Compositions and methods of use for treating abnormal inflammation in periocular glands or at the ocular surface

Abstract

To provide: pharmaceutical compositions adapted for the periocular transdermal delivery of one or more lipophilic compounds; methods of use thereof; and kits comprising such pharmaceutical compositions.SOLUTION: Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a lipophilic compound and a pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of the lipophilic compound to one or more periorbital glands and / or the ocular surface tissues of a subject. Further provided herein are methods of using such pharmaceutical compositions for providing relief of one or more signs or symptoms of an ocular disease, methods of using one or more Meibomian glands (and meibum therein) as a drug delivery system for a lipophilic compound (e.g., a steroid) to the ocular surface, and kits related thereto.SELECTED DRAWING: Figure 6

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 589,493, filed November 21, 2017, entitled "COMPOSITIONS AND METHODS OF USE FOR TREATING ABERRANT INFLAMMATION IN PERI-OCULAR SECRETORY GLANDS OR AT THE OCULAR SURFACE," the contents of which are incorporated by reference in their entirety.

[0002] FIELD OF THE INVENTION The present disclosure relates to pharmaceutical compositions adapted for periocular transdermal delivery of one or more lipophilic compounds; methods of use thereof; and kits containing such pharmaceutical compositions. [Background technology]

[0003] background Topical eye drops have become the delivery method of choice for eye care practitioners, especially for diseases such as dry eye, uveitis, bacterial conjunctivitis, and glaucoma, because the ocular surface is considered the primary target tissue for drug delivery. When eye drops enter the eye, three segments of the anterior segment (i.e., the cornea, conjunctiva, and sclera) serve as pathways for drug absorption, with the cornea being the primary route for ocular penetration. Eye drops are recognized to have significant advantages over other delivery methods, including minimizing adverse systemic effects and avoiding first-pass metabolism, which limits the concentration of drug that ultimately reaches target tissues (Abelson et al., 2012).

[0004] However, topical eye drops have several drawbacks: (1) they are physically difficult for patients to administer; (2) there are physical and physiological barriers that protect the eye and significantly reduce the amount of drug delivered (e.g., low corneal permeability, blink reflex, and tear turnover); and (3) epithelial tight junctions impede the diffusion of larger molecules.

[0005] The lacrimal glands are a pair of exocrine glands, one for each eye. They are located in the superior lateral portion of each orbit, in the lacrimal fossa formed by the frontal bone. The lacrimal glands are the main contributors to the aqueous layer of the tear film. The meibomian glands are sebaceous glands in the eyelids, within the tarsal plate, that provide meibum, which prevents evaporation of the eye's tear film.

[0006] Disruption of normal lacrimal and meibomian gland function can result in aqueous-deficient and / or evaporative forms of dry eye disease (DED), as well as numerous "plus" inflammatory ocular diseases, such as exacerbated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, and anterior blepharitis (see, e.g., the Tear Film and Ocular Surface Society 2011 report on meibomian gland dysfunction (MGD); Nichols et al., 2011). Dry eye disease is a multifactorial disorder of the ocular surface characterized by loss of tear film homeostasis and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neuronal sensory abnormalities play a pathogenetic role (Craig et al., 2017). Regardless of what initiated a patient's DED (e.g., allergic eye disease, topical preservative toxicity, or xerophthalmia), the patient ultimately enters into a series of inflammatory events that perpetuate the disease. This inflammatory response can infiltrate the gland itself. Indeed, tear dysfunction occurs when the lacrimal functional unit (LFU), comprised of the lacrimal gland, the ocular surface, and the sensory and motor nerves connecting these tissues, is no longer able to maintain a stable precorneal tear film (Beuerman et al., 1998; Stern et al., 1998a; Stern et al., 1998b). Disease or dysfunction of one or more components of the LFU can result in an altered tear film. While the etiology of DED is multifactorial, ample evidence supports the hypothesis that signs and symptoms are driven by inflammation of one or more components of the LFU.

[0007] Corticosteroid pharmacology targets inflammatory mediators underlying the signs and symptoms of DED. Numerous studies and reports support the short-term use of topical corticosteroid eye drops in treating patients with DED (Avunduk et al., 2003; DEWS, 2007; Pflugfelder et al., 1999; Yang et al., 2006). However, topical ocular corticosteroids administered as eye drops are generally recommended only for short-term use because long-term use can result in ocular adverse events, including elevated intraocular pressure (IOP), cataracts, and ocular infections (Becker, 1964; Bowling and Russell, 2011; Dinning, 1976).

[0008] Although steroid ointments / creams are widely prescribed to control long-term or chronic non-ocular inflammatory conditions (due to their poor penetration / penetration), the long-term use of current steroid ointment / cream formulations on or near the eye is strongly discouraged because ocular use of these formulations can induce serious adverse events, such as elevated IOP (which can lead to ocular hypertension or glaucoma or can cause blindness), posterior subcapsular cataract, delayed corneal epithelial healing, corticosteroid uveitis, mydriasis and ptosis, infection, and other possible side effects (e.g., transient ocular discomfort, steroid-induced calcification, etc.). In fact, topical application of a typical dexamethasone ointment formulation to the eyelids of children has been shown to acutely elevate IOP. "Hypertensive reactions after application of dexamethasone ointment to the eyelids frequently occurred in children, especially those under 5 years of age" (Lee et al., Korean J Ophthalmol. 2006 Sep;20(3):166-70, p. 166). Thus, there is a lack of suitable steroid formulations / administration routes for long-term or even chronic treatment of ocular inflammatory conditions.

[0009] All references cited herein, including patent applications, patent publications, and non-patent literature, are incorporated by reference in their entirety as if each individual reference was specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0010] overview To meet these and other needs, the present disclosure provides pharmaceutical compositions adapted for periocular transdermal delivery of one or more lipophilic compounds. In some embodiments, the pharmaceutical compositions are adapted for periocular transdermal delivery and significantly enhance the ocular safety of the delivered lipophilic compounds by: (1) reducing the concentration of permeation enhancers in the pharmaceutical composition compared to the concentrations used in standard ointments / creams or ophthalmic formulations; (2) using permeation enhancers (not typically found in topical steroid ointment / cream formulations) (e.g., Tween-80) that are suitable for percutaneous delivery of compounds into the eyelid; (3) formulating the pharmaceutical composition to achieve improved spreadability on the periocular surface compared to ointment bases; and (4) formulating the pharmaceutical composition to avoid flow from the periocular surface onto the corneal surface. (5) the use of novel steroids, such as the compounds of Formula I, which have been specifically developed to enable the glucocorticoid receptor to transrepress gene activation with little or no transactivation, to reduce the side effects of glucocorticoids thought to be mediated by transactivation; (6) the use of the meibomian glands, meibum, and other fatty structures in the eyelid as drug depots for lipophilic compounds for sustained delivery to the ocular surface; and / or (7) the use of the meibomian glands and meibum as novel drug delivery systems for pharmaceutical formulations of lipophilic compounds applied periocularly to the outside of the upper and / or lower eyelids. Thus, the present disclosure relates, in part, to a safer method for treating ocular surface conditions and periocular glands and within the eyelids by transdermal administration of pharmaceutical formulations as described herein (e.g., via topical application of the formulation to the outside of the upper and / or lower eyelid) to deliver therapeutically active concentrations of lipophilic compounds to the meibomian glands, lacrimal glands, accessory lacrimal glands, and the ocular surface. Without wishing to be bound by theory, it is believed that lipophilic compounds (e.g., steroids) preferentially accumulate / distribute in lipid-producing (e.g., meibum) periocular glands (e.g., meibomian glands) and other fatty / lipophilic structures in the eyelids.Thus, the present disclosure is believed to provide a novel therapeutic strategy for treating inflammation within the tear functional unit (LFU), other ocular inflammatory diseases, ocular bacterial infections, glaucoma, and ocular hypertension by delivering antiglaucoma agents, antibiotics, and other lipophilic compounds via transdermal periocular delivery that reduces or avoids some or all of the adverse events associated with the use of standard topical formulations in ophthalmic settings, such as elevated IOP, BAK hypersensitivity, and precorneal tear film breakdown (e.g., blurred vision). Furthermore, the present disclosure is believed to provide a novel strategy for longer-term / chronic ophthalmic therapy than can be used with current short-term topical ocular regimens (e.g., corticosteroids).

[0011] Thus, in one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a lipophilic compound and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the lipophilic compound to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a lipophilic compound and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the lipophilic compound to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periocular delivery. In some embodiments, the lipophilic compound is not delivered systemically to the subject. In some embodiments, the lipophilic compound is not delivered to the subject's tears or tear duct. In some embodiments, the lipophilic compound is not delivered by direct application to the subject's ocular surface. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, the one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof. In some embodiments, the lipophilic compound is delivered to the ocular surface of the subject via the meibomian glands and meibum, hi some embodiments, the lipophilic compound is selected from the group consisting of a steroid, an antibiotic, an immunomodulatory agent, an integrin antagonist, an anti-inflammatory agent, and an anti-glaucoma or ocular anti-hypertension agent.

[0012] In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a steroid and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the steroid to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In some embodiments, the pharmaceutical composition is specifically formulated for periocular delivery. In some embodiments, the steroid is not delivered systemically to the subject. In some embodiments, the steroid is not delivered to the subject's tears or tear ducts. In some embodiments, the steroid is not delivered by direct application to the subject's ocular surface. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, the one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof. In some embodiments, the steroid is delivered to the subject's ocular surface via the meibomian glands and meibum.

[0013] The steroid can be any steroid. In some embodiments that may be combined with any of the preceding embodiments, the steroid is selected from the compound of Formula I, fluocinolone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and ester derivatives thereof. In some embodiments, the steroid is selected from the compound of Formula I, difluprednate, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, and ester derivatives thereof. In some embodiments, the steroid is a compound of Formula I. In some embodiments, the pharmaceutical composition comprises a steroid at a concentration of 0.001% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises a steroid at a concentration of 0.01% to 2% w / w.

[0014] In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of an antibiotic and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the antibiotic to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of an antibiotic and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the antibiotic to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periocular delivery. In some embodiments, the antibiotic is not delivered systemically to the subject. In some embodiments, the antibiotic is not delivered to the subject's tears or tear ducts. In some embodiments, the antibiotic is not delivered by direct application to the subject's ocular surface. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, the one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof. In some embodiments, the antibiotic is delivered to the subject's ocular surface via the meibomian glands and meibum.

[0015] The antibiotic can be any antibiotic. In some embodiments, the antibiotic is selected from the group consisting of sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, and tetracyclines. In some embodiments, the antibiotic is selected from the group consisting of azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxifloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, and sulfacetamide. In some embodiments, the pharmaceutical composition comprises the antibiotic at a concentration of 0.01% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises the antibiotic at a concentration of 0.1% to 2% w / w.

[0016] In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of an immunomodulatory agent and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the immunomodulatory agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of an immunomodulatory agent and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the immunomodulatory agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periocular delivery. In some embodiments, the immunomodulatory agent is not delivered systemically to the subject. In some embodiments, the immunomodulatory agent is not delivered to the subject's tears or tear duct. In some embodiments, the immunomodulatory agent is not delivered by direct application to the subject's ocular surface. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, the one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof. In some embodiments, the immunomodulatory agent is delivered to the ocular surface of the subject via the meibomian glands and meibum.

[0017] The immunomodulatory agent can be any immunomodulatory agent. In some embodiments, the immunomodulatory agent is selected from the group consisting of a calcineurin inhibitor and a thalidomide analog. In some embodiments, the immunomodulatory agent is selected from the group consisting of cyclosporin A, voclosporin, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide. In some embodiments, the immunomodulatory agent is cyclosporin A. In some embodiments, the pharmaceutical composition comprises an immunomodulatory agent at a concentration of 0.01% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises an immunomodulatory agent at a concentration of 0.1% to 2% w / w.

[0018] In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of an integrin antagonist and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the integrin antagonist to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of an integrin antagonist and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the integrin antagonist to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periocular delivery. In some embodiments, the integrin antagonist is not delivered systemically to the subject. In some embodiments, the integrin antagonist is not delivered to the subject's tears or tear ducts. In some embodiments, the integrin antagonist is not delivered by direct application to the subject's ocular surface. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, the one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof. In some embodiments, the integrin antagonist is delivered to the ocular surface of the subject via the meibomian glands and meibum.

[0019] The integrin antagonist can be any integrin antagonist. In some embodiments, the integrin antagonist is selected from the group consisting of lifitegrast and GW559090, and ester derivatives thereof. In some embodiments, the pharmaceutical composition comprises the integrin antagonist at a concentration of 0.01% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises the integrin antagonist at a concentration of 0.1% to 5% w / w.

[0020] In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of an anti-inflammatory agent and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the anti-inflammatory agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of an anti-inflammatory agent and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the anti-inflammatory agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periocular delivery. In some embodiments, the anti-inflammatory agent is not delivered systemically to the subject. In some embodiments, the anti-inflammatory agent is not delivered to the subject's tears or tear duct. In some embodiments, the anti-inflammatory agent is not delivered by direct application to the subject's ocular surface. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, the one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof. In some embodiments, the anti-inflammatory agent is delivered to the ocular surface of the subject via the meibomian glands and meibum.

[0021] The anti-inflammatory agent can be any anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is selected from the group consisting of omega-3 fatty acids and nonsteroidal anti-inflammatory drugs (NSAIDs). In some embodiments, the omega-3 fatty acids are selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combination thereof. In some embodiments, the NSAID is selected from the group consisting of bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and any combination thereof. In some embodiments, the anti-inflammatory agent is selected from flurbiprofen and ketorolac. In some embodiments, the pharmaceutical composition comprises the anti-inflammatory agent at a concentration of 0.001% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises the anti-inflammatory agent at a concentration of 0.1% to 2% w / w.

[0022] In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of an anti-glaucoma or anti-ocular hypertension agent and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the anti-glaucoma or anti-ocular hypertension agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of an anti-glaucoma or anti-ocular hypertension agent and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the anti-glaucoma or anti-ocular hypertension agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periocular delivery. In some embodiments, the anti-glaucoma or anti-ocular hypertension agent is not delivered systemically to the subject. In some embodiments, the anti-glaucoma or anti-ocular hypertension agent is not delivered to the subject's tears or tear duct. In some embodiments, the anti-glaucoma or anti-ocular hypertension agent is not delivered by direct application to the subject's ocular surface. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, the one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof. In some embodiments, the anti-glaucoma agent or anti-ocular hypertension agent is delivered to the subject's ocular surface via the meibomian glands and meibum.

[0023] Anti-glaucoma or anti-ocular hypertension agent can be any anti-glaucoma or anti-ocular hypertension agent.In some embodiments, anti-glaucoma or anti-ocular hypertension agent is selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, latanoprostene bunod, timolol, betaxolol, levobunolol, dorzolamide, brinzolamide and acetazolamide.In some embodiments, anti-glaucoma or anti-ocular hypertension agent is selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, latanoprostene bunod, timolol, betaxolol, levobunolol, metipranolol, brimonidine, clonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, methazolamide, netarsudil and any combination thereof. In some embodiments, the anti-glaucoma agent is selected from bimatoprost, latanoprost, travoprost, brimonidine, brinzolamide, netarsudil, and timolol. In some embodiments, the anti-glaucoma agent is bimatoprost. In some embodiments, the pharmaceutical composition comprises the anti-glaucoma agent at a concentration of 0.0001% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises the anti-glaucoma agent or anti-ocular hypertension agent at a concentration of 0.01% to 2% w / w.

[0024] In some embodiments that can be combined with any of the preceding embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of an additional steroid. In some embodiments, the additional steroid is selected from the compound of Formula I, fluocinolone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and its ester derivatives. In some embodiments, the lipophilic compound and the additional steroid are different.

[0025] In some embodiments that may be combined with any of the preceding embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more antibiotics. In some embodiments, the one or more antibiotics are selected from sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, tetracyclines, and any combination thereof. In some embodiments, the one or more antibiotics are selected from azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxifloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, sulfacetamide, and any combination thereof. In some embodiments, the one or more antibiotics are selected from azithromycin, gentamicin, tobramycin, bacitracin, besifloxacin, gatifloxacin, moxifloxacin, chloramphenicol, and doxycycline. In some embodiments, the pharmaceutical composition comprises one or more antibiotics at a concentration of 0.01% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises one or more antibiotics at a concentration of 0.1% to 2% w / w. In some embodiments, the lipophilic compound and the one or more antibiotics are different.

[0026] In some embodiments that may be combined with any of the preceding embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more immunomodulatory agents. In some embodiments, the one or more immunomodulatory agents are selected from a calcineurin inhibitor, a thalidomide analog, and any combination thereof. In some embodiments, the one or more immunomodulatory agents are selected from cyclosporin A, voclosporin, tacrolimus, pimecrolimus, thalidomide, lenalidomide, pomalidomide, and any combination thereof. In some embodiments, the immunomodulatory agent is cyclosporin A. In some embodiments, the pharmaceutical composition comprises one or more immunomodulatory agents at a concentration of 0.01% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises one or more immunomodulatory agents at a concentration of 0.1% to 2% w / w. In some embodiments, the lipophilic compound and the one or more immunomodulatory agents are different.

[0027] In some embodiments that may be combined with any of the preceding embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more integrin antagonists. In some embodiments, the one or more integrin antagonists are selected from lifitegrast, GW559090, ester derivatives thereof, and any combination thereof. In some embodiments, the integrin antagonist is GW559090. In some embodiments, the pharmaceutical composition comprises one or more integrin antagonists at a concentration of 0.01% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises one or more integrin antagonists at a concentration of 0.1% to 5% w / w. In some embodiments, the lipophilic compound and the one or more integrin antagonists are different.

[0028] In some embodiments that may be combined with any of the preceding embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more anti-inflammatory agents. In some embodiments, the one or more anti-inflammatory agents are selected from omega-3 fatty acids, nonsteroidal anti-inflammatory drugs (NSAIDs), and any combination thereof. In some embodiments, the omega-3 fatty acids are selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combination thereof. In some embodiments, the NSAIDs are selected from bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and any combination thereof. In some embodiments, the one or more anti-inflammatory agents are selected from flurbiprofen and ketorolac. In some embodiments, the pharmaceutical composition comprises one or more anti-inflammatory agents at a concentration of 0.001% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises one or more anti-inflammatory agents at a concentration of 0.1% to 2% w / w. In some embodiments, the lipophilic compound and the one or more anti-inflammatory agents are different.

[0029] In some embodiments that can be combined with any of the above-mentioned embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more antiglaucoma drugs or anti-ocular hypertension drugs.In some embodiments, one or more antiglaucoma drugs or anti-ocular hypertension drugs are selected from bimatoprost, latanoprost, travoprost, tafluprost, latanoprost, timolol, betaxolol, levobunolol, metipranolol, brimonidine, clonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, methazolamide, netarsudil, and any combination thereof.In some embodiments, the antiglaucoma drug or anti-ocular hypertension drug is selected from bimatoprost, latanoprost, travoprost, brimonidine, brinzolamide, netarsudil, and timolol.In some embodiments, the antiglaucoma drug is bimatoprost. In some embodiments, the pharmaceutical composition comprises one or more anti-glaucoma or anti-ocular hypertension agents at a concentration of 0.0001% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises one or more anti-glaucoma or anti-ocular hypertension agents at a concentration of 0.01% to 2% w / w. In some embodiments, the lipophilic compound and the one or more anti-glaucoma or anti-ocular hypertension agents are different.

[0030] In some embodiments that may be combined with any of the preceding embodiments, the pharmaceutically acceptable carrier is selected from an ointment, cream, lotion, gel, emulsion, suspension, oil, foam, transdermal patch, spray, and any combination thereof. In some embodiments, the pharmaceutically acceptable carrier is an ointment. In some embodiments, the ointment comprises a paraffinic or water-miscible ointment base. In some embodiments, the ointment comprises 61.5% w / w white soft paraffin, 8% w / w mineral oil, 8% w / w propylene glycol, 5% w / w St. cyclomethicone-5NF, 5% w / w labrasol, 5% w / w propylene carbonate, 2.5% w / w steareth 2, 2.5% w / w St. emulsifier 10, and 2.5% w / w St. elastomer-10. In some embodiments, the pharmaceutically acceptable carrier is a cream. In some embodiments, the cream comprises an oil-in-water base or a water-in-oil base, 48% w / w soft paraffin, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w ST-emulsifier-10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w dibasic sodium phosphate, 0.05% w / w citric acid, 0.02% w / w propylparaben, and an appropriate amount of purified water. In some embodiments, the cream comprises 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, 0.02% w / w propylparaben, and an appropriate amount of purified water.In some embodiments, the cream comprises 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, 0.02% w / w benzalkonium chloride, and an appropriate amount of purified water. In some embodiments, the cream comprises 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, and an appropriate amount of purified water, and is preservative-free.

[0031] In some embodiments, the one or more active pharmaceutical ingredients are incorporated at a desired final concentration (w / w) into a cream vehicle composed of 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, 0.02% w / w propylparaben, and an appropriate amount of purified water. In some embodiments, the cream vehicle comprises 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, 0.02% w / w benzalkonium chloride, and an appropriate amount of purified water. In some embodiments, the cream vehicle comprises 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, and an appropriate amount of purified water, and is preservative-free.

[0032] In some embodiments, one or more active pharmaceutical ingredients are incorporated at a desired final concentration by substituting an equal amount of white petrolatum or paraffin (w / w). For example, one such embodiment contains 46% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, 0.02% w / w propylparaben, 2% w / w compound of Formula I, and an appropriate amount of purified water. Another such embodiment is preservative-free and comprises 46% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, 2% w / w compound of formula I, and a q.s. of purified water.

[0033] In some embodiments, the pharmaceutical composition comprises a lipophilic compound at a concentration of about 0.001% to about 10% weight / weight (w / w), about 0.0001% to about 10% weight / weight (w / w), or about 0.0001% to about 5% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises a lipophilic compound at a concentration of about 0.01% to about 2% w / w.

[0034] In some embodiments, the pharmaceutically acceptable carrier comprises benzalkonium chloride (BAK). In some embodiments, the pharmaceutically acceptable carrier comprises 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.06% w / w anhydrous dibasic sodium phosphate, 0.05% w / w anhydrous citric acid, 0.02% w / w benzalkonium chloride, and purified water. In some embodiments, the pharmaceutically acceptable carrier is preservative-free. In some embodiments, the pharmaceutically acceptable carrier comprises white soft paraffin / petrolatum, mineral oil, propylene glycol, ST-cyclomethicone-5NF, ST-emulsifier-10, ST-elastomer-10, dibasic sodium phosphate, citric acid, and purified water. In some embodiments, the pharmaceutically acceptable carrier comprises 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, and purified water.

[0035] In some embodiments that can be combined with any of the above-mentioned embodiments, the subject is a human or a non-human animal.In some embodiments that can be combined with any of the above-mentioned embodiments, the subject suffers from, or is suspected and / or suspected to suffer from, inflammation of one or more periorbital glands.In some embodiments that can be combined with any of the above-mentioned embodiments, the subject suffers from an ocular disease.In some embodiments, the ocular disease is selected from periocular gland inflammation, meibomianitis, dry eye disease, allergic ocular disease, topical preservative toxicity, xerophthalmia, loss of tear film homeostasis, tear film instability and hyperosmolarity, ocular surface inflammation and damage, neuronal paresthesia, meibomian gland dysfunction, exacerbated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof.

[0036] In another aspect, provided herein is a method for providing preventive, palliative, or therapeutic relief of one or more signs or symptoms of an ocular disease in a subject, comprising administering any of the pharmaceutical compositions described herein to the subject.In some embodiments, the subject is a human or a non-human animal.In some embodiments, the subject is suffering from, or is suspected and / or suspected to be suffering from, inflammation of one or more periorbital glands.In some embodiments, the subject is suffering from an ocular disease.In some embodiments, the ocular disease is selected from periocular gland inflammation, meibomianitis, dry eye disease, allergic ocular disease, topical preservative toxicity, xerophthalmia, loss of tear film homeostasis, tear film instability and hyperosmolarity, ocular surface inflammation and damage, neuronal paresthesia, meibomian gland dysfunction, exacerbated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof.

[0037] In some embodiments that may be combined with any of the preceding embodiments, the pharmaceutical composition is topically administered to the outer portion of the subject's eyelid, including the superior lateral portion of the orbit. In some embodiments, the pharmaceutical composition is topically administered to the outer portion of the subject's upper eyelid and / or lower eyelid. In some embodiments, the lipophilic compound is delivered to the subject's ocular surface via the meibomian gland. In some embodiments, the pharmaceutical composition is administered once, twice, three times, four times, five times, six times, or more times daily. In some embodiments, the pharmaceutical composition is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or more, 24 weeks, 36 weeks, 48 ​​weeks, or more. In some embodiments, long-term administration of the pharmaceutical composition does not cause ocular adverse events in the subject. In some embodiments, the ocular adverse events are selected from elevated intraocular pressure, cataracts, ocular infections, and any combination thereof. In some embodiments, the lipophilic compound is not delivered systemically to the subject by administration of the pharmaceutical composition. In some embodiments, the lipophilic compound is not delivered to the tears or lacrimal ducts of the subject by administration of the pharmaceutical composition. In some embodiments, the lipophilic compound is not delivered directly to the ocular surface of the subject by administration of the pharmaceutical composition.

[0038] In another aspect, provided herein is an article of manufacture or kit comprising any of the pharmaceutical compositions described herein. In some embodiments, the article of manufacture or kit further comprises a package insert containing instructions for administering the pharmaceutical composition.

[0039] [The present invention 1001] A method for providing preventative, palliative, or therapeutic relief of one or more signs or symptoms of an eye disease in a subject, comprising administering to the subject any of the pharmaceutical compositions of inventions 1014 to 1076. [The present invention 1002] 1001. The method of claim 1001, wherein the subject is a human or non-human animal. [The present invention 1003] The method of invention 1001 or invention 1002, wherein the ocular disease is selected from the group consisting of periocular gland inflammation, meibomianitis, dry eye disease, allergic eye disease, topical preservative toxicity, xerophthalmia, loss of tear film homeostasis, tear film instability and hyperosmolarity, ocular surface inflammation and damage, neuronal paresthesia, meibomian gland dysfunction, exacerbated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof. [The present invention 1004] The method of any of claims 1001 to 1003, wherein the pharmaceutical composition is administered topically to the outer portion of the subject's eyelid, including the superior lateral portion of the subject's orbit. [The present invention 1005] The method of claim 1004, wherein the pharmaceutical composition is administered topically to the outer portion of the upper and / or lower eyelid of the subject. [The present invention 1006] The method of any of claims 1001 to 1005, wherein the lipophilic compound is delivered to the ocular surface of the subject via the meibomian glands. [The present invention 1007] The method of any of claims 1001 to 1006, wherein the pharmaceutical composition is administered once, twice, three times, four times, five times, six times or more per day. [The present invention 1008] Any of the methods of inventions 1001 to 1007, wherein the pharmaceutical composition is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more, 24 weeks, 36 weeks, 48 ​​weeks or more. [The present invention 1009] The method of any of claims 1001 to 1008, wherein long-term administration of the pharmaceutical composition does not result in adverse ocular events in the subject. [The present invention 1010] 1009. The method of claim 10, wherein the ocular adverse event is selected from the group consisting of elevated intraocular pressure, cataracts, ocular infections, and any combination thereof. [The present invention 1011] The method of any of claims 1001 to 1010, wherein the lipophilic compound is not delivered systemically to the subject. [The present invention 1012] The method of any of claims 1001 to 1011, wherein the lipophilic compound is not delivered to the subject's tears or lacrimal ducts. [The present invention 1013] The method of any of claims 1001 to 1012, wherein the lipophilic compound is not delivered directly to the ocular surface of the subject. [The present invention 1014] (a) a therapeutically effective amount of a lipophilic compound; and (b) a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of a lipophilic compound to one or more periorbital glands of a subject; 1. A pharmaceutical composition comprising: A pharmaceutical composition that is specially formulated for periocular delivery. [The present invention 1015] The pharmaceutical composition of invention 1014, wherein the lipophilic compound is not delivered systemically to the subject. [The present invention 1016] The pharmaceutical composition of invention 1014 or invention 1015, wherein the lipophilic compound is not delivered to the tears or lacrimal duct of the subject. [The present invention 1017] The pharmaceutical composition of any of claims 1014 to 1016, wherein the lipophilic compound is not delivered directly to the ocular surface of the subject. [The present invention 1018] 8. The pharmaceutical composition of any of claims 1014 to 1017, which is not a liquid topical ophthalmic suspension, emulsion, or solution. [The present invention 1019] 19. The pharmaceutical composition of any of claims 1014 to 1018, wherein the one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof. [The present invention 1020] 1019. The pharmaceutical composition of any of claims 1014 to 1019, wherein the lipophilic compound is delivered to the ocular surface of the subject via the meibomian glands. [The present invention 1021] The pharmaceutical composition of any one of claims 1014 to 1020, wherein the lipophilic compound is a steroid. [The present invention 1022] the steroid is selected from the group consisting of the compound of formula I, fluocinolone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and ester derivatives thereof; The compound of formula I has the structure: A pharmaceutical composition of the present invention 1021 comprising TIFF0007796783000001.tif56128. [The present invention 1023] The pharmaceutical composition of invention 1021 or invention 1022, wherein the steroid is selected from the group consisting of the compound of formula I, difluprednate, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, and ester derivatives thereof. [The present invention 1024] 1024. The pharmaceutical composition of any one of claims 1021 to 1023, wherein the steroid is a compound of formula I. [The present invention 1025] 1020. The pharmaceutical composition of any one of claims 1014 to 1020, wherein the lipophilic compound is an antibiotic. [The present invention 1026] 1025. The pharmaceutical composition of the present invention, wherein the antibiotic is selected from the group consisting of sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, and tetracyclines. [The present invention 1027] The pharmaceutical composition of claim 1025 or 1026, wherein the antibiotic is selected from the group consisting of azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxifloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, and sulfacetamide. [The present invention 1028] 1020. The pharmaceutical composition of any one of claims 1014 to 1020, wherein the lipophilic compound is an immunomodulatory agent. [The present invention 1029] The pharmaceutical composition of claim 1028, wherein the immunomodulatory agent is selected from the group consisting of a calcineurin inhibitor and a thalidomide analog. [The present invention 1030] The pharmaceutical composition of claim 1028 or claim 1029, wherein the immunomodulatory agent is selected from the group consisting of cyclosporin A, voclosporin, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide. [The present invention 1031] The pharmaceutical composition of any one of claims 1014 to 1020, wherein the lipophilic compound is an integrin antagonist. [The present invention 1032] The pharmaceutical composition of the present invention 1031, wherein the integrin antagonist is selected from the group consisting of lifitegrast, GW559090, and ester derivatives thereof. [The present invention 1033] The pharmaceutical composition of any one of claims 1014 to 1020, wherein the lipophilic compound is an anti-inflammatory agent. [The present invention 1034] The pharmaceutical composition of claim 1033, wherein the anti-inflammatory agent is selected from the group consisting of omega-3 fatty acids and nonsteroidal anti-inflammatory drugs (NSAIDs). [This invention 1035] 1034. The pharmaceutical composition of claim 1034, wherein the omega-3 fatty acid is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combination thereof. [The present invention 1036] The pharmaceutical composition of the present invention 1034, wherein the NSAID is selected from the group consisting of bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and any combination thereof. [This invention 1037] 1020. The pharmaceutical composition of any of claims 1014 to 1020, wherein the lipophilic compound is an anti-glaucoma agent or an ocular anti-hypertension agent. [The present invention 1038] The pharmaceutical composition of the present invention 1037, wherein the anti-glaucoma or anti-ocular hypertension agent is selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, latanoprost bunod, timolol, betaxolol, levobunolol, metipranolol, brimonidine, clonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, methazolamide, netarsudil, and any combination thereof. [This invention 1039] 1038. The pharmaceutical composition of any of claims 1014 to 1038, comprising a lipophilic compound at a concentration of about 0.001% to about 10% weight / weight (w / w), about 0.0001% to about 10% weight / weight (w / w), or about 0.0001% to about 5% weight / weight (w / w). [The present invention 1040] 1039. The pharmaceutical composition of any of claims 1014 to 1039, comprising a steroid at a concentration of about 0.01% to about 2% w / w. [The present invention 1041] The pharmaceutical composition of any of claims 1014 to 1040, further comprising a therapeutically effective amount of an additional steroid. [The present invention 1042] 1041. The pharmaceutical composition of the present invention, wherein the additional steroid is selected from the group consisting of a compound of formula I, fluocinolone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and ester derivatives thereof. [This invention 1043] The pharmaceutical composition of invention 1041 or invention 1042, wherein the lipophilic compound and the additional steroid are different. [This invention 1044] The pharmaceutical composition of any of claims 1014 to 1043, further comprising a therapeutically effective amount of one or more antibiotics. [This invention 1045] The pharmaceutical composition of the present invention 1044, wherein the one or more antibiotics are selected from the group consisting of sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, tetracyclines, and any combination thereof. [The present invention 1046] The pharmaceutical composition of claim 1044 or 1045, wherein the one or more antibiotics are selected from the group consisting of azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxifloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, sulfacetamide, and any combination thereof. [This invention 1047] The pharmaceutical composition of any of claims 1044 to 1046, wherein the lipophilic compound and the one or more antibiotics are different. [This invention 1048] 8. The pharmaceutical composition of any of claims 1014 to 1047, further comprising a therapeutically effective amount of one or more immunomodulatory agents. [This invention 1049] The pharmaceutical composition of claim 1048, wherein the one or more immunomodulatory agents are selected from the group consisting of calcineurin inhibitors, thalidomide analogs, and any combination thereof. [The present invention 1050] The pharmaceutical composition of claim 1048 or claim 1049, wherein the one or more immunomodulatory agents are selected from the group consisting of cyclosporin A, voclosporin, tacrolimus, pimecrolimus, thalidomide, lenalidomide, pomalidomide, and any combination thereof. [This invention 1051] The pharmaceutical composition of any of claims 1048 to 1050, wherein the lipophilic compound and the one or more immunomodulatory agents are different. [This invention 1052] 10. The pharmaceutical composition of any of claims 1014 to 1051, further comprising a therapeutically effective amount of one or more integrin antagonists. [This invention 1053] The pharmaceutical composition of the present invention 1052, wherein the one or more integrin antagonists are selected from the group consisting of lifitegrast, GW559090, ester derivatives thereof, and any combination thereof. [This invention 1054] The pharmaceutical composition of invention 1052 or invention 1053, wherein the lipophilic compound and the one or more integrin antagonists are different. [This invention 1055] The pharmaceutical composition of any of claims 1014 to 1054, further comprising a therapeutically effective amount of one or more anti-inflammatory agents. [The present invention 1056] The pharmaceutical composition of the present invention 1055, wherein the one or more anti-inflammatory agents are selected from the group consisting of omega-3 fatty acids, nonsteroidal anti-inflammatory drugs (NSAIDs), and any combination thereof. [This invention 1057] 1056. The pharmaceutical composition of claim 1056, wherein the omega-3 fatty acid is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combination thereof. [This invention 1058] 1056. The pharmaceutical composition of claim 1056, wherein the NSAID is selected from the group consisting of bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and any combination thereof. [This invention 1059] 1059. The pharmaceutical composition of any of claims 1055 to 1058, wherein the lipophilic compound and the one or more anti-inflammatory agents are different. [The present invention 1060] 1059. The pharmaceutical composition of any of claims 1014 to 1059, further comprising a therapeutically effective amount of one or more anti-glaucoma or anti-ocular hypertension agents. [This invention 1061] The pharmaceutical composition of the present invention 1060, wherein the one or more anti-glaucoma or anti-ocular hypertension agents are selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, latanoprost bunod, timolol, betaxolol, levobunolol, metipranolol, brimonidine, clonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, methazolamide, netarsudil, and any combination thereof. [The present invention 1062] The pharmaceutical composition of invention 1060 or invention 1061, wherein the lipophilic compound and the one or more anti-glaucoma or anti-ocular hypertension agents are different. [This invention 1063] The pharmaceutical composition of any of claims 1014 to 1062, wherein the pharmaceutically acceptable carrier is selected from the group consisting of an ointment, cream, lotion, gel, emulsion, suspension, oil, foam, transdermal patch, spray, and any combination thereof. [This invention 1064] 1063. The pharmaceutical composition of claim 1063, wherein the ointment comprises a paraffinic or water-miscible ointment base. [This invention 1065] The pharmaceutical composition of invention 1063 or invention 1064, wherein the ointment comprises 61.5% w / w white soft paraffin, 8% w / w mineral oil, 8% w / w propylene glycol, 5% w / w St. cyclomethicone-5NF, 5% w / w labrasol, 5% w / w propylene carbonate, 2.5% w / w steareth 2, 2.5% w / w St. emulsifier 10, and 2.5% w / w St. elastomer-10. [The present invention 1066] 1063. The pharmaceutical composition of claim 1063, wherein the cream comprises an oil-in-water base or a water-in-oil base. [This invention 1067] The pharmaceutical composition of invention 1063 or invention 1066, wherein the cream comprises 48% w / w white soft paraffin, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w ST-emulsifier, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w dibasic sodium phosphate, 0.05% w / w citric acid, 0.02% w / w propylparaben, and purified water. [The present invention 1068] The pharmaceutical composition of invention 1063 or invention 1066, wherein the cream comprises 48% w / w white soft paraffin, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w cyclomethicone, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w anhydrous sodium phosphate dibasic, 0.046% w / w anhydrous citric acid, 0.02% w / w propylparaben, and purified water. [This invention 1069] The pharmaceutical composition of any one of claims 1063 and 1066 to 1068, wherein the cream contains benzalkonium chloride (BAK). [The present invention 1070] A pharmaceutical composition according to any one of claims 1063 and 1066 to 1069, wherein the cream comprises 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.06% w / w anhydrous dibasic sodium phosphate, 0.05% w / w anhydrous citric acid, 0.02% w / w benzalkonium chloride, and purified water. [This invention 1071] The pharmaceutical composition of any one of claims 1063 and 1066 to 1070, wherein the cream is preservative-free. [This invention 1072] 1071. The pharmaceutical composition of claim 1071, wherein the preservative-free cream comprises white soft paraffin / petrolatum, mineral oil, propylene glycol, ST-cyclomethicone-5NF, emulsifier-10, ST-elastomer-10, dibasic sodium phosphate, citric acid, and purified water. [This invention 1073] The pharmaceutical composition of invention 1071 or invention 1072, wherein the preservative-free cream comprises 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.06% w / w anhydrous dibasic sodium phosphate, 0.05% w / w anhydrous citric acid, and purified water. [This invention 1074] The pharmaceutical composition of any one of claims 1014 to 1073, wherein the subject is a human or non-human animal. [This invention 1075] The pharmaceutical composition of any one of claims 1014 to 1074, wherein the subject is suffering from an eye disease. [This invention 1076] The pharmaceutical composition of the present invention 1075, wherein the ocular disease is selected from the group consisting of periocular gland inflammation, meibomianitis, dry eye disease, allergic eye disease, topical preservative toxicity, xerophthalmia, loss of tear film homeostasis, tear film instability and hyperosmolarity, ocular surface inflammation and damage, neuronal paresthesia, meibomian gland dysfunction, exacerbated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof. [This invention 1077] (a) any one of the pharmaceutical compositions of the present invention 1014 to 1076; and (b) a package insert containing instructions for administering the pharmaceutical composition; Includes a kit. It is understood that one, some, or all of the features of the various embodiments described above and herein can be combined to form other embodiments of the present disclosure. These and other aspects of the present disclosure will be apparent to those skilled in the art. These and other aspects of the present disclosure are further described in the following details. [Brief explanation of the drawings]

[0040] [Figure 1]

[0033] Figure 1 shows the mean daytime intraocular pressure (IOP) during a 4-week treatment period with the indicated treatments administered topically to the eye. Raw IOP data were analyzed using a mixed-effects model. Data are presented as fitted IOP mean values ​​± 95% confidence limits; * indicates p<0.05 compared to the dexamethasone-treated group. [Figure 2] Figure 1 shows the change in tear formation during 7 days of topical application of the indicated treatments. Repeated measures analysis followed by Sidak's test was performed; GW870086 = compound of formula I; * indicates p<0.05 when compared to the atropine + vehicle treatment group. [Figure 3] Figure 3 shows the physical stiffness of various cream samples and high-viscosity standards equilibrated at 37°C in glass vials and inverted for 5 minutes. The samples in Figure 3A are 2% Formula I compound cream (left), placebo cream (center), and high-viscosity polybutene standard N62000 (right); the samples in Figure 3B are 2% dexamethasone cream (vial C, left), 2% loteprednol etabonate cream (vial B, center), and 2% cyclosporine A cream (vial A, right). The adhesion of the samples to the inside of the glass vial walls was not caused by sample flow but by accidental adhesion from the pipette during sample transfer into the vial. This did not interfere with the observation of meniscus flow or changes upon heat treatment and inversion. [Figure 4A] The results of step strain stress relaxation measurements are shown for some of the samples: (a) white petrolatum at 25° C. (FIG. 4A). [Figure 4B]The results of step strain stress relaxation measurements are shown for some of the samples: (b) white petrolatum at 37° C. (FIG. 4B). [Figure 4C] The results of step strain stress relaxation measurements are shown for some of the samples: (c) placebo cream at 25° C. (FIG. 4C). [Figure 4D] The results of step strain stress relaxation measurements are shown for some of the samples: (d) 2% triamcinolone acetonide (sample K) cream at 25°C (Figure 4D). [Figure 5] Figure 1 shows epidermal, dermal, and receptor fluid levels of the compound of Formula I 46 hours after topical application of a 2% compound of Formula I cream to the epidermis. Results were obtained from six replicates of an in vitro skin permeation study using human cadaver skin samples mounted in Franz diffusion cells; the receptor fluid was in contact with the dermis. [Figure 6]

[0023] Figure 1 shows ocular exposure levels in minipigs' eyes after twice-daily eyelid administration of 2% compound of Formula I cream for 7.5 days, at 2, 4, 8, and 24 hours after the final dose on day 8. [Figure 7] 1 is a process flow chart for the manufacture of a cream containing a compound of Formula I. DETAILED DESCRIPTION OF THE INVENTION

[0041] Detailed Description Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a lipophilic compound and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the lipophilic compound to one or more periorbital glands (e.g., meibomian glands, lacrimal glands, and / or accessory lacrimal glands) of a subject. In some embodiments, the pharmaceutical composition is specially formulated for periocular delivery in accordance with the teachings herein. Further provided herein are methods for providing preventative, palliative, and / or therapeutic relief of one or more signs or symptoms of an ocular disease (e.g., an ocular inflammatory condition, a bacterial infection, or glaucoma), comprising administering a therapeutically effective amount of any of the pharmaceutical compositions of the present disclosure to a subject in need thereof. Further provided herein are articles of manufacture or kits comprising one or more of the pharmaceutical compositions described herein.

[0042] Topical eye drops have become the delivery method of choice for eye care practitioners, especially for diseases such as dry eye, uveitis, bacterial conjunctivitis, and glaucoma, because the ocular surface is considered the primary target tissue for drug delivery. However, the rapid turnover of ocular tears poses serious challenges for eye drops. The tear film has a volume of only approximately 7 μL. Eye drops are approximately 30–50 μL, depending on the surface tension characteristics of the drug; therefore, only a maximum of 1–3% of the active pharmaceutical ingredient (API) in a topical eye drop penetrates the intended target tissue in the eye. The remainder of the eye drop is washed away from the tear film through the nasolacrimal system. Due to the constant production and drainage of tears (0.5–2.2 μL / min), the contact time of the drug with ocular tissues is approximately 1 minute (Abelson et al., 2012). Methods to increase drug retention time in the treated eye include high viscosity solutions (e.g., Tobradex ST) and new technologies, such as mucosal penetration technologies (e.g., Kala Pharmaceuticals, KPI-121), bioadhesive gels, and fibrin sealant-based approaches (Gaudana R et al., 2010). Periocular delivery routes for ocular conditions include subconjunctival, sub-Tenon, retrobulbar, and peribulbar administration (see Figure 1 in Gaudana R et al., 2010).

[0043] Applying drugs directly to the eyelid has been envisioned as a drug delivery route for eyelid conditions such as meibomian gland dysfunction (MGD) and blepharitis. Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian glands (located in the eyelids) typically characterized by terminal duct obstruction and / or qualitative / quantitative changes in glandular secretions (Nichols et al., 2011). Blepharitis is inflammation of the eyelid. Local eyelid delivery has been envisioned for diseases affecting the eyelid because Abelson and colleagues (2012) stated, "If you want to treat a localized condition, the more localized the delivery, the better the outcome. What better example of this need could there be than delivering a therapeutic agent for blepharitis directly to the affected eyelid?"

[0044] MacKeen et al. (1995) reported a unique drug delivery system that consisted of applying a petrolatum ointment vehicle to the lower eyelid. The ointment melts at skin temperature and gradually migrates across the skin onto the ocular surface. This movement of the petrolatum ointment was referred to as "supracutaneous." For this method to work, the lower eyelid musculature must move the drug toward and across the lid margin. Thus, this drug delivery method assumes that the applied drug does not penetrate the skin of the lower eyelid, but instead migrates on the surface of the skin around the eyelid, where it physically mixes with the tear film (see also Tsubota et al., 1999).

[0045] The pharmaceutical compositions and methods of the present invention are based on the unexpected finding that, when properly formulated in a suitable vehicle, they do not melt and flow or migrate onto the ocular surface after topical periocular application to one or both eyelids, but instead penetrate into the eyelid along with their API payload, a lipophilic drug delivered locally to the eyelid, in a manner that allows them to access the meibomian glands, meibum, and other fatty structures within the eyelid (which can themselves act as drug depots providing sustained delivery to the ocular surface). Thus, "the more localized the delivery, the better the results" is not an accurate way to conceive of delivering lipophilic compounds to the ocular surface. The drug delivery methods of the present invention also rely on penetration of the eyelid skin, which is inconsistent with the prior art, which assumes eyelid skin as a barrier to successful ocular surface drug delivery.

[0046] Commonly used lipophilic, topical, ocular therapeutic agents that could benefit from this new delivery method include treatments for dry eye disease (e.g., RESTASIS® and corticosteroids), glaucoma (e.g., latanoprost), and inflammatory eye diseases, including bacterial conjunctivitis (e.g., AzaSite).

[0047] Pflugfelder and colleagues (2004) demonstrated that topical corticosteroids can achieve the goal of short-term treatment of acute exacerbations of DED signs or symptoms. They evaluated loteprednol etabonate ophthalmic suspension (0.5%) administered four times daily versus placebo for the treatment of DED in patients with delayed tear clearance. In patients with at least moderate clinical inflammation, significant differences in clinical signs (nasal and tarsal hyperemia) between groups were observed as early as week 2 and persisted through week 4 of the study. Furthermore, improvements in redness visual analog scale (VAS) scores were consistently 20% better in loteprednol-treated patients compared with vehicle-treated patients.

[0048] Leveraging the known safety profile of loteprednol etabonate, Kala Pharmaceuticals, Inc. is developing KPI-121 as a novel nanoparticle formulation of loteprednol etabonate using mucus-penetrating particle (MPP) technology. In October 2017, Kala filed an IND for KPI-121 1% as a treatment for inflammation and pain after ocular surgery. In January 2018, they announced top-line results for KPI-121 0.25% for the temporary relief of signs and symptoms of DED. Two Phase 3 DED studies (STRIDE 1 and STRIDE 2) demonstrated that KPI-121 0.25% administered four times daily (QID) could provide a statistically significant reduction in conjunctival hyperemia and a slight reduction in the severity of ocular discomfort at Day 15. These local ocular delivery routes pose several significant challenges to successful treatment implementation: (1) QID dosing is inconvenient for patients and likely leads to low compliance; (2) the need for frequent dosing to maintain therapeutically active drug levels for anti-inflammatory efficacy; (3) potential safety concerns associated with frequent dosing; and (4) the need for a vehicle that may itself alter the functional characteristics of the normal tear film.

[0049] In addition to seeking sustained-release formulations for inflammatory ocular conditions to improve patient compliance by establishing more sustained suppression of inflammation, thereby reducing dosing frequency and increasing efficacy, sustained-release formulations are being developed for glaucoma to further eliminate preservatives such as benzalkonium chloride (BAK) and for bacterial conjunctivitis to prevent the regrowth phase. Thus, a need exists across ophthalmic conditions for sustained-release formulations that are minimally invasive, reduce dosing frequency, maintain consistent therapeutic drug exposure at the site of action, minimize precorneal tear film disruption, and reduce ocular exposure to formulation excipients.

[0050] I. Pharmaceutical Compositions Some aspects of the present disclosure relate to pharmaceutical compositions comprising a therapeutically effective amount of a lipophilic compound and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the lipophilic compound to one or more periocular glands (e.g., meibomian glands, lacrimal glands, and / or accessory lacrimal glands) of a subject. The term "periocular" refers to the area within the orbit surrounding the eyeball, including the eyelids and the lateral orbit. Periocular glands are glands in the area around the eyeball, including, for example, meibomian glands, lacrimal glands, and / or accessory lacrimal glands. In some embodiments, the pharmaceutical composition is specially formulated for periocular delivery. In some embodiments, the pharmaceutically acceptable carrier is adapted for periocular transdermal delivery by (1) reducing the concentration of permeation enhancer in the carrier compared to the concentration used in standard ointments / creams or ophthalmic formulations; (2) using a permeation enhancer (not typically found in topical steroid ointment / cream formulations) (e.g., Tween-80) that is suitable for transdermal delivery of the compound into the eyelid; (3) formulating the pharmaceutical composition to achieve improved spreadability over the periocular surface compared to ointment bases; and / or (4) formulating the pharmaceutical composition to avoid flow from the periocular surface onto the corneal surface.In some embodiments, the pharmaceutical composition is adapted for periocular transdermal delivery and significantly enhances the ocular safety of the delivered lipophilic compound by: (1) reducing the concentration of permeation enhancers in the pharmaceutical composition compared to the concentrations used in standard ointments / creams or ophthalmic formulations; (2) using permeation enhancers (not typically found in topical steroid ointment / cream formulations) (e.g., Tween-80) that are suitable for transdermal delivery of compounds into the eyelid; (3) formulating the pharmaceutical composition to achieve improved spreadability on the periocular surface compared to ointment bases; and (4) formulating the pharmaceutical composition to avoid flow from the periocular surface onto the corneal surface. (5) the use of novel steroids, such as the compounds of Formula I, which have been specifically developed to enable the glucocorticoid receptor to transrepress gene activation with little or no transactivation, to reduce the side effects of glucocorticoids thought to be mediated by transactivation; (6) the use of the meibomian glands, meibum, and other fatty structures in the eyelid as drug depots for lipophilic compounds for sustained delivery to the ocular surface; and / or (7) the use of the meibomian glands and meibum as novel drug delivery systems for pharmaceutical formulations of lipophilic compounds applied periocularly to the outside of the upper and / or lower eyelids.

[0051] In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of at least one additional steroid, antibiotic, immunomodulator, integrin antagonist, anti-inflammatory agent, and / or anti-glaucoma or anti-ocular hypertension agent, in any combination. In some embodiments that include a lipophilic compound and further comprise at least one additional steroid, antibiotic, immunomodulator, integrin antagonist, anti-inflammatory agent, and / or anti-glaucoma or anti-ocular hypertension agent, the lipophilic compound is different from the at least one additional steroid, antibiotic, immunomodulator, integrin antagonist, anti-inflammatory agent, and / or anti-glaucoma or anti-ocular hypertension agent. In some embodiments, the pharmaceutical composition is specially formulated for periocular delivery in accordance with the teachings herein.

[0052] In some embodiments, the lipophilic compound is not delivered systemically when the pharmaceutical composition is administered to a subject. In some embodiments, the lipophilic compound is not delivered by direct application into the subject's tears and / or tear ducts. In some embodiments, the lipophilic compound is not delivered by direct application to the subject's ocular surface (e.g., cornea, conjunctiva). In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or suspension (i.e., eye drops). In some embodiments, the lipophilic compound is a steroid. In some embodiments, the lipophilic compound is an antibiotic. In some embodiments, the lipophilic compound is an immunomodulatory agent. In some embodiments, the lipophilic compound is an integrin antagonist. In some embodiments, the lipophilic compound is an anti-inflammatory agent. In some embodiments, the lipophilic compound is an anti-glaucoma agent or an anti-ocular hypertension agent.

[0053] steroid In some aspects, the present disclosure relates to a pharmaceutical composition comprising a steroid as a lipophilic compound.Therefore, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a steroid and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the steroid to one or more periocular glands (e.g., oil-secreting periocular glands) of a subject, wherein the pharmaceutical composition is specifically formulated for periocular delivery.For example, any suitable steroid known in the art can be used in the pharmaceutical composition of the present disclosure, including the compound of Formula I, fluocinolone, medrysone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, and testosterone, or any ester derivative thereof.In some embodiments, the steroid is a glucocorticoid. In some embodiments, the steroid is a compound of formula I, difluprednate, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, or any ester derivative thereof. In some embodiments, the steroid is a compound of formula I. As used herein, "compound of formula I" refers to the compound 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylic acid cyanomethyl ester. See, for example, U.S. Patent No. 7,291,609, including its preparation method. The structure of the compound of formula I is shown below. TIFF0007796783000002.tif76128

[0054] In some embodiments, the pharmaceutical composition comprises a steroid at a concentration of 0.001% to 10% weight / weight (w / w). For example, the pharmaceutical composition may comprise a steroid at a concentration of about 0.001% to about 10%, about 0.001% to about 9%, about 0.001% to about 8%, about 0.001% to about 7%, about 0.001% to about 6%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, or about 0.001% to about 0.05%. , about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.01% to about 10%, about 0.01% to about 9%, about 0.01% to about 8%, about 0.01% to about 7%, about 0.01% to about 6%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to About 0.05%, about 0.05% to about 10%, about 0.05% to about 9%, about 0.05% to about 8%, about 0.05% to about 7%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3%, about 0.05% to about 2%, about 0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 0.1% to about 10%, about 0.1% to about 9%, about 0.1% to about 8%, About 0.1% to about 7%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.5% to about 10%, about 0.5% to about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 10%, about 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 3% The steroid may be included at a concentration of about 0.01% to about 2% w / w, such as about 0.01% to about 5%, about 3% to about 4%, about 4% to about 10%, about 4% to about 9%, about 4% to about 8%, about 4% to about 7%, about 4% to about 6%, about 4% to about 5%, about 5% to about 10%, about 5% to about 9%, about 5% to about 8%, about 5% to about 7%, about 5% to about 6%, about 6% to about 10%, about 6% to about 9%, about 6% to about 8%, about 6% to about 7%, about 7% to about 10%, about 7% to about 9%, about 7% to about 8%, about 8% to about 10%, about 8% to about 9%, or about 9% to about 10% w / w. In some embodiments, the pharmaceutical composition includes a steroid at a concentration of about 0.01% to about 2% w / w. In some embodiments, the pharmaceutical composition comprises a steroid at any of the following concentrations: about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w / w.

[0055] antibiotics In some aspects, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an antibiotic as a lipophilic compound. In some embodiments, the pharmaceutical composition comprises two or more antibiotics (e.g., two or more, three or more, four or more, five or more, etc.). Thus, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an antibiotic and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the antibiotic to one or more periocular (e.g., oil-secreting periocular) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periocular delivery. For example, any suitable antibiotic known in the art can be used in the pharmaceutical composition of the present disclosure, including sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, tetracyclines, and any combination thereof. Examples of such antibiotics include, but are not limited to, azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxifloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, and sulfacetamide.

[0056] In some embodiments, the pharmaceutical composition comprises an antibiotic at a concentration of 0.0001% to 10% weight / weight (w / w). For example, the pharmaceutical composition may contain from about 0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, from about 0.0001% to about 0.00 1%, about 0.0001% to about 0.0005%, about 0.0005% to about 10%, about 0.0005% to about 9%, about 0.0005% to about 8%, about 0.0005% to about 7%, about 0.0005% to about 6%, about 0.0005% to about 5%, about 0.0005% to about 4%, about 0.0005% to about 3%, about 0.0005% to about 2%, about 0.0005% to about 1%, about 0.0005% to about 0.5%, about 0.0005% to about 0.1%, about 0.0005% to about 0.05%, about 0.0005% to about 0.01%, about 0.0005% to about 0.005%, about 0.00 0.05% to approximately 0.001%, approximately 0.001% to approximately 10%, approximately 0.001% to approximately 9%, approximately 0.001% to approximately 8%, approximately 0.001% to approximately 7%, approximately 0.001% to approximately 6%, approximately 0.001% to approximately 5%, approximately 0.001% to approximately 4%, approximately 0.001% to approximately 3%, approximately 0.001% to approximately 2%, approximately 0.001% to approximately 1%, approximately 0.001% to approximately 0.5%, approximately 0.001% to approximately 0.1%, approximately 0.001% to approximately 0.05%, approximately 0.001% to approximately 0.01%, approximately 0.001% to approximately 0.005%, approximately 0.01% to approximately 10%, approximately 0.01% to approximately 9%, approximately 0.01% ~ about 8%, about 0.01% to about 7%, about 0.01% to about 6%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 10%, about 0.05% to about 9%, about 0.05% to about 8%, about 0.05% to about 7%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3%, about 0.05% to about 2%, about 0.05% to about 1%, about 0.0.05% to approximately 0.5%, approximately 0.05% to approximately 0.1%, approximately 0.1% to approximately 10%, approximately 0.1% to approximately 9%, approximately 0.1% to approximately 8%, approximately 0.1% to approximately 7%, approximately 0.1% to approximately 6%, approximately 0.1% to approximately 5%, approximately 0.1% to approximately 4%, approximately 0.1% to approximately 3%, approximately 0.1% to approximately 2%, approximately 0.1% to approximately 1%, approximately 0.1% to approximately 0.5%, approximately 0.5% to approximately 10%, approximately 0.5% ~ about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1 % to about 2%, about 2% to about 10%, about 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 3% to about 5%, about 3% to about 4%, about 4% to about 10%, about 4% to about 9%, about 4% to about 8% , about 4% to about 7%, about 4% to about 6%, about 4% to about 5%, about 5% to about 10%, about 5% to about 9%, about 5% to about 8%, about 5% to about 7%, about 5% to about 6%, about 6% to about 10%, about 6% to about 9%, about 6% to about 8%, about 6% to about 7%, about 7% to about 10%, about 7% to about 9%, about 7% to about 8%, about 8% to about 10%, about 8% to about 9%, or about 9% to about 10% w / w. In some embodiments, the pharmaceutical composition contains an antibiotic at a concentration of 0.0001% to 5% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3 %,0.35%,0.4%,0.45%,0.5%,0.55%,0.6%,0.65%,0.7%,0.75%,0.8%,0.85%,0.9%,0.95%,1%,1.25%,1.5%,1.75%,2%,2.25%,2.5%,2.75%,3%,3.5%,4%,4.5%,5%,5.5%,6%,6.5%,7%,7.5%,8%,8.Contains antibiotics at either 5%, 9%, 9.5%, or 10% w / w concentrations.

[0057] Immunomodulatory drugs In some aspects, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an immunomodulatory agent as a lipophilic compound. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) immunomodulatory agents. Thus, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an immunomodulatory agent and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the immunomodulatory agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periocular delivery. Any suitable immunomodulatory agent known in the art can be used in the pharmaceutical composition of the present disclosure, including, for example, calcineurin inhibitors, thalidomide analogs, and any combination thereof. Examples of such immunomodulatory agents include, but are not limited to, cyclosporin A, voclosporin, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide. In some embodiments, the immunomodulatory agent is cyclosporin A.

[0058] In some embodiments, the pharmaceutical composition comprises an immunomodulatory agent at a concentration of 0.0001% to 5% weight / weight (w / w).For example, the pharmaceutical composition may contain about 0.0001% to about 5%, about 0.0001% to about 4%, about 0.0001% to about 3%, about 0.0001% to about 2%, about 0.0001% to about 1%, about 0.0001% to about 0.5%, about 0.0001% to about 0.1%, about 0.0001% to about 0.05%, about 0.0001% to about 0.01%, about 0.0001% to about 0.005%, about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 5%, about 0.0005% to about 4%, about 0.0005% to about 3%, about 0.0005% to about 2%, About 0.0005% to about 1%, about 0.0005% to about 0.5%, about 0.0005% to about 0.1%, about 0.0005% to about 0.05%, about 0.0005% to about 0.01%, about 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 5%, about 0.005% to about 4%, about 0.005% to about 3%, about 0.005% to about 2%, about 0.005% to about 1%, about 0.005% to about 0.5%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3 %, about 0.05% to about 2%, about 0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 5%, about 3% to about 4%, or about 4% to about 5% It may contain an immunomodulatory agent in w / w concentration.In some embodiments, the pharmaceutical composition comprises an immunomodulatory agent at a concentration of any of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, or 5% w / w.

[0059] Integrin antagonists In some aspects, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an integrin antagonist as a lipophilic compound. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) integrin antagonists. Thus, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an integrin antagonist and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the integrin antagonist to one or more periocular (e.g., oil-secreting periocular) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periocular delivery. For example, any suitable integrin antagonist known in the art can be used in the pharmaceutical composition of the present disclosure, including lifitegrast, GW559090, its ester derivatives, and any combination thereof. In some embodiments, the pharmaceutical composition comprises GW559090 (see Krauss et al. Invest. Ophthalmol. Vis. Sci. 2015;56(10):5888-95).

[0060] In some embodiments, the pharmaceutical composition comprises the integrin antagonist at a concentration of 0.0001% to 10% weight / weight (w / w). For example, the pharmaceutical composition may contain from about 0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, from about 0.0001% to about 0 0.001%, approximately 0.0001% to approximately 0.0005%, approximately 0.0005% to approximately 10%, approximately 0.0005% to approximately 9%, approximately 0.0005% to approximately 8%, approximately 0.0005% to approximately 7%, approximately 0.0005% to approximately 6%, approximately 0.0005% to approximately 5%, approximately 0.0005% to approximately 4%, approximately 0.0005% to approximately 3%, approximately 0.0005% to approximately 2%, approximately 0.0005% to approximately 1%, approximately 0.0005% to approximately 0.5%, approximately 0.0005% to approximately 0.1%, approximately 0.0005% to approximately 0.05%, approximately 0.0005% to approximately 0.01%, approximately 0.0005% to approximately 0.005 , about 0.0005% to about 0.001%, about 0.001% to about 10%, about 0.001% to about 9%, about 0.001% to about 8%, about 0.001% to about 7%, about 0.001% to about 6%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.01% to about 10%, about 0.01% to about 9%, about 0.01% to about 8%, about 0.01% to about 7%, about 0.01% to about 6%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 10%, about 0.05% to about 9%, about 0.05% to about 8%, about 0.05% to about 7%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3%, about 0.05% to about 2%, about 0.0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 0.1% to about 10%, about 0.1% to about 9%, about 0.1% to about 8%, about 0.1% to about 7%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.5% to about 10%, about 0.5% to about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to About 3%, about 1% to about 2%, about 2% to about 10%, about 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 3% to about 5%, about 3% to about 4%, about 4% to about 10%, about 4% to about 9%, about 4% to The integrin antagonist may be contained at a concentration of about 8%, about 4% to about 7%, about 4% to about 6%, about 4% to about 5%, about 5% to about 10%, about 5% to about 9%, about 5% to about 8%, about 5% to about 7%, about 5% to about 6%, about 6% to about 10%, about 6% to about 9%, about 6% to about 8%, about 6% to about 7%, about 7% to about 10%, about 7% to about 9%, about 7% to about 8%, about 8% to about 10%, about 8% to about 9%, or about 9% to about 10% w / w. In some embodiments, the pharmaceutical composition comprises about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0. 35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.Contains integrin antagonists at either 5% or 10% w / w concentration.

[0061] anti-inflammatory agents In some aspects, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an anti-inflammatory agent as a lipophilic compound.In some embodiments, the pharmaceutical composition comprises two or more (for example, two or more, three or more, four or more, five or more, etc.) anti-inflammatory agents.Therefore, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an anti-inflammatory agent and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the anti-inflammatory agent to one or more periocular (for example, oil-secreting periocular) glands of a subject, wherein the pharmaceutical composition is specially formulated for periocular delivery.For example, any suitable anti-inflammatory agent known in the art can be used in the pharmaceutical composition of the present disclosure, including omega-3 fatty acids, nonsteroidal anti-inflammatory drugs (NSAIDs), and any combination thereof.Examples of suitable omega-3 fatty acids may include, but are not limited to, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combination thereof. Examples of suitable NSAIDS can include, but are not limited to, bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and any combination thereof.

[0062] In some embodiments, the pharmaceutical composition comprises an anti-inflammatory agent at a concentration of 0.0001% to 5% weight / weight (w / w).For example, the pharmaceutical composition may contain about 0.0001% to about 5%, about 0.0001% to about 4%, about 0.0001% to about 3%, about 0.0001% to about 2%, about 0.0001% to about 1%, about 0.0001% to about 0.5%, about 0.0001% to about 0.1%, about 0.0001% to about 0.05%, about 0.0001% to about 0.01%, about 0.0001% to about 0.005%, about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 5%, about 0.0005% to about 4%, about 0.0005% to about 3%, about 0.0005% to about 2%, About 0.0005% to about 1%, about 0.0005% to about 0.5%, about 0.0005% to about 0.1%, about 0.0005% to about 0.05%, about 0.0005% to about 0.01%, about 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 5%, about 0.005% to about 4%, about 0.005% to about 3%, about 0.005% to about 2%, about 0.005% to about 1%, about 0.005% to about 0.5%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3 %, about 0.05% to about 2%, about 0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 5%, about 3% to about 4%, or about 4% to about 5% It may contain an anti-inflammatory agent in w / w concentration.In some embodiments, the pharmaceutical composition comprises an anti-inflammatory agent at a concentration of any of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, or 5% w / w.

[0063] Antiglaucoma or anti-ocular hypertension medications In some aspects, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an antiglaucoma or anti-ocular hypertension agent as a lipophilic compound. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) antiglaucoma or anti-ocular hypertension agents. Thus, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an antiglaucoma or anti-ocular hypertension agent and a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of the antiglaucoma or anti-ocular hypertension agent to one or more periocular (e.g., oil-secreting periocular) glands of a subject, wherein the pharmaceutical composition is specially formulated for periocular delivery. For example, any suitable antiglaucoma or anti-ocular hypertension agent known in the art can be used in the pharmaceutical composition of the present disclosure, including prostaglandin analogs, beta-blockers, alpha2 agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and any combination thereof. Examples of suitable prostaglandin analogues include, but are not limited to, bimatoprost, latanoprost, travoprost, tafluprost, latanoprostene bunod, and any combination thereof.Examples of suitable beta-blockers include, but are not limited to, timolol, betaxolol, levobunolol, metipranolol, and any combination thereof.Examples of suitable alpha 2 agonists include, but are not limited to, brimonidine, clonidine, apraclonidine, and any combination thereof.Examples of suitable carbonic anhydrase inhibitors include, but are not limited to, dorzolamide, brinzolamide, acetazolamide, methazolamide, and any combination thereof.Examples of suitable Rho kinase inhibitors include, but are not limited to, netarsudil, and any combination thereof.

[0064] In some embodiments, the pharmaceutical composition comprises an anti-glaucoma or anti-ocular hypertension agent at a concentration of 0.0001% to 10% weight / weight (w / w). For example, the pharmaceutical composition may contain from about 0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, from about 0.0001% to about 0 0.001%, approximately 0.0001% to approximately 0.0005%, approximately 0.0005% to approximately 10%, approximately 0.0005% to approximately 9%, approximately 0.0005% to approximately 8%, approximately 0.0005% to approximately 7%, approximately 0.0005% to approximately 6%, approximately 0.0005% to approximately 5%, approximately 0.0005% to approximately 4%, approximately 0.0005% to approximately 3%, approximately 0.0005% to approximately 2%, approximately 0.0005% to approximately 1%, approximately 0.0005% to approximately 0.5%, approximately 0.0005% to approximately 0.1%, approximately 0.0005% to approximately 0.05%, approximately 0.0005% to approximately 0.01%, approximately 0.0005% to approximately 0.005 , about 0.0005% to about 0.001%, about 0.001% to about 10%, about 0.001% to about 9%, about 0.001% to about 8%, about 0.001% to about 7%, about 0.001% to about 6%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.01% to about 10%, about 0.01% to about 9%, about 0.01% to about 8%, about 0.01% to about 7%, about 0.01% to about 6%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 10%, about 0.05% to about 9%, about 0.05% to about 8%, about 0.05% to about 7%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3%, about 0.05% to about 2%, about 0.0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 0.1% to about 10%, about 0.1% to about 9%, about 0.1% to about 8%, about 0.1% to about 7%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.5% to about 10%, about 0.5% to about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to About 3%, about 1% to about 2%, about 2% to about 10%, about 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 3% to about 5%, about 3% to about 4%, about 4% to about 10%, about 4% to about 9%, about 4% to The anti-glaucoma agent or anti-ocular hypertension agent may be contained at a concentration of about 8%, about 4% to about 7%, about 4% to about 6%, about 4% to about 5%, about 5% to about 10%, about 5% to about 9%, about 5% to about 8%, about 5% to about 7%, about 5% to about 6%, about 6% to about 10%, about 6% to about 9%, about 6% to about 8%, about 6% to about 7%, about 7% to about 10%, about 7% to about 9%, about 7% to about 8%, about 8% to about 10%, about 8% to about 9%, or about 9% to about 10% w / w. In some embodiments, the pharmaceutical composition comprises about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0. 35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.Contains antiglaucoma or anti-ocular hypertension agents at either 5% or 10% w / w concentration.

[0065] Pharmaceutically acceptable carrier In some aspects, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of a steroid to one or more periorbital glands of a subject. In some embodiments, the pharmaceutically acceptable carrier is adapted for periocular transdermal delivery by (1) reducing the concentration of permeation enhancer in the carrier compared to the concentration used in standard steroid ointment / cream formulations; (2) using a permeation enhancer (not typically found in topical steroid ointment / cream formulations) (e.g., Tween-80) that is suitable for percutaneous delivery of steroid into the eyelid; (3) formulating the pharmaceutical composition to achieve improved spreadability on the periocular surface compared to ointment bases; and / or (4) formulating the pharmaceutical composition to avoid flow from the periocular surface onto the corneal surface.

[0066] In some embodiments, the pharmaceutically acceptable carrier comprises one or more (e.g., one or more, two or more, three or more, four or more, five or more, etc.) permeation enhancers. As used herein, "permeation enhancer" or "penetration enhancer" can refer to a compound or mixture of compounds that interacts with one or more skin components to facilitate drug penetration into and / or through the skin. For example, surfactants (e.g., ionic (anionic, cationic, zwitterionic) surfactants (e.g., sodium lauryl sulfate, sodium laurate, etc.), nonionic surfactants (e.g., Tween-80, other polysorbates, etc.), and any combination thereof), bile salts and derivatives thereof (e.g., sodium glycolate, sodium deoxycholate, etc.), fatty acids and derivatives thereof (e.g., oleic acid, caprylic acid, esters of fatty acids, e.g., isopropyl myristate, etc.), chelating agents (e.g., EDTA, citric acid, etc.), sulfoxides (e.g., DMSO, DMA, DMF, etc.), polyols (e.g., diethylene glycol monoethyl ether, PG, polyethylene glycol (PEG), glycerol, polyglycols, etc.), alcohols, Any suitable permeation enhancer known in the art may be used in the pharmaceutical compositions described herein, including (e.g., alkanols, alkenols, glycols, etc.), hydrocarbons (e.g., alkanes, alkenes, halogenated alkanes, squalene, squalene, mineral oil, etc.), amines, amides (e.g., cyclic amides, acyclic amides, azones, pyrrolidones, urea and its derivatives, etc.), others (e.g., terpenes and terpenoids, essential oils (e.g., eucalyptus oil, peppermint oil, turpentine, etc.), phospholipids, cyclic oligosaccharides (e.g., cyclodextrins), amino acids and thioacyl derivatives of amino acids, alkylaminoesters and oxazolidinones, enzymes, ketones (e.g., macrocyclic ketones), etc.), hyaluronic acid, benzalkonium chloride, and any combination thereof.

[0067] In some embodiments, the pharmaceutically acceptable carrier is adapted for periocular transdermal delivery by including a reduced concentration of permeation enhancer compared to the concentration of permeation enhancer used in typical steroid ointment / cream formulations. In some embodiments, the pharmaceutically acceptable carrier includes a permeation enhancer at a concentration of about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 35%, about 20%, about 15%, about 10%, about 5%, about 1%, about 0.1%, or about 0.01% compared to the concentration of permeation enhancer used in typical steroid ointment / cream formulations for dermal application. In some embodiments, the pharmaceutically acceptable carrier contains about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, or about 100-fold less permeation enhancer than the concentration of permeation enhancer used in a typical steroid ointment / cream formulation for skin application. For example, if a typical steroid ointment contains 3% w / w of a given permeation enhancer (e.g., hydroxypropyl methylcellulose), a pharmaceutical composition of the present disclosure may contain about 2.85%, about 2.7%, about 2.55%, about 2.4%, about 2.25%, about 2.1%, about 1.95%, about 1.8%, about 1.65%, about 1.5%, about 1.35%, about 1.2%, about 1.05%, about 0.9%, about 0.75%, about 0.6%, about 0.45%, about 0.3%, about 0.03%, or about 0.003% w / w of the same permeation enhancer.

[0068] In some embodiments, the pharmaceutically acceptable carrier is adapted for periocular transdermal delivery by including a permeation enhancer suitable for transdermal delivery of steroid into the subject's eyelid (e.g., but not completely through the topical surface). In some embodiments, the permeation enhancer suitable for transdermal delivery into the eyelid is a permeation enhancer that is particularly suitable for transdermal delivery adjacent to the eye and / or is not typically found in topical steroid ointment / cream formulations (for use on other areas of the subject's body, such as the hands or feet). Examples of permeation enhancers suitable for delivery into the subject's eyelid may include, but are not limited to, Tween-80, polyethylene glycol (PEG), diethylene glycol monoethyl ether, essential oils, hyaluronic acid, benzalkonium chloride (BAK), and / or any combination thereof.

[0069] In some embodiments, the pharmaceutically acceptable carrier is adapted for periocular transdermal delivery by formulating the carrier so that (1) it achieves improved spreadability on the periocular surface compared to ointment bases; and / or (2) it avoids flow from the periocular surface onto the corneal surface. After applying a typical steroid ointment or cream to the skin, the body heat absorbed by the cream or ointment reduces viscosity and / or yield stress, reducing adhesion on the contact surface, such as periocular skin. The reduced adhesion after heat absorption is problematic for ointments or creams applied to the eyelids, because the reduced adhesion can cause the cream or ointment to spread / flow on the ocular surface. In some embodiments, the pharmaceutically acceptable carrier comprises improved spreadability properties and rheological characteristics, resulting in easier administration and spreading on the eyelid surface, and resulting in the lack of flow, especially at the subject's body temperature (e.g., 31 ° C, 33 ° C, 35 ° C, 37 ° C, etc.) after application to the subject's skin. In some embodiments, the pharmaceutical composition of the present disclosure is formulated so that the adhesiveness of the formulation does not change significantly after application to the subject's skin (e.g., eyelid).Examples of suitable additives that provide suitable adhesiveness of the formulation may include, for example, additives that increase the viscosity of the formulation, such as wax, paraffin, and elastomer.In some embodiments, the viscosity of the pharmaceutically acceptable carrier does not change significantly when heated from room temperature (e.g., 25°C) to a temperature closer to the subject's body temperature (e.g., 31°C, 33°C, 35°C, 37°C, etc.). In some embodiments, the viscosity of the pharmaceutically acceptable carrier does not change by more than about 10%, more than about 9%, more than about 8%, more than about 7%, more than about 6%, more than about 5%, more than about 4%, more than about 3%, more than about 2%, more than about 1%, more than about 0.5%, more than about 0.1%, or more than about 0.01% when heated from room temperature (e.g., approximately 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C) to a temperature closer to the subject's body temperature (e.g., approximately 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, or 37°C).

[0070] In some embodiments, the pharmaceutically acceptable carrier is an ointment, cream, lotion, gel, emulsion, suspension, oil, foam, transdermal patch, spray, or any combination thereof. In some embodiments, the pharmaceutically acceptable carrier is an ointment. In some embodiments, the pharmaceutically acceptable carrier is a cream. In some embodiments, the pharmaceutically acceptable carrier is a buffer, such as phosphate, citrate, and other organic acids; antioxidants, such as ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers. , such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates such as glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; polyols such as glycerol (e.g., formulations containing 10% glycerol) or propylene glycol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as polyethylene glycol (PEG). A complete discussion of pharmaceutically acceptable carriers is available in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., NJ 1991).

[0071] In some embodiments, pharmaceutically acceptable carrier further comprises one or more additional components.The example of additional components can include but is not limited to: binder (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose etc.); filler (for example, lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethylcellulose, polyacrylate or calcium hydrogen phosphate etc.); lubricant (for example, magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metal stearates, hydrogenated vegetable oils, corn starch, polyethylene glycol, sodium benzoate, sodium acetate etc.); disintegrant (for example, starch, sodium starch glycolate etc.); wetting agent (for example, sodium lauryl sulfate etc.); salt solution; alcohol; polyethylene glycol; gelatin; lactose; amylase; magnesium stearate; talc; silicic acid; viscous paraffin; hydroxymethylcellulose; polyvinylpyrrolidone; fragrance; colorant; moisturizer; sunscreen etc.

[0072] In some embodiments, the pharmaceutically acceptable carrier is an ointment comprising a water-miscible ointment base. In some embodiments, the pharmaceutically acceptable carrier is an ointment comprising a paraffin-based ointment base. In some embodiments, the ointment comprises one or more (e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or all 9) of white soft paraffin, mineral oil, propylene glycol, ST cyclomethicone-5NF, Labrasol, propylene carbonate, steareth 2, ST emulsifier 10, and ST elastomer-10. In some embodiments, the ointment comprises white soft paraffin, mineral oil, propylene glycol, ST cyclomethicone-5NF, Labrasol, propylene carbonate, steareth 2, ST emulsifier 10, and ST elastomer-10. In some embodiments, the ointment comprises about 61.5% w / w white soft paraffin, about 8% w / w mineral oil, about 8% w / w propylene glycol, about 5% w / w ST Cyclomethicone-5NF, about 5% w / w Labrasol, about 5% w / w propylene carbonate, about 2.5% w / w Steareth 2, about 2.5% w / w St. Emulsifier 10, and about 2.5% w / w St. Elastomer-10.

[0073] In some embodiments, the pharmaceutically acceptable carrier is a cream that comprises an oil-in-water base.In some embodiments, the pharmaceutically acceptable carrier is a cream that comprises a water-in-oil base.In some embodiments, the cream comprises one or more (for example, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or all 13) of white soft paraffin / petrolatum, mineral oil, propylene glycol, cyclomethicone, ST-cyclomethicone-5NF, emulsifier 10, ST-emulsifier, ST-elastomer-10, methylparaben, dibasic sodium phosphate, citric acid, propylparaben, and purified water. In some embodiments, the cream comprises white soft paraffin / petrolatum, mineral oil, propylene glycol, ST-cyclomethicone-5NF, ST-emulsifier, ST-elastomer-10, methylparaben, dibasic sodium phosphate, citric acid, propylparaben, and purified water. In some embodiments, the cream comprises about 48% w / w white soft paraffin / petrolatum, about 8% w / w mineral oil, about 8% w / w propylene glycol, about 6.6% w / w ST-cyclomethicone-5NF, about 3.3% w / w ST-emulsifier, about 2% w / w ST-elastomer-10, about 0.08% w / w methylparaben, about 0.06% w / w dibasic sodium phosphate, about 0.05% w / w citric acid, about 0.02% w / w propylparaben, and an amount of purified water. In some embodiments, the cream comprises white soft paraffin / petrolatum, mineral oil, propylene glycol, cyclomethicone, emulsifier 10, ST-elastomer-10, methylparaben, anhydrous dibasic sodium phosphate, anhydrous citric acid, propylparaben, and purified water. In some embodiments, the cream comprises about 48% w / w white soft paraffin / petrolatum, about 8% w / w mineral oil, about 8% w / w propylene glycol, about 6.6% w / w cyclomethicone, about 3.3% w / w emulsifier 10, about 2% w / w ST-elastomer-10, about 0.08% w / w methylparaben, about 0.06% w / w anhydrous dibasic sodium phosphate, about 0.046% w / w anhydrous citric acid, about 0.02% w / w propylparaben, and a quantity of purified water.

[0074] In some embodiments, the cream contains white soft paraffin / petrolatum, mineral oil, propylene glycol, ST-cyclomethicone-5NF, ST-emulsifier-10, ST-elastomer-10, dibasic sodium phosphate, citric acid, and purified water, and is preservative-free. In some embodiments, the cream contains 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.06% w / w anhydrous dibasic sodium phosphate, 0.05% w / w anhydrous citric acid, and an appropriate amount of purified water, and is preservative-free.

[0075] The pharmaceutical compositions and formulations of the present disclosure can be prepared by mixing steroid with one or more pharmaceutically acceptable carriers.The formulations used for in vivo administration are generally sterile.Sterility can be easily achieved, for example, by filtering through sterile filtration membrane, by heat exposure, and / or by gamma irradiation.

[0076] Additional lipophilic compounds In some embodiments, the pharmaceutical compositions of the present disclosure further comprise at least one (e.g., at least one, at least two, at least three, at least four, or at least five, etc.) additional lipophilic compound. Accordingly, in some embodiments, the pharmaceutical compositions provided herein further comprise one or more lipophilic compounds selected from the group consisting of steroids, antibiotics, immunomodulatory agents, integrin antagonists, anti-inflammatory agents, anti-glaucoma agents, and anti-ocular hypertension agents, and combinations thereof.

[0077] Steroids as additional lipophilic compounds In some embodiments, the pharmaceutical composition of the present disclosure further comprises at least one additional steroid. In some embodiments, the pharmaceutical composition comprises at least two (e.g., at least two, at least three, at least four, at least five, etc.) additional steroids. Any suitable steroid known in the art can be used as one or more additional steroids in the pharmaceutical composition, including, for example, the compound of Formula I, fluocinolone, medrysone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, and testosterone, or any ester derivative thereof. In some embodiments, the additional steroid is a glucocorticoid. In some embodiments, at least one additional steroid is a steroid different from the first steroid in the pharmaceutical composition. For example, the first steroid can be a compound of Formula I and the additional steroids can be triamcinolone acetonide, dexamethasone, and / or loteprednol etabonate.

[0078] In some embodiments, the pharmaceutical composition comprises one or more additional steroids at a concentration of 0.001% to 10% weight / weight (w / w). For example, the pharmaceutical composition may comprise one or more additional steroids at a concentration of about 0.001% to about 10%, about 0.001% to about 9%, about 0.001% to about 8%, about 0.001% to about 7%, about 0.001% to about 6%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, or about 0.001% to about 0.05%. , about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.01% to about 10%, about 0.01% to about 9%, about 0.01% to about 8%, about 0.01% to about 7%, about 0.01% to about 6%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to About 0.05%, about 0.05% to about 10%, about 0.05% to about 9%, about 0.05% to about 8%, about 0.05% to about 7%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3%, about 0.05% to about 2%, about 0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 0.1% to about 10%, about 0.1% to about 9%, about 0.1% to about 8%, About 0.1% to about 7%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.5% to about 10%, about 0.5% to about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 10%, about 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 3% The additional steroid may be included at a concentration of about 5%, about 3% to about 4%, about 4% to about 10%, about 4% to about 9%, about 4% to about 8%, about 4% to about 7%, about 4% to about 6%, about 4% to about 5%, about 5% to about 10%, about 5% to about 9%, about 5% to about 8%, about 5% to about 7%, about 5% to about 6%, about 6% to about 10%, about 6% to about 9%, about 6% to about 8%, about 6% to about 7%, about 7% to about 10%, about 7% to about 9%, about 7% to about 8%, about 8% to about 10%, about 8% to about 9%, or about 9% to about 10% w / w. In some embodiments, the pharmaceutical composition comprises an additional steroid at any of the following concentrations: about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w / w.

[0079] In some embodiments, the pharmaceutically acceptable steroid or formulation thereof has the added advantage of not causing thinning of the skin.

[0080] Antibiotics as additional lipophilic compounds In some embodiments, the pharmaceutical compositions of the present disclosure further comprise a therapeutically effective amount of one or more antibiotics. In some embodiments, the pharmaceutical compositions comprise two or more (e.g., two or more, three or more, four or more, five or more, etc.) antibiotics. Any suitable antibiotic known in the art can be used in the pharmaceutical compositions of the present disclosure, including, for example, sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, tetracyclines, and any combination thereof. Examples of such antibiotics include, but are not limited to, azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxifloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, and sulfacetamide.

[0081] In some embodiments, the pharmaceutical composition comprises one or more antibiotics at a concentration of 0.0001% to 10% weight / weight (w / w). For example, the pharmaceutical composition may contain from about 0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, from about 0.0001% to about 0 0.001%, approximately 0.0001% to approximately 0.0005%, approximately 0.0005% to approximately 10%, approximately 0.0005% to approximately 9%, approximately 0.0005% to approximately 8%, approximately 0.0005% to approximately 7%, approximately 0.0005% to approximately 6%, approximately 0.0005% to approximately 5%, approximately 0.0005% to approximately 4%, approximately 0.0005% to approximately 3%, approximately 0.0005% to approximately 2%, approximately 0.0005% to approximately 1%, approximately 0.0005% to approximately 0.5%, approximately 0.0005% to approximately 0.1%, approximately 0.0005% to approximately 0.05%, approximately 0.0005% to approximately 0.01%, approximately 0.0005% to approximately 0.005 , about 0.0005% to about 0.001%, about 0.001% to about 10%, about 0.001% to about 9%, about 0.001% to about 8%, about 0.001% to about 7%, about 0.001% to about 6%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.01% to about 10%, about 0.01% to about 9%, about 0.01% to about 8%, about 0.01% to about 7%, about 0.01% to about 6%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 10%, about 0.05% to about 9%, about 0.05% to about 8%, about 0.05% to about 7%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3%, about 0.05% to about 2%, about 0.0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 0.1% to about 10%, about 0.1% to about 9%, about 0.1% to about 8%, about 0.1% to about 7%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.5% to about 10%, about 0.5% to about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to About 3%, about 1% to about 2%, about 2% to about 10%, about 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 3% to about 5%, about 3% to about 4%, about 4% to about 10%, about 4% to about 9%, about 4% to The pharmaceutical composition may contain one or more antibiotics at a concentration of about 8%, about 4% to about 7%, about 4% to about 6%, about 4% to about 5%, about 5% to about 10%, about 5% to about 9%, about 5% to about 8%, about 5% to about 7%, about 5% to about 6%, about 6% to about 10%, about 6% to about 9%, about 6% to about 8%, about 6% to about 7%, about 7% to about 10%, about 7% to about 9%, about 7% to about 8%, about 8% to about 10%, about 8% to about 9%, or about 9% to about 10% w / w. In some embodiments, the pharmaceutical composition contains one or more antibiotics at a concentration of 0.0001% to 5% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25% %,0.275%,0.3%,0.35%,0.4%,0.45%,0.5%,0.55%,0.6%,0.65%,0.7%,0.75%,0.8%,0.85%,0.9%,0.95%,1%,1.25%,1.5%,1.75%,2%,2.25%,2.5%,2.75%,3%,3.5%,4%,4.5%,5%,5.Contains one or more antibiotics at a concentration of 5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w / w.

[0082] Immunomodulators as additional lipophilic compounds In some embodiments, the pharmaceutical composition of the present disclosure further comprises a therapeutically effective amount of one or more immunomodulatory agents. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) immunomodulatory agents. Any suitable immunomodulatory agent known in the art can be used in the pharmaceutical composition of the present disclosure, including, for example, calcineurin inhibitors, thalidomide analogs, and any combination thereof. Examples of such immunomodulatory agents include, but are not limited to, cyclosporin A, voclosporin, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide.

[0083] In some embodiments, the pharmaceutical composition comprises one or more immunomodulatory agents at a concentration of 0.0001% to 5% weight / weight (w / w).For example, the pharmaceutical composition may contain about 0.0001% to about 5%, about 0.0001% to about 4%, about 0.0001% to about 3%, about 0.0001% to about 2%, about 0.0001% to about 1%, about 0.0001% to about 0.5%, about 0.0001% to about 0.1%, about 0.0001% to about 0.05%, about 0.0001% to about 0.01%, about 0.0001% to about 0.005%, about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 5%, about 0.0005% to about 4%, about 0.0005% to about 3%, about 0.0005% to about 2%, About 0.0005% to about 1%, about 0.0005% to about 0.5%, about 0.0005% to about 0.1%, about 0.0005% to about 0.05%, about 0.0005% to about 0.01%, about 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 5%, about 0.005% to about 4%, about 0.005% to about 3%, about 0.005% to about 2%, about 0.005% to about 1%, about 0.005% to about 0.5%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3 %, about 0.05% to about 2%, about 0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 5%, about 3% to about 4%, or about 4% to about 5% It may contain one or more immunomodulatory agents in w / w concentrations.In some embodiments, the pharmaceutical composition comprises about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, or 5% and one or more immunomodulatory agents in any of the following w / w concentrations:

[0084] Integrin antagonists as additional lipophilic compounds In some embodiments, the pharmaceutical composition of the present disclosure further comprises a therapeutically effective amount of one or more integrin antagonists. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) integrin antagonists. For example, any suitable integrin antagonist known in the art can be used in the pharmaceutical composition of the present disclosure, including lifitegrast, GW559090, its ester derivatives, and any combination thereof. In some embodiments, the pharmaceutical composition comprises GW559090 (see Krauss et al. Invest. Ophthalmol. Vis. Sci. 2015;56(10):5888-95).

[0085] In some embodiments, the pharmaceutical composition comprises one or more integrin antagonists at a concentration of 0.0001% to 10% weight / weight (w / w). For example, the pharmaceutical composition may contain from about 0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, from about 0.0001% to about 0 0.001%, approximately 0.0001% to approximately 0.0005%, approximately 0.0005% to approximately 10%, approximately 0.0005% to approximately 9%, approximately 0.0005% to approximately 8%, approximately 0.0005% to approximately 7%, approximately 0.0005% to approximately 6%, approximately 0.0005% to approximately 5%, approximately 0.0005% to approximately 4%, approximately 0.0005% to approximately 3%, approximately 0.0005% to approximately 2%, approximately 0.0005% to approximately 1%, approximately 0.0005% to approximately 0.5%, approximately 0.0005% to approximately 0.1%, approximately 0.0005% to approximately 0.05%, approximately 0.0005% to approximately 0.01%, approximately 0.0005% to approximately 0.005 , about 0.0005% to about 0.001%, about 0.001% to about 10%, about 0.001% to about 9%, about 0.001% to about 8%, about 0.001% to about 7%, about 0.001% to about 6%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.01% to about 10%, about 0.01% to about 9%, about 0.01% to about 8%, about 0.01% to about 7%, about 0.01% to about 6%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 10%, about 0.05% to about 9%, about 0.05% to about 8%, about 0.05% to about 7%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3%, about 0.05% to about 2%, about 0.0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 0.1% to about 10%, about 0.1% to about 9%, about 0.1% to about 8%, about 0.1% to about 7%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.5% to about 10%, about 0.5% to about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to About 3%, about 1% to about 2%, about 2% to about 10%, about 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 3% to about 5%, about 3% to about 4%, about 4% to about 10%, about 4% to about 9%, about 4% to The one or more integrin antagonists may be included at a concentration of about 8%, about 4% to about 7%, about 4% to about 6%, about 4% to about 5%, about 5% to about 10%, about 5% to about 9%, about 5% to about 8%, about 5% to about 7%, about 5% to about 6%, about 6% to about 10%, about 6% to about 9%, about 6% to about 8%, about 6% to about 7%, about 7% to about 10%, about 7% to about 9%, about 7% to about 8%, about 8% to about 10%, about 8% to about 9%, or about 9% to about 10% w / w. In some embodiments, the pharmaceutical composition comprises about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0. 35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.Contains one or more integrin antagonists at either a 5% or 10% w / w concentration.

[0086] Anti-inflammatory agents as additional lipophilic compounds In some embodiments, the pharmaceutical composition of the present disclosure further comprises a therapeutically effective amount of one or more anti-inflammatory agents. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) anti-inflammatory agents. Any suitable anti-inflammatory agent known in the art can be used in the pharmaceutical composition of the present disclosure, including, for example, omega-3 fatty acids, nonsteroidal anti-inflammatory drugs (NSAIDs), and any combination thereof. Examples of suitable omega-3 fatty acids can include, but are not limited to, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combination thereof. Examples of suitable NSAIDs can include, but are not limited to, bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and any combination thereof.

[0087] In some embodiments, the pharmaceutical composition comprises one or more anti-inflammatory agents at a concentration of 0.0001% to 5% weight / weight (w / w).For example, the pharmaceutical composition may contain about 0.0001% to about 5%, about 0.0001% to about 4%, about 0.0001% to about 3%, about 0.0001% to about 2%, about 0.0001% to about 1%, about 0.0001% to about 0.5%, about 0.0001% to about 0.1%, about 0.0001% to about 0.05%, about 0.0001% to about 0.01%, about 0.0001% to about 0.005%, about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 5%, about 0.0005% to about 4%, about 0.0005% to about 3%, about 0.0005% to about 2%, About 0.0005% to about 1%, about 0.0005% to about 0.5%, about 0.0005% to about 0.1%, about 0.0005% to about 0.05%, about 0.0005% to about 0.01%, about 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 5%, about 0.005% to about 4%, about 0.005% to about 3%, about 0.005% to about 2%, about 0.005% to about 1%, about 0.005% to about 0.5%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3 %, about 0.05% to about 2%, about 0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.1%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 5%, about 3% to about 4%, or about 4% to about 5% It may contain one or more anti-inflammatory agents in w / w concentrations.In some embodiments, the pharmaceutical composition comprises about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, or 5% and one or more anti-inflammatory agents in any w / w concentration.

[0088] Antiglaucoma and antiocular hypertension agents as additional lipophilic compounds In some embodiments, the pharmaceutical composition of the present disclosure further comprises a therapeutically effective amount of one or more antiglaucoma or anti-ocular hypertension agents. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) antiglaucoma or anti-ocular hypertension agents. Any suitable antiglaucoma or anti-ocular hypertension agent known in the art can be used in the pharmaceutical composition of the present disclosure, including, for example, prostaglandin analogs, beta-blockers, alpha2 agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and any combination thereof. Examples of suitable prostaglandin analogs include, but are not limited to, bimatoprost, latanoprost, travoprost, tafluprost, latanoprostene bunod, and any combination thereof. Examples of suitable beta-blockers include, but are not limited to, timolol, betaxolol, levobunolol, metipranolol, and any combination thereof. Suitable examples of alpha 2 agonists may include brimonidine, clonidine, apraclonidine, and any combination thereof.Suitable examples of carbonic anhydrase inhibitors may include but are not limited to dorzolamide, brinzolamide, acetazolamide, methazolamide, and any combination thereof.Suitable examples of Rho kinase inhibitors may include but are not limited to netarsudil, and any combination thereof.

[0089] In some embodiments, the pharmaceutical composition comprises one or more anti-glaucoma or anti-ocular hypertension agents at a concentration of 0.0001% to 10% weight / weight (w / w). For example, the pharmaceutical composition may contain about 0.0001% to about 10%, about 0.0001% to about 9%, about 0.0001% to about 8%, about 0.0001% to about 7%, about 0.0001% to about 6%, about 0.0001% to about 5%, about 0.0001% to about 4%, about 0.0001% to about 3%, about 0.0001% to about 2%, about 0.0001% to about 1%, about 0.0001% to about 0.5%, about 0.0001% to about 0.1%, about 0.0001% to about 0.05%, about 0.0001% to about 0.01%, about 0.0001% to about 0.005%, about 0.0001% ~ about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 10%, about 0.0005% to about 9%, about 0.0005% to about 8%, about 0.0005% to about 7%, about 0.0005% to about 6%, about 0.0005% to about 5%, about 0.0005% to about 4%, about 0.0005% to about 3%, about 0.0005% to about 2%, about 0.0005% to about 1%, about 0.0005% to about 0.5%, about 0.0005% to about 0.1%, about 0.0005% to about 0.05%, about 0.0005% to about 0.01%, about 0.0005% to about 0 0.005%, about 0.0005% to about 0.001%, about 0.001% to about 10%, about 0.001% to about 9%, about 0.001% to about 8%, about 0.001% to about 7%, about 0.001% to about 6%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.01% to about 10%, About 0.01% to about 9%, about 0.01% to about 8%, about 0.01% to about 7%, about 0.01% to about 6%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 10%, about 0.05% to about 9%, about 0.05% to about 8%, about 0.05% to about 7%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3%, about 0.0.05% to approximately 2%, approximately 0.05% to approximately 1%, approximately 0.05% to approximately 0.5%, approximately 0.05% to approximately 0.1%, approximately 0.1% to approximately 10%, approximately 0.1% to approximately 9%, approximately 0.1% to approximately 8%, approximately 0.1% to approximately 7%, approximately 0.1% to approximately 6%, approximately 0.1% to approximately 5%, approximately 0.1% to approximately 4%, approximately 0.1% to approximately 3%, approximately 0.1% to approximately 2%, approximately 0.1% to approximately 1%, approximately 0.1% to approximately 0.5 , about 0.5% to about 10%, about 0.5% to about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4 , about 1% to about 3%, about 1% to about 2%, about 2% to about 10%, about 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 3% to about 5%, about 3% to about 4%, about 4% to about 10%, about 4% to about 9%, about The composition may contain one or more anti-glaucoma or anti-ocular hypertension agents at a concentration of 4% to about 8%, about 4% to about 7%, about 4% to about 6%, about 4% to about 5%, about 5% to about 10%, about 5% to about 9%, about 5% to about 8%, about 5% to about 7%, about 5% to about 6%, about 6% to about 10%, about 6% to about 9%, about 6% to about 8%, about 6% to about 7%, about 7% to about 10%, about 7% to about 9%, about 7% to about 8%, about 8% to about 10%, about 8% to about 9%, or about 9% to about 10% w / w. In some embodiments, the pharmaceutical composition comprises about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0. 35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.Contains one or more antiglaucoma or anti-ocular hypertension agents at either 5% or 10% w / w concentration.

[0090] II. Method Certain aspects of the present disclosure relate to methods of providing preventative, palliative, and / or therapeutic relief of one or more signs or symptoms of an ocular disease (e.g., an ocular inflammatory condition, a bacterial infection, or glaucoma), comprising administering a therapeutically effective amount of any of the pharmaceutical compositions of the present disclosure to a subject in need thereof. In some embodiments, the present disclosure relates to methods of treating an ocular disease (e.g., an ocular inflammatory condition, a bacterial infection, or glaucoma), comprising administering a therapeutically effective amount of any of the pharmaceutical compositions of the present disclosure to a subject in need thereof. In some embodiments, the subject has or is at risk of developing the ocular disease (e.g., an ocular inflammatory condition, a bacterial infection, or glaucoma).

[0091] In some embodiments, the lipid structures of the eyelid (e.g., meibomian glands, meibum, other fatty tissues) serve as a drug depot for the periocularly delivered pharmaceutical compositions provided herein, with the meibum serving as the drug delivery vehicle.

[0092] In some embodiments, the subject is a non-human animal, including, but not limited to, domestic animals (e.g., cows, sheep, cats, dogs, horses, etc.), non-human primates (e.g., monkeys), rabbits, and rodents (e.g., mice, hamsters, rats, etc.). In some embodiments, the subject is a human. In some embodiments, the subject suffers from one or more (e.g., one or more, two or more, three or more, four or more, five or more, etc.) eye diseases and / or conditions. Examples of ocular diseases and / or conditions may include, but are not limited to, periocular gland inflammation, meibomianitis, dry eye disease, allergic eye disease, topical preservative toxicity, xerophthalmia, loss of tear film homeostasis, tear film instability and hyperosmolarity, ocular surface inflammation and damage, neuronal paresthesia, meibomian gland dysfunction, exacerbated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof.

[0093] In some embodiments, the pharmaceutical compositions of the present disclosure are administered topically to a subject. As used herein, "topically administered," "topical administration," or "administering topically" refers to the delivery of a composition to a subject by directly or otherwise contacting a formulation containing the composition with a portion of the subject's skin. This term can encompass several routes of administration, including, but not limited to, topical and transdermal. Topical administration can be used as a means to deliver a composition to the epidermis or dermis of a subject, or to a specific layer thereof.

[0094] In some embodiments, the pharmaceutical composition of the present disclosure is topically administered to the outer portion of one or all of the subject's eyelids (including the upper lateral portion of one or both of the subject's orbits). In some embodiments, the pharmaceutical composition is topically administered to the outer portion of the upper eyelid and / or lower eyelid of one or both of the subject's eyes. In some embodiments, the pharmaceutical composition is not administered directly and / or indirectly to the ocular surface.

[0095] In some embodiments, the pharmaceutical compositions of the present disclosure are topically administered to one or all outer portions of a subject's eyelids (including the superior lateral portions of one or both of the subject's orbits) to deliver a lipophilic compound (e.g., a steroid) to one or more meibomian glands of the subject. In some embodiments, one or more components (e.g., a steroid) in the pharmaceutical composition are delivered to the subject's ocular surface via one or more meibomian glands. In some embodiments, one or more components (e.g., a steroid) in the pharmaceutical composition are delivered to the subject's ocular surface via the meibum.

[0096] In some embodiments, the pharmaceutical compositions of the present disclosure are administered one or more times per day (e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more times, etc.). In some embodiments, the pharmaceutical compositions of the present disclosure are administered for 1, 2, 3, 4, 5, 6, 7 or more consecutive days. In some embodiments, the pharmaceutical compositions of the present disclosure are administered for 1, 2, 3, 4, 5, 6, 7 or more non-consecutive days. In some embodiments, the pharmaceutical compositions of the present disclosure are administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more consecutive weeks. In some embodiments, the pharmaceutical compositions of the present disclosure are administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more non-consecutive weeks. In some embodiments, the pharmaceutical compositions of the present disclosure are administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more consecutive months. In some embodiments, the pharmaceutical compositions of the present disclosure are administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more non-consecutive months. In some embodiments, treatment is initiated with a loading dose followed by dose tapering. In some embodiments, treatment is initiated with a loading dose followed by continuous treatment at lower doses.

[0097] In some embodiments, the exposure level of the lipophilic compound in the eyelid, bulbar conjunctiva, cornea, iris / ciliary body (ICB), and / or aqueous humor (AQH) remains constant or substantially constant for up to 24 hours after application of the final periocular dose. In some embodiments, the concentration of the lipophilic compound in one or more compartments selected from the group consisting of the eyelid, bulbar conjunctiva, cornea, iris / ciliary body (ICB), and aqueous humor (AQH) differs by less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% when comparing the concentrations at 2 hours and 24 hours after application of the final periocular dose. In some embodiments, the concentration of the lipophilic compound in one or more compartments selected from the group consisting of the eyelid, bulbar conjunctiva, cornea, iris / ciliary body (ICB), and aqueous humor (AQH) 24 hours after application of the final periocular dose is within 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the concentration of the lipophilic compound 2 hours after application of the final periocular dose. In some embodiments, the concentration of the lipophilic compound in the eyelid 24 hours after application of the final periocular dose is within 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the concentration of the lipophilic compound 2 hours after application of the final periocular dose. In some embodiments, the concentration of the lipophilic compound in the eyelid 24 hours after application of the final periocular dose is 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% or more of the concentration of the lipophilic compound 2 hours after application of the final periocular dose. In some embodiments, the concentration of the lipophilic compound in one or more compartments selected from the group consisting of the eyelid, bulbar conjunctiva, cornea, iris / ciliary body (ICB), and aqueous humor (AQH) 24 hours after application of the final periocular dose is 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% or more of the concentration of the lipophilic compound 2 hours after application of the final periocular dose.In some embodiments, the concentration of the lipophilic compound in the eyelid 24 hours after application of the final periocular dose is 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% or more of the concentration of the lipophilic compound 2 hours after application of the final periocular dose.

[0098] In some embodiments, topical administration of a pharmaceutical composition as described herein provides preventative, palliative, and / or therapeutic relief of one or more symptoms of ocular disease in a subject.In some embodiments, topical administration of a pharmaceutical composition as described herein reduces or eliminates one or more symptoms of ocular disease in a subject.Examples of signs or symptoms of ocular disease include, but are not limited to, redness of the eye and / or eyelid margin, tearing, dry eyes, itchy, stinging, or burning sensation in the eye or orbit, blurred vision, difficulty driving at night, night blindness, dry conjunctiva, dry cornea, corneal ulcers, Bitot's spots, eye fatigue, foreign body sensation in the eye, light sensitivity, fibrous mucus in or around the eye, swelling of the conjunctiva and / or eyelid, swelling of the eyelid and / or Symptoms may include dry, flaky, and / or damaged skin of the orbit, oily eyelids, eyelid sticking, abnormal eyelash growth, loss of eyelashes, discomfort or pain in the eye, eyelid, and / or orbit, chronic and transient punctate keratopathy, filamentous keratopathy, recurrent corneal erosions, persistent epithelial defects, corneal melting, ocular surface failure, blepharospasm, mucopurulent discharge, the appearance of chalazions, and any combination thereof.

[0099] In some embodiments, topical administration of a pharmaceutical composition as described herein reduces inflammation in one or more periorbital glands (e.g., one or more, two or more, or all three of the meibomian glands, lacrimal glands, and / or accessory lacrimal glands) of a subject. In some embodiments, topical administration of a pharmaceutical composition as described herein reduces inflammation in one or more periorbital glands by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% compared to the inflammation observed before administration of the pharmaceutical composition. In some embodiments, topical administration of pharmaceutical compositions reduces the inflammation in one or more periorbital glands by about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 100-fold, or about 1000-fold compared to the inflammation observed before administration of pharmaceutical compositions.In some embodiments, topical administration of pharmaceutical compositions as described herein eliminates the inflammation in one or more periorbital glands of a subject.Methods for measuring periorbital gland inflammation are known in the art, including, for example, using laser intravital confocal microscope (IVCM) (see Qazi et al. Investigative Ophthalmology & Visual Science March 2012, Vol.53, 593).

[0100] In some embodiments, the topical administration (e.g., long-term / sustained administration) of the pharmaceutical composition as described herein does not cause adverse events in the subject.Examples of adverse events may include, but are not limited to, increased intraocular pressure, cataract formation or worsening, eye infection, and any combination thereof.In some embodiments, the topical administration of the pharmaceutical composition does not increase / increase the intraocular pressure in the subject.

[0101] In some embodiments, the lipophilic compound is not delivered systemically to the subject by administration of the pharmaceutical composition. In some embodiments, the lipophilic compound is not delivered to the tears or lacrimal duct of the subject by administration of the pharmaceutical composition. In some embodiments, the lipophilic compound is not delivered directly to the ocular surface of the subject by administration of the pharmaceutical composition.

[0102] III. ARTICLE OF MANUFACTURE OR KITS Certain aspects of the present disclosure relate to articles of manufacture or kits containing one or more of the pharmaceutical compositions described herein. In some embodiments, the articles of manufacture or kits include a label and / or package insert containing instructions for use of the one or more pharmaceutical compositions. In some embodiments, the one or more pharmaceutical compositions are provided in a container. In some embodiments, the components of the pharmaceutical compositions are provided in a single container or in two or more separate containers. In some embodiments, the articles of manufacture or kits include a container and a label or package insert on or associated with the container. Suitable containers may include, for example, tubes, bottles, vials, bags, etc. The containers may be formed from a variety of suitable materials, such as glass, plastic (e.g., polyvinyl chloride, polyolefin, or polyethylene), metal, and / or alloys (e.g., stainless steel). The articles of manufacture or kits may further include other materials desirable from a commercial and user standpoint, including buffers, diluents, filters, syringes, applicators, etc.

[0103] The foregoing description is believed to be sufficient to enable one skilled in the art to practice the present disclosure. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the disclosure in any way. Indeed, various modifications of the present disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims.

[0104] IV. Definition Before describing the present disclosure in detail, it is to be understood that this disclosure is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting.

[0105] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a molecule" optionally includes combinations of two or more such molecules, and the like.

[0106] As used herein, the term "about" refers to a normal error range for each value that is readily apparent to one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) aspects related to that value or parameter itself.

[0107] As used herein, the term "and / or," when in a phrase such as "A and / or B," is intended to include both A and B; A or B; A alone; and B alone. Similarly, as used herein, the term "and / or," when in a phrase such as "A, B, and / or C," is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; and C alone.

[0108] As used herein, the terms "individual," "patient," or "subject" refer to mammals. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates, such as monkeys), rabbits, and rodents (e.g., mice, hamsters, and rats). In some embodiments, the individual, patient, or subject is a human.

[0109] As used herein, the term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredients contained therein to be effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered.

[0110] As used herein, the term "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject.

[0111] As used herein, the term "prevention" includes providing prophylactic treatment with respect to the onset or recurrence of one or more signs or symptoms of a disorder in an individual who may be predisposed to, susceptible to, or at risk of developing the disorder, but who has not yet been diagnosed with the disorder.

[0112] As used herein, the individual who is "at risk" of developing a disorder may or may not have detectable disease or disease symptoms, and may or may not have detected disease or disease symptoms before the treatment method described herein. "At risk" means that the individual has one or more risk factors, which are measurable parameters that correlate with the development of a disorder, as known in the art.The individual who has one or more of these risk factors has a higher probability of developing a disorder than the individual who does not have one or more of these risk factors.

[0113] As used herein, the term "treatment" refers to a clinical intervention designed to change the natural course of the individual or cell being treated during the clinical pathological course. Desired treatment effects include, for example, slowing the rate of disease progression, improving or alleviating the disease state, and improving prognosis. For example, an individual is "treated" successfully if one or more signs or symptoms associated with the disorder are alleviated or eliminated. For example, an individual is "treated" successfully if one or more symptoms associated with inflammatory disease are alleviated or eliminated, including, but not limited to, a reduction in symptoms caused by the disease, an increase in the quality of life of those suffering from the disease, a reduction in the dose of other drugs required to treat the disease, and / or a delay in the progression of the disease.

[0114] An "effective amount" refers to at least an amount effective, at dosages and for periods of time necessary, to achieve a desired or stated effect, including a therapeutic or prophylactic result. An effective amount can be provided in one or more administrations.

[0115] " Therapeutically effective amount " is at least the minimum concentration required to produce measurable improvement of one or more signs or symptoms of specific disorders.The therapeutically effective amount herein can vary according to factors such as patient's disease state, age, sex and weight.The therapeutically effective amount also means that the therapeutically beneficial effect outweighs the harmful effect of treatment.

[0116] The term "periocular" refers to the area surrounding the eyeball but within the orbit, including the eyelids and lateral orbit.

[0117] "Periorbital glands" are glands in the area around the eyeball, including, for example, the meibomian glands, lacrimal glands, and / or accessory lacrimal glands. [Example]

[0118] Example 1: Effect of treatment with compounds of formula I on intraocular pressure (IOP) and tear formation The compound of Formula I is a fluorinated glucocorticoid with anti-inflammatory activity (see U.S. Patent No. 7,288,536). The compound of Formula I exhibited near-full agonism in various human in vitro assays of glucocorticoid receptor-mediated transrepression activity and partial responses in numerous assays of glucocorticoid receptor-mediated transactivation. In vivo, the compound of Formula I exhibited potent anti-inflammatory activity after intratracheal administration in models of pulmonary inflammation in mice and rats, and showed activity similar to that of fluticasone propionate (FP) in local delayed-type hypersensitivity otitis, tyrosine aminotransferase induction, and chronic house dust mite models in mice. Interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) stimulate the release of the proinflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) from various cell types through activation of the NFκB pathway. FP and compounds of Formula I can potently and efficiently transrepress this activation across multiple systems (A549, HeLa, MG63, 16HBE, and H9 cell lines), the same inflammatory markers that are elevated in patients with abnormal inflammation of the periocular glands (DEWS, 2007).

[0119] To test the effect of the compound of Formula I on intraocular pressure (IOP), eight female cynomolgus monkeys, aged 11–14 years at the start of the study, with unilateral (OS) ocular hypertension induced by a prior photocoagulation (laser) procedure on the trabecular meshwork (TM) were used. Laser-induced ocular hypertension had been created in the study animals at least 9 years earlier. Animals and treatments were randomized according to a 4x4 replicated Williams Latin square design. Following random assignment of numbers 1–8, the eight primates were randomized into four treatment groups (A–D) with two animals in each group. Treatment was concealed from the investigator until all data were collected and entered into a database. Treatment groups A–D were as follows: the compound of Formula I (10 mg / mL suspension in placebo vehicle), mapracorat (10 mg / mL suspension in placebo vehicle), Maxidex® (1 mg / mL), and placebo control.

[0120] Topical bilateral treatments were administered in a randomized, masked, floss-over format. All four treatments were studied in parallel, with two animals per treatment group during each 4-week treatment period. The assigned, masked formulation (A, B, C, or D) was administered in a 25 μL volume to both eyes (OU) three times daily (TID; 8:30 AM, 1:00 PM, and 5:00 PM). Treatment periods were separated by a 4-week washout / recovery period without topical treatment. The first period (Period 1) was preceded by a 2-week run-in period, during which all animals received a topical placebo TID.

[0121] Conscious animals were seated in custom-made chairs, and IOP was measured with a pneumotonometer (Classic 30, Reichert Depew) after topical application of proparacaine hydrochloride (0.13%) to both eyes (Figure 1). Two to three measurements were performed for each eye and averaged. Data were saved and archived. During the preparation and treatment periods, daytime IOP was determined twice weekly at approximately 8:30 AM, 1:00 PM, and 5:00 PM. Each animal received topical instillation of the appropriate drug formulation A, B, C, or D immediately after bilateral IOP measurements. During the washout period, daytime IOP was measured in both eyes once weekly at approximately 8:30 AM, 1:00 PM, and 5:00 PM. Surprisingly, topical treatment with the compound of Formula I for 4 weeks did not elevate IOP in primates (Figure 1). Indeed, IOP in eyes treated with the compound of Formula I was similar to eyes treated with vehicle alone and significantly lower than with dexamethasone treatment, demonstrating that the compound of Formula I does not produce the IOP elevation typically associated with topical corticosteroids (e.g., dexamethasone).

[0122] Next, the effect of treatment with the compound of formula I on tear formation was examined. Rabbits were placed in a restrainer, and 1% atropine sulfate eye drops (30 μL) were instilled into the inferior conjunctival sac of each eye four times daily. Fifteen minutes after administration of each dose of atropine sulfate, each eye received 30 μL of eye drops containing the active ingredient, vehicle, or saline. Tear volume was then assessed by the Schirmer test (FIG. 2). A Schirmer strip was carefully placed in the posterior (i.e., temporal) inferior fornix for 60 seconds, and the wetted area was read in millimeters as an indicator of tear volume. Surprisingly, when administered to the ocular surface in vivo for 7 days, the compound of formula I prevented the decline in tear formation in a model of dry eye disease, similar to topical dexamethasone (FIG. 2).

[0123] In summary, the data presented herein demonstrate that the compound of Formula I is equally effective as a topical corticosteroid (e.g., dexamethasone) in treating dry eye disease, but does not induce the negative side effect of IOP elevation typically associated with administration of corticosteroid compounds to the eye. The lack of effect on IOP indicates the improved and desirable safety profile of the compound of Formula I compared to other steroids such as dexamethasone.

[0124] Example 2: Characterization of Periocular Cream Formulations The following active pharmaceutical ingredients (APIs) were mixed with cream vehicles to prepare creams containing 2% API by weight for this study and allowed to stand at room temperature for 24 hours before testing: cyclosporine A (Sample A), loteprednol etabonate (Sample B), dexamethasone (Sample C), ketorolac tromethamine (Sample D), gatifloxacin USP (Sample E), gentamicin sulfate (Sample F), prednisolone (Sample G), flurbiprofen (Sample H), azithromycin dihydrate (Sample J), ​​triamcinolone acetonide (Sample K), and doxycycline hydrochloride (Sample L). The vehicle cream contained 48% w / w white soft petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w anhydrous sodium phosphate dibasic, 0.0546% w / w anhydrous citric acid, 0.02% w / w propylparaben, and an appropriate amount of purified water. The compound of formula I was incorporated into a cream having the following final composition: 2% w / w compound of formula I, 46% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, 0.02% w / w propylparaben, and an appropriate amount of purified water.

[0125] The results of the flow visualization studies were qualitative and photographically documented for each sample and test condition. Using a wide-mouth disposable pipette, approximately 1 ml of a small amount of 2% API-containing cream was placed into a Kimble 1-dram glass vial (15 x 45 mm). The vials were capped and labeled A through L on the glass vials, as referenced in the previous paragraph. For each test, in sets of two or three vials, the sample vials were placed into a thermostated Couette rheometer cup at 37°C and equilibrated at 37°C for a minimum of 10 minutes. After 10 minutes, the sample glass vial was removed, marked with a red line at the fluid surface or meniscus, inverted, and returned to the 37°C rheometer cup. At two time periods, 2 minutes and 5 minutes, the vials were removed and photographed to document the behavior of the cream.

[0126] Preliminary measurements were performed on vehicle cream and 2% Formula I compound cream in comparison with high viscosity polybutene standard N62000. The vehicle cream and 2% Formula I compound cream showed no discernible flow at 37°C at 2 and 5 minutes, in contrast to the N62000 high viscosity polymer standard, where bulk flow was observed (Figure 3A). The same procedure was used for 2% API-containing experimental cream samples prepared from the 11 compounds listed above, also tested at 37°C. This simple test shows that none of the 11 prepared 2% API-containing creams showed discernible flow under the specified test conditions, as shown for three of the creams in Figure 3B. In summary, the yield stress at 37°C appears to be strong enough to prevent flow under the influence of gravity under the test conditions.

[0127] The stress relaxation yield stress test used a rheometer and a 10% step strain stress relaxation measurement on a 25 mm cone and plate. The test applies an instantaneous motion as a step strain to the sample at t=0, and then measures the shear stress relaxation. For Newtonian fluids, the relaxation is immediate. For non-Newtonian fluids, there can be delayed stress relaxation, with a distribution of relaxation times with a relaxation to zero. Non-Newtonian fluids with a yield stress exhibit a distribution of relaxation times with a non-zero stress relaxation (or an infinite relaxation time), which is the equivalent of a yield stress. Tests were performed at both 25°C and 37°C.

[0128] Measurements with Ultima white petrolatum were compared with vehicle creams and 2% API-containing creams of the compound of Formula I and the 11 APIs mentioned above. The prepared 2% API creams, vehicle creams, and Ultima white petrolatum all exhibited yield stress as determined by these step-strain stress relaxation measurements. There is some variability in the data. This may be due to insufficient mixing of the API in each vehicle cream, air entrapment during mixing, the particle size of the API used in this study, and other factors. Regardless of the source of variability, each 2% API-containing cream exhibited a yield stress, as did the vehicle cream and white petrolatum. The curves (several examples in Figures 4A–D) show highly consistent stress relaxation to non-zero shear stress values. Noting that the creams are highly shear-sensitive, the results are summarized in the following table (Table 1) for each sample in each test, including Ultima petrolatum, at both 25°C and 37°C; 1–5 replicates.

[0129] (Table 1) TIFF0007796783000003.tif143128

[0130] For comparison, the yield stress values ​​(in Pa) for the vehicle cream were 4.1, 3.3, 2.9, and 1.0, 1.0, 1.5 (each with 3 replicates) at 25 and 37° C., respectively. The yield stress values ​​(in Pa) for the 2% compound of Formula I cream were 2.2, 2.8, and 1.0, 0.9, 0.9 (each with 2-3 replicates) at 25 and 37° C., respectively. For comparison, the stress relaxation function for the high viscosity polybutene N62000 standard showed a rapid decline to zero in less than 1 second at room temperature.

[0131] For all samples, except for Samples F and G, the yield stress decreased with increasing temperature from 25°C to 37°C. The yield stress of Ultima Vaseline was much higher than that of the 2% API-containing or vehicle cream samples, indicating the more difficult spreading of Ultima Vaseline onto contact surfaces, such as the eyelid. All 2% API creams exhibited extensional viscosity behavior, which may be strain thickening. This is a material property that may contribute to increased adhesion on contact surfaces, further counteracting the effects of gravity and limiting flow. More importantly, extensional viscosity may enhance physical stability, preventing settling of the active ingredient. These data suggest that all of the cream formulations are easier to apply to the intended surface (eyelid) compared to ointments. Due to the lower yield stress of the API-containing and vehicle creams, these formulations are easier for consumers to use and apply compared to petrolatum alone. In contrast, high-viscosity polymers such as N62000 are unlikely to be suitable for this invention. These data clearly demonstrate that the goal of developing a cream formulation that is easy to apply to a contact surface such as the eyelid and that does not run after application to the eyelid to prevent the formulation from running onto the ocular surface has been achieved with the formulation of the present invention.

[0132] Example 3: Skin penetration of periocular cream An in vitro skin permeation model using human cadaver skin mounted on Franz diffusion cells (FDC) was selected to determine the dermal permeation of a compound of Formula I applied as a 2% cream to the epidermal surface. Transdermal flux into the receptor fluid was measured over a 46-hour period after application of the formulation. At the end of the 46-hour incubation period, the skin was tape-stripped and heat-separated according to established methods, and the concentration of the compound of Formula I was measured in the remaining epidermis and dermis. The applied formulation consisted of 2% w / w compound of formula I, 46% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, 0.02% w / w propylparaben, and an appropriate amount of purified water. A vehicle cream consisting of 48% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, 0.02% w / w propylparaben, and an appropriate amount of purified water was also tested as a negative control.

[0133] Human cadaver skin from the hind limb of a single donor, dermatomed to a thickness of approximately 250 μm, was obtained from a commercial source and cut into pieces of approximately 2 cm x 2 cm, with each such piece cut to a length of 0.55 cm. 2The skin samples were placed in an FDC with a diffusion area and a 3.3 mL receiver volume. The stratum corneum and dermis were in contact with the donor and receptor compartments, respectively. After an integrity check (impedance analysis), 10 μL of cream sample was applied to the epidermal surface of each FDC. Aliquots of receptor fluid (composed of phosphate-buffered saline pH 7.4 containing 0.01 wt% Na azide and 1 wt% Brij 020) were sampled 4, 8, 24, and 46 hours after application of the test article and refrigerated until analysis. At the end of the 46-hour period, the epidermal surface of each skin sample was wiped clean and washed twice with 200 μL of a 1:1 volume water / ethanol mixture. The skin was then patted dry using a Kimwipe and tape-stripped three times with cellophane tape to remove the outermost layer of the stratum corneum. The remaining skin was then divided into epidermal and dermal compartments. The compound of formula I was extracted with 3 mL of a 1:1 volume mixture of DMSO / isopropanol at 40° C. for 24 hours.

[0134] High-performance liquid chromatography-UV ("HPLC-UV") analytical method and LC-MS / MS method were performed to detect the compound of Formula I in skin and receptor fluid samples, respectively, using mobile phases A (0.05 mL trifluoroacetic acid (TFA) in 1000 mL LC-MS grade water) and B (0.05 mL TFA in 1000 mL LC-MS grade acetonitrile). The lower limit of quantitation (LLOQ) for the compound of Formula I for the LC-MS / MS method was determined to be in the range of 6-10 ng / mL.

[0135] The accumulation of the compound of Formula I in the epidermis and dermis, as well as in the receptor fluid, at each time point is shown in Figure 5. A negative control using vehicle cream is also shown. The compound of Formula I accumulated at 2.89 + / - 0.32 μg / cm in the epidermis. 2 and 0.73 + / - 0.21 μg / cm in the dermis. 2The compound of Formula I was only detected in the receptor fluid and not in the transdermal receptor fluid. The compound of Formula I is lipophilic with low aqueous solubility (the solubility limit of the compound of Formula I in the receptor fluid was determined to be approximately 35.8 μg / mL, sufficient to maintain submerged status throughout the experiment), and the data very clearly demonstrate a much more favorable partitioning of the compound of Formula I into lipid-containing compartments, such as tissues, compared with hydrophilic compartments, such as the receptor fluid. This characteristic likely translates into lipid-containing compartments in the eyelid in general, such as the meibomian glands, meibum, and other fatty structures, converting them into a drug depot and "sustained-release" delivery mechanism to the ocular surface (via the meibum) for periocularly administered lipophilic compounds.

[0136] Example 4: Ocular and systemic exposure following periocular cream administration To initially determine the maximum tolerated dosage, two Hanford minipigs were topically dosed twice daily (BID) approximately 6 hours apart with increasing doses (25, 50, 75, 100 μL) of a cream (consisting of 2% w / w compound of Formula I, 46% w / w white petrolatum, 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w anhydrous sodium phosphate dibasic, 0.05% w / w anhydrous citric acid, 0.02% w / w propylparaben, and an appropriate amount of purified water) to the upper and lower eyelids of one eye over a 4-day period to determine ocular and skin tolerance and the maximum feasible amount of cream formulation on each eyelid. The study variables evaluated were mortality, clinical observation of disease or response to treatment, ocular observation using a modified Hackett McDonald grading system, and skin Draize scoring. The cream was generally well tolerated at all four doses administered BID. Due to ease of application and minimal risk of cream transfer to the ocular surface, a dose of 75 μL per eyelid was determined to be the maximum feasible dose, which covered the entire minipig eyelid with a thin layer of test article formulation without dripping, running, or spilling of the formulation onto the ocular surface. The 75 μL dose was then used for subsequent studies.

[0137] To determine ocular exposure and pharmacokinetics after topical cream administration to the eyelids, a cream containing 2% of the compound of Formula I was applied to the eyelids of eight Hanford minipigs BID for 7 days, with one additional application on day 8, for a total of 15 topical doses. After the last dose on day 8, two animals were euthanized 2, 4, 8, and 24 hours after the last dose, and the eyes were collected for dissection into the following tissues and fluids: eyelid (including palpebral conjunctiva), bulbar conjunctiva, cornea, iris / ciliary body (ICB), and aqueous humor (AQH). Plasma was also collected (before dose application on days 1 and 8 and before euthanasia). It was decided not to collect meibum. Because the amount expressible from the eyelid margin was found to be minimal, and the procedure of expressing meibum through manipulation / rubbing / compression of the eyelid would have compromised the eyelid tissue, making it unavailable for further analysis. Meibum was thought to be the only lipid compartment in the eyelid that could act as a depot for lipophilic compounds; the meibomian glands and other adipose tissues were the others. Attempting to express meibum from the ducts, thereby rendering the eyelid itself unavailable for further analysis, would not have allowed for evaluation of drug content in other potential lipid structures in the eyelid. Therefore, a decision was made to evaluate drug exposure in the eyelid as an intact tissue to capture all potential drug depots.

[0138] Three different extraction and analytical methods were developed for the determination of the compound of Formula I in (i) plasma and aqueous humor; (ii) bulbar conjunctiva, cornea, and ICB; and (iii) eyelid. The assay ranges were 0.1–100 ng / mL, 1–1000 ng / g, and 1–1000 ng / g, respectively. Briefly, the analytical methods were as follows: (i) plasma and aqueous humor standards were from minipigs and rabbits, respectively; (ii) bulbar conjunctiva, cornea, and ICB standards were from rabbit cornea; and (iii) eyelid standard was from pig skin. The internal standard working solution for analytical purposes was 20.0 ng / mL in acetonitrile with 1% formic acid (v / v). 13 C2 15N-labeled compound of Formula I was added to each sample. The tissue / fluid sample extraction procedures included: (i) plasma / aqueous humor samples; (ii) homogenization of bulbar conjunctiva, cornea, and ICB in acetonitrile; and (iii) eyelid digestion in a 1:1 acetonitrile:ammonium hydroxide solution at 37°C for 1.5 hours, followed by the addition of acetonitrile, homogenization, and neutralization with formic acid. In all cases, this was followed by the addition of an internal standard working solution, vortexing, and centrifugation. Samples were then analyzed by LC-MS / MS using mobile phases A (water with 0.1% formic acid) and B (acetonitrile with 0.1% formic acid).

[0139] After 15 topical applications over 7.5 days, the highest ocular exposure levels of the compound of Formula I after the final application were detected in the eyelid tissue (peak mean concentration of 30,613 ng / g 4 hours after the final dose), followed by the bulbar conjunctiva (mean value of 1,931 ng / g 4 hours after the final dose), the cornea (mean value of 452 ng / g 8 hours after the final dose), the ICB (mean value of 20.48 ng / g 24 hours after the final dose), and the aqueous humor (mean value of 5.81 ng / g 8 hours after the final dose) (Figure 6). Even taking into account the high protein binding of approximately 99%, resulting in "free" drug concentrations in all tissues that are approximately 1 / 100 of the total measured concentration, these concentration ranges represent pharmacologically active concentrations of the compound of Formula I. Unexpectedly, in each compartment, exposure levels remained nearly constant for up to 24 hours after the final periocular dose application. This exposure profile, quite different from that of typical eye drop applications, strongly suggests a drug depot in the eyelid that "feeds" downstream compartments (conjunctiva, cornea, ICB, aqueous humor) over at least a 24-hour period. Because lipophilic compounds preferentially partition into lipid compartments rather than into aqueous hydrophilic compartments, as demonstrated for the compound of Formula I by the skin permeation study described above, it can be concluded that lipid structures of the eyelid (e.g., meibomian glands, meibum, other adipose tissues) serve as drug depots for periocularly delivered drugs, with meibum being the drug delivery vehicle because it is constitutively produced by the meibomian glands and secreted onto the corneal surface. These conclusions are related to and consistent with the lipophilicity of the compound of Formula I, and therefore are expected to generally be substituted similarly, if not equally, for all other lipophilic compounds.

[0140] Furthermore, this 24-hour exposure profile following periocular administration of lipophilic compounds, such as compounds of Formula I, allows for a once-daily application regimen, which represents a significant benefit for patients who are often required to administer steroids or other eye drops up to four to six or more times daily. A once-daily application regimen offers improved safety and patient convenience compared to eye drops that must be administered more frequently.

[0141] Another significant advantage of periocular application is the larger dosage volume, which allows for greater flexibility in delivering a wide range of drug doses compared to eye drop application, allowing for more drugs to be applied once a day than eye drops, leading to the aforementioned patient benefits.The volume of eye drops is typically limited to approximately 30 μL per eye per administration, or in some cases up to approximately 40 μL per eye.75 μL per eyelid per dosage volume, or 150 μL per eye, is equivalent to at least four times the dose volume per administration.

[0142] In addition to the larger dosage volume as described above, a further benefit of periocular application is that a larger percentage of the drug is available for delivery to target tissues on the ocular surface. Eye drop application, in particular, is known to deliver only a small portion of the API applied as part of an eye drop formulation. This is because eye drops applied to the ocular surface are rapidly drained from the ocular surface via the nasolacrimal duct, and therefore are understood to deliver only up to about 1% of the API "payload" contained in the eye drop delivered to the ocular surface tissues (cornea and conjunctiva). In contrast, periocular administration delivers essentially 100% or nearly 100% of the API contained in the periocular formulation to the eyelid tissues. Taken together with the larger delivery volume of periocular application formulations compared to topical application eye drops, the periocular route represents a significantly greater dosage advantage of API to ocular surface tissues compared to the topical eye drop route.

[0143] Plasma exposure to the compound of Formula I in this study (up to 24 hours after the last periocular application) was variable but generally low or below the lower limit of quantitation of 0.1 ng / mL (Figure 6). The maximum plasma concentration of 2.22 ng / mL was observed 24 hours after the final day 8 dose. Results showed no or very low systemic accumulation after multiple topical eyelid applications for 7.5 days.

[0144] Plasma exposure was also determined in another 7-day study in minipigs. The compound of formula I was formulated at 4% w / w and 6% w / w, and also in a cream consisting of 44% w / w or 42% w / w white petrolatum, respectively, and 8% w / w mineral oil, 8% w / w propylene glycol, 6.6% w / w ST-cyclomethicone-5NF, 3.3% w / w emulsifier 10, 2% w / w ST-elastomer-10, 0.08% w / w methylparaben, 0.06% w / w anhydrous dibasic sodium phosphate, 0.05% w / w anhydrous citric acid, 0.02% w / w propylparaben, and an appropriate amount of purified water. The cream formulations were applied periocularly to the upper and lower eyelids of the right eyes of three minipigs at a dose volume of 75 μL per eyelid, three times daily (TID) for each concentration at 8-hour intervals for 6 days, and once in the morning on day 7. Plasma levels of the compound of Formula I were then assessed for up to 7 days after the final dose.

[0145] Dermal administration of 4% (18 mg / eye / day) and 6% (27 mg / eye / day) compound of Formula I cream to the upper and lower eyelids of one eye of Hanford minipigs was well tolerated. There were no test article-related effects on body weight, clinical observations, tonometry (intraocular pressure), hematology, or serum chemistry.

[0146] Plasma TK parameters (C) for the compound of Formula I were measured in female minipigs receiving multiple doses of the compound of Formula I cream at 18 mg / eye / day and 27 mg / eye / day. max , T max , AUC last , AUC 0-24 ) were low and variable. Plasma concentrations persisted for at least 2 to 7 days after the last administered dose.

[0147] This is an interesting and unexpected finding because the data indicate that the ocular drug depot (established after 7 days of periocular cream application) releases drug over an extended period of time, such that in some animals, systemic levels of the compound of Formula I are higher than those of the final periocular cream application. rearThis suggests that the drug delivery could be measured for up to 7 days. Conceptually, these findings are entirely consistent with extended delivery from the meibomian gland / meibum drug depot to the systemic circulation and possibly the ocular surface.

[0148] Example 5: Manufacturing Process Periocular application requires a sterile manufacturing process for ophthalmic drug products, regardless of the presence or absence of preservatives in the formulation. The manufacturing process, as outlined in Figure 7, is based on the combination of a hydrophilic component and a lipophilic component under aseptic conditions, each of which has been separately pre-sterilized by an appropriate sterilization process, such as filtration, heating, gamma, beta, or alpha irradiation, or other methods. The pre-sterilized API (heating, gamma, beta, or alpha irradiation, or other methods) is incorporated into the pre-sterilized lipophilic component at an appropriate temperature using an appropriate mixing process. This lipophilic component is then mixed with the pre-sterilized hydrophilic component at a predetermined mixing ratio using an appropriate process, such as stirring, shaking, vortexing, sonication, etc., at an appropriate temperature. The final mixture is then cooled to the appropriate temperature required for the filling process into an appropriate container for the final drug product, whether for clinical or commercial use.

[0149] In one embodiment, the manufacturing process for a cream containing the compound of Formula I, as described in this application and in Figure 7, requires a high-speed homogenization procedure to incorporate the API and a gentle mixing / stirring procedure to combine the lipophilic and hydrophilic components. In the same embodiment, the lipophilic component is heated to 55-60°C for the incorporation of the API, such as the compound of Formula I, and the mixing process with the hydrophilic component. The final product is then gradually cooled to below 30°C before being filled into final containers for clinical studies or commercial use.

[0150] In other embodiments, the lipophilic component is heated to a temperature necessary to liquefy the component and make it suitable for sterilization by filtration, or not heated at all, including temperature ranges of 1-10°C, 10-20°C, 20-30°C, 30-40°C, 40-50°C, 50-60°C, 60-70°C, 70-80°C, 80-90°C, 90-100°C, 100-110°C, 110-120°C, 120-130°C, 130-140°C, 140-150°C, 150-160°C, and 160-170°C.

[0151] In other embodiments, the incorporation of the API requires low, high, or medium mixing speeds at specific temperatures within the ranges of 1-10° C., 10-20° C., 20-30° C., 30-40° C., 40-50° C., 50-60° C., 60-70° C., 70-80° C., 80-90° C., 90-100° C., 100-110° C., 110-120° C., 120-130° C., 130-140° C., 140-150° C., 150-160° C., and 160-170° C. The process may include mixing, shaking, stirring, vortexing, sonication, etc.

[0152] In other embodiments, mixing of the hydrophilic and lipophilic components is accomplished at room temperature or at temperatures ranging from 1-10°C, 10-20°C, 20-30°C, 30-40°C, 40-50°C, 50-60°C, 60-70°C, 70-80°C, 80-90°C, 90-100°C, 100-110°C, 110-120°C, 120-130°C, 130-140°C, 140-150°C, 150-160°C, and 160-170°C.

[0153] In other embodiments, the final product is then cooled slowly or rapidly to the temperature required for filling into the final container for clinical studies or commercial use. This cooling process requires slow, rapid, or medium speed mixing, or no mixing at all.

Claims

1. a) a therapeutically effective amount of a compound of Formula I; and b) a pharmaceutically acceptable carrier adapted for periocular transdermal delivery of a compound of Formula I to one or more periorbital glands of a human subject having dry eye disease; 1. A pharmaceutical composition for treating dry eye disease in a human subject, comprising: topically administering the pharmaceutical composition to the outer portion of the upper eyelid and / or lower eyelid of a human subject; the pharmaceutical composition is administered once each day it is administered; the pharmaceutical composition comprises a compound of formula I in a concentration of 0.01% to 1% weight / weight (w / w); The compound of formula I has the structure: having Pharmaceutical compositions.

2. 10. The pharmaceutical composition of claim 1, which is not a liquid topical ophthalmic suspension, emulsion, or solution.

3. the one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof; and / or The compound of formula I is delivered to the ocular surface of a human subject via the meibomian gland.

3. The pharmaceutical composition of claim 1 or 2.

4. A pharmaceutical composition according to any one of claims 1 to 3, comprising a compound of formula I at a concentration of 0.01% to 0.5% w / w.

5. A pharmaceutical composition according to any one of claims 1 to 4, comprising a compound of formula I at a concentration of 0.05% to 0.5% w / w.

6. A pharmaceutical composition according to any one of claims 1 to 4, comprising a compound of formula I at a concentration of 0.01% to 0.1% w / w.

7. A pharmaceutical composition according to any one of claims 1 to 3, comprising a compound of formula I at a concentration of 0.1% to 1% w / w.

8. A pharmaceutical composition according to any one of claims 1 to 3 and 7, comprising a compound of formula I at a concentration of 0.1% to 0.5% w / w.

9. A pharmaceutical composition described in any one of claims 1 to 3, comprising a compound of formula I at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% w / w.

10. A pharmaceutical composition according to any one of claims 1 to 6 and 9, comprising a compound of formula I at a concentration of 0.05% w / w.

11. A pharmaceutical composition according to any one of claims 1 to 5 and 7 to 9, comprising a compound of formula I at a concentration of 0.2% w / w.

12. A therapeutically effective amount of an additional steroid, wherein the compound of Formula I and the additional steroid are different; a therapeutically effective amount of one or more antibiotics; a therapeutically effective amount of one or more immunomodulatory agents; a therapeutically effective amount of one or more integrin antagonists; a therapeutically effective amount of one or more anti-inflammatory agents, wherein the one or more anti-inflammatory agents are different from the compound of Formula I; or a therapeutically effective amount of one or more anti-glaucoma or anti-ocular anti-hypertension agents 12. The pharmaceutical composition of any one of claims 1 to 11, further comprising:

13. The pharmaceutical composition of any one of claims 1 to 12, formulated in the form of an ointment, cream, lotion, gel, emulsion, suspension, oil, foam, transdermal patch, or spray.

14. A pharmaceutical composition according to any one of claims 1 to 13, formulated in the form of an ointment.

15. A pharmaceutical composition according to any one of claims 1 to 13, formulated in the form of a cream.

16. The pharmaceutical composition of claim 15, wherein the cream comprises white soft paraffin / petrolatum, mineral oil, propylene glycol, ST-cyclomethicone-5NF, dibasic sodium phosphate, citric acid, and purified water.

17. The pharmaceutical composition of claim 15 or 16, wherein the cream comprises white soft paraffin / petrolatum, mineral oil, propylene glycol, ST-cyclomethicone-5NF, methylparaben, dibasic sodium phosphate, citric acid, propylparaben, and purified water.

18. a) a pharmaceutical composition according to any one of claims 1 to 17; and b) a package insert containing instructions for administering the pharmaceutical composition to the outer portion of the upper and / or lower eyelid of a human subject with dry eye disease.

10. A kit for treating dry eye disease in a human subject, comprising:

19. Use of a pharmaceutical composition described in any one of claims 1 to 17 in the manufacture of a medicament for providing preventive, palliative, or therapeutic relief of one or more signs or symptoms of dry eye disease in a human subject by administration to the outer portion of the upper and / or lower eyelid of the human subject.

20. The use of claim 19, wherein the compound of formula I is delivered to the ocular surface of a human subject via the meibomian gland.

21. The compound of formula I is not delivered systemically to a human subject, and / or the compound of formula I is not delivered to the tears or lacrimal ducts of a human subject, and / or The compound of formula I is not delivered directly to the ocular surface of a human subject; 21. Use according to claim 19 or 20.

22. The use of any one of claims 19 to 21, wherein the medicament is administered for 1, 2, 3, 4, 5, 6, or 7 or more consecutive days.

23. The method of claim 22, wherein the medicament is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more consecutive weeks; and / or the medication is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more consecutive months; Use according to any one of claims 19 to 22.

24. The use of any one of claims 19 to 21, wherein the medicament is administered for 1, 2, 3, 4, 5, 6, or 7 or more non-consecutive days.

25. The method of claim 25, wherein the medicament is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more non-consecutive weeks; and / or the medication is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more non-consecutive months; Use according to any one of claims 19 to 21 and 24.

26. The use described in any one of claims 19 to 25, wherein long-term administration of the medicament does not cause ocular adverse events in human subjects.

27. ​​The use described in claim 26, wherein the ocular adverse event is selected from the group consisting of increased intraocular pressure, cataracts, ocular infections, and any combination thereof.

28. A pharmaceutical composition described in any one of claims 1 to 17, for providing preventative, palliative, or therapeutic relief of one or more signs or symptoms of dry eye disease in a human subject upon administration to the outer portion of the upper and / or lower eyelid of the human subject.

29. The pharmaceutical composition of claim 28, wherein the compound of formula I is delivered to the ocular surface of a human subject via the meibomian gland.

30. The compound of formula I is not delivered systemically to a human subject, and / or the compound of Formula I is not delivered to the tears or lacrimal ducts of a human subject; and / or The compound of formula I is not delivered directly to the ocular surface of a human subject; 30. The pharmaceutical composition of claim 28 or 29.

31. A pharmaceutical composition described in any one of claims 28 to 30, administered for 1, 2, 3, 4, 5, 6, or 7 or more consecutive days.

32. The method of claim 31, wherein the therapeutic agent is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more consecutive weeks; and / or administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more consecutive months; 32. The pharmaceutical composition of any one of claims 28 to 31.

33. The pharmaceutical composition of any one of claims 28 to 30, administered for 1, 2, 3, 4, 5, 6, or 7 or more non-consecutive days.

34. The method of claim 34, wherein the method is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more non-consecutive weeks; and / or administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more non-consecutive months; 34. The pharmaceutical composition of any one of claims 28 to 30 and 33.

35. A pharmaceutical composition described in any one of claims 28 to 34, wherein long-term administration of the pharmaceutical composition does not cause ocular adverse events in human subjects.

36. The pharmaceutical composition of claim 35, wherein the ocular adverse event is selected from the group consisting of increased intraocular pressure, cataracts, ocular infections, and any combination thereof.

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