quality of life assessment, aggravating factors, and associated factors, using numerical rating scales (0- 10). In certain embodiments, the methods provided herein improve the numerical ratings in one or more portions of the survey. In certain embodiments, the methods further comprise measuring or determining a capsaicin-evoked corneal pain response in said subject’s eye prior to the administration step. [0066] In certain embodiments, the methods provided herein reduce neutrophilic infiltration of the treated eye. For example, neutrophilic infiltration is measured by staining cornea cells with fluorescent counting beads to calculate absolute numbers of immune cells per cornea. In certain embodiments, the methods provide a statistically significant decrease in the absolute numbers of immune cells that is deemed clinically significant. In certain embodiments, the methods further comprise measuring or determining the level of neutrophilic infiltration in said subject’s eye prior to the administration step.

[0067] In certain embodiments, the methods provided herein reduces the pain score of the treated eye. For example, the pain score of the treated eye can be measured using OPAS, a multi-dimensional survey that assesses eye pain intensity within the past 24 hours and two weeks, non-eye pain intensity, quality of life assessment, aggravating factors, and associated factors, using numerical rating scales (0-10). In certain embodiments, the methods provided herein improve the numerical ratings in one or more portions of the survey. In certain embodiments, the methods further comprise measuring or determining a pain score in said subject’s eye prior to the administration step.

[0068] In certain embodiments, the methods provided herein are effective against

Demodex folliculorum infestation. For example, the extent of Demodex infestation is determined by standardized skin surface biopsy and direct microscopic examination. In certain embodiments, the methods improve the Demodex folliculorum infestation by decreasing the Demodex mite count. In certain embodiments, the methods further comprise measuring or determining the level of Demodex folliculorum infestation in said subject’s eye prior to the administration step.

Methods of Preparing

[0069] In another aspect, provided herein is a method of preparing an ophthalmic composition as disclosed herein, said method comprising combining the permeation enhancer and the CB1 receptor modulator. For example, in certain embodiments, the method of preparing provided herein comprises combining glycerol monolaurate and quercetin. In certain embodiments, the method of preparing the ophthalmic composition as disclosed herein further comprises combining with an additional formulation component. In certain embodiments the ophthalmic composition is an ophthalmic semisolid preparation, solution, emulsion, suspension, or colloid. In certain embodiments, the ophthalmic composition is an ointment, a cream, a gel, or a lotion. [0070] In another aspect, provided herein is a method of preparing an ophthalmic composition as disclosed herein, said method comprising combining the permeation enhancer, the CB1 receptor modulator, and the CB2 receptor modulator. For example, in certain embodiments, the method of preparing provided herein comprises combining glycerol monolaurate, quercetin, and beta-caryophyllene. In certain embodiments, the method of preparing the ophthalmic composition as disclosed herein further comprises combining with an additional formulation component. In certain embodiments, the ophthalmic composition is an ophthalmic semisolid preparation, solution, emulsion, suspension, or colloid. In certain embodiments, the ophthalmic composition is an ophthalmic ointment, a cream, a gel, or a lotion.

[0071] In certain embodiments, the method of preparing the ophthalmic composition as disclosed herein further comprises combining with an additional formulation component, said additional formulation component comprising petrolatum, one or more essential oils, wax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, propylene glycol monocaprylate, C12-C15 alkyl benzoate, one or more moisturizers, one ormore herbs, or combinations thereof. For example, in certain embodiments, the essential oils are eucalyptus oil, camphor oil, lavender oil, fennel oil, thyme, mint oil, aloe, rosemary, seabuck, myrrh, eyebright, chamomile, arnica, marigold, echinacea, calendula, tea tree, tea bush, chocolate berry (aronia), ginkgo, ginseng, blueberry, elderberry, anise, jojoba, ylang ylang, castor oil, peppermint oil, abies koreana oil, soy bean, sesame oil, olive oil, almond oil, wheat germ oil, corn oil, or sunflower oil. For example, in certain embodiments, the moisturizer is dexpanthenol. For example, in certain embodiments, the herb is hypericum perforatum.

[0072] In certain embodiments, the method of preparing the ophthalmic composition as disclosed herein further comprises combining with an additional formulation component, said additional formulation component comprising petrolatum, beeswax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, or propylene glycol monocaprylate, or combinations thereof.

[0073] In certain embodiments, the method for preparing the ophthalmic composition as disclosed herein further comprises combining with Epishield ointment.

EXAMPLES

[0074] Example 1 :

Manufacturing Protocol [0075] The following manufacturing protocol was used for preparing the compositions to be evaluated in permeation studies.

[0076] The hydrophobic phase was prepared by weighing out 3% wt. cetyl alcohol, a quantity sufficient of white petrolatum, 12% wt. lanolin, 10% wt. beeswax, 1% wt. lactic acid, and 2% wt. diethyl sebacate in a stainless-steel vessel. Using a water bath, the hydrophobic components were heated to 70°C until all components were melted and no lumps were visible. After heating, the melted clear liquid was removed from the water bath for cool down. The clear liquid was mixed slowly with an overhead mixture until it reached a temperature of 30- 35°C. The active pharmaceutical ingredient (API) phase was added once a temperature of 30- 35°C was reached.

[0077] The API phase was prepared by weighing 3% wt. propylene glycol monocaprylate and 3% wt. DMSO in a glass beaker covered in aluminum foil. Quercetin was added and mixed with a stir plate until a deep green solution is formed. Beta-caryophyllene was then added and the entire API phase was immediately added into the congealing ointment.

[0078] The mixture was cooled to 25°C and transferred into an appropriate container closure. Weights were then recorded.

Permeation Protocol

[0079] The following study protocol was used for evaluating the permeation of the compositions across the skin. The study is designed to perform an in vitro skin permeation testing (IVPT) to evaluate the skin penetration of the compositions across ex vivo human cryopreserved cadaver eyelid tissue.

[0080] The IVPT study is a 24-hour study that evaluates skin penetration of example compositions containing a lipase inhibitor, a CB1 receptor modulator, and a CB2 receptor modulator. In particular, the lipase inhibitor, CB1 receptor modulator, and CB2 receptor modulator were GML, quercetin, and beta-caryophyllene, respectively.

[0081] The following parameters were used for the IVPT study. The IVPT study across human cadaver eyelid tissue used an automated in-line flow-through diffusion cell system. The human cadaver eyelid tissue was obtained from two donors and had a thickness of 500± 250pm. Four replicate test formulation cells were prepared along with one control cell for each composition tested. Table 1 and Table 2 depict the study design dosing chart and the dosing chart on cells for two formulations.

Table 1

Table note: *D: Donor; R: Replicate; LT: Left Eye; RT: Right Eye; F: Formulation

Table 2

[0082] Composition 1, Composition 2, Composition 3, and Composition 4 were prepared with components detailed in Table 3. Compositions 1, 2, 3, and 4 contained 3% wt. cetyl alcohol, 12% wt. lanolin, 10% wt. beeswax, 1% wt. lactic acid, and 2% wt. diethyl sebacate, 3% wt. propylene glycol monocaprylate, 3% wt. DMSO, and a quantity sufficient of white petrolatum. Composition 1 further contained 1% glycerol monolaurate, 0.5% quercetin and 0.1% beta-caryophyllene. Composition 2 further contained 1% glycerol monolaurate, 0.5% quercetin and 1.0% beta-caryophyllene. Composition 3 contained 0.5% quercetin and 0.1% beta-caryophyllene, absent glycerol monolaurate. Composition 4 further contained 0.5% quercetin and 1.0% beta-caryophyllene, absent glycerol monolaurate.

Table 3

[0083] The dosing surface area, according to the IVPT study, was 1 cm², and for each formulation evaluated, an amount of 50 pL/cm² was administered per eyelid. The receiving medium flow rate was set at 30 pL/minutes. The tissue was kept at a temperature of 32°C ± 1°C during the study. Sampling was conducted at the following intervals: pre-dose (To), 0.5h, Ih, 2h, 4h, 8h 12h, 18h and 24h.

[0084] The cryopreserved, human cadaver eyelid tissue was stored at -80°C, and thawed at room temperature on the day of use.

[0085] Transdermal epidermal water loss (TEWL) was measured to characterize skin tissue barrier function. The TEWL value was measured to estimate tissue integrity using a vapometer. A low TEWL value is generally a characteristic feature of an intact tissue barrier function. The TEWL was measured and recorded for each diffusion cell before test article application. If any eyelid tissue had a comparatively high TEWL value, the eyelid tissue was removed and replaced because of possible leakage or compromised tissue integrity.

[0086] An automated in-line flow through diffusion cell system (PermeGear Collector FC 33, Version 3.1) was used to assess the active pharmaceutical ingredient in the tissue permeation experiment.

[0087] An ambient environmentally controlled laboratory temperature range of 21 °C ± 2°C and a humidity range of 50% ± 20% relative humidity was maintained throughout the IVPT study. The flow through diffusion cell system was equilibrated with receptor media.

[0088] The heater and circulator were set such that the surface of the skin is maintained at 32°C ± 1°C. The diffusion cells were placed and heated in supports of moving arm of system to maintain the skin surface temperature (at 32°C ± 1°C).

[0089] The cells were connected to multi-channel peristaltic pumps and the outlet of the diffusion cells were directed to drip into 20 mL scintillation vials.

[0090] Sections of skin tissue were cut into 1.5 x 1.5 cm sections and mounted in the diffusion cells, with epidermal layers/stratum corneum side up. Donor compartment blocks were placed on the skin tissue (donor chamber on stratum corneum) and secured using stainless steel clamps to provide a leak proof seal. Air bubbles were removed by inverting diffusion cells and confirmed visually by glass windows on the underside of the diffusion cells.

[0091] The pumps were adjusted to maintain a flowrate of 30 pL/min (1.8 mL/h) to provide adequate sink conditions. The diffusion cells were equilibrated for approximately 30 min. Any cell showing water accumulation on top of the tissue was removed from analysis. After equilibration, an infrared or appropriate thermometer was used to measure the temperature of each cell. The skin tissue surface temperature was stable at 32°C ± 1°C. The To samples were collected before dosing for 30 mins at 30 pL/min (1.8 mL/h).

[0092] Test articles were uniformly dispensed in an alternating sequence on successive diffusion cells onto the skin tissue surface using a positive displacement pipette, set to deliver appropriately 50 pL volume. The donor chambers were kept close to ambient conditions.

[0093] Fractions were collected at the following intervals: pre-dose (To), 0.5h, Ih, 2h, 4h, 8h, 12h, 18h and 24h.

[0094] Recovery of the formulation on the surface of the skin tissue was performed by cleaning with 1 dry cotton swab, 1 wet cotton swab dipped in wash solvent of 70% ethanol (v/v), and 1 dry cotton swab followed by one consecutive tape strip. Swabs and tape strips were collected in labeled vials for analysis. The undosed skin samples were cleaned first followed by treated skin on a clean dissection board.

[0095] The washed and tape stripped skin were placed on aluminum foil with dermis side down. The cleaned tissue was placed in respective pre-weighed labeled vials and weight of tissues will be recorded. The undosed skin samples were processed first and placed in vial, followed by treated skin.

[0096] The cleaned tissues were placed in respective pre-weighed labelled vials and weight of tissues were recorded. Tissue samples were then homogenized according to tissue method development and recorded in the study notebook.

[0097] All samples were stored at 2-8°C for short-term storage (less than a week) or -20°C for long-term storage (more than a week) until analysis by LC-MS/MS.

[0098] The receptor solution samples, tissue samples, tapes, and swabs were analyzed for the active pharmaceutical ingredient using a LC-MS/MS quantitation method.

[0099] The permeation profile of quercetin and beta-caryophyllene compositions into the receiving fluid was calculated as cumulative amounts, flux or rate of permeation, and tissue penetration.

Quantitation Protocol

[00100] The permeation of the CB1 modulator and the CB2 modulator, quercetin and [3- caryophyllene, respectively, were determined by liquid chromatography mass spectrometry (LC-MS/MS) methods for quantitation.

[00101] Method of quantitation of quercetin: [00102] The following solutions were prepared for use in running the quantitation methods on the LC-MS/MS system. Mobile Phase A, 0.1% Formic Acid in Water, was prepared by combining 1.00 mL of formic acid and 1000 mL of water and was stored at room temperature. Mobile Phase B, 1 : 1 (v/v) Acetonitrile: Methanol was prepared by combining 500 mL acetonitrile and 500 mL methanol and was stored at room temperature. Strong autosampler wash, 20:80 (v/v) DMSO: Methanol was prepared by combining 200 mL DMSO and 800 mL methanol and was stored at room temperature. Weak autosampler wash, 0.1% Formic Acid in Water, was prepared by combining 1.00 mL formic acid and 1000 mL of water and was stored at room temperature. Seal wash, 90: 10 (v/v) Water: Acetonitrile, was prepared by combining 100 mL acetonitrile and 900 mL water and was stored at room temperature. A solution of 1 : 1 (v/v) DMSO: Methanol was prepared by combining 10 mL DMSO and 10 mL methanol and was stored at room temperature. The receiving medium, 3% Brij 020 in lx PBS pH 7.4 was prepared by dissolving 1.5 gram Brij 020 in 50 mL lx PBS pH 7.4.

[00103] Quercetin Calibration Standard Stock Solution (Q-SS-1): The stock solution of the calibration standard of quercetin (Q-SS-1) was prepared by weighing approximately 5 mg of quercetin into a 20 mL amber glass scintillation vial. Then an appropriate amount of diluent was added, 1 : 1 (v/v) DMSO: Methanol, to the vial to dissolve the material and bring to a concentration of 0.500 mg/mL. The Q-SS-1 solution was stored at <20°C.

[00104] Quercetin Calibration Standards (Q-CS): Quercetin calibration standards were prepared, daily, in polypropylene containers using the prepared receiving medium as the diluent, 3% Brij 020 in lx PBS pH 7.4. Table 4 lists the concentration of the quercetin calibration standards for developing a linearity curve.

Table 4

Table note: * An additional Q-CS 1 was prepared to inject as Lowest Level of Quantitation System Suitability Test (LLOQ SST). [00105] Quercetin Quality Control Stock Solution (Q-SS-2): The stock solution (Quality Control, SS-2) was prepared by weighing approximately 5 mg of quercetin into a 20 mL amber glass scintillation vial. An appropriate amount of diluent was added, 1 : 1 (v/v) DMSO: Methanol, to the vial to dissolve the material and bring to a concentration of 0.500 mg/mL. Stock solution (Q-SS-2) was stored at <-20°C.

[00106] Quercetin Quality Control Samples (Q-QC): Quercetin quality control samples were prepared, daily, in polypropylene containers using receiving medium as the diluent, 3% Brij 020 in lx PBS pH 7.4. Table 5 lists the concentration of the quercetin quality control samples.

Table 5

[00107] Internal Standard Stock Solution (IS): Internal standard stock solutions were prepared by accurately weighing approximately 5.0 mg of quercetin-ds into a 20 mL amber glass scintillation vial. An appropriate amount of diluent was added, 1 : 1 (v/v) DMSO: Methanol, to the vial to dissolve the material and bring to a concentration of 0.500 mg/mL. Vortex and mix well. Stock solutions should be stored at <-20°C.

[00108] Working Internal Standard Stock Solution (WIS): A working internal standard solution was prepared by diluting the internal standard stock solution to a concentration of 50.0 ng/mL using methanol as the diluent. The internal standard working solution was stored at <- 20°C. Table 6 lists the working internal standard concentration.

Table 6

[00109] Quercetin Sample Preparation Method: Samples were prepared according to the following sample preparation method. Each prepared standards and quality control samples were vortexed for approximately three seconds prior to aliquoting into the 96-well plate. In a 96-well plate, 50.0 pL of sample was added to each designated standard and quality control well. 50.0 pL of blank matrix (3% Brij 020 in lx PBS pH 7.4) was added to each designated blank well. The QC0 sample was a blank to which the WIS is added. 200 pL of WIS was added to all samples and QC0 blank wells. 200 pL of WIS Diluent (Methanol) was added to all blank and carryover blank wells. The plate was capped and centrifuged at 3000 RPM for 1 minute at 5°C. The plate was mixed on a plate shaker for 5 minutes at 1500 RPM. The plate was centrifuged at 3000 RPM for 5 minutes at 5°C. 100 pL of supernatant was transferred to a new 96-well plate. 200 pL of 0.1% Formic Acid in Water was added. The plate was capped and mixed on a plate shaker for 5 minutes at 1500 RPM. The plate was centrifuged at 3000 RPM for 1 minutes at 5°C. The plate was stored in the autosampler at nominal 8°C until analysis.

[00110] Quercetin Quantitation LC-MS/MS Method: Liquid chromatography was performed on a Waters Acquity UPLC, H-Class quintenary pump at an autosampler temperature of 8°C using a Waters, Atlantis, dC18, 5pm, 2.1 x 50 mm column (P/N 186001293) at ambient temperature. Mobile Phase A was 0.1% Formic Acid in Water and Mobile Phase B was 1 :1 (v/v) Acetonitrile: Methanol. The flow rate was 0.500 mL/min. The total run time was 5.30 minutes. The injection volume was 25 pL. Sample Manager Purge/Weak Wash was 0.1% Formic Acid in Water and the Sample Manager Wash/Strong Wash was 20:80 (v/v) DMSO: Methanol. The retention time of quercetin was 1.20 minutes (+/- 0.3 min). The gradient method used is listed in Table 7.

Table 7

[00111] Mass spectrometry was performed on a AB Sciex 5500+ triple quadrupole mass spectrometer in positive ESI turbo spray mode, using the following parameters listed in Table 8. MRM transitions for Quercetin and Quercetin-d3 (i.e., triple deuterated quercetin; used as an Internal Standard) were 303.3/229.2 and 306.2/232.2, respectively.

Table 8

[00112] Calibration standards were used to generate a linear regression. Recovery of each calibrator was calculated with a weighting set at 1/x².

[00113] Non-zero calibrators were accepted if ± 20% of the nominal concentration, except for the lower limit of quantitation (LLOQ), where the calibrator should be ± 25% of the nominal concentration. 75% and a minimum of six non-zero calibrator levels had to meet the ± 20% of the nominal concentration criteria in each run for acceptance, otherwise the standard was removed and the regression was repeated beginning with the standard that had the largest deviation from criteria. This process was repeated until only acceptable standards were included in the regression.

[00114] Blank samples were reviewed for peaks present at the retention time of quercetin to determine interference percentage by the following equation:

Area of Interference Peak %Interference = - - - - - - - x 100

Average LLOQ Standard Peak Area

[00115] Blank samples were accepted if the area of any peaks at the analyte retention time did not exceed 20% of the average analyte peak area of accepted LLOQ standards, the internal standard response in the blank did not exceed 5% of the average internal standard response of the calibrators and QCs. If the carryover blank was greater than 20% of the average peak area seen in acceptable LLOQ standards, then the samples were assessed to see if the carryover was a systematic effect throughout the run. Sample analysis was repeated for those affected samples as needed. [00116] Sensitivity was assessed by review of the LLOQ injection for peak response of quercetin. The LLOQ was accepted if the analyte response was at least five times the analyte response of the blank. If the LLOQ did not meet this criteria, the next higher calibrator was selected as the new LLOQ. If the ULOQ failed, the next lower calibrator was used as the new ULOQ, provided the resulting calibration curve met acceptance criteria and did not change the calibration model.

[00117] Figures 1 A and IB illustrate sample chromatograms of the quercetin and quercetin- d3 (IS) LLOQ, respectively. The LLOQ was 5.0 ng/mL in 3.0% Brij in lx PBS pH 7.4. Figures 2A and 2B illustrate sample chromatograms of the quercetin and quercetin-d3 (IS) ULOQ, respectively. The ULOQ was 5000 ng/mL ULOQ Standard in 3.0% Brij in lx PBS pH 7.4. [00118] Method of quantitation of beta-caryophyllene:

[00119] The following solutions were prepared for use in running the beta caryophyllene quantitation method on the LC-MS/MS system. Mobile Phase A/Weak Wash, 0.1% Formic Acid in 5 mM Ammonium acetate, was prepared by adding 385 mg ammonium acetate and 1000 mL water and 1 mL formic acid, and was stored at room temperate. Recon Solution, 1 : 1 (v/v) Acetonitrile: 0.1% Formic Acid in 5 mM Ammonium Acetate was prepared by combining 100 mL acetonitrile and 100 mL 0.1% formic acid in 5 mM ammonium acetate, and was stored at room temperature. Receiving Medium, 3% Brij 020 in lx PBS pH 7.4 was prepared by dissolving 1.5 grams Brij 020 in 50 mL of lx PBS pH 7.4, and was stored at 5°C ±3°C.

[00120] Beta-caryophyllene Calibration Standard Stock Solution (BCP-SS-1): Betacaryophyllene calibration standard stock solution (BCP-SS-1) was prepared by extracting betacaryophyllene on a wet ice bath to limit time exposure to ambient temperature. The calibration standards were prepared by accurately weighing approximately 40 mg of beta-caryophyllene into a 20 mL amber glass scintillation vial. An appropriate amount of diluent, acetonitrile, was added to the vial to dissolve the material and obtain a concentration of 20 mg/mL. The solution was stored at -20°C±3°C.

[00121] Beta-caryophyllene Calibration Standards (BCP-CS): Beta-caryophyllene calibration standards were prepared, daily, in polypropylene containers using the prepared receiving medium as the diluent, 3% Brij 020 in lx PBS pH 7.4. Table 9 lists the concentration of the standards for developing a linearity curve.

Table 9

Table note: *An additional BCP-S1 was prepared to inject as the Lowest Level of Quantitation System Suitability Test (LLOQ SST).

[00122] Beta-caryophyllene Quality Control Stock Solution (BCP-SS-2): The stock solution (BCP-SS-2) was prepared by weighing approximately 40 mg of beta-caryophyllene into a 20 mL amber glass scintillation vial. An appropriate amount of diluent, Acetonitrile, was added to the vial to dissolve the material and bring the concentration of 20 mg/mL. The stock solution was stored at -20°C±3°C.

[00123] Beta-caryophyllene Quality Control Samples (BCP-QC): Quality control (QC) samples were prepared, daily, in polypropylene containers, using receiving medium as the diluent, 3% Brij 020 in lx PBS pH 7.4. Table 10 lists the concentration of the standards.

Table 10

[00124] Beta-caryophyllene Sample Preparation: Samples were prepared according to the following preparation method. Each prepared standards and quality control samples were vortexed for approximately three seconds prior to aliquoting into the 96-well plate. In a 96- well plate, 50.0 pL of sample was added to each designated standard and quality control well. 50.0 pL of blank matrix (3% Brij 020 in lx PBS pH 7.4) was added to each designated blank well. 300 pL of Recon solution (Acetonitrile: 0.1% Formic Acid in 5 mM Ammonium Acetate (1 : 1, v/v)) was added to all samples. The plate was capped and centrifuged at 3000 RPM for 1 minute at 5°C. The plate was mixed on a plate shaker for 5 minutes at 1500 RPM. The plate was centrifuged at 3000 RPM for 5 minutes at 5°C. The plate was stored in the autosampler at nominal 8°C until analysis. [00125] Beta-caryophyllene Quantitation LC-MS/MS Method: Liquid chromatography was performed on a Waters Acquity UPLC, H-Class quintenary pump at an autosampler temperature of 8°C using a Waters, Atlantis, dC18, 5pm, 2.1 x 50 mm column (P/N 186001293) at ambient temperature. Mobile Phase A was 0.1% Formic Acid in 5 mM Ammonium Acetate and Mobile Phase B was Methanol. The flow rate was 0.700 mL/min. The total run time was 4.0 minutes. The injection volume was 10 pL. Sample Manager Purge/Weak Wash was 0.1% Formic Acid in 5 mM Ammonium Acetate and the Sample Manager Wash/Strong Wash was Methanol. The retention time of beta-caryophyllene was 2.8 minutes (+/- 0.3 min). The gradient method used is listed in Table 11.

Table 11

[00126] Mass spectrometry was performed on a AB Sciex 6500+ triple quadrupole mass spectrometer in positive atmospheric pressure chemical ionization (APCI) mode, using the following parameters listed in Table 12. MRM transitions for beta-caryophyllene were 205.107/109.200.

Table 12

[00127] Calibration standards were used to generate a linear regression. Non-zero calibrators were accepted if ± 20% of the nominal concentration, except for the lower limit of quantitation (LLOQ), where the calibrator should be ± 25% of the nominal concentration. 75% and a minimum of six non-zero calibrator levels had to meet the ± 20% of the nominal concentration criteria in each run for acceptance, otherwise the standard was removed and the regression was repeated beginning with the standard that had the largest deviation from criteria. This process was repeated until only acceptable standards were included in the regression.

[00128] Blank samples were reviewed for peaks present at the retention time of quercetin to determine interference percentage by the following equation:

Area of Interference Peak %Interference = - , , ; - — — — - x 100

Average LLOQ Standard Peak Area

[00129] Blank samples were accepted if the area of any peaks at the analyte retention time did not exceed 20% of the average analyte peak area of accepted LLOQ standards, the internal standard response in the blank did not exceed 5% of the average internal standard response of the calibrators and QCs. If the carryover blank was greater than 20% of the average peak area seen in acceptable LLOQ standards, then the samples were assessed to see if the carryover was a systematic effect throughout the run. Sample analysis was repeated for those affected samples as needed.

[00130] Sensitivity was assessed by review of the LLOQ injection for peak response of quercetin. The LLOQ was accepted if the analyte response was at least five times the analyte response of the blank. If the LLOQ did not meet this criteria, the next higher calibrator was selected as the new LLOQ. If the ULOQ failed, the next lower calibrator was used as the new ULOQ, provided the resulting calibration curve met acceptance criteria and did not change the calibration model.

[00131] The concentration of beta-caryophyllene was calculated in each QC sample using the calibration curve. QCs were accepted if 67% of QCs were ±20% of their nominal concentration and 50% of QCs per level were ±20% of their nominal concentration.

[00132] Figures 3 and 4 illustrate sample chromatograms of the beta-caryophyllene LLOQ and ULOQ, respectively. The LLOQ was 2 pg/mL and the ULOQ was 1000 pg/mL.

Composition Permeation Test Results

[00133] From each treated skin tissue sample, the detection and quantification of quercetin was measured as follows: from the media over a 24-hour period (Tables 13-16), from cotton swabs and tissue strips following completion of the 24-hour period (Tables 17-20), and finally from the homogenized eyelid tissue (Tables 21-24). Similarly, from each treated skin tissue sample, the detection and quantification of beta-caryophyllene was measured as follows: from the cotton swabs and tissue strips following completion of the 24-hour period (Tables 25-28). Beta-caryophyllene was not detected in the media or homogenized eyelid tissue. [00134] Evaluation of the media included the following measurements and calculations: (1) time (h); (2) concentration (ng/mL); (3) volume collected (mL); (4) total amount/cell (ng); (5) cumulative amount (ng); (6) amount permeated (ng/cm²); and (7) flux (ng/cm²/h). The time (h) was the point at which the sample was collected from the media over a 24-hour period. The concentration (ng/mL) was a measurement of the concentration of the active pharmaceutical ingredient (API; quercetin or beta-caryophyllene) in the sample collected from the media. The volume collected (mL) was the volume of the sample collected from the media. The total amount/cell (ng) was the measured total amount of API in the diffusion cell sample. The cumulative amount (ng) was the calculated sum of the previous time point API amounts (ng) to determine the total API permeated through the eyelid. The amount of API permeated (ng/cm²) measured the amount of API permeated through the eyelid per 1 cm² dose surface area. The flux (ng/cm²/h) was a calculation of the rate of permeation through the eyelid.

[00135] Evaluation of the cotton swabs and tape strips included the following measurements and calculations: (1) concentration in cotton swabs (ng/mL); (2) concentration in tape strips; (3) cotton swabs total (ng); (4) tape strips total (ng); (5) % API in cotton swabs per applied dose (ng); (6) % API in tape strips per applied dose (ng); and (7) % API in tape strips per applied dose (ng). The concentration in cotton swabs (ng/mL) was the concentration of the API in the collected cotton swab sample. The concentration in the tape strips (ng/mL) was the concentration of the API in the collected tape strip sample. The cotton swabs total (ng) and tape strips total (ng) are the total API measured in the samples. The % API in cotton swabs per applied dose and % API in tape strips per applied dose measured the percent of API in the samples based on the composition dose administered of 250000 (ng) for all samples.

[00136] Evaluation of the tissue included the following measurements and calculations: (1) TEWL (g/m²h); (2) thickness (mm); (3) drug concentration (ng/mL); (4) total tissue API (ng); (5) % APEapplied dose-total tissue; and (6) total tissue API (ng/cm²). The transdermal epidermal water loss (TEWL) (g/m²h) measured tissue integrity to estimate skin tissue barrier function. The thickness (mm) of each eyelid was measured. The total tissue API (ng) was a measurement of the total API detected in the homogenized eyelid tissue. The % API/applied dose-total tissue was a measurement of the percent of API in the tissue based on the composition dose administered of 250000 (ng). The total tissue API (ng/cm²) was a measurement of the total API in the tissue per 1 cm² dose surface area.

Table 13 _

Quercetin in Media: Composition 1

Table 14

| 24 | 0,00 | 10,8409 | 0,000 | 498,472 | 498,472 | 0,000 |

Table 15

Table 16

24 29.4 | 11,2476 | 330,679 | 1225,340 | 1225,340 | 55,113

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

[00137] The data from this example demonstrated that topical administration of the Compositions 1-4 onto a peri-ocular surface, here an eyelid, resulted in transdermal penetration of quercetin through the eyelid. The data above further showed that, comparing Compositions 1-2 relative to Compositions 3-4, the rate of quercetin transdermal penetration improved in the presence of GML.

EXEMPLARY EMBODIMENTS

[00138] One or more than one (including for instance all) of the following exemplary Embodiments may comprise each of the other embodiments or parts thereof.

[00139] Al. An ophthalmic composition, comprising a lipase inhibitor and a CB1 receptor modulator.

[00140] A2. An ophthalmic composition, comprising a lipase inhibitor and a CB2 receptor modulator.

[00141] A3. An ophthalmic composition, comprising a lipase inhibitor, a CB1 receptor modulator, and a CB2 receptor modulator.

[00142] A4. The composition of any of one of Embodiments A1-A3, wherein the lipase inhibitor is present in the ophthalmic composition at a concentration of 0.1 to 5.0 wt.%.

[00143] A5. The composition of any of one of Embodiments A1-A4, wherein the lipase inhibitor is present in the ophthalmic composition at a concentration of 1.0 wt.%.

[00144] A6. The composition of any one of Embodiments A1-A5, wherein the lipase inhibitor is glycerol monolaurate, myrtenol, Intsia palembanica extracts, or Brazilin.

[00145] A7. The composition of any one of Embodiments A1-A6, wherein the lipase inhibitor enhances transdermal permeation of said composition.

[00146] A8. The composition of any one of Embodiments A1-A7, wherein the lipase inhibitor is GML.

[00147] A9. The composition of Embodiment A8, wherein the GML is present in the ophthalmic composition at a concentration that maintains the ocular microbiome.

[00148] A10. The composition of any of one of Embodiments A1-A9, wherein the composition further comprises a permeation enhancer.

[00149] Al l. The composition of Embodiment A10, wherein the permeation enhancer is present in the ophthalmic composition at a concentration of 0.1 to 5.0 wt.%.

[00150] A12. The composition of Embodiments A10-A11, wherein the permeation enhancer is present in the ophthalmic composition at a concentration of 1.0 wt.%.

[00151] A13. The composition of Embodiment A10, wherein the permeation enhancer is present in the ophthalmic composition at a concentration % wt. selected from the group consisting of: 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0 wt. %. [00152] A14. The composition of any of one of Embodiments A10-A13, wherein the permeation enhancer is glycerol monolaurate (GML), an essential oil, tea tree oil, peppermint oil, eucalyptus oil, Chenopodium, ylang-ylang, L-menthol, oleic acid, sorbitan monooleate, methyl laurate, ethylene vinyl acetate, glycerol monooleate, lauryl acetate, lauryl lactate, myristyl acetate, a sulphoxide, an azone, a pyrrolidone, an alcohol, an alkanol, a glycol, a fatty acid ester, or a fatty alcohol.

[00153] A15. The composition of any of one of Embodiments Al or A3-A14, wherein the

CB1 receptor modulator is present in the ophthalmic composition at a concentration of 0.02 to 5.0 wt.%.

[00154] A16. The composition of any of one of Embodiments Al or A3-A15, wherein the

CB1 receptor modulator is present in the ophthalmic composition at a concentration of 0.5 wt.%.

[00155] A17. The composition of any of one of Embodiments Al or A3-A16, wherein the

CB1 receptor modulator is a CB1 receptor selective modulator.

[00156] A18. The composition of any of one of Embodiments Al or A3-A16, wherein the

CB1 receptor modulator is a CB1 receptor full agonist.

[00157] A19. The composition of any of one of Embodiments Al or A3-A16, wherein the

CB1 receptor modulator is a CB1 receptor partial-agonist.

[00158] A20. The composition of any of one of Embodiments Al or A3-A16, wherein the

CB1 receptor modulator is a CB1 receptor positive allosteric modulator.

[00159] A21. The composition of any of one of Embodiments Al or A3-A16, wherein the

CB1 receptor modulator is a CB1 receptor antagonist.

[00160] A22. The composition of any of one of Embodiments Al or A3-A16, wherein the

CB1 receptor modulator is a CB1 receptor inhibitor.

[00161] A23. The composition of any of one of Embodiments Al or A3-A22, wherein the

CB1 receptor modulator is a naturally occurring or non-naturally occurring modulator.

[00162] A24. The composition of any of one of Embodiments Al or A3-A23, wherein the

CB1 receptor modulator is a flavonoid.

[00163] A25. The composition of Embodiment A24, wherein the flavonoid is quercetin.

[00164] A26. The composition of any of one of Embodiments A2-A25, wherein the CB2 receptor modulator is present in the ophthalmic composition at a concentration in the range of 0.01 to 5.0 wt.%.

[00165] A27. The composition of any of one of Embodiments A2-A26, wherein the CB2 receptor modulator is present in the ophthalmic composition at a concentration at 0.1 wt. %. [00166] A28. The composition of any of one of Embodiments A2-A27, wherein the CB2 receptor modulator is present in the ophthalmic composition at a concentration at 1.0 wt. %.

[00167] A29. The composition of any of one of Embodiments A2-A28, wherein the CB2 receptor modulator is a CB2 receptor selective modulator.

[00168] A30. The composition of any of one of Embodiments A2-A29, wherein the CB2 receptor modulator is a CB2 receptor full agonist.

[00169] A31. The composition of any of one of Embodiments A2-A30, wherein the CB2 receptor modulator is a CB2 receptor partial agonist.

[00170] A32. The composition of any of one of Embodiments A2-A31, wherein the CB2 receptor modulator is a CB2 receptor positive allosteric modulator.

[00171] A33. The composition of any of one of Embodiments A2-A32, wherein the CB2 receptor modulator is a CB2 receptor antagonist.

[00172] A34. The composition of any of one of Embodiments A2-A33, wherein the CB2 receptor modulator is a CB2 receptor inhibitor.

[00173] A35. The composition of any of one of Embodiments A2-A34, wherein the CB2 receptor modulator is a naturally occurring or non-naturally occurring modulator.

[00174] A36. The composition of any of one of Embodiments A2-A35, wherein the CB2 receptor modulator is a terpene.

[00175] A37. The composition of Embodiment A36, wherein the terpene is betacaryophyllene.

[00176] A38. The composition of any of one of Embodiments A1-A37, wherein the ophthalmic composition is a semisolid preparation, a solution, an emulsion, a suspension, or a colloid.

[00177] A39. The composition of any of one of Embodiments A1-A38, wherein the ophthalmic composition is an ointment, cream, gel, lotion, spray, or eye drop.

[00178] A40. The composition of any of one of the above Embodiments A1-A39, wherein the ophthalmic composition is a delayed-release composition.

[00179] A41. The composition of any of one of Embodiments A1-A40, wherein the ophthalmic composition further comprises petrolatum, one or more essential oils, wax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, propylene glycol monocaprylate, C12-C15 alkyl benzoate, one or more moisturizers, or one or more herbs, or combinations thereof.

[00180] A42. The composition of any of one of Embodiments A1-A41, wherein the ophthalmic composition comprises petrolatum, beeswax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, or propylene glycol monocaprylate, or combinations thereof. [00181] A43. The composition of any of one of Embodiments A1-A42, wherein the ophthalmic composition is for use as a topical treatment released from an ophthalmic device.

[00182] A44. The composition of Embodiments A43, wherein the ophthalmic device is a contact lens.

[00183] A45. The composition of any of one of Embodiments A1-A44, wherein the ophthalmic composition is a transdermal ophthalmic composition.

[00184] A46. The composition of any of one of Embodiments A1-A45, wherein the ophthalmic composition is for use as a transdermal treatment of dry eye disorders.

[00185] Bl. A method for treating an ocular disease or an ocular disorder in a subject, comprising administering the ophthalmic composition of any one of Embodiments A1-A46 on the peri-ocular surface of a subject’s eye, wherein the subject has an ocular disease or an ocular disorder.

[00186] B2. The method of Embodiment Bl, wherein the ocular disease or ocular disorder is a dry eye disorder.

[00187] B3. The method of Embodiment Bl, wherein the ocular disease or ocular disorder is meibomian gland dysfunction (MGD).

[00188] B4. A method for treating contact lens discomfort in an eye of a subj ect, comprising administering the ophthalmic composition of any one of Embodiments A1-A46 on the periocular surface of a subject’s eye, wherein the subject has contact lens discomfort in at least one eye.

[00189] B5. A method for mitigating ocular microbiome dysbiosis in an eye of a subject, comprising administering the ophthalmic composition of any one of Embodiments A1-A46 on the peri-ocular surface of a subject’s eye, wherein the subject has ocular microbiome dysbiosis in at least one eye.

[00190] B6. A method for reducing inflammation in an eye of a subject, comprising administering the ophthalmic composition of any one of Embodiments A1-A46 on the periocular surface of a subject’s eye, wherein the subject has inflammation in at least one eye.

[00191] B7. A method for reducing lipase production in an eye of a subject, comprising administering the ophthalmic composition of any one of Embodiments A1-A46 on the periocular surface of a subject’s eye, wherein the subject has lipase production in at least one eye. [00192] B8. A method for reducing neuropathic pain in an eye of a subject, comprising administering the ophthalmic composition of any one of Embodiments A1-A46 on the periocular surface of a subject’s eye, wherein the subject has neuropathic pain in at least one eye. [00193] B9. A method for increasing wound healing in an eye of a subject, comprising administering the ophthalmic composition of any one of Embodiments A1-A46 on the periocular surface of a subject’s eye, wherein the subject has a wound in at least one eye.

[00194] BIO. A method for providing neuroprotective effects in an eye of a subject, comprising administering the ophthalmic composition of any one of Embodiments A1-A46 on the peri-ocular surface of a subject’s eye, wherein the subject has decreased neuroprotection in at least one eye.

[00195] Bl 1. A method for improving the Ocular Surface Disease Index (OSD I) in an eye of a subject, comprising administering the ophthalmic composition of any one of Embodiments A1-A46 on the peri-ocular surface of a subject’s eye, wherein the subject has a poor OSDI score in at least one eye.

[00196] B12. A method for improving the meibum quality gland expressibility in an eye of a subject, comprising administering the ophthalmic composition of any one of Embodiments A1-A46 on the peri-ocular surface of a subject’s eye, wherein the subject has a poor meibum gland expressibility in at least one eye.

[00197] B13. A method of transdermally delivering a CB1 receptor modulator to an ocular surface comprising administering the ophthalmic composition of any one of Embodiments Al or A3-A46 on the peri-ocular surface of a subject’s eye.

[00198] B14. A method of transdermally delivering a CB2 receptor modulator to an ocular surface comprising administering the ophthalmic composition of any one of Embodiments A2- A46 on the peri-ocular surface of a subject’s eye.

[00199] Bl 5. A method of transdermally delivering a CB1 receptor modulator and a CB2 receptor modulator to an ocular surface comprising administering the ophthalmic composition of any one of Embodiments A3-A46 on the peri-ocular surface of a subject’s eye.

[00200] Bl 6. The method of any one of Embodiments Bl -Bl 5, wherein the ophthalmic composition is administered once daily.

[00201] Bl 7. The method of any one of Embodiments Bl -Bl 6, wherein the ophthalmic composition is administered twice daily.

[00202] B18. The method of any one of Embodiments B1-B17, wherein the ophthalmic composition is administered once in the morning and once at night.

[00203] Bl 9. The method of any one of Embodiments Bl -Bl 8, wherein the ophthalmic composition is administered in one pea-sized amount.

[00204] B20. The method of any one of Embodiments Bl -Bl 9, wherein the ophthalmic composition is administered in two pea-sized amounts. [00205] B21. The method of any one of Embodiments B1-B20, wherein the ophthalmic composition is topically administered to the peri-ocular surface of the subject’s eye.

[00206] B22. The method of any one of Embodiments B1-B21, wherein the ophthalmic composition is administered to the meibomian glands via the peri-ocular surface of the subject’s eye.

[00207] B23. The method of any one of Embodiments B1-B22, wherein the method maintains the ocular microbiome of the subject’s eye.

[00208] B24. The method of any one of Embodiments B1-B23, wherein the method reestablishes equilibrium of the ocular microbiome of the subject’s eye.

[00209] B25. The method of any one of Embodiments B1-B24, wherein the method alters the diversity of the microbiota in said subject’s eye to that of a healthy eye.

[00210] B26. The method of any one of Embodiments B 1-B25, wherein the method further comprises measuring or determining the diversity of microbiota in said subject’s eye prior to the administration step.

[00211] B27. The method of any one of Embodiments B1-B26, wherein the method provides minimal anti -microbial effect to the subject’s eye.

[00212] B28. The method of any one of Embodiments B 1-B27, wherein the method reduces inflammation of the subject’s eye.

[00213] B29. The method of any one of Embodiments B 1-B28, wherein the method further comprises measuring or determining the level of inflammation in said subj ect’ s eye prior to the administration step.

[00214] B30. The method of any one of Embodiments B 1-B29, wherein the method reduces inflammation of the subject’s eye by reducing production of an inflammatory mediator.

[00215] B31. The method of any one of Embodiments B1-B30, wherein the method modulates the level of an inflammatory mediator in the subject’s eye.

[00216] B32. The method of any one of Embodiments B1-B31, wherein the inflammatory mediator is selected from inducible nitric oxide synthase (iNOS), interleukin 1 beta (IL-ip), interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF-a), nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), cyclooxygenase 1 and 2 (COX-1 and COX-2) or peroxisome proliferator-activated receptors alpha (PPAR-a).

[00217] B33. The method of any one of Embodiments Bl -B32, wherein the method further comprises measuring or determining the level of an inflammatory mediator in said subject’s eye prior to the administration step. [00218] B34. The method of any one of Embodiments B 1-B33, wherein the method reduces neuropathic pain of the subject’s eye.

[00219] B35. The method of any one of Embodiments B 1-B34, wherein the method further comprises measuring or determining the level of neuropathic pain in said subject’s eye prior to the administration step.

[00220] B36. The method of any one of Embodiments B1-B35, wherein the method increases wound healing of the subject’s eye.

[00221] B37. The method of any one of Embodiments B 1-B36, wherein the method further comprises measuring or determining the level wound healing in said subject’s eye prior to the administration step.

[00222] B38. The method of any one of Embodiments B1-B37, wherein the method increases lacrimal gland function of the subject’s eye.

[00223] B39. The method of any one of Embodiments B 1-B38, wherein the method further comprises measuring or determining the level of lacrimal gland function in said subject’s eye prior to the administration step.

[00224] B40. The method of any one of Embodiments B 1-B39, wherein the method reduces lipase production in the subject’s eye.

[00225] B41. The method of any one of Embodiments B 1 -B40, wherein the method further comprises measuring or determining the level of lipase production in said subject’s eye prior to the administration step.

[00226] B42. The method of any one of Embodiments B1-B41, wherein the method provides a neuroprotective effect to the subject’s eye.

[00227] B43. The method of any one of Embodiments B 1 -B42, wherein the method further comprises measuring or determining the neuroprotective effect in said subject’s eye prior to the administration step.

[00228] B44. The method of any one of Embodiments B1-B43, wherein the method improves Ocular Surface Disease Index (OSDI) of the subject’s eye.

[00229] B45. The method of any one of Embodiments B 1-B44, wherein the method further comprises measuring or determining an Ocular Surface Disease Index (OSDI) in said subject’s eye prior to the administration step.

[00230] B46. The method of any one of Embodiments B1-B45, wherein the method improves meibum quality gland expressibility. [00231] B47. The method of any one of Embodiments B 1-B46, wherein the method further comprises measuring or determining the meibum quality gland expressibility in said subject’s eye prior to the administration step.

[00232] B48. The method of any one of Embodiments B1-B47, wherein the method modulates a TRPV1 receptor on the ocular surface of the subject’s eye.

[00233] B49. The method of any one of Embodiments B 1-B48, wherein the method further comprises measuring or determining the activity of a TRPV1 receptor on the ocular surface of said subject’s eye prior to the administration step.

[00234] B50. The method of any one of Embodiments B1-B49, wherein the TRPV1 receptor is inhibited by CB1 receptor activation.

[00235] B51. The method of any one of Embodiments B1-B50, wherein the method modulates a 5-HT1A receptor on the ocular surface of the subject’s eye.

[00236] B52. The method of any one of Embodiments B 1-B51, wherein the method further comprises measuring or determining the activity of a 5-HT1 A receptor on the ocular surface of said subject’s eye prior to the administration step.

[00237] B53. The method of any one of Embodiments Bl-B 52, wherein the method reduces a capsaicin-evoked corneal pain response of the subject’s eye.

[00238] B54. The method of any one of Embodiments B 1-B53, wherein the method further comprises measuring or determining a capsaicin-evoked corneal pain response in said subject’s eye prior to the administration step.

[00239] B55. The method of any one of Embodiments B 1-B54, wherein the method reduces neutrophilic infiltration of the subject’s eye.

[00240] B56. The method of any one of Embodiments B 1-B55, wherein the method further comprises measuring or determining the level of neutrophilic infiltration in said subject’s eye prior to the administration step.

[00241] B57. The method of any one of Embodiments B 1-B56, wherein the method reduces a pain score of the subject’s eye.

[00242] B58. The method of any one of Embodiments B 1-B57, wherein the method further comprises measuring or determining a pain score in said subject’s eye prior to the administration step.

[00243] B59. The method of any one of Embodiments B1-B58, wherein the method is effective against Demodex folliculorum infestation. [00244] B60. The method of any one of Embodiments B 1-B59, wherein the method further comprises measuring or determining the level of Demodex folliculorum infestation in said subject’s eye prior to the administration step.

[00245] C 1. A method of preparing the ophthalmic composition of any one of Embodiments Al or A3-A46, comprising combining the lipase inhibitor and the CB1 receptor modulator.

[00246] C2. A method of preparing the ophthalmic composition of any one of Embodiments

A2-A46, comprising combining the lipase inhibitor and the CB2 receptor modulator.

[00247] C3. A method of preparing the ophthalmic composition of any one of Embodiments A3-A46, comprising combining the lipase inhibitor, the CB1 receptor modulator, and the CB2 receptor modulator.

[00248] C4. A method of preparing the ophthalmic composition of any one of Embodiments

A10-A46, comprising combining the lipase inhibitor, the CB1 receptor modulator, the CB2 receptor modulator, and the permeation enhancer.

[00249] C5. The method of any one of Embodiments C1-C4, wherein the method further comprises combining with Epishield ointment.

[00250] C6. The method of any one of Embodiments C1-C5, wherein the method further comprises combining with petrolatum, one or more essential oils, wax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, propylene glycol monocaprylate, C12-C15 alkyl benzoate, one or more moisturizers, or one or more herbs, or combinations thereof.

[00251] C7. The method of any one of Embodiments C1-C6, wherein the method further comprises combining with petrolatum, beeswax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, or propylene glycol monocaprylate, or combinations thereof.

[00252] C8. The method of any one of Embodiments C1-C7, wherein the essential oils may be jojoba, ylang ylang, castor oil, peppermint oil, abies koreana oil, soy bean, sesame oil, olive oil, almond oil, wheat germ oil, com oil, canola oil, or sunflower oil, eucalyptus oil, camphor oil, lavender oil, fennel oil, thyme, mint oil, aloe, rosemary, seabuck, myrrh, eyebright, chamomile, arnica, marigold, echinacea, calendula, tea tree, tea bush, chocolate berry (aronia), ginkgo, ginseng, blueberry, elderberry, lavender, or anise.

Claims

CLAIMS:

1. An ophthalmic composition, comprising a lipase inhibitor and a CB1 receptor modulator.

2. An ophthalmic composition, comprising a lipase inhibitor and a CB2 receptor modulator.

3. An ophthalmic composition, comprising a lipase inhibitor, a CB1 receptor modulator, and a CB2 receptor modulator.

4. The composition of any of one of claims 1-3, wherein the lipase inhibitor is present in the ophthalmic composition at a concentration of 0.1 to 5.0 wt.%.

5. The composition of any of one of claims 1-4, wherein the lipase inhibitor is present in the ophthalmic composition at a concentration of 1.0 wt.%.

6. The composition of any one of claims 1-5, wherein the lipase inhibitor is glycerol monolaurate, myrtenol, Intsia palembanica extracts, or Brazilin.

7. The composition of any one of claims 1-6, wherein the lipase inhibitor enhances transdermal permeation of said composition.

8. The composition of any one of claims 1-7, wherein the lipase inhibitor is GML.

9. The composition of claim 8, wherein the GML is present in the ophthalmic composition at a concentration that maintains the ocular microbiome.

10. The composition of any of one of claims 1-9, wherein the composition further comprises a permeation enhancer.

11. The composition of claim 10, wherein the permeation enhancer is present in the ophthalmic composition at a concentration of 0.1 to 5.0 wt.%.

12. The composition of claims 10-11, wherein the permeation enhancer is present in the ophthalmic composition at a concentration of 1.0 wt.%.

13. The composition of claim 10, wherein the permeation enhancer is present in the ophthalmic composition at a concentration % wt. selected from the group consisting of: 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0 wt. %.

14. The composition of any of one of claims 10-13, wherein the permeation enhancer is glycerol monolaurate (GML), an essential oil, tea tree oil, peppermint oil, eucalyptus oil, Chenopodium, ylang-ylang, L-menthol, oleic acid, sorbitan monooleate, methyl laurate, ethylene vinyl acetate, glycerol monooleate, lauryl acetate, lauryl lactate, myristyl acetate, a sulphoxide, an azone, a pyrrolidone, an alcohol, an alkanol, a glycol, a fatty acid ester, or a fatty alcohol.

15. The composition of any of one of claims 1 or 3-14, wherein the CB1 receptor modulator is present in the ophthalmic composition at a concentration of 0.02 to 5.0 wt.%.

16. The composition of any of one of claims 1 or 3-15, wherein the CB1 receptor modulator is present in the ophthalmic composition at a concentration of 0.5 wt.%.

17. The composition of any of one of claims 1 or 3-16, wherein the CB1 receptor modulator is a CB1 receptor selective modulator.

18. The composition of any of one of claims 1 or 3-16, wherein the CB1 receptor modulator is a CB1 receptor full agonist.

The composition of any of one of claims 1 or 3-16, wherein the CB1 receptor modulator is a CB1 receptor partial-agonist.

20. The composition of any of one of claims 1 or 3-16, wherein the CB1 receptor modulator is a CB1 receptor positive allosteric modulator.

21. The composition of any of one of claims 1 or 3-16, wherein the CB1 receptor modulator is a CB1 receptor antagonist.

22. The composition of any of one of claims 1 or 3-16, wherein the CB1 receptor modulator is a CB1 receptor inhibitor.

23. The composition of any of one of claims 1 or 3-22, wherein the CB1 receptor modulator is a naturally occurring or non-naturally occurring modulator.

24. The composition of any of one of claims 1 or 3-23, wherein the CB1 receptor modulator is a flavonoid.

25. The composition of claim 24, wherein the flavonoid is quercetin.

26. The composition of any of one of claims 2-25, wherein the CB2 receptor modulator is present in the ophthalmic composition at a concentration in the range of 0.01 to 5.0 wt.%.

27. The composition of any of one of claims 2-26, wherein the CB2 receptor modulator is present in the ophthalmic composition at a concentration at 0.1 wt. %.

28. The composition of any of one of claims 2-27, wherein the CB2 receptor modulator is present in the ophthalmic composition at a concentration at 1.0 wt. %.

29. The composition of any of one of claims 2-28, wherein the CB2 receptor modulator is a CB2 receptor selective modulator.

30. The composition of any of one of claims 2-29, wherein the CB2 receptor modulator is a CB2 receptor full agonist.

31. The composition of any of one of claims 2-30, wherein the CB2 receptor modulator is a CB2 receptor partial agonist.

32. The composition of any of one of claims 2-31, wherein the CB2 receptor modulator is a CB2 receptor positive allosteric modulator.

33. The composition of any of one of claims 2-32, wherein the CB2 receptor modulator is a CB2 receptor antagonist.

34. The composition of any of one of claims 2-33, wherein the CB2 receptor modulator is a CB2 receptor inhibitor.

35. The composition of any of one of claims 2-34, wherein the CB2 receptor modulator is a naturally occurring or non-naturally occurring modulator.

36. The composition of any of one of claims 2-35, wherein the CB2 receptor modulator is a terpene.

37. The composition of claim 36, wherein the terpene is beta-caryophyllene.

38. The composition of any of one of claims 1-37, wherein the ophthalmic composition is a semisolid preparation, a solution, an emulsion, a suspension, or a colloid.

39. The composition of any of one of claims 1-38, wherein the ophthalmic composition is an ointment, cream, gel, lotion, spray, or eye drop.

40. The composition of any of one of the above claims 1-39, wherein the ophthalmic composition is a delayed-release composition.

41. The composition of any of one of claims 1-40, wherein the ophthalmic composition further comprises petrolatum, one or more essential oils, wax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, propylene glycol monocaprylate, C12-C15 alkyl benzoate, one or more moisturizers, or one or more herbs, or combinations thereof.

42. The composition of any of one of claims 1-41, wherein the ophthalmic composition comprises petrolatum, beeswax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, or propylene glycol monocaprylate, or combinations thereof.

43. The composition of any of one of claims 1-42, wherein the ophthalmic composition is for use as a topical treatment released from an ophthalmic device.

44. The composition of claims 43, wherein the ophthalmic device is a contact lens.

45. The composition of any of one of claims 1-44, wherein the ophthalmic composition is a transdermal ophthalmic composition.

46. The composition of any of one of claims 1-45, wherein the ophthalmic composition is for use as a transdermal treatment of dry eye disorders.

47. A method for treating an ocular disease or an ocular disorder in a subject, comprising administering the ophthalmic composition of any one of claims 1-46 on the periocular surface of a subj ect’ s eye, wherein the subj ect has an ocular disease or an ocular disorder.

48. The method of claim 47, wherein the ocular disease or ocular disorder is a dry eye disorder.

49. The method of claim 47, wherein the ocular disease or ocular disorder is meibomian gland dysfunction (MGD).

50. A method for treating contact lens discomfort in an eye of a subject, comprising administering the ophthalmic composition of any one of claims 1-46 on the peri-ocular surface of a subject’s eye, wherein the subject has contact lens discomfort in at least one eye.

51. A method for mitigating ocular microbiome dysbiosis in an eye of a subject, comprising administering the ophthalmic composition of any one of claims 1-46 on the periocular surface of a subject’s eye, wherein the subject has ocular microbiome dysbiosis in at least one eye.

52. A method for reducing inflammation in an eye of a subject, comprising administering the ophthalmic composition of any one of claims 1-46 on the peri-ocular surface of a subject’s eye, wherein the subject has inflammation in at least one eye.

53. A method for reducing lipase production in an eye of a subject, comprising administering the ophthalmic composition of any one of claims 1-46 on the peri-ocular surface of a subject’s eye, wherein the subject has lipase production in at least one eye.

54. A method for reducing neuropathic pain in an eye of a subject, comprising administering the ophthalmic composition of any one of claims 1-46 on the peri-ocular surface of a subject’s eye, wherein the subject has neuropathic pain in at least one eye.

55. A method for increasing wound healing in an eye of a subject, comprising administering the ophthalmic composition of any one of claims 1-46 on the peri-ocular surface of a subject’s eye, wherein the subject has a wound in at least one eye.

56. A method for providing neuroprotective effects in an eye of a subject, comprising administering the ophthalmic composition of any one of claims 1-46 on the periocular surface of a subject’s eye, wherein the subject has decreased neuroprotection in at least one eye.

57. A method for improving the Ocular Surface Disease Index (OSDI) in an eye of a subject, comprising administering the ophthalmic composition of any one of claims 1-46 on the peri-ocular surface of a subject’s eye, wherein the subject has a poor OSDI score in at least one eye.

58. A method for improving the meibum quality gland expressibility in an eye of a subject, comprising administering the ophthalmic composition of any one of claims 1-46 on the peri-ocular surface of a subject’s eye, wherein the subject has a poor meibum gland expressibility in at least one eye.

59. A method of transdermally delivering a CB1 receptor modulator to an ocular surface comprising administering the ophthalmic composition of any one of claims 1 or 3-46 on the peri-ocular surface of a subject’s eye.

60. A method of transdermally delivering a CB2 receptor modulator to an ocular surface comprising administering the ophthalmic composition of any one of claims 2-46 on the peri-ocular surface of a subject’s eye.

61. A method of transdermally delivering a CB1 receptor modulator and a CB2 receptor modulator to an ocular surface comprising administering the ophthalmic composition of any one of claims 3-46 on the peri-ocular surface of a subject’s eye.

62. The method of any one of claims 47-61, wherein the ophthalmic composition is administered once daily.

63. The method of any one of claims 47-62, wherein the ophthalmic composition is administered twice daily.

64. The method of any one of claims 47-63, wherein the ophthalmic composition is administered once in the morning and once at night.

65. The method of any one of claims 47-64, wherein the ophthalmic composition is administered in one pea-sized amount.

66. The method of any one of claims 47-65, wherein the ophthalmic composition is administered in two pea-sized amounts.

67. The method of any one of claims 47-66, wherein the ophthalmic composition is topically administered to the peri-ocular surface of the subject’s eye.

68. The method of any one of claims 47-67, wherein the ophthalmic composition is administered to the meibomian glands via the peri-ocular surface of the subject’s eye.

69. The method of any one of claims 47-68, wherein the method maintains the ocular microbiome of the subject’s eye.

70. The method of any one of claims 47-69, wherein the method reestablishes equilibrium of the ocular microbiome of the subject’s eye.

71. The method of any one of claims 47-70, wherein the method alters the diversity of the microbiota in said subject’s eye to that of a healthy eye.

72. The method of any one of claims 47-71, wherein the method further comprises measuring or determining the diversity of microbiota in said subject’s eye prior to the administration step.

73. The method of any one of claims 47-72, wherein the method provides minimal anti-microbial effect to the subject’s eye.

74. The method of any one of claims 47-73, wherein the method reduces inflammation of the subject’s eye.

75. The method of any one of claims 47-74, wherein the method further comprises measuring or determining the level of inflammation in said subject’s eye prior to the administration step.

76. The method of any one of claims 47-75, wherein the method reduces inflammation of the subject’s eye by reducing production of an inflammatory mediator.

77. The method of any one of claims 47-76, wherein the method modulates the level of an inflammatory mediator in the subject’s eye.

78. The method of any one of claims 47-77, wherein the inflammatory mediator is selected from inducible nitric oxide synthase (iNOS), interleukin 1 beta (IL-1 P), interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF-a), nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), cyclooxygenase 1 and 2 (COX-1 and COX-2) or peroxisome proliferator-activated receptors alpha (PPAR-a).

79. The method of any one of claims 47-78, wherein the method further comprises measuring or determining the level of an inflammatory mediator in said subject’s eye prior to the administration step.

80. The method of any one of claims 47-79, wherein the method reduces neuropathic pain of the subject’s eye.

81. The method of any one of claims 47-80, wherein the method further comprises measuring or determining the level of neuropathic pain in said subject’s eye prior to the administration step.

82. The method of any one of claims 47-81, wherein the method increases wound healing of the subject’s eye.

83. The method of any one of claims 47-82, wherein the method further comprises measuring or determining the level wound healing in said subject’s eye prior to the administration step.

84. The method of any one of claims 47-83, wherein the method increases lacrimal gland function of the subject’s eye.

85. The method of any one of claims 47-84, wherein the method further comprises measuring or determining the level of lacrimal gland function in said subject’s eye prior to the administration step.

86. The method of any one of claims 47-85, wherein the method reduces lipase production in the subject’s eye.

87. The method of any one of claims 47-86, wherein the method further comprises measuring or determining the level of lipase production in said subject’s eye prior to the administration step.

88. The method of any one of claims 47-87, wherein the method provides a neuroprotective effect to the subject’s eye.

89. The method of any one of claims 47-88, wherein the method further comprises measuring or determining the neuroprotective effect in said subject’s eye prior to the administration step.

90. The method of any one of claims 47-89, wherein the method improves Ocular

Surface Disease Index (OSDI) of the subject’s eye.

91. The method of any one of claims 47-90, wherein the method further comprises measuring or determining an Ocular Surface Disease Index (OSDI) in said subject’s eye prior to the administration step.

92. The method of any one of claims 47-91, wherein the method improves meibum quality gland expressibility.

93. The method of any one of claims 47-92, wherein the method further comprises measuring or determining the meibum quality gland expressibility in said subject’s eye prior to the administration step.

94. The method of any one of claims 47-93, wherein the method modulates a TRPV1 receptor on the ocular surface of the subject’s eye.

95. The method of any one of claims 47-94, wherein the method further comprises measuring or determining the activity of a TRPV1 receptor on the ocular surface of said subject’s eye prior to the administration step.

96. The method of any one of claims 47-95, wherein the TRPV1 receptor is inhibited by CB1 receptor activation.

97. The method of any one of claims 47-96, wherein the method modulates a 5- HT1 A receptor on the ocular surface of the subject’s eye.

98. The method of any one of claims 47-97, wherein the method further comprises measuring or determining the activity of a 5-HT1A receptor on the ocular surface of said subject’s eye prior to the administration step.

99. The method of any one of claims 47-98, wherein the method reduces a capsaicin-evoked corneal pain response of the subject’s eye.

100. The method of any one of claims 47-99, wherein the method further comprises measuring or determining a capsaicin-evoked corneal pain response in said subject’s eye prior to the administration step.

101. The method of any one of claims 47-100, wherein the method reduces neutrophilic infiltration of the subject’s eye.

102. The method of any one of claims 47-101, wherein the method further comprises measuring or determining the level of neutrophilic infiltration in said subject’s eye prior to the administration step.

103. The method of any one of claims 47-101, wherein the method reduces a pain score of the subject’s eye.

104. The method of any one of claims 47-103, wherein the method further comprises measuring or determining a pain score in said subject’s eye prior to the administration step.

105. The method of any one of claims 47-104, wherein the method is effective against Demodex folliculorum infestation.

106. The method of any one of claims 47-105, wherein the method further comprises measuring or determining the level of Demodex folliculorum infestation in said subject’s eye prior to the administration step.

107. A method of preparing the ophthalmic composition of any one of claims 1 or 3- 46, comprising combining the lipase inhibitor and the CB1 receptor modulator.

108. A method of preparing the ophthalmic composition of any one of claims 2-46, comprising combining the lipase inhibitor and the CB2 receptor modulator.

109. A method of preparing the ophthalmic composition of any one of claims 3-46, comprising combining the lipase inhibitor, the CB1 receptor modulator, and the CB2 receptor modulator.

110. A method of preparing the ophthalmic composition of any one of claims 10-46, comprising combining the lipase inhibitor, the CB1 receptor modulator, the CB2 receptor modulator, and the permeation enhancer.

111. The method of any one of claims 107-110, wherein the method further comprises combining with Epishield ointment.

112. The method of any one of claims 107-111, wherein the method further comprises combining with petrolatum, one or more essential oils, wax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, propylene glycol monocaprylate, C12-C15 alkyl benzoate, one or more moisturizers, or one or more herbs, or combinations thereof.

113. The method of any one of claims 107-112, wherein the method further comprises combining with petrolatum, beeswax, lanolin, cetyl alcohol, lactic acid, diethyl sebacate, DMSO, or propylene glycol monocaprylate, or combinations thereof.

114. The method of any one of claims 107-113, wherein the essential oils may be jojoba, ylang ylang, castor oil, peppermint oil, abies koreana oil, soy bean, sesame oil, olive oil, almond oil, wheat germ oil, com oil, canola oil, or sunflower oil, eucalyptus oil, camphor oil, lavender oil, fennel oil, thyme, mint oil, aloe, rosemary, seabuck, myrrh, eyebright, chamomile, arnica, marigold, echinacea, calendula, tea tree, tea bush, chocolate berry (aronia), ginkgo, ginseng, blueberry, elderberry, lavender, or anise.