Compositions and methods for treating abnormal inflammation in the periorbital glands or on the ocular surface

Abstract

The present invention provides a pharmaceutical composition adapted for periocular transdermal delivery of one or more lipophilic compounds; a method of use thereof; and a kit containing such a pharmaceutical composition. [Solution] The present invention provides 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 glands and / or ocular surface tissues of interest. The present invention further provides a method of using such a pharmaceutical composition to provide relief of one or more signs or symptoms of an eye disease, a method of using one or more meibomian glands (and meibums therein) as a drug delivery system for a lipophilic compound (e.g., a steroid) to the ocular surface, and a kit related thereto.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 589,493, filed on November 21, 2017, entitled "COMPOSITIONS AND METHODS OF USE FOR TREATING ABERRANT INFLAMMATION IN PERI-OCULAR SECRETORY GLANDS OR AT THE OCULAR SURFACE," which is incorporated in its entirety by reference.

[0002] Field of Invention This disclosure relates to pharmaceutical compositions adapted for periocular transdermal delivery of one or more lipophilic compounds; methods of use thereof; and kits comprising such pharmaceutical compositions. [Background technology]

[0003] background Topical eye drops are the optimal delivery method for eye care providers, particularly for conditions such as dry eye, uveitis, bacterial conjunctivitis, and glaucoma, because the ocular surface is considered the primary target tissue for drug delivery. Once eye drops are applied to the eye, three parts of the anterior segment (i.e., the cornea, conjunctiva, and sclera) act as pathways for drug absorption, with the cornea being the primary pathway for ocular penetration. Eye drops are recognized as having significant advantages over other delivery methods, including minimizing harmful systemic effects and avoiding first-pass metabolism, which limits the concentration of the drug ultimately reaching the target tissue (Abelson et al, 2012).

[0004] However, topical eye drops have several drawbacks: (1) they are physically difficult for patients to manage; (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 hinder the diffusion of larger molecules.

[0005] The lacrimal glands are a pair of exocrine glands, one for each eye. They are located in the upper lateral part of each orbit, within the lacrimal fovea, which is 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, inside the tarsal plate, responsible for supplying meibomian oil, which prevents the evaporation of the tear film of the eye.

[0006] Disruption of the normal function of the lacrimal and meibomian glands can lead to the tear-deficient and / or evaporative forms of dry eye disease (DED), as well as numerous "plus" inflammatory eye diseases, such as exacerbated inflammatory ocular surface diseases, 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 disease of the ocular surface characterized by loss of tear film homeostasis and ocular symptoms, where tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neuronal paresthesia play a pathogenic role (Craig et al., 2017). Whatever initiates a patient's DED (e.g., allergic eye disease, topical preservative toxicity, or xerophthalmos), the patient eventually enters a series of inflammatory events that perpetuate the disease. This inflammatory response can infiltrate the gland itself. In fact, tear dysfunction occurs when the lacrimal functional unit (LFU), which consists of the lacrimal glands, 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, the hypothesis that signs and symptoms are driven by inflammation of one or more components of the LFU is supported by sufficient evidence.

[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 the treatment of patients with DED (Avunduk et al., 2003; DEWS, 2007; Pflugfelder et al., 1999; Yang et al., 2006). However, topical ophthalmic corticosteroids administered as eye drops are generally recommended only for short-term use, because long-term use can lead to 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 low penetration / permeability), long-term use of current steroid ointment / cream formulations on or near the eye is strongly discouraged. This is because ocular use of these formulations can induce serious adverse events, such as elevated IOP (which may lead to ocular hypertension or glaucoma, or induce blindness), posterior subcapsular cataract, delayed corneal epithelial healing, corticosteroid uveitis, mydriasis and ptosis, infection, and other possible side effects (e.g., transient eye discomfort, steroid-induced calcium deposition). In fact, topical application of typical dexamethasone ointment formulations to the eyelids of children has been shown to cause a rapid increase in IOP. "Intraocular hypertension reactions frequently occurred after dexamethasone ointment application to the eyelids, particularly in children under 5 years of age" (see Lee et al., Korean J Ophthalmol. 2006 Sep;20(3):166-70, p. 166). Therefore, there is a lack of appropriate steroid preparations / routes of administration for the long-term or even chronic treatment of ocular inflammatory conditions.

[0009] All references incorporated herein, including patent applications, patent publications, and non-patent literature, are incorporated herein by reference in whole, as if each individual reference were specifically and individually indicated so as to be incorporated by reference. [Overview of the project]

[0010] overview To satisfy the above and other needs, pharmaceutical compositions adapted for periocular transdermal delivery of one or more lipophilic compounds are disclosed herein. In some embodiments, the pharmaceutical compositions are adapted for periocular transdermal delivery and significantly enhance the ocular safety of the delivered lipophilic compound by: (1) reducing the concentration of the permeation enhancer in the pharmaceutical composition compared to the concentrations used in standard ointments / creams or ophthalmic formulations; (2) using a permeation enhancer suitable for perdermal delivery of the compound into the eyelid (not typically found in topical steroid ointment / cream formulations) (e.g., Tween-80); (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 to the corneal surface. (5) Use novel steroids such as compounds of formula I (which have been specifically developed so that the glucocorticoid receptor can trans-suppress gene activation and have little to no transactivation) to reduce the side effects of glucocorticoids that are thought to be mediated by transactivation; (6) Use meibomian glands, meibums, and other fatty structures in the eyelids as drug depots for lipophilic compounds for sustained delivery to the ocular surface; and / or (7) Use of meibomian glands and meibums as novel drug delivery systems for pharmaceutical formulations of lipophilic compounds applied periorbitally to the outer part of the upper and / or lower eyelids. Accordingly, this disclosure relates in part to a safer method for treating ocular surface conditions as well as periorbital glands and intraocular eyelids by transdermal administration of pharmaceutical formulations such as those described herein (e.g., via topical application of the formulation to the outer surface of the upper and / or lower eyelids) to deliver therapeutically active concentrations of lipophilic compounds to the meibomian glands, lacrimal glands, accessory lacrimal glands, and ocular surface. While we do not wish to be bound by theory, it is thought that lipophilic compounds (e.g., steroids) preferentially accumulate / distribute into lipid-producing (e.g., meibomian) periorbital glands (e.g., meibomian glands) and other fatty / lipophilic structures in the eyelids.Accordingly, this disclosure is considered to provide a novel therapeutic strategy for treating inflammation within the tear functional unit (LFU), other ocular inflammatory diseases, bacterial infections of the eye, glaucoma, and ocular hypertension by delivering antiglaucoma agents, antibiotics, and other lipophilic compounds via percutaneous periorbital delivery that reduces or avoids some or all of the adverse events associated with the use of standard topical formulations in an ophthalmic setting, such as elevated IOP, BAK hypersensitivity, and precorneal tear film breakdown (e.g., blurred vision). Furthermore, this disclosure is considered to provide a novel strategy for long-term / chronic ophthalmic therapy that may be used with current short-term topical ophthalmic regimens (e.g., corticosteroids).

[0011] Accordingly, in one aspect, the following pharmaceutical composition is provided herein, comprising a therapeutically effective amount of a lipophilic compound and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the lipophilic compound to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, the following pharmaceutical composition is provided herein, comprising a therapeutically effective amount of a lipophilic compound and a pharmaceutically acceptable carrier adapted for periorbital 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 periorbital delivery. In some aspects, the lipophilic compound is not delivered systemically to the subject. In some aspects, the lipophilic compound is not delivered to the tears or lacrimal ducts of the subject. In some aspects, the lipophilic compound is not delivered by direct application to the ocular surface of the subject. In some aspects, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some aspects, 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 target ocular surface via the meibomian glands and meibums. In some embodiments, the lipophilic compound is selected from the group consisting of steroids, antibiotics, immunomodulators, integrin antagonists, anti-inflammatory agents, and antiglaucoma agents or ocular anti-hypertension agents.

[0012] In one aspect, the following pharmaceutical compositions are provided herein, comprising a therapeutically effective amount of a steroid and a pharmaceutically acceptable carrier adapted for periorbital 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 periorbital delivery. In some embodiments, the steroid is not delivered systemically to the subject. In some embodiments, the steroid is not delivered to the tears or lacrimal ducts of the subject. In some embodiments, the steroid is not delivered by direct application to the ocular surface of the subject. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, 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 ocular surface of the subject via the meibomian glands and meibomian glands.

[0013] The steroid can be any steroid. In some embodiments, which may be combined with any of the embodiments described above, the steroid is selected from the compounds of formula I, fluocinolone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and their ester derivatives. In some embodiments, the steroid is selected from the compounds of formula I, difluprednate, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, and their ester derivatives. In some embodiments, the steroid is a compound of formula I. In some embodiments, the pharmaceutical composition contains a steroid at a concentration of 0.001% to 10% w / w. In some embodiments, the pharmaceutical composition contains a steroid at a concentration of 0.01% to 2% w / w.

[0014] In one aspect, the following pharmaceutical compositions are provided herein, comprising a therapeutically effective amount of an antibiotic and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the antibiotic to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, the following pharmaceutical compositions are provided herein, comprising a therapeutically effective amount of an antibiotic and a pharmaceutically acceptable carrier adapted for periorbital 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 periorbital delivery. In some aspects, the antibiotic is not delivered systemically to the subject. In some aspects, the antibiotic is not delivered to the tears or lacrimal ducts of the subject. In some aspects, the antibiotic is not delivered by direct application to the ocular surface of the subject. In some aspects, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some aspects, 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 aspects, the antibiotic is delivered to the ocular surface of the subject via the meibomian glands and meibomian glands.

[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, oxyfloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, and sulfacetamide. In some embodiments, the pharmaceutical composition contains the antibiotic at a concentration of 0.01% to 10% w / w. In some embodiments, the pharmaceutical composition contains the antibiotic at a concentration of 0.1% to 2% w / w.

[0016] In one aspect, the following pharmaceutical composition is provided herein, comprising a therapeutically effective amount of an immunomodulator and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the immunomodulator to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, the following pharmaceutical composition is provided herein, comprising a therapeutically effective amount of an immunomodulator and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the immunomodulator to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periorbital delivery. In some embodiments, the immunomodulator is not delivered systemically to the subject. In some embodiments, the immunomodulator is not delivered to the tears or lacrimal ducts of the subject. In some embodiments, the immunomodulator is not delivered by direct application to the ocular surface of the subject. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, 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, immunomodulatory drugs are delivered to the target ocular surface via the meibomian glands and meibums.

[0017] The immunomodulator can be any immunomodulator. In some embodiments, the immunomodulator is selected from the group consisting of calcineurin inhibitors and thalidomide analogs. In some embodiments, the immunomodulator is selected from the group consisting of cyclosporine A, voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide. In some embodiments, the immunomodulator is cyclosporine A. In some embodiments, the pharmaceutical composition contains the immunomodulator at a concentration of 0.01% to 10% w / w. In some embodiments, the pharmaceutical composition contains the immunomodulator at a concentration of 0.1% to 2% w / w.

[0018] In one aspect, the following pharmaceutical composition is provided herein: comprising a therapeutically effective amount of an integrin antagonist and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the integrin antagonist to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, the following pharmaceutical composition is provided herein: comprising a therapeutically effective amount of an integrin antagonist and a pharmaceutically acceptable carrier adapted for periorbital 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 periorbital 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 tears or lacrimal ducts of the subject. In some embodiments, the integrin antagonist is not delivered by direct application to the ocular surface of the subject. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, 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, integrin antagonists are delivered to the target ocular surface via the meibomian glands and meibums.

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

[0020] In one aspect, the following pharmaceutical compositions are provided herein, comprising a therapeutically effective amount of an anti-inflammatory agent and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the anti-inflammatory agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, the following pharmaceutical compositions are provided herein, comprising a therapeutically effective amount of an anti-inflammatory agent and a pharmaceutically acceptable carrier adapted for periorbital 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 periorbital 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 tears or lacrimal ducts of the subject. In some embodiments, the anti-inflammatory agent is not delivered by direct application to the ocular surface of the subject. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, 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 target via the meibomian glands and meibums.

[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 acid is 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 contains the anti-inflammatory agent at a concentration of 0.001% to 10% w / w. In some embodiments, the pharmaceutical composition contains the anti-inflammatory agent at a concentration of 0.1% to 2% w / w.

[0022] In one aspect, the following pharmaceutical composition is provided herein: comprising a therapeutically effective amount of an antiglaucoma agent or antihypertensive agent and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the antiglaucoma agent or antihypertensive agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject. In one aspect, the following pharmaceutical composition is provided herein: comprising a therapeutically effective amount of an antiglaucoma agent or antihypertensive agent and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the antiglaucoma agent or antihypertensive agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for periorbital delivery. In some aspects, the antiglaucoma agent or antihypertensive agent is not delivered systemically to the subject. In some aspects, the antiglaucoma agent or antihypertensive agent is not delivered to the tears or lacrimal ducts of the subject. In some aspects, the antiglaucoma agent or antihypertensive agent is not delivered by direct application to the ocular surface of the subject. In some embodiments, the pharmaceutical composition is not a liquid topical ophthalmic suspension, emulsion, or solution. In some embodiments, 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 antiglaucoma agent or antihypertensive agent is delivered to the target ocular surface via the meibomian glands and meibum.

[0023] The anti-glaucoma agent or anti-hypertensive agent can be any anti-glaucoma agent or any anti-hypertensive agent. In some embodiments, the anti-glaucoma agent or anti-hypertensive agent is selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, latanoprostene bunod, timolol, betaxolol, levobunolol, dorzolamide, brinzolamide, and acetazolamide. In some embodiments, the anti-glaucoma agent or anti-hypertensive 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 an anti-glaucoma agent at a concentration of 0.0001% to 10% weight / weight (w / w). In some embodiments, the pharmaceutical composition comprises an anti-glaucoma agent or anti-hypertensive agent at a concentration of 0.01% to 2% w / w.

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

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

[0026] In some embodiments that can be combined with any of the foregoing 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 calcineurin inhibitors, thalidomide analogs, and any combination thereof. In some embodiments, the one or more immunomodulatory agents are selected from cyclosporine A, voclosporin, tacrolimus, pimecrolimus, thalidomide, lenalidomide, pomalidomide, and any combination thereof. In some embodiments, the immunomodulatory agent is cyclosporine 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 can be combined with any of the foregoing 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 refiglutant, GW559090, its ester derivatives, 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, which may be combined with any of the embodiments described above, 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% 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 one or more anti-inflammatory agents differ.

[0029] In some embodiments that can be combined with any of the embodiments described above, the pharmaceutical composition further comprises a therapeutically effective amount of one or more antiglaucoma agents or antihypertensive agents. In some embodiments, one or more antiglaucoma agents or antihypertensive agents are selected from bimatoprost, latanoprost, travoprost, tafluprost, latanoprostenbunod, timolol, betaxolol, levobunolol, metipranolol, brimonidine, clonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, metazolamide, netalusdil, and any combination thereof. In some embodiments, the antiglaucoma agent or antihypertensive agent is selected from bimatoprost, latanoprost, travoprost, brimonidine, brinzolamide, netalusdil, and timolol. In some embodiments, the antiglaucoma agent is bimatoprost. In some embodiments, the pharmaceutical composition comprises one or more antiglaucoma agents or antihypertensive agents at a concentration of 0.0001% to 10% w / w. In some embodiments, the pharmaceutical composition comprises one or more antiglaucoma agents or antihypertensive agents at a concentration of 0.01% to 2% w / w. In some embodiments, the lipophilic compound and the one or more antiglaucoma agents or antihypertensive agents are different.

[0030] In some embodiments that can be combined with any of the embodiments described above, the pharmaceutically acceptable carrier is selected from ointments, creams, lotions, gels, emulsions, suspensions, oils, foams, transdermal patches, sprays, 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. In some embodiments, the cream comprises 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 dibasic sodium phosphate, 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 dibasic sodium phosphate, 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 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.

[0031] In some embodiments, one or more pharmaceutically active ingredients are incorporated at a desired final concentration (w / w) into a cream vehicle comprising 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 dibasic sodium phosphate, 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 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, 0.02% w / w benzalkonium chloride, and an appropriate amount of purified water. In some embodiments, the cream vehicle 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.

[0032] In some embodiments, one or more pharmaceutically active ingredients are incorporated at a desired final concentration by substituting an equal amount of white petrolatum or paraffin (w / w). As an example, one such embodiment 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, 0.08% w / w methylparaben, 0.06% w / w anhydrous dibasic sodium phosphate, 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 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, 0.06% w / w anhydrous dibasic sodium phosphate, 0.05% w / w anhydrous citric acid, 2% w / w compound of formula I and an appropriate amount of purified water.

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

[0034] In some embodiments, the pharmaceutically acceptable carrier contains benzalkonium chloride (BAK). In some embodiments, the pharmaceutically acceptable carrier 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, 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 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. 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, and purified water.

[0035] In some embodiments that may be combined with any of the embodiments described above, the subject is human or a non-human animal. In some embodiments that may be combined with any of the embodiments described above, the subject has, is suspected of having, or is presumed to have, inflammation of one or more periorbital glands. In some embodiments that may be combined with any of the embodiments described above, the subject has an eye disease. In some embodiments, the eye disease is selected from inflammation of the periorbital glands, meibomian gland inflammation, dry eye disease, allergic eye disease, topical preservative toxicity, xerophthalmos, loss of tear film homeostasis, tear film instability and hyperosmolarity, ocular surface inflammation and injury, neuronal paresthesia, meibomian gland dysfunction, aggravated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof.

[0036] In another aspect, the present invention provides a method for providing prophylactic, mitigating, or therapeutic relief of one or more signs or symptoms of an ocular disease in a subject, comprising the step of administering one of the pharmaceutical compositions described herein to the subject. In some embodiments, the subject is human or non-human animal. In some embodiments, the subject has, is suspected of having, or is suspected of having, one or more periorbital gland inflammations. In some embodiments, the subject has an ocular disease. In some embodiments, the ocular disease is selected from periorbital gland inflammation, meibomian gland inflammation, dry eye disease, allergic eye disease, topical preservative toxicity, xerophthalmos, loss of tear film homeostasis, tear film instability and hyperosmolarity, ocular surface inflammation and injury, neuronal paresthesia, meibomian gland dysfunction, aggravated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof.

[0037] In some embodiments, which may be combined with any of the embodiments described above, the pharmaceutical composition is administered topically to the lateral portion of the eyelid of the subject, including the superior lateral portion of the orbit. In some embodiments, the pharmaceutical composition is administered topically to the lateral portion of the upper and / or lower eyelid of the subject. In some embodiments, the lipophilic compound is delivered to the ocular surface of the subject via the meibomian glands. In some embodiments, the pharmaceutical composition is administered once, twice, three, four, five, six times, or more times daily. In some embodiments, the pharmaceutical composition is administered for one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or more, twenty-four weeks, thirty-six weeks, forty-eight 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, ocular adverse events are selected from increased 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 subject's tears or lacrimal ducts by administration of the pharmaceutical composition. In some embodiments, the lipophilic compound is not delivered directly to the subject's ocular surface by administration of the pharmaceutical composition.

[0038] In another aspect, the Specified Publication provides a manufactured article or kit comprising any of the pharmaceutical compositions described herein. In some embodiments, the manufactured article or kit further includes a package insert containing instructions for administering the pharmaceutical composition.

[0039] [Invention 1001] A method for providing preventive, mitigating, or therapeutic relief of one or more signs or symptoms of an eye disease in a subject, comprising the step of administering a pharmaceutical composition according to any of items 1014 to 1076 of the present invention to the subject. [Invention 1002] The method of the present invention 1001, wherein the subject is a human or a non-human animal. [Invention 1003] The method of Invention 1001 or Invention 1002, wherein the eye disease is selected from the group consisting of inflammation of the periocular glands, meibomian gland inflammation, dry eye disease, allergic eye disease, topical preservative toxicity, xerophthalmos, loss of tear film homeostasis, tear film instability and hyperosmolarity, ocular surface inflammation and injury, neuronal paresthesia, meibomian gland dysfunction, aggravated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof. [Invention 1004] A method according to any one of the present invention 1001 to 1003, comprising topically administering a pharmaceutical composition to the lateral portion of the eyelid of a subject, including the superior lateral portion of the orbit of the subject. [Invention 1005] The method of the present invention 1004, comprising topically administering a pharmaceutical composition to the outer portion of the upper and / or lower eyelid of a target. [Invention 1006] A method according to any one of the present invention 1001 to 1005, wherein a lipophilic compound is delivered to the surface of the eye of a target via the meibomian glands. [Invention 1007] A method according to any of the present invention 1001 to 1006, wherein the pharmaceutical composition is administered once, twice, three, four, five, six times, or more times per day. [Invention 1008] A method according to any of the present invention 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. [Invention 1009] A method according to any one of the present invention 1001 to 1008, wherein long-term administration of a pharmaceutical composition does not cause ocular adverse events in the target population. [Invention 1010] The method of the present invention 1009, wherein the ocular adverse event is selected from the group consisting of increased intraocular pressure, cataract, ocular infection, and any combination thereof. [Invention 1011] A method according to any of the present invention 1001 to 1010, wherein the lipophilic compound is not delivered systemically to the target. [Invention 1012] A method according to any of the present invention 1001 to 1011, wherein the lipophilic compound is not delivered to the target tear or lacrimal duct. [Invention 1013] Any method 1001 to 1012 of the present invention, wherein the lipophilic compound is not directly delivered to the target ocular surface. [Invention 1014] (a) therapeutically effective amounts of lipophilic compounds; and (b) A pharmaceutically acceptable carrier adapted for periocular transdermal delivery of a lipophilic compound to one or more periorbital glands of a target; A pharmaceutical composition containing, A pharmaceutical composition specifically formulated for periorbital delivery. [Invention 1015] A pharmaceutical composition according to the present invention 1014, wherein the lipophilic compound is not delivered systemically to the subject. [Invention 1016] A pharmaceutical composition of the present invention 1014 or 1015, wherein the lipophilic compound is not delivered to the target tear or lacrimal duct. [Invention 1017] A pharmaceutical composition according to any one of the present invention 1014 to 1016, wherein the lipophilic compound is not directly delivered to the target ocular surface. [Invention 1018] A pharmaceutical composition according to any of the present invention 1014 to 1017, which is not a liquid topical ophthalmic suspension, emulsion, or solution. [Invention 1019] A pharmaceutical composition according to any one of the present invention 1014 to 1018, wherein one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof. [Invention 1020] A pharmaceutical composition according to any one of the present invention 1014 to 1019, wherein a lipophilic compound is delivered to the target ocular surface via the meibomian glands. [Invention 1021] A pharmaceutical composition according to any of the present invention 1014 to 1020, wherein the lipophilic compound is a steroid. [Invention 1022] The steroid is selected from the group consisting of compounds of formula I, fluocinolone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and their ester derivatives; The compound of formula I has the following structure: A pharmaceutical composition of the present invention 1021, comprising TIFF2026048951000002.tif56128. [Invention 1023] A pharmaceutical composition of the present invention 1021 or 1022, wherein the steroid is selected from the group consisting of compounds of formula I, difluprednate, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, and their ester derivatives. [Invention 1024] A pharmaceutical composition according to any one of the invention 1021 to 1023, wherein the steroid is a compound of formula I. [Invention 1025] A pharmaceutical composition according to any of invention 1014 to 1020, wherein the lipophilic compound is an antibiotic. [Invention 1026] A pharmaceutical composition of the present invention 1025, wherein the antibiotic is selected from the group consisting of sulfonamide drugs, macrolide drugs, chloramphenicol, aminoglycoside drugs, fluoroquinolone drugs, vancomycin, and tetracycline drugs. [Invention 1027] A pharmaceutical composition of Invention 1025 or Invention 1026, wherein the antibiotic is selected from the group consisting of azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxyfloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, and sulfacetamide. [Invention 1028] A pharmaceutical composition according to any one of the present invention 1014 to 1020, wherein the lipophilic compound is an immunomodulator. [Invention 1029] A pharmaceutical composition of the present invention 1028, wherein the immunomodulator is selected from the group consisting of calcineurin inhibitors and thalidomide analogs. [Invention 1030] A pharmaceutical composition according to Invention 1028 or Invention 1029, wherein the immunomodulator is selected from the group consisting of cyclosporine A, voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide. [Invention 1031] A pharmaceutical composition according to any one of the present invention 1014 to 1020, wherein the lipophilic compound is an integrin antagonist. [Invention 1032] A pharmaceutical composition according to Invention 1031, wherein the integrin antagonist is selected from the group consisting of rifitegrast, GW559090, and its ester derivatives. [Invention 1033] A pharmaceutical composition according to any one of the present invention 1014 to 1020, wherein the lipophilic compound is an anti-inflammatory agent. [Invention 1034] A pharmaceutical composition of the present invention 1033, wherein the anti-inflammatory agent is selected from the group consisting of omega-3 fatty acids and nonsteroidal anti-inflammatory drugs (NSAIDs). [Invention 1035] The pharmaceutical composition of the present invention 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. [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. [Invention 1037] A pharmaceutical composition according to any one of the present invention 1014 to 1020, wherein the lipophilic compound is an antiglaucoma agent or an ocular anti-hypertension agent. [Invention 1038] A pharmaceutical composition of the present invention 1037, wherein the antiglaucoma agent or antihypertensive agent is selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, latanoprostenbunod, timolol, betaxolol, levobunolol, metipranolol, brimonidine, clonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, metazolamide, netalusdil, and any combination thereof. [Invention 1039] A pharmaceutical composition according to any of invention 1014 to 1038, comprising a lipophilic compound at a concentration of approximately 0.001% to approximately 10% by weight / weight (w / w), approximately 0.0001% to approximately 10% by weight / weight (w / w), or approximately 0.0001% to approximately 5% by weight / weight (w / w). [Invention 1040] A pharmaceutical composition according to any of the invention items 1014 to 1039, comprising a steroid at a concentration of approximately 0.01% to approximately 2% w / w. [Invention 1041] A pharmaceutical composition according to any one of the present invention 1014 to 1040, further comprising an additional therapeutically effective amount of steroid. [Invention 1042] A pharmaceutical composition of the present invention 1041, wherein the additional steroid is selected from the group consisting of compounds of formula I, fluocinolone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and their ester derivatives. [Invention 1043] A pharmaceutical composition of the present invention 1041 or 1042, wherein the lipophilic compound and additional steroids are different. [Invention 1044] A pharmaceutical composition according to any one of the present invention 1014 to 1043, further comprising a therapeutically effective amount of one or more antibiotics. [Invention 1045] A pharmaceutical composition of the present invention 1044, wherein one or more antibiotics are selected from the group consisting of sulfonamide drugs, macrolide drugs, chloramphenicol, aminoglycoside drugs, fluoroquinolone drugs, vancomycin, tetracycline drugs, and any combination thereof. [Invention 1046] A pharmaceutical composition of Invention 1044 or Invention 1045, wherein one or more antibiotics are selected from the group consisting of azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxyfloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, sulfacetamide, and any combination thereof. [Invention 1047] A pharmaceutical composition according to any one of the invention 1044 to 1046, wherein the lipophilic compound and one or more antibiotics are different. [Invention 1048] A pharmaceutical composition according to any one of the present invention 1014 to 1047, further comprising one or more immunomodulatory agents in a therapeutically effective amount. [Invention 1049] A pharmaceutical composition of the present invention 1048, wherein one or more immunomodulatory agents are selected from the group consisting of calcineurin inhibitors, thalidomide analogs, and any combination thereof. [Invention 1050] A pharmaceutically acceptable composition according to Invention 1048 or Invention 1049, wherein one or more immunomodulatory agents are selected from the group consisting of cyclosporine A, voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, pomalidomide, and any combination thereof. [Invention 1051] A pharmaceutical composition according to any one of the present invention 1048 to 1050, wherein the lipophilic compound and one or more immunomodulatory agents are different. [Invention 1052] A pharmaceutical composition according to any one of the present invention 1014 to 1051, further comprising a therapeutically effective amount of one or more integrin antagonists. [Invention 1053] A pharmaceutical composition according to the present invention 1052, wherein one or more integrin antagonists are selected from the group consisting of rifitegrast, GW559090, its ester derivatives, and any combination thereof. [Invention 1054] A pharmaceutical composition according to Invention 1052 or Invention 1053, wherein the lipophilic compound and one or more integrin antagonists are different. [Invention 1055] A pharmaceutical composition according to any one of the present invention 1014 to 1054, further comprising one or more anti-inflammatory agents in a therapeutically effective amount. [Invention 1056] A pharmaceutical composition according to the present invention 1055, wherein 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. [Invention 1057] The pharmaceutical composition of the present invention 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. [Invention 1058] The pharmaceutical composition of the present invention 1056, wherein the NSAID is selected from the group consisting of bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and any combination thereof. [Invention 1059] A pharmaceutical composition according to any one of the invention 1055 to 1058, wherein the lipophilic compound and one or more anti-inflammatory agents are different. [Invention 1060] A pharmaceutical composition according to any one of the present invention 1014 to 1059, further comprising one or more antiglaucoma agents or anti-ocular hypertension agents in a therapeutically effective amount. [Invention 1061] A pharmaceutical composition of the present invention 1060, wherein one or more antiglaucoma agents or antihypertensive agents are selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, latanoprostenbunod, timolol, betaxolol, levobunolol, metipranolol, brimonidine, clonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, metazolamide, netalusdil, and any combination thereof. [Invention 1062] A pharmaceutical composition of the present invention 1060 or 1061, wherein the lipophilic compound and one or more antiglaucoma agents or anti-ocular hypertension agents are different. [Invention 1063] A pharmaceutical composition according to any of invention 1014 to 1062, wherein the pharmaceutically acceptable carrier is selected from the group consisting of ointments, creams, lotions, gels, emulsions, suspensions, oils, foams, transdermal patches, sprays, and any combination thereof. [Invention 1064] A pharmaceutical composition according to the present invention 1063, wherein the ointment comprises a paraffin-based or water-miscible ointment base. [Invention 1065] A pharmaceutical composition of Invention 1063 or Invention 1064, comprising an ointment containing 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. [Invention 1066] A pharmaceutical composition according to Invention 1063, wherein the cream comprises an oil-in-water base or a water-in-oil base. [Invention 1067] A pharmaceutical composition according to Invention 1063 or Invention 1066, comprising a cream containing 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. [Invention 1068] A pharmaceutical composition according to Invention 1063 or Invention 1066, comprising a cream containing 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 dibasic sodium phosphate, 0.046% w / w anhydrous citric acid, 0.02% w / w propylparaben, and purified water. [Invention 1069] A pharmaceutical composition according to any of invention 1063 and 1066-1068, wherein the cream contains benzalkonium chloride (BAK). [Invention 1070] A pharmaceutical composition according to any of Invention 1063 and 1066-1069, 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. [Invention 1071] A pharmaceutical composition according to any of invention 1063 and 1066-1070, wherein the cream is preservative-free. [Invention 1072] A preservative-free cream comprising white soft paraffin / petrolatum, mineral oil, propylene glycol, ST-cyclomethicone-5NF, emulsifier-10, ST-elastomer-10, dibasic sodium phosphate, citric acid, and purified water, is a pharmaceutical composition of the present invention 1071. [Invention 1073] A preservative-free cream comprising 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, the pharmaceutical composition of Invention 1071 or Invention 1072. [Invention 1074] A pharmaceutical composition according to any of the present invention 1014 to 1073, wherein the target is a human or a non-human animal. [Invention 1075] A pharmaceutical composition according to any of the present invention 1014 to 1074, wherein the subject is suffering from an eye disease. [Invention 1076] A pharmaceutical composition of the present invention 1075, wherein the eye disease is selected from the group consisting of inflammation of the periocular glands, meibomian gland inflammation, dry eye disease, allergic eye disease, topical preservative toxicity, xerophthalmos, loss of homeostasis of the tear film, tear film instability and hyperosmolarity, inflammation and injury of the ocular surface, neuronal paresthesia, meibomian gland dysfunction, aggravated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof. [Invention 1077] (a) Any pharmaceutical composition of the present invention 1014 to 1076; and (b) Package insert containing instructions for administering the pharmaceutical composition A kit that includes this. It will be understood that one, some, or all of the characteristics of the various embodiments described above and herein may be combined to form other embodiments of the Disclosure. These and other aspects of the Disclosure will be apparent to those skilled in the art. These and other aspects of the Disclosure are further described by the following details. [Brief explanation of the drawing]

[0040] [Figure 1] The mean diurnal intraocular pressure (IOP) during the 4-week treatment period with the described treatment involving local administration to the eye is shown. Raw IOP data were analyzed using a mixed-effects model. Data are presented as fitted IOP mean ± 95% confidence intervals; * indicates p<0.05 compared to the dexamethasone treatment group. [Figure 2] The changes in tear formation over 7 days following topical application of the indicated treatment are shown. Repeated measurement analysis followed by the Sidak test was performed; GW870086 = compound of formula I; * indicates p < 0.05 compared to the atropine + vehicle treatment group. [Figure 3] The physical rigidity of various cream samples and high-viscosity standards is shown in glass vials, equilibrated at 37°C and inverted for 5 minutes. In Figure 3A, the samples are 2% formula I compound cream (left), placebo cream (center), and high-viscosity polybutene standard N62000 (right); in Figure 3B, the samples are 2% dexamethasone cream (vial C, left), 2% ethaprednol ethanolate cream (vial B, center), and 2% cyclosporine A cream (vial A, right). Adhesion of samples on the inside of the glass vial walls was not caused by sample flow, but rather by accidental adhesion from the pipette during sample transfer to the vial. This did not interfere with the observation of meniscus flow or change during heat treatment and inversion. [Figure 4A] The results of step strain stress relaxation measurements for some samples are shown: (a) White petrolatum at 25°C (Figure 4A). [Figure 4B]The results of step strain stress relaxation measurements for some samples are shown: (b) White petrolatum at 37°C (Figure 4B). [Figure 4C] The results of step strain stress relaxation measurements for some of the samples are shown: (c) Placebo cream at 25°C (Figure 4C). [Figure 4D] The results of step strain stress relaxation measurements for some of the samples are shown: (d) 2% triamcinolone acetonide (sample K) cream at 25°C (Figure 4D). [Figure 5] The levels of the compound of formula I in the epidermis, dermis, and receptor fluid 46 hours after topical application of a 2% cream of the compound of formula I to the epidermis are shown. Results were obtained from six replicates of an in vitro skin penetration study using human cadaver skin samples placed in Franz diffusion cells; the receptor fluid was in contact with the dermis. [Figure 6] This shows the ocular exposure levels in the eyes of miniature pigs after twice-daily eyelid administration of a 2% compound I cream over 7.5 days. Time points are 2, 4, 8, and 24 hours after the final dose on day 8. [Figure 7] Process flowchart for the production of a cream containing the compound of formula I. [Modes for carrying out the invention]

[0041] Detailed explanation This specification provides 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 perioboribular glands of a subject (e.g., meibomian glands, lacrimal glands, and / or accessory lacrimal glands). In some embodiments, the pharmaceutical compositions are specifically formulated for perioboribular delivery in accordance with the teachings herein. This specification further provides a method for providing prophylactic, mitigating, and / or therapeutic relief of one or more signs or symptoms of an eye disease (e.g., an ocular inflammatory condition, a bacterial infection, or glaucoma), comprising the step of administering a therapeutically effective amount of any of the pharmaceutical compositions of this disclosure to a subject in need thereof. This specification further provides manufacturing articles or kits comprising one or more of the pharmaceutical compositions described herein.

[0042] Topical eye drops are the optimal delivery method for eye care providers, particularly for conditions 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 tears in the eye poses a serious problem for eye drops. The tear film has a volume of only about 7 μL. Eye drops, depending on the surface tension characteristics of the drug, amount to about 30-50 μL; therefore, only up to 1-3 percent of the active pharmaceutical ingredient (API) in topical eye drops penetrates the intended target tissue in the eye. The remainder of the eye drops flows out of the tear film through the nasolacrimal system. And due to the constant production and drainage of tears (0.5-2.2 μL / min), the drug's contact time with ocular tissue is only about 1 minute (Abelson et al, 2012). Methods to increase the retention time of the drug in the treated eye include high-viscosity liquid formulations (e.g., Tobradex ST) and new technologies, such as mucosal penetration techniques (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's capsule, retrobulbar, and peribulbar administration (see Figure 1 in Gaudana R et al, 2010).

[0043] Direct application of drugs to the eyelids was considered 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), generally characterized by terminal duct obstruction and / or qualitative / quantitative changes in glandular secretions (Nichols et al, 2011). Blepharitis is inflammation of the eyelids. Topical eyelid delivery was considered for diseases affecting the eyelids because Abelson and collaborators (2012) stated, "If you want to treat a topical condition, the more topical the delivery, the better the results will be. What is a better example for this need than directly delivering a drug for blepharitis to the affected eyelid?"

[0044] MacKeen et al (1995) reported a unique drug delivery system consisting of applying a petrolatum ointment vehicle to the lower eyelid. The ointment melts at skin temperature and gradually moves across the skin to the ocular surface. This movement of the petrolatum ointment was referred to as "supracutaneous." For this method to work, the muscular system of the lower eyelid must move the drug toward and beyond the eyelid margin. Thus, this drug delivery method assumes that the applied drug does not penetrate the skin of the lower eyelid, but instead moves across 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, when appropriately formulated in a suitable vehicle, are based on the unexpected finding that, after topical periorbital application to one or both eyelids, they do not melt and do not flow or migrate onto the ocular surface, but instead penetrate into the eyelid together with its API payload, the lipophilic drug delivered topically to the eyelid, in a manner that allows access to the meibomian glands, meibums, and other fatty structures within the eyelid (which can themselves act as drug depots resulting in sustained delivery to the ocular surface). Thus, the notion that "the more localized the delivery, the better the results will be" is not a precise way of conceiving of delivering lipophilic compounds to the ocular surface. The drug delivery method of the present invention also relies on penetration of the eyelid skin, which is inconsistent with the prior art that assumes the eyelid skin as a barrier to successful ocular surface drug delivery.

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

[0047] Pflugfelder and collaborators (2004) demonstrated that topical corticosteroids can achieve the goal of short-term treatment of acute exacerbations of DED signs or symptoms. They evaluated 0.5% ethaprednol ophthalmic suspension administered four times daily compared to placebo for the treatment of DED in patients with delayed tear clearance. Significant differences in clinical signs (nasal and tarsal congestion) between the groups were observed as early as week 2 in patients with at least moderate clinical inflammation and persisted throughout week 4 of the study. Furthermore, improvement in Erythrovis Visual Analog Scale (VAS) scores was consistently 20% better in ethaprednol-treated patients compared to vehicle-treated patients.

[0048] Leveraging the known safety profile of loteprednol ethanolate, Kala Pharmaceuticals, Inc. is developing KPI-121 as a novel nanoparticle formulation of loteprednol ethanolate using mucopenetrating particle (MPP) technology. In October 2017, Kala filed an IND for KPI-121 1% as a treatment for inflammation and pain following ophthalmic surgery. In January 2018, they published top-line results for KPI-121 0.25% for transient relief of signs and symptoms of ocular edema (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 on day 15. These local ocular delivery routes present several significant challenges to the successful implementation of treatment: (1) QID dosing is inconvenient for patients and is likely to result in low compliance; (2) frequent dosing is necessary to maintain therapeutically active drug levels for anti-inflammatory efficacy; (3) there are potential safety concerns associated with frequent dosing; and (4) there is a 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 eye conditions to improve patient adherence by reducing medication frequency and enhancing efficacy, sustained-release formulations are being developed to further eliminate preservatives such as benzalkonium chloride (BAK) in glaucoma and to prevent the re-proliferative phase in bacterial conjunctivitis. Therefore, there is a need across ophthalmic conditions for sustained-release formulations that are minimally invasive, reduce medication frequency, maintain a constant drug exposure at the site of action, minimize pre-corneal tear film breakdown, and reduce ocular exposure to formulation excipients.

[0050] I. Pharmaceutical Composition Aspects of this disclosure relate to 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 glands of a target (e.g., meibomian glands, lacrimal glands, and / or accessory lacrimal glands). The term “periorbital” refers to the intraorbital region surrounding the eyeball, including the eyelids and the lateral orbital portion. Perioorbital glands are glands in the region around the eyeball, including, for example, meibomian glands, lacrimal glands, and / or accessory lacrimal glands. In some embodiments, the pharmaceutical composition is formulated specifically for periocular delivery. In some embodiments, pharmaceutically acceptable carriers are adapted for periorbital transdermal delivery by (1) reducing the concentration of the permeation enhancer in the carrier compared to the concentrations used in standard ointments / creams or ophthalmic formulations; (2) using a permeation enhancer suitable for transdermal delivery of the compound into the eyelid (not typically found in topical steroid ointment / cream formulations) (e.g., Tween-80); (3) formulating the pharmaceutical composition to achieve improved spreadability on the periorbital surface compared to ointment bases; and / or (4) formulating the pharmaceutical composition to avoid flow from the periorbital 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 lipophilic compound being delivered by: (1) reducing the concentration of the penetration enhancer in the pharmaceutical composition compared to the concentrations used in standard ointments / creams or ophthalmic formulations; (2) using a penetration enhancer suitable for perdermal delivery of the compound into the eyelid (not typically found in topical steroid ointment / cream formulations) (e.g., Tween-80); (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 to the corneal surface. (5) Using novel steroids such as compounds of formula I (which have been specifically developed so that the glucocorticoid receptor can trans-suppress gene activation and have little to no transactivation) to reduce the side effects of glucocorticoids that are thought to be mediated by transactivation; (6) Using meibomian glands, meibums, and other fatty structures in the eyelids as drug depots for lipophilic compounds for sustained delivery to the ocular surface; and / or (7) Using meibomian glands and meibums as novel drug delivery systems for pharmaceutical formulations of lipophilic compounds applied periorbitally to the outer part of the upper and / or lower eyelids.

[0051] In some embodiments, the pharmaceutical composition further comprises, in any combination, at least one additional steroid, antibiotic, immunomodulator, integrin antagonist, anti-inflammatory agent, and / or antiglaucoma agent or anti-ocular hypertension agent in a therapeutically effective amount. In some embodiments, the lipophilic compound further comprises at least one additional steroid, antibiotic, immunomodulator, integrin antagonist, anti-inflammatory agent, and / or antiglaucoma agent 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 antiglaucoma agent or anti-ocular hypertension agent. In some embodiments, the pharmaceutical composition is specifically formulated for periorbital 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 lacrimal 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 immunomodulator. 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, this disclosure relates to pharmaceutical compositions comprising a steroid as a lipophilic compound. Accordingly, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a steroid and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the steroid to one or more periorbital (e.g., oil-secreting periorbital) glands of a target, wherein the pharmaceutical composition is specifically formulated for periorbital delivery. Any suitable steroid known in the art, including, for example, compounds of formula I, fluocinolone, medlizone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, and testosterone, or any ester derivative thereof, may be used in the pharmaceutical compositions of this disclosure. 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-tetramethy(cyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylic acid cyanomethyl ester. See, for example, U.S. Patent No. 7,291,609, which includes a method for producing the same. The structure of a compound of formula I is shown below. TIFF2026048951000003.tif76128

[0054] In some embodiments, the pharmaceutical composition contains a steroid at a concentration of 0.001% to 10% w / w. For example, the pharmaceutical composition may contain approximately 0.001% to 10%, approximately 0.001% to 9%, approximately 0.001% to 8%, approximately 0.001% to 7%, approximately 0.001% to 6%, approximately 0.001% to 5%, approximately 0.001% to 4%, approximately 0.001% to 3%, approximately 0.001% to 2%, approximately 0.001% to 1%, approximately 0.001% to 0.5%, approximately 0.001% to 0.1%, and approximately 0.001% to 0.05%. Approximately 0.001% to 0.01%, approximately 0.001% to 0.005%, approximately 0.01% to 10%, approximately 0.01% to 9%, approximately 0.01% to 8%, approximately 0.01% to 7%, approximately 0.01% to 6%, approximately 0.01% to 5%, approximately 0.01% to 4%, approximately 0.01% to 3%, approximately 0.01% to 2%, approximately 0.01% to 1%, approximately 0.01% to 0.5%, approximately 0.01% to 0.1%, approximately 0.01% Approximately 0.05%, approximately 0.05% to approximately 10%, approximately 0.05% to approximately 9%, approximately 0.05% to approximately 8%, approximately 0.05% to approximately 7%, approximately 0.05% to approximately 6%, approximately 0.05% to approximately 5%, approximately 0.05% to approximately 4%, approximately 0.05% to approximately 3%, approximately 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 7%, approximately 0.1% to 6%, approximately 0.1% to 5%, approximately 0.1% to 4%, approximately 0.1% to 3%, approximately 0.1% to 2%, approximately 0.1% to 1%, approximately 0.1% to 0.5%, approximately 0.5% to 10%, approximately 0.5% to 9%, approximately 0.5% to 8%, approximately 0.5% to 7%, approximately 0.5% to 6%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to approximately 1%, approximately 1% to approximately 10%, approximately 1% to approximately 9%, approximately 1% to approximately 8%, approximately 1% to approximately 7%, approximately 1% to approximately 6%, approximately 1% to approximately 5%, approximately 1% to approximately 4%, approximately 1% to approximately 3%, approximately 1% to approximately 2%, approximately 2% to approximately 10%, approximately 2% to approximately 9%, approximately 2% to approximately 8%, approximately 2% to approximately 7%, approximately 2% to approximately 6%, approximately 2% to approximately 5%, approximately 2% to approximately 4%, approximately 2% to approximately 3%, approximately 3% to approximately 10%, approximately 3% to approximately 9%, approximately 3% to approximately 8%, approximately 3% to approximately 7%, approximately 3% to approximately 6%, approximately 3% Steroids may be contained in concentrations of approximately 5%, 3% to 4%, 4% to 10%, 4% to 9%, 4% to 8%, 4% to 7%, 4% to 6%, 4% to 5%, 5% to 10%, 5% to 9%, 5% to 8%, 5% to 7%, 5% to 6%, 6% to 10%, 6% to 9%, 6% to 8%, 6% to 7%, 7% to 10%, 7% to 9%, 7% to 8%, 6% to 7%, 7% to 10%, 7% to 9%, 7% to 8%, 8% to 10%, 8% to 9%, or 9% to 10% w / w. In some embodiments, the pharmaceutical composition contains steroids at a concentration of approximately 0.01% to 2% w / w. In some embodiments, the pharmaceutical composition contains a steroid at any of the following concentrations: approximately 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, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of 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 antibiotic and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the antibiotic to one or more periorbital (e.g., oil-secreting periorbital) glands of a target, wherein the pharmaceutical composition is specifically formulated for periorbital delivery. Any suitable antibiotic known in the art, including, for example, sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, tetracyclines, and any combination thereof, may be used in the pharmaceutical compositions of this disclosure. Examples of such antibiotics include, but are not limited to, azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxyfloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, and sulfacetamide.

[0056] In some embodiments, the pharmaceutical composition contains an antibiotic at a concentration of 0.0001% to 10% by weight (w / w). For example, pharmaceutical compositions include approximately 0.0001% to 10%, approximately 0.0001% to 9%, approximately 0.0001% to 8%, approximately 0.0001% to 7%, approximately 0.0001% to 6%, approximately 0.0001% to 5%, approximately 0.0001% to 4%, approximately 0.0001% to 3%, approximately 0.0001% to 2%, approximately 0.0001% to 1%, approximately 0.0001% to 0.5%, approximately 0.0001% to 0.1%, approximately 0.0001% to 0.05%, approximately 0.0001% to 0.01%, approximately 0.0001% to 0.005%, and approximately 0.0001% to 0.00 1%, 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%, approximately 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% ~8%, approx. 0.01%~approx. 7%, approx. 0.01%~approx. 6%, approx. 0.01%~approx. 5%, approx. 0.01%~approx. 4%, approx. 0.01%~approx. 3%, approx. 0.01%~approx. 2%, approx. 0.01%~approx. 1%, approx. 0.01%~approx. 0.5%, approx. 0.01%~approx. 0.1%, approx. 0.01%~approx. 0.05%, approx. 0.05%~approx. 10%, approx. 0.05%~approx. 9%, approx. 0.05%~approx. 8%, approx. 0.05%~approx. 7%, approx. 0.05%~approx. 6%, approx. 0.05%~approx. 5%, approx. 0.05%~approx. 4%, approx. 0.05%~approx. 3%, approx. 0.05%~approx. 2%, approx. 0.05%~approx. 1%, approx. 0.0.5% 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% ~9%, 0.5%~8%, 0.5%~7%, 0.5%~6%, 0.5%~5%, 0.5%~4%, 0.5%~3%, 0.5%~2%, 0.5%~1%, 1%~10%, 1%~9%, 1%~8%, 1%~7%, 1%~6%, 1%~5%, 1%~4%, 1%~3%, 1% %~approx. 2%, approx. 2%~approx. 10%, approx. 2%~approx. 9%, approx. 2%~approx. 8%, approx. 2%~approx. 7%, approx. 2%~approx. 6%, approx. 2%~approx. 5%, approx. 2%~approx. 4%, approx. 2%~approx. 3%, approx. 3%~approx. 10%, approx. 3%~approx. 9%, approx. 3%~approx. 8%, approx. 3%~approx. 7%, approx. 3%~approx. 6%, approx. 3%~approx. 5%, approx. 3%~approx. 4%, approx. 4%~approx. 10%, approx. 4%~approx. 9%, approx. 4%~approx. 8% The composition may contain antibiotics at concentrations of approximately 4% to 7%, 4% to 6%, 4% to 5%, 5% to 10%, 5% to 9%, 5% to 8%, 5% to 7%, 5% to 6%, 6% to 10%, 6% to 9%, 6% to 8%, 6% to 7%, 7% to 10%, 7% to 9%, 7% to 8%, 8% to 10%, 8% to 9%, or 9% to 10% w / w. In some embodiments, the pharmaceutical composition contains antibiotics at concentrations of 0.0001% to 5% w / w. In some aspects, the pharmaceutical composition is approximately 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 a concentration of 5%, 9%, 9.5%, or 10% w / w.

[0057] Immunomodulatory drugs In some aspects, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of an immunomodulator 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.) immunomodulators. Thus, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an immunomodulator and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the immunomodulator to one or more periorbital (e.g., oil-secreting periorbital) glands of a target, wherein the pharmaceutical composition is specifically formulated for periorbital delivery. Any suitable immunomodulator known in the art, including, for example, calcineurin inhibitors, thalidomide analogs, and any combination thereof, may be used in the pharmaceutical compositions of this disclosure. Examples of such immunomodulators include, but are not limited to, cyclosporine A, voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide. In some embodiments, the immunomodulator is cyclosporine A.

[0058] In some embodiments, the pharmaceutical composition contains an immunomodulator at a concentration of 0.0001% to 5% by weight (w / w).For example, pharmaceutical compositions include approximately 0.0001% to 5%, approximately 0.0001% to 4%, approximately 0.0001% to 3%, approximately 0.0001% to 2%, approximately 0.0001% to 1%, approximately 0.0001% to 0.5%, approximately 0.0001% to 0.1%, approximately 0.0001% to 0.05%, approximately 0.0001% to 0.01%, approximately 0.0001% to 0.005%, approximately 0.0001% to 0.001%, approximately 0.0001% to 0.005%, approximately 0.0005% to 5%, approximately 0.0005% to 4%, approximately 0.0005% to 3%, approximately 0.0005% to 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%, approximately 0.0005% to approximately 0.001%, 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 0.005% to approximately 5%, approximately 0.005% to approximately 4%, approximately 0.005% to approximately 3%, approximately 0.005% to approximately 2%, approximately 0.005% to approximately 1%, approximately 0.005% to approximately 0.5%, approximately 0.005% to approximately 0.1%, approximately 0.005% to approximately 0.05%, approximately 0.005% to approximately 0.01%, approximately 0.01% to approximately 5%, approximately 0.01% to approximately 4%, approximately 0.01% to approximately 3%, approximately 0.01% to approximately 2%, approximately 0.01% to approximately 1%, approximately 0.01% to approximately 0.5%, approximately 0.01% to approximately 0.1%, approximately 0.01% to approximately 0.05%, approximately 0.05% to approximately 5%, approximately 0.05% to approximately 4%, approximately 0.05% to approximately 3 %, approximately 0.05% to 2%, approximately 0.05% to 1%, approximately 0.05% to 0.5%, approximately 0.05% to 0.1%, approximately 0.1% to 5%, approximately 0.1% to 4%, approximately 0.1% to 3%, approximately 0.1% to 2%, approximately 0.1% to 1%, approximately 0.1% to 0.5%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to 1%, approximately 1% to 5%, approximately 1% to 4%, approximately 1% to 3%, approximately 1% to 2%, approximately 2% to 5%, approximately 2% to 4%, approximately 2% to 3%, approximately 3% to 5%, approximately 3% to 4%, or approximately 4% to 5% It may contain immunomodulatory agents at w / w concentrations.In some embodiments, the pharmaceutical composition contains an immunomodulator at any of the following concentrations: approximately 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, this disclosure relates to pharmaceutical compositions 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 periorbital transdermal delivery of the integrin antagonist to one or more periorbital (e.g., oil-secreting periorbital) glands of a target, wherein the pharmaceutical composition is specifically formulated for periorbital delivery. Any suitable integrin antagonist known in the art, including, for example, Lifitegrast, GW559090, its ester derivatives, and any combination thereof, may be used in the pharmaceutical compositions of this disclosure. In some embodiments, the pharmaceutical composition contains GW559090 (see Krauss et al. Invest. Ophthalmol. Vis. Sci. 2015;56(10):5888-95).

[0060] In some embodiments, the pharmaceutical composition contains an integrin antagonist at a concentration of 0.0001% to 10% by weight (w / w). For example, pharmaceutical compositions include approximately 0.0001% to 10%, approximately 0.0001% to 9%, approximately 0.0001% to 8%, approximately 0.0001% to 7%, approximately 0.0001% to 6%, approximately 0.0001% to 5%, approximately 0.0001% to 4%, approximately 0.0001% to 3%, approximately 0.0001% to 2%, approximately 0.0001% to 1%, approximately 0.0001% to 0.5%, approximately 0.0001% to 0.1%, approximately 0.0001% to 0.05%, approximately 0.0001% to 0.01%, approximately 0.0001% to 0.005%, and approximately 0.0001% to 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% Approximately 0.0005% 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% to 8%, approximately 0.01% to 7%, approximately 0.01% to 6%, approximately 0.01% to 5%, approximately 0.01% to 4%, approximately 0.01% to 3%, approximately 0.01% to 2%, approximately 0.01% to 1%, approximately 0.01% to 0.5%, approximately 0.01% to 0.1%, approximately 0.01% to 0.05%, approximately 0.05% to 10%, approximately 0.05% to 9%, approximately 0.05% to 8%, approximately 0.05% to 7%, approximately 0.05% to 6%, approximately 0.05% to 5%, approximately 0.05% to 4%, approximately 0.05% to 3%, approximately 0.05% to 2%, approximately 0.0.5% 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%, approximately 0.5% to approximately 10%, approximately 0.5% to 9%, approximately 0.5% to 8%, approximately 0.5% to 7%, approximately 0.5% to 6%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to 1%, approximately 1% to 10%, approximately 1% to 9%, approximately 1% to 8%, approximately 1% to 7%, approximately 1% to 6%, approximately 1% to 5%, approximately 1% to 4%, approximately 1% to Approximately 3%, approximately 1% to approximately 2%, approximately 2% to approximately 10%, approximately 2% to approximately 9%, approximately 2% to approximately 8%, approximately 2% to approximately 7%, approximately 2% to approximately 6%, approximately 2% to approximately 5%, approximately 2% to approximately 4%, approximately 2% to approximately 3%, approximately 3% to approximately 10%, approximately 3% to approximately 9%, approximately 3% to approximately 8%, approximately 3% to approximately 7%, approximately 3% to approximately 6%, approximately 3% to approximately 5%, approximately 3% to approximately 4%, approximately 4% to approximately 10%, approximately 4% to approximately 9%, approximately 4% to It may contain integrin antagonists at concentrations of approximately 8%, 4%-7%, 4%-6%, 4%-5%, 5%-10%, 5%-9%, 5%-8%, 5%-7%, 5%-6%, 6%-10%, 6%-9%, 6%-8%, 6%-7%, 7%-10%, 7%-9%, 7%-8%, 8%-10%, 8%-9%, or 9%-10% w / w. In some aspects, the pharmaceutical composition contains approximately 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 an integrin antagonist at either a 5% or 10% w / w concentration.

[0061] Anti-inflammatory drugs In some aspects, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of an anti-inflammatory 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.) anti-inflammatory agents. Thus, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an anti-inflammatory agent and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the anti-inflammatory agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a target, wherein the pharmaceutical composition is specifically formulated for periorbital delivery. Any suitable anti-inflammatory agent known in the art, including, for example, omega-3 fatty acids, nonsteroidal anti-inflammatory drugs (NSAIDs), and any combination thereof, may be used in the pharmaceutical compositions of this disclosure. Examples of suitable omega-3 fatty acids include, but are not limited to, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combination thereof. Suitable NSAIDs include, but are not limited to, bromfenac, diclofenac, indomethacin, flurbiprofen, ketrolac, nepafenac, and any combination thereof.

[0062] In some embodiments, the pharmaceutical composition contains an anti-inflammatory agent at a concentration of 0.0001% to 5% by weight (w / w).For example, pharmaceutical compositions include approximately 0.0001% to 5%, approximately 0.0001% to 4%, approximately 0.0001% to 3%, approximately 0.0001% to 2%, approximately 0.0001% to 1%, approximately 0.0001% to 0.5%, approximately 0.0001% to 0.1%, approximately 0.0001% to 0.05%, approximately 0.0001% to 0.01%, approximately 0.0001% to 0.005%, approximately 0.0001% to 0.001%, approximately 0.0001% to 0.005%, approximately 0.0005% to 5%, approximately 0.0005% to 4%, approximately 0.0005% to 3%, approximately 0.0005% to 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%, approximately 0.0005% to approximately 0.001%, 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 0.005% to approximately 5%, approximately 0.005% to approximately 4%, approximately 0.005% to approximately 3%, approximately 0.005% to approximately 2%, approximately 0.005% to approximately 1%, approximately 0.005% to approximately 0.5%, approximately 0.005% to approximately 0.1%, approximately 0.005% to approximately 0.05%, approximately 0.005% to approximately 0.01%, approximately 0.01% to approximately 5%, approximately 0.01% to approximately 4%, approximately 0.01% to approximately 3%, approximately 0.01% to approximately 2%, approximately 0.01% to approximately 1%, approximately 0.01% to approximately 0.5%, approximately 0.01% to approximately 0.1%, approximately 0.01% to approximately 0.05%, approximately 0.05% to approximately 5%, approximately 0.05% to approximately 4%, approximately 0.05% to approximately 3 %, approximately 0.05% to 2%, approximately 0.05% to 1%, approximately 0.05% to 0.5%, approximately 0.05% to 0.1%, approximately 0.1% to 5%, approximately 0.1% to 4%, approximately 0.1% to 3%, approximately 0.1% to 2%, approximately 0.1% to 1%, approximately 0.1% to 0.5%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to 1%, approximately 1% to 5%, approximately 1% to 4%, approximately 1% to 3%, approximately 1% to 2%, approximately 2% to 5%, approximately 2% to 4%, approximately 2% to 3%, approximately 3% to 5%, approximately 3% to 4%, or approximately 4% to 5% It may contain an anti-inflammatory agent at a w / w concentration.In some embodiments, the pharmaceutical composition contains an anti-inflammatory agent at any of the following concentrations: approximately 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 drugs or anti-ocular hypertension agents In some aspects, this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an antiglaucoma agent or antihypertensive 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 agents or antihypertensive agents. Thus, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an antiglaucoma agent or antihypertensive agent and a pharmaceutically acceptable carrier adapted for periorbital transdermal delivery of the antiglaucoma agent or antihypertensive agent to one or more periorbital (e.g., oil-secreting periorbital) glands of a target, wherein the pharmaceutical composition is formulated specifically for periorbital delivery. Any suitable antiglaucoma agent or antihypertensive agent known in the art, including, for example, prostaglandin analogs, β-blockers, α2 agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and any combination thereof, may be used in the pharmaceutical compositions of this disclosure. Suitable prostaglandin analogs include, but are not limited to, bimatoprost, latanoprost, travoprost, tafluprost, latanoprostenbunod, and any combination thereof. Suitable beta-blockers include, but are not limited to, timolol, betaxolol, levobunolol, metipranolol, and any combination thereof. Suitable alpha-2 agonists include, but are not limited to, brimonidine, clonidine, apraclonidine, and any combination thereof. Suitable carbonic anhydrase inhibitors include, but are not limited to, dorzolamide, brinzolamide, acetazolamide, metazolamide, and any combination thereof. Suitable Rho kinase inhibitors include, but are not limited to, netalusdil, and any combination thereof.

[0064] In some embodiments, the pharmaceutical composition contains an antiglaucoma agent or an antihypertensive agent at a concentration of 0.0001% to 10% by weight (w / w). For example, pharmaceutical compositions include approximately 0.0001% to 10%, approximately 0.0001% to 9%, approximately 0.0001% to 8%, approximately 0.0001% to 7%, approximately 0.0001% to 6%, approximately 0.0001% to 5%, approximately 0.0001% to 4%, approximately 0.0001% to 3%, approximately 0.0001% to 2%, approximately 0.0001% to 1%, approximately 0.0001% to 0.5%, approximately 0.0001% to 0.1%, approximately 0.0001% to 0.05%, approximately 0.0001% to 0.01%, approximately 0.0001% to 0.005%, and approximately 0.0001% to 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% Approximately 0.0005% 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% to 8%, approximately 0.01% to 7%, approximately 0.01% to 6%, approximately 0.01% to 5%, approximately 0.01% to 4%, approximately 0.01% to 3%, approximately 0.01% to 2%, approximately 0.01% to 1%, approximately 0.01% to 0.5%, approximately 0.01% to 0.1%, approximately 0.01% to 0.05%, approximately 0.05% to 10%, approximately 0.05% to 9%, approximately 0.05% to 8%, approximately 0.05% to 7%, approximately 0.05% to 6%, approximately 0.05% to 5%, approximately 0.05% to 4%, approximately 0.05% to 3%, approximately 0.05% to 2%, approximately 0.0.5% 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%, approximately 0.5% to approximately 10%, approximately 0.5% to 9%, approximately 0.5% to 8%, approximately 0.5% to 7%, approximately 0.5% to 6%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to 1%, approximately 1% to 10%, approximately 1% to 9%, approximately 1% to 8%, approximately 1% to 7%, approximately 1% to 6%, approximately 1% to 5%, approximately 1% to 4%, approximately 1% to Approximately 3%, approximately 1% to approximately 2%, approximately 2% to approximately 10%, approximately 2% to approximately 9%, approximately 2% to approximately 8%, approximately 2% to approximately 7%, approximately 2% to approximately 6%, approximately 2% to approximately 5%, approximately 2% to approximately 4%, approximately 2% to approximately 3%, approximately 3% to approximately 10%, approximately 3% to approximately 9%, approximately 3% to approximately 8%, approximately 3% to approximately 7%, approximately 3% to approximately 6%, approximately 3% to approximately 5%, approximately 3% to approximately 4%, approximately 4% to approximately 10%, approximately 4% to approximately 9%, approximately 4% to It may contain antiglaucoma agents or antihypertensive agents at concentrations of approximately 8%, 4%-7%, 4%-6%, 4%-5%, 5%-10%, 5%-9%, 5%-8%, 5%-7%, 5%-6%, 6%-10%, 6%-9%, 6%-8%, 6%-7%, 7%-10%, 7%-9%, 7%-8%, 8%-10%, 8%-9%, or 9%-10% w / w. In some aspects, the pharmaceutical composition contains approximately 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 an antiglaucoma agent or antihypertensive agent at either a 5% or 10% w / w concentration.

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

[0066] In some embodiments, a 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” may refer to a compound or mixture of compounds that interact with one or more skin components to promote 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 their derivatives (e.g., sodium glycolate, sodium deoxycholate, etc.), fatty acids and their derivatives (e.g., oleic acid, caprylic acid, fatty acid esters, 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, polyglycol, etc.), alcohols Any suitable permeation enhancer known in the art, including alkanols, alkenols, glycols, hydrocarbons (e.g., alkanes, alkenes, halogenated alkanes, squalene, mineral oil, etc.), amines, amides (e.g., cyclic amides, acyclic amides, azone, pyrrolidone, urea and its derivatives, etc.), others (e.g., terpenes and terpenoids, essential oils (e.g., eucalyptus oil, peppermint oil, turpentine oil, 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, may be used in the pharmaceutical compositions described herein.

[0067] In some embodiments, the pharmaceutically acceptable carrier is adapted for periocular transdermal delivery by containing a reduced concentration of permeation enhancer compared to the concentration of the permeation enhancer used in typical steroid ointment / cream formulations. In some embodiments, the pharmaceutically acceptable carrier contains a concentration of permeation enhancer of approximately 95%, approximately 90%, approximately 85%, approximately 80%, approximately 75%, approximately 70%, approximately 65%, approximately 60%, approximately 55%, approximately 50%, approximately 45%, approximately 40%, approximately 35%, approximately 30%, approximately 35%, approximately 20%, approximately 15%, approximately 10%, approximately 5%, approximately 1%, approximately 0.1%, or approximately 0.01% compared to the concentration of permeation enhancer used in typical steroid ointment / cream formulations for skin application. In some embodiments, a pharmaceutically acceptable carrier contains about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, or 100 times less of the penetration enhancer compared to the concentration of the penetration enhancer used in a typical steroid ointment / cream formulation for skin application. For example, if a typical steroid ointment contains a given penetration enhancer (e.g., hydroxypropyl methylcellulose) at 3% w / w, the pharmaceutical compositions of this disclosure may contain the same penetration enhancer at 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.

[0068] In some embodiments, pharmaceutically acceptable carriers are adapted for periorbital transdermal delivery by including a penetration enhancer suitable for transdermal delivery of steroids into the eyelids of the subject (e.g., not entirely through the topical surface). In some embodiments, the penetration enhancer suitable for transdermal delivery into the eyelids is one that is particularly suitable for transdermal delivery adjacent to the eye and / or is not typically found in topical steroid ointment / cream formulations (intended for use in other areas of the subject's body, such as the hands or feet). Examples of penetration enhancers suitable for delivery into the eyelids of the subject 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, pharmaceutically acceptable carriers are adapted for periocular transdermal delivery by formulating the carrier to (1) achieve improved spreadability on the periocular surface compared to ointment bases; and / or (2) avoid flow from the periocular surface onto the corneal surface. After application of a typical steroid ointment or cream to the skin, the body heat absorbed by the cream or ointment reduces viscosity and / or yield strength, decreasing adhesion on contact surfaces such as periocular skin. This decrease in adhesion after heat absorption is problematic for ointments or creams applied to the eyelids because it can lead to the cream or ointment spreading / flowing on the ocular surface. In some embodiments, pharmaceutically acceptable carriers include improved spreadability and rheological features, resulting in easier administration and spreading on the eyelid surface, and particularly after application to the skin of the subject, resulting in the absence of flow at the subject's body temperature (e.g., 31°C, 33°C, 35°C, 37°C, etc.). In some embodiments, the pharmaceutical compositions of this disclosure are formulated such that the adhesion of the formulation does not change significantly after application to the target skin (e.g., eyelids). Examples of suitable additives that provide suitable adhesion to the formulation include, for example, additives that increase the viscosity of the formulation, such as waxes, paraffins, and elastomers. 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 target body temperature (e.g., 31°C, 33°C, 35°C, 37°C, etc.). In some embodiments, the pharmaceutically acceptable viscosity of the 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., about 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C) to a temperature closer to the body temperature of the subject (e.g., about 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, or 37°C).

[0070] In some embodiments, pharmaceutically acceptable carriers are ointments, creams, lotions, gels, emulsions, suspensions, oils, foams, transdermal patches, sprays, 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 buffering agent, e.g., phosphates, citrates, and other organic acids; antioxidants, e.g., ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens, e.g., methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, e.g., serum albumin, gelatin, or immunoglobulins; hydrophilic polymers This includes, for example, polyvinylpyrrolidone; amino acids, for example, glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, for example, glucose, mannose, or dextrin; chelating agents, for example, EDTA; sugars, for example, sucrose, mannitol, trehalose, or sorbitol; polyols, for example, glycerol (e.g., formulations containing 10% glycerol) or propylene glycol; salt-forming counterions, for example, sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, for example, 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, a pharmaceutically acceptable carrier further comprises one or more additional components. Examples of additional components include, but are not limited to, binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethylcellulose, polyacrylate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metal stearate, hydrogenated vegetable oil, corn starch, polyethylene glycol, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); humectants (e.g., sodium lauryl sulfate, etc.); salt solutions; alcohols; polyethylene glycol; gelatin; lactose; amylase; magnesium stearate; talc; silicic acid; viscous paraffin; hydroxymethylcellulose; polyvinylpyrrolidone; fragrances; colorants; humectants; sunscreens; and the like.

[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 paraffinic 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 comprising an oil-in-water base. In some embodiments, the pharmaceutically acceptable carrier is a cream comprising a water-in-oil base. In some embodiments, the cream 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, 9 or more, 10 or more, 11 or more, 12 or more, or all 13) of the following: 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 appropriate 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 an appropriate amount 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 this disclosure may be prepared by mixing a steroid with one or more pharmaceutically acceptable carriers. Formulations used for in vivo administration are generally sterile. Sterility can be readily achieved, for example, by filtration through a sterile filtration membrane, by thermal 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 additional lipophilic compound (e.g., at least one, at least two, at least three, at least four, or at least five). Accordingly, in some embodiments, the pharmaceutical compositions provided herein further comprise one or more lipophilic compounds selected from the group consisting of steroids, antibiotics, immunomodulators, 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 compositions of the present disclosure further comprise at least one additional steroid. In some embodiments, the pharmaceutical compositions comprise 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, including, for example, compounds of formula I, fluocinolone, medlisone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, and testosterone, or any ester derivative thereof, may be used as one or more additional steroids in the pharmaceutical composition. In some embodiments, the additional steroids are glucocorticoids. 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 may be a compound of formula I, and the additional steroids may be triamcinolone acetonide, dexamethasone, and / or loteprednol etavonate.

[0078] In some embodiments, the pharmaceutical composition contains one or more additional steroids at a concentration of 0.001% to 10% w / w. For example, the pharmaceutical composition may contain approximately 0.001% to 10%, approximately 0.001% to 9%, approximately 0.001% to 8%, approximately 0.001% to 7%, approximately 0.001% to 6%, approximately 0.001% to 5%, approximately 0.001% to 4%, approximately 0.001% to 3%, approximately 0.001% to 2%, approximately 0.001% to 1%, approximately 0.001% to 0.5%, approximately 0.001% to 0.1%, and approximately 0.001% to 0.05%. Approximately 0.001% to 0.01%, approximately 0.001% to 0.005%, approximately 0.01% to 10%, approximately 0.01% to 9%, approximately 0.01% to 8%, approximately 0.01% to 7%, approximately 0.01% to 6%, approximately 0.01% to 5%, approximately 0.01% to 4%, approximately 0.01% to 3%, approximately 0.01% to 2%, approximately 0.01% to 1%, approximately 0.01% to 0.5%, approximately 0.01% to 0.1%, approximately 0.01% Approximately 0.05%, approximately 0.05% to approximately 10%, approximately 0.05% to approximately 9%, approximately 0.05% to approximately 8%, approximately 0.05% to approximately 7%, approximately 0.05% to approximately 6%, approximately 0.05% to approximately 5%, approximately 0.05% to approximately 4%, approximately 0.05% to approximately 3%, approximately 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 7%, approximately 0.1% to 6%, approximately 0.1% to 5%, approximately 0.1% to 4%, approximately 0.1% to 3%, approximately 0.1% to 2%, approximately 0.1% to 1%, approximately 0.1% to 0.5%, approximately 0.5% to 10%, approximately 0.5% to 9%, approximately 0.5% to 8%, approximately 0.5% to 7%, approximately 0.5% to 6%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to approximately 1%, approximately 1% to approximately 10%, approximately 1% to approximately 9%, approximately 1% to approximately 8%, approximately 1% to approximately 7%, approximately 1% to approximately 6%, approximately 1% to approximately 5%, approximately 1% to approximately 4%, approximately 1% to approximately 3%, approximately 1% to approximately 2%, approximately 2% to approximately 10%, approximately 2% to approximately 9%, approximately 2% to approximately 8%, approximately 2% to approximately 7%, approximately 2% to approximately 6%, approximately 2% to approximately 5%, approximately 2% to approximately 4%, approximately 2% to approximately 3%, approximately 3% to approximately 10%, approximately 3% to approximately 9%, approximately 3% to approximately 8%, approximately 3% to approximately 7%, approximately 3% to approximately 6%, approximately 3% May contain additional steroids at concentrations of approximately 5%, 3%-4%, 4%-10%, 4%-9%, 4%-8%, 4%-7%, 4%-6%, 4%-5%, 5%-10%, 5%-9%, 5%-8%, 5%-7%, 5%-6%, 6%-10%, 6%-9%, 6%-8%, 6%-7%, 7%-10%, 7%-9%, 7%-8%, 8%-10%, or 9%-10% w / w. In some embodiments, the pharmaceutical composition contains additional steroids at any of the following concentrations: approximately 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, pharmaceutically acceptable steroids or their formulations have the additional advantage of not causing skin thinning.

[0080] Antibiotics as additional lipophilic compounds In some embodiments, the pharmaceutical compositions of the Disclosure further comprise a therapeutically effective amount of one or more antibiotics. In some embodiments, the pharmaceutical compositions comprise two or more antibiotics (e.g., two or more, three or more, four or more, five or more, etc.). Any suitable antibiotic known in the Art, including, for example, sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, tetracyclines, and any combination thereof, may be used in the pharmaceutical compositions of the Disclosure. Examples of such antibiotics include, but are not limited to, azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxyfloxacin, 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% by weight (w / w). For example, pharmaceutical compositions include approximately 0.0001% to 10%, approximately 0.0001% to 9%, approximately 0.0001% to 8%, approximately 0.0001% to 7%, approximately 0.0001% to 6%, approximately 0.0001% to 5%, approximately 0.0001% to 4%, approximately 0.0001% to 3%, approximately 0.0001% to 2%, approximately 0.0001% to 1%, approximately 0.0001% to 0.5%, approximately 0.0001% to 0.1%, approximately 0.0001% to 0.05%, approximately 0.0001% to 0.01%, approximately 0.0001% to 0.005%, and approximately 0.0001% to 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% Approximately 0.0005% 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% to 8%, approximately 0.01% to 7%, approximately 0.01% to 6%, approximately 0.01% to 5%, approximately 0.01% to 4%, approximately 0.01% to 3%, approximately 0.01% to 2%, approximately 0.01% to 1%, approximately 0.01% to 0.5%, approximately 0.01% to 0.1%, approximately 0.01% to 0.05%, approximately 0.05% to 10%, approximately 0.05% to 9%, approximately 0.05% to 8%, approximately 0.05% to 7%, approximately 0.05% to 6%, approximately 0.05% to 5%, approximately 0.05% to 4%, approximately 0.05% to 3%, approximately 0.05% to 2%, approximately 0.0.5% 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%, approximately 0.5% to approximately 10%, approximately 0.5% to 9%, approximately 0.5% to 8%, approximately 0.5% to 7%, approximately 0.5% to 6%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to 1%, approximately 1% to 10%, approximately 1% to 9%, approximately 1% to 8%, approximately 1% to 7%, approximately 1% to 6%, approximately 1% to 5%, approximately 1% to 4%, approximately 1% to Approximately 3%, approximately 1% to approximately 2%, approximately 2% to approximately 10%, approximately 2% to approximately 9%, approximately 2% to approximately 8%, approximately 2% to approximately 7%, approximately 2% to approximately 6%, approximately 2% to approximately 5%, approximately 2% to approximately 4%, approximately 2% to approximately 3%, approximately 3% to approximately 10%, approximately 3% to approximately 9%, approximately 3% to approximately 8%, approximately 3% to approximately 7%, approximately 3% to approximately 6%, approximately 3% to approximately 5%, approximately 3% to approximately 4%, approximately 4% to approximately 10%, approximately 4% to approximately 9%, approximately 4% to The composition may contain one or more antibiotics at concentrations of approximately 8%, approximately 4% to approximately 7%, approximately 4% to approximately 6%, approximately 4% to approximately 5%, approximately 5% to approximately 10%, approximately 5% to approximately 9%, approximately 5% to approximately 8%, approximately 5% to approximately 7%, approximately 5% to approximately 6%, approximately 6% to approximately 10%, approximately 6% to approximately 9%, approximately 6% to approximately 8%, approximately 6% to approximately 7%, approximately 7% to approximately 10%, approximately 7% to approximately 9%, approximately 7% to approximately 8%, approximately 8% to approximately 10%, approximately 8% to approximately 9%, or approximately 9% to approximately 10% w / w. In some embodiments, the pharmaceutical composition contains one or more antibiotics at concentrations of 0.0001% to 5% w / w. In some aspects, the pharmaceutical composition is approximately 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.It contains one or more antibiotics at any of the following concentrations: 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 compositions of the Disclosure further comprise a therapeutically effective amount of one or more immunomodulators. 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.) immunomodulators. Any suitable immunomodulators known in the Art, including, for example, calcineurin inhibitors, thalidomide analogs, and any combination thereof, may be used in the pharmaceutical compositions of the Disclosure. Examples of such immunomodulators include, but are not limited to, cyclosporine A, voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide.

[0083] In some embodiments, the pharmaceutical composition comprises one or more immunomodulators at a concentration of 0.0001% to 5% by weight (w / w).For example, pharmaceutical compositions include approximately 0.0001% to 5%, approximately 0.0001% to 4%, approximately 0.0001% to 3%, approximately 0.0001% to 2%, approximately 0.0001% to 1%, approximately 0.0001% to 0.5%, approximately 0.0001% to 0.1%, approximately 0.0001% to 0.05%, approximately 0.0001% to 0.01%, approximately 0.0001% to 0.005%, approximately 0.0001% to 0.001%, approximately 0.0001% to 0.005%, approximately 0.0005% to 5%, approximately 0.0005% to 4%, approximately 0.0005% to 3%, approximately 0.0005% to 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%, approximately 0.0005% to approximately 0.001%, 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 0.005% to approximately 5%, approximately 0.005% to approximately 4%, approximately 0.005% to approximately 3%, approximately 0.005% to approximately 2%, approximately 0.005% to approximately 1%, approximately 0.005% to approximately 0.5%, approximately 0.005% to approximately 0.1%, approximately 0.005% to approximately 0.05%, approximately 0.005% to approximately 0.01%, approximately 0.01% to approximately 5%, approximately 0.01% to approximately 4%, approximately 0.01% to approximately 3%, approximately 0.01% to approximately 2%, approximately 0.01% to approximately 1%, approximately 0.01% to approximately 0.5%, approximately 0.01% to approximately 0.1%, approximately 0.01% to approximately 0.05%, approximately 0.05% to approximately 5%, approximately 0.05% to approximately 4%, approximately 0.05% to approximately 3 %, approximately 0.05% to 2%, approximately 0.05% to 1%, approximately 0.05% to 0.5%, approximately 0.05% to 0.1%, approximately 0.1% to 5%, approximately 0.1% to 4%, approximately 0.1% to 3%, approximately 0.1% to 2%, approximately 0.1% to 1%, approximately 0.1% to 0.5%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to 1%, approximately 1% to 5%, approximately 1% to 4%, approximately 1% to 3%, approximately 1% to 2%, approximately 2% to 5%, approximately 2% to 4%, approximately 2% to 3%, approximately 3% to 5%, approximately 3% to 4%, or approximately 4% to 5% It may contain one or more immunomodulators at w / w concentrations.In some aspects, the pharmaceutical composition is approximately 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%. Contains one or more immunomodulators at any w / w concentration.

[0084] Integrin antagonists as additional lipophilic compounds In some embodiments, the pharmaceutical compositions of the Disclosure further comprise a therapeutically effective amount of one or more integrin antagonists. In some embodiments, the pharmaceutical compositions comprise two or more integrin antagonists (e.g., two or more, three or more, four or more, five or more, etc.). Any suitable integrin antagonist known in the Art, including, for example, rifitegrast, GW559090, its ester derivatives, and any combination thereof, may be used in the pharmaceutical compositions of the Disclosure. In some embodiments, the pharmaceutical compositions comprise 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% by weight (w / w). For example, pharmaceutical compositions include approximately 0.0001% to 10%, approximately 0.0001% to 9%, approximately 0.0001% to 8%, approximately 0.0001% to 7%, approximately 0.0001% to 6%, approximately 0.0001% to 5%, approximately 0.0001% to 4%, approximately 0.0001% to 3%, approximately 0.0001% to 2%, approximately 0.0001% to 1%, approximately 0.0001% to 0.5%, approximately 0.0001% to 0.1%, approximately 0.0001% to 0.05%, approximately 0.0001% to 0.01%, approximately 0.0001% to 0.005%, and approximately 0.0001% to 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% Approximately 0.0005% 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% to 8%, approximately 0.01% to 7%, approximately 0.01% to 6%, approximately 0.01% to 5%, approximately 0.01% to 4%, approximately 0.01% to 3%, approximately 0.01% to 2%, approximately 0.01% to 1%, approximately 0.01% to 0.5%, approximately 0.01% to 0.1%, approximately 0.01% to 0.05%, approximately 0.05% to 10%, approximately 0.05% to 9%, approximately 0.05% to 8%, approximately 0.05% to 7%, approximately 0.05% to 6%, approximately 0.05% to 5%, approximately 0.05% to 4%, approximately 0.05% to 3%, approximately 0.05% to 2%, approximately 0.0.5% 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%, approximately 0.5% to approximately 10%, approximately 0.5% to 9%, approximately 0.5% to 8%, approximately 0.5% to 7%, approximately 0.5% to 6%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to 1%, approximately 1% to 10%, approximately 1% to 9%, approximately 1% to 8%, approximately 1% to 7%, approximately 1% to 6%, approximately 1% to 5%, approximately 1% to 4%, approximately 1% to Approximately 3%, approximately 1% to approximately 2%, approximately 2% to approximately 10%, approximately 2% to approximately 9%, approximately 2% to approximately 8%, approximately 2% to approximately 7%, approximately 2% to approximately 6%, approximately 2% to approximately 5%, approximately 2% to approximately 4%, approximately 2% to approximately 3%, approximately 3% to approximately 10%, approximately 3% to approximately 9%, approximately 3% to approximately 8%, approximately 3% to approximately 7%, approximately 3% to approximately 6%, approximately 3% to approximately 5%, approximately 3% to approximately 4%, approximately 4% to approximately 10%, approximately 4% to approximately 9%, approximately 4% to It may contain one or more integrin antagonists at concentrations of approximately 8%, approximately 4% to approximately 7%, approximately 4% to approximately 6%, approximately 4% to approximately 5%, approximately 5% to approximately 10%, approximately 5% to approximately 9%, approximately 5% to approximately 8%, approximately 5% to approximately 7%, approximately 5% to approximately 6%, approximately 6% to approximately 10%, approximately 6% to approximately 9%, approximately 6% to approximately 8%, approximately 6% to approximately 7%, approximately 7% to approximately 10%, approximately 7% to approximately 9%, approximately 7% to approximately 8%, approximately 8% to approximately 10%, approximately 8% to approximately 9%, or approximately 9% to approximately 10% w / w. In some aspects, the pharmaceutical composition contains approximately 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.It contains one or more integrin antagonists at a concentration of either 5% or 10% w / w.

[0086] Anti-inflammatory agents as additional lipophilic compounds In some embodiments, the pharmaceutical compositions of the Disclosure further comprise a therapeutically effective amount of one or more anti-inflammatory agents. 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.) anti-inflammatory agents. Any suitable anti-inflammatory agents known in the Art, including, for example, omega-3 fatty acids, nonsteroidal anti-inflammatory drugs (NSAIDs), and any combination thereof, may be used in the pharmaceutical compositions of the Disclosure. Examples of suitable omega-3 fatty acids include, but are not limited to, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combination thereof. Examples of suitable NSAIDs 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% by weight (w / w).For example, pharmaceutical compositions include approximately 0.0001% to 5%, approximately 0.0001% to 4%, approximately 0.0001% to 3%, approximately 0.0001% to 2%, approximately 0.0001% to 1%, approximately 0.0001% to 0.5%, approximately 0.0001% to 0.1%, approximately 0.0001% to 0.05%, approximately 0.0001% to 0.01%, approximately 0.0001% to 0.005%, approximately 0.0001% to 0.001%, approximately 0.0001% to 0.005%, approximately 0.0005% to 5%, approximately 0.0005% to 4%, approximately 0.0005% to 3%, approximately 0.0005% to 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%, approximately 0.0005% to approximately 0.001%, 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 0.005% to approximately 5%, approximately 0.005% to approximately 4%, approximately 0.005% to approximately 3%, approximately 0.005% to approximately 2%, approximately 0.005% to approximately 1%, approximately 0.005% to approximately 0.5%, approximately 0.005% to approximately 0.1%, approximately 0.005% to approximately 0.05%, approximately 0.005% to approximately 0.01%, approximately 0.01% to approximately 5%, approximately 0.01% to approximately 4%, approximately 0.01% to approximately 3%, approximately 0.01% to approximately 2%, approximately 0.01% to approximately 1%, approximately 0.01% to approximately 0.5%, approximately 0.01% to approximately 0.1%, approximately 0.01% to approximately 0.05%, approximately 0.05% to approximately 5%, approximately 0.05% to approximately 4%, approximately 0.05% to approximately 3 %, approximately 0.05% to 2%, approximately 0.05% to 1%, approximately 0.05% to 0.5%, approximately 0.05% to 0.1%, approximately 0.1% to 5%, approximately 0.1% to 4%, approximately 0.1% to 3%, approximately 0.1% to 2%, approximately 0.1% to 1%, approximately 0.1% to 0.5%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to 1%, approximately 1% to 5%, approximately 1% to 4%, approximately 1% to 3%, approximately 1% to 2%, approximately 2% to 5%, approximately 2% to 4%, approximately 2% to 3%, approximately 3% to 5%, approximately 3% to 4%, or approximately 4% to 5% It may contain one or more anti-inflammatory agents in w / w concentrations.In some aspects, the pharmaceutical composition is approximately 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%. It contains one or more anti-inflammatory agents at any w / w concentration.

[0088] Antiglaucoma and antihypertensive agents as additional lipophilic compounds In some embodiments, the pharmaceutical compositions of the Disclosure further comprise a therapeutically effective amount of one or more antiglaucoma or antihypertensive agents. 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.) antiglaucoma or antihypertensive agents. Any suitable antiglaucoma or antihypertensive agent known in the Art, including, for example, prostaglandin analogs, β-blockers, α2 agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and any combination thereof, may be used in the pharmaceutical compositions of the Disclosure. Examples of suitable prostaglandin analogs include, but are not limited to, bimatoprost, latanoprost, travoprost, tafluprost, latanoprostenbunod, and any combination thereof. Examples of suitable β-blockers include, but are not limited to, timolol, betaxolol, levovunolol, metipranolol, and any combination thereof. Suitable α2 agonists include brimonidine, clonidine, apraclonidine, and any combination thereof. Suitable carbonic anhydrase inhibitors include, but are not limited to, dorzolamide, brinzolamide, acetazolamide, metazolamide, and any combination thereof. Suitable Rho kinase inhibitors include, but are not limited to, netalusdil and any combination thereof.

[0089] In some embodiments, the pharmaceutical composition comprises one or more antiglaucoma agents or antihypertensive agents at a concentration of 0.0001% to 10% by weight (w / w). For example, pharmaceutical compositions include approximately 0.0001% to 10%, approximately 0.0001% to 9%, approximately 0.0001% to 8%, approximately 0.0001% to 7%, approximately 0.0001% to 6%, approximately 0.0001% to 5%, approximately 0.0001% to 4%, approximately 0.0001% to 3%, approximately 0.0001% to 2%, approximately 0.0001% to 1%, approximately 0.0001% to 0.5%, approximately 0.0001% to 0.1%, approximately 0.0001% to 0.05%, approximately 0.0001% to 0.01%, approximately 0.0001% to 0.005%, and approximately 0.0001%. ~approximately 0.001%, approximately 0.0001%~approximately 0.0005%, approximately 0.0005%~approximately 10%, approximately 0.0005%~approximately 9%, approximately 0.0005%~approximately 8%, approximately 0.0005%~approximately 7%, approximately 0.0005%~approximately 6%, approximately 0.0005%~approximately 5%, approximately 0.0005%~approximately 4%, approximately 0.0005%~approximately 3%, approximately 0.0005%~approximately 2%, approximately 0.0005%~approximately 1%, approximately 0.0005%~approximately 0.5%, approximately 0.0005%~approximately 0.1%, approximately 0.0005%~approximately 0.005%, approximately 0.0005%~approximately 0.01%, approximately 0.0005%~approximately 0 0.005%, approximately 0.0005% 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 0.001%, approximately 0.001% to approximately 0.005%, approximately 0.01% to approximately 10%, Approximately 0.01% to 9%, approximately 0.01% to 8%, approximately 0.01% to 7%, approximately 0.01% to 6%, approximately 0.01% to 5%, approximately 0.01% to 4%, approximately 0.01% to 3%, approximately 0.01% to 2%, approximately 0.01% to 1%, approximately 0.01% to 0.5%, approximately 0.01% to 0.1%, approximately 0.01% to 0.05%, approximately 0.05% to 10%, approximately 0.05% to 9%, approximately 0.05% to 8%, approximately 0.05% to 7%, approximately 0.05% to 6%, approximately 0.05% to 5%, approximately 0.05% to 4%, approximately 0.05% to 3%, approximately 0.0.5% 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% Approximately 0.5% to 10%, approximately 0.5% to 9%, approximately 0.5% to 8%, approximately 0.5% to 7%, approximately 0.5% to 6%, approximately 0.5% to 5%, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to 1%, approximately 1% to 10%, approximately 1% to 9%, approximately 1% to 8%, approximately 1% to 7%, approximately 1% to 6%, approximately 1% to 5%, approximately 1% to 4% Approximately 1% to 3%, approximately 1% to 2%, approximately 2% to 10%, approximately 2% to 9%, approximately 2% to 8%, approximately 2% to 7%, approximately 2% to 6%, approximately 2% to 5%, approximately 2% to 4%, approximately 2% to 3%, approximately 3% to 10%, approximately 3% to 9%, approximately 3% to 8%, approximately 3% to 7%, approximately 3% to 6%, approximately 3% to 5%, approximately 3% to 4%, approximately 4% to 10%, approximately 4% to 9%, approximately It may contain one or more antiglaucoma agents or antihypertensive agents at concentrations of approximately 4% to 8%, approximately 4% to 7%, approximately 4% to 6%, approximately 4% to 5%, approximately 5% to 10%, approximately 5% to 9%, approximately 5% to 8%, approximately 5% to 7%, approximately 5% to 6%, approximately 6% to 10%, approximately 6% to 9%, approximately 6% to 8%, approximately 6% to 7%, approximately 7% to 10%, approximately 7% to 9%, approximately 7% to 8%, approximately 8% to 10%, approximately 8% to 9%, or approximately 9% to 10% w / w. In some aspects, the pharmaceutical composition contains approximately 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.It contains one or more antiglaucoma agents or antihypertensive agents at a concentration of either 5% or 10% w / w.

[0090] II. Method Aspects of this disclosure relate to a method for providing the preventive, mitigating, and / or therapeutic relief of one or more signs or symptoms of an eye disease (e.g., an ocular inflammatory condition, a bacterial infection, or glaucoma), comprising the step of administering a therapeutically effective amount of any of the pharmaceutical compositions of this disclosure to a subject in need. In some embodiments, this disclosure relates to a method for treating an eye disease (e.g., an ocular inflammatory condition, a bacterial infection, or glaucoma), comprising the step of administering a therapeutically effective amount of any of the pharmaceutical compositions of this disclosure to a subject in need. In some embodiments, the subject has or is at risk of developing an eye disease (e.g., an ocular inflammatory condition, a bacterial infection, or glaucoma).

[0091] In some embodiments, lipid structures of the eyelid (e.g., meibomian glands, meibum, or other adipose tissue) serve as drug depots for periorbital delivered pharmaceutical compositions provided herein, with meibum serving as a drug delivery vehicle.

[0092] In some embodiments, the subjects are non-human animals, including, but not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, horses, etc.), non-human primates (e.g., monkeys), rabbits, and rodents (e.g., mice, hamsters, rats, etc.). In some embodiments, the subjects are humans. In some embodiments, the subjects suffer 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 eye diseases and / or conditions include, but are not limited to, inflammation of the periocular glands, meibomian gland inflammation, dry eye disease, allergic eye disease, topical preservative toxicity, xerophthalmos, loss of tear film homeostasis, tear film instability and hyperosmolarity, ocular surface inflammation and injury, neuronal paresthesia, meibomian gland dysfunction, aggravated 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 this disclosure are administered topically to a subject. As used herein, “administered topically,” “topically,” or “administer topically” means the delivery of a composition to a subject by directly or otherwise bringing a formulation containing the composition into contact with a portion of the subject’s skin. This term may encompass several routes of administration, including but not limited to topical and transdermal. Topical administration may be used as a means of delivering a composition to the epidermis or dermis, or a particular layer thereof, of a subject.

[0094] In some embodiments, the pharmaceutical composition of this disclosure is administered topically to the lateral portion of one or all of the eyelids of the subject (including the superior lateral portion of one or both orbits of the subject). In some embodiments, the pharmaceutical composition is administered topically to the lateral portion of the upper and / or lower eyelids of one or both eyes of the subject. 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 administered topically to the lateral portion of one or all of the eyelids of a subject (including the superior lateral portion of one or both orbits of the subject) 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 of the pharmaceutical composition (e.g., a steroid) are delivered to the ocular surface of the subject via one or more meibomian glands. In some embodiments, one or more components of the pharmaceutical composition (e.g., a steroid) are delivered to the ocular surface of the subject via meibomian glands.

[0096] In some embodiments, the pharmaceutical compositions of the Disclosure are administered once or more times per day (e.g., once or twice, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more times, etc.). In some embodiments, the pharmaceutical compositions of the Disclosure are administered for one, two, three, four, five, six, or seven consecutive days or longer. In some embodiments, the pharmaceutical compositions of the Disclosure are administered for one, two, three, four, five, six, or seven consecutive days or longer. In some embodiments, the pharmaceutical compositions of the Disclosure are administered for one, two, three, four, five, six, or seven consecutive weeks or longer. In some embodiments, the pharmaceutical compositions of the Disclosure are administered for one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve consecutive weeks or longer. In some embodiments, the pharmaceutical compositions of the Disclosure are administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer, for consecutive months. In some embodiments, the pharmaceutical compositions of the Disclosure are administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer, for non-consecutive months. In some embodiments, treatment is initiated with a loading dose, followed by dose escalation. In some embodiments, treatment is initiated with a loading dose, followed by sustained treatment at lower doses.

[0097] In some embodiments, exposure levels of lipophilic compounds in the eyelids, conjunctiva, cornea, iris / ciliary body (ICB), and / or aqueous humor (AQH) remain constant or substantially constant for up to 24 hours after the final periorbital dose is applied. In some embodiments, the concentrations of lipophilic compounds in one or more compartments selected from the group consisting of the eyelids, conjunctiva, cornea, iris / ciliary body (ICB), and aqueous humor (AQH) differ by only 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 concentrations at 2 hours and 24 hours after the final periorbital dose is applied. In some embodiments, the concentration of the lipophilic compound in one or more compartments selected from the group consisting of the eyelid, conjunctiva, cornea, iris / ciliary body (ICB), and aqueous humor (AQH) 24 hours after the application of the final periorbital 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 the application of the final periorbital dose. In some embodiments, the concentration of the lipophilic compound in the eyelid 24 hours after the application of the final periorbital 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 the application of the final periorbital dose. In some embodiments, the concentration of the lipophilic compound in the eyelid 24 hours after the application of the final periorbital 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 the application of the final periorbital dose. In some embodiments, the concentration of the lipophilic compound in one or more compartments selected from the group consisting of the eyelid, conjunctiva, cornea, iris / ciliary body (ICB), and aqueous humor (AQH) 24 hours after the application of the final periorbital 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 the application of the final periorbital dose.In some embodiments, the concentration of the lipophilic compound in the eyelid 24 hours after the final periorbital 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 the final periorbital dose.

[0098] In some embodiments, topical administration of a pharmaceutical composition as described herein provides prophylactic, mitigating, and / or therapeutic relief of one or more signs of an eye disease in a subject. In some embodiments, topical administration of a pharmaceutical composition as described herein reduces or eliminates one or more signs of an eye disease in a subject. Examples of signs or symptoms of an eye disease include, but are not limited to, redness of the eye and / or eyelid margin, lacrimation, dry eye, itching, stinging or burning sensation of the eye or orbit, blurred vision, difficulty driving at night, night blindness, xerosis, xerosis, corneal ulcer, Vitot's spot, eye fatigue, foreign body sensation in the eye, photosensitivity, fibrous mucus in or around the eye, swelling of the conjunctiva and / or eyelids, eyelids and / or These may include dry, flaky, and / or damaged skin of the orbit, oily eyelids, eyelid adhesion, abnormal eyelash growth, eyelash loss, discomfort or pain of the eye, eyelids, and / or orbit, chronic and transient punctate keratopathy, filamentous keratopathy, recurrent corneal erosion, persistent epithelial defects, corneal lysis, ocular surface insufficiency, blepharospasm, mucopurulent discharge, appearance of chalazion, 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 of a target (e.g., one or more, two or more, or all three of the meibomian glands, lacrimal glands, and / or accessory lacrimal glands). 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 a pharmaceutical composition reduces inflammation in one or more periorbital glands by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 100, or 1000 times compared to inflammation observed before administration of the pharmaceutical composition. In some embodiments, topical administration of a pharmaceutical composition as described herein eliminates inflammation in one or more periorbital glands of a subject. For example, methods for measuring periorbital gland inflammation, including the use of a laser bioconfocal microscope (IVCM), are known in the art (see Qazi et al. Investigative Ophthalmology & Visual Science March 2012, Vol. 53, 593).

[0100] In some embodiments, topical administration (e.g., long-term / continuous administration) of pharmaceutical compositions as described herein does not cause adverse events in the subject. Examples of adverse events include, but are not limited to, increased intraocular pressure, formation or worsening of cataracts, ocular infections, and any combination thereof. In some embodiments, topical administration of pharmaceutical compositions does not increase / elevate 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 subject's tears or lacrimal ducts by administration of the pharmaceutical composition. In some embodiments, the lipophilic compound is not delivered directly to the subject's ocular surface by administration of the pharmaceutical composition.

[0102] III. Manufactured articles or kits Aspects of this disclosure relate to a manufactured article or kit comprising one or more of the pharmaceutical compositions described herein. In some embodiments, the manufactured article or kit includes a label and / or accompanying documentation containing instructions for the use of one or more pharmaceutical compositions. In some embodiments, one or more pharmaceutical compositions are provided in a container. In some embodiments, the components of the pharmaceutical composition are provided in a single container or in two or more separate containers. In some embodiments, the manufactured article or kit includes a container and a label or accompanying documentation on or associated with the container. Suitable containers may include, for example, tubes, bottles, vials, bags, etc. Containers may be formed from a variety of suitable materials such as glass, plastics (e.g., polyvinyl chloride, polyolefin, or polyethylene), metals, and / or alloys (e.g., stainless steel). The manufactured article or kit may further include other materials desirable from a commercial and user perspective, including buffers, diluents, filters, syringes, applicators, etc.

[0103] The foregoing description is considered sufficient to enable those skilled in the art to implement the disclosure. The following examples are provided for illustrative purposes only and are not intended in any way to limit the scope of the disclosure. In fact, various modifications of the disclosure, in addition to those indicated and described herein, will be 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 this disclosure in detail, it should be understood that this disclosure is not limited to any particular composition or biological system, and that these may, of course, vary. It should also be understood that the terms used herein are for the purpose of describing a particular aspect only and are not intended to be limiting.

[0105] As used herein, the singular forms “a,” “an,” and “the” refer to multiple objects unless the context explicitly indicates otherwise. For example, a reference to “a molecule” optionally includes two or more such molecules, etc.

[0106] Where used herein, the term “about” refers to the normal range of error for each value, which is readily apparent to those skilled in the art. References to “about” values ​​or parameters herein include (and describe) aspects relating to the value or parameter itself.

[0107] As used herein, the term "and / or" is intended to include both A and B; A or B; A (alone); and B (alone) in phrases such as "A and / or B". Similarly, as used herein, the term "and / or" is intended to include each of the following embodiments in phrases such as "A, B, and / or C": 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, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates, e.g., monkeys), rabbits, and rodents (e.g., mice, hamsters, and rats). In some embodiments, the individual, patient, or subject is human.

[0109] As used herein, the term “pharmaceutical preparation” means a preparation that is in a form that enables the biological activity of the active ingredient contained herein to be effective, and that does not contain any additional ingredients that are unacceptably toxic to the subject to which the preparation is administered.

[0110] As used herein, the term “pharmaceutically acceptable carrier” refers to a component of a pharmaceutical preparation other than the active ingredient that is non-toxic to the subject.

[0111] As used herein, the term “prevention” includes providing preventive measures in relation to the onset or recurrence of one or more signs or symptoms of a disorder in an individual. An individual may be predisposed to, susceptible to, or at risk of developing a disorder, but has not yet been diagnosed with a disorder.

[0112] As used herein, an individual “at risk” of developing a disability may or may not have a detectable disease or symptoms of a disease, and may or may not have exhibited a detectable disease or symptoms of a disease prior to 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 disability, as are known in the art. An individual having one or more of these risk factors has a higher probability of developing a disability than an individual not having one or more of these risk factors.

[0113] As used herein, the term “treatment” refers to a clinical intervention designed to alter the natural course of an individual or cell being treated during the course of clinicopathology. Desired treatment effects include, for example, a slowing of disease progression, improvement or mitigation of the disease state, and improvement of prognosis. For example, an individual is successfully “treated” if one or more signs or symptoms associated with the disorder are reduced or eliminated. For example, an individual is successfully “treated” if one or more symptoms associated with an inflammatory disease are reduced or eliminated, including, but not limited to, a reduction in disease-related symptoms, an increase in the quality of life of the person with the disease, a reduction in the dosage of other medications required to treat the disease, and / or a delay in disease progression.

[0114] "Effective dose" refers to the minimum effective amount in the dosage and duration required to achieve the desired or described effect, including therapeutic or prophylactic outcomes. An effective dose may be provided in one or more doses.

[0115] The "therapeutic dose" is the minimum concentration required to produce a measurable improvement in one or more signs or symptoms of a particular disorder. The therapeutic dose as used herein may vary depending on factors such as the patient's disease state, age, sex, and weight. The therapeutic dose is also defined as the amount at which the therapeutic benefits outweigh the adverse effects of the treatment.

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

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

[0118] Example 1: Effects of treatment with compound 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 showed near-complete agonism in various human in vitro assays of glucocorticoid receptor-mediated trans-inhibitory activity and partial response in numerous assays of glucocorticoid receptor-mediated trans-activation. In vivo, the compound of formula I showed potent anti-inflammatory activity after intratracheal administration in mouse and rat models of pneumonia and exhibited activity similar to fluticasone propionate (FP) in mouse models of local delayed-type hypersensitivity otitis, tyrosine aminotransferase induction, and chronic house dust mite. Interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) stimulate the release of the inflammatory 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 trans-inhibit this activation across numerous cell lines (A549, HeLa, MG63, 16HBE, and H9). These are 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 with unilateral (OS) ocular hypertension induced by pre-photocoagulation (laser) procedure to the trabecular network (TM) were used, aged 11–14 years at the start of the study. Laser-induced ocular hypertension had been induced in the study animals at least 9 years prior. Animals and treatments were randomized according to a 4x4 replication Williams-type Latin square layout. Following random assignment of numbers 1–8, the eight primates were randomized into four treatment groups (A–D) of two animals each, and the treatments were kept secret from the researchers until all data had been collected and entered into the database. Treatment groups A–D were as follows: 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] Local bilateral treatment was performed in a randomized, masked floss-over format. All four treatments were examined in parallel in two animals per treatment group for each 4-week treatment period. The assigned, masked formulation (A, B, C, or D) was administered to both eyes (OU) three times daily (TID; 8:30 a.m., 1 p.m., and 5 p.m.). Treatment periods were separated by a 4-week washout / recovery period without local treatment. A 2-week preparation period preceded the first period (Period 1), during which all animals received placebo topically at TID.

[0121] Conscious animals were seated in custom-made chairs, and 0.13% propalacaine hydrochloride was applied topically to both eyes. IOP was then measured using an air tonometer (Classic 30, Reichert Depew) (Figure 1). Two to three measurements were taken for each eye and averaged. The data were saved and stored in an archive. During the preparation and treatment periods, daytime IOP was determined twice a week, approximately at 8:30 a.m., 1 p.m., and 5 p.m. For each animal, topical application of the appropriate drug formulation A, B, C, or D was performed immediately after bilateral IOP measurement. During the washout period, daytime IOP was measured once a week in both eyes, approximately at 8:30 a.m., 1 p.m., and 5 p.m. Surprisingly, topical treatment with the compound of formula I over four weeks did not increase IOP in primates (Figure 1). In fact, IOP levels in eyes treated with the compound of formula I were similar to those in eyes treated with the vehicle alone and significantly lower than those treated with dexamethasone, 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 investigated. Rabbits were placed on a restraint device, and 1% atropine sulfate eye drops (30 μL) were administered 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 solution. Tear volume was then assessed by the Schirmer test (Figure 2). A Schirmer strip was carefully placed in the posterior (i.e., temporal) inferior fornix for 60 seconds, and the moistened area was read in millimeters as an indicator of tear volume. Surprisingly, when administered in vivo to the ocular surface for 7 days, the compound of formula I prevented the reduction of tear formation, similar to topical dexamethasone, in a model of dry eye disease (Figure 2).

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

[0124] Example 2: Determination of the characteristics of the periocular cream formulation The following active pharmaceutical ingredients (APIs) were mixed with a cream vehicle for the preparation of a cream containing 2% API by weight for this study and allowed to stand at room temperature for 24 hours prior to testing: cyclosporine A (Sample A), loteprednol etavonate (Sample B), dexamethasone (Sample C), ketrolactromethamine (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 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 dibasic sodium phosphate, 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 dibasic sodium phosphate, 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 each sample and each test condition was recorded by photograph. Using a wide-mouth disposable pipette, a small amount of 2% API-containing cream, approximately 1 ml, was placed into a Kimble 1-drum glass vial, 15x45 mm. The vial was capped and labeled A-L on the glass vial as referenced in the preceding paragraph. For each test, in sets of two or three vials, the sample vials were placed in a Quett rheometer cup with a thermostat 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 on the fluid surface or meniscus, inverted, and returned to the 37°C rheometer cup. At two intervals, 2 minutes and 5 minutes, the vial was removed, photographed, and the movement of the cream was recorded.

[0126] Preliminary measurements were performed on vehicle cream and 2% Formula I compound cream in comparison to the high-viscosity polybutene standard N62000. In contrast to the N62000 high-viscosity polymer standard, in which bulk flow was observed, neither the vehicle cream nor the 2% Formula I compound cream showed any discernible flow at 37°C at 2 and 5 minutes (Figure 3A). The same procedure was used for experimental cream samples containing 2% API, prepared from the 11 compounds listed above, and further tested at 37°C. This simple test shows that none of the 11 prepared 2% API-containing creams showed any 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 was performed using a rheometer and 10% step strain stress relaxation measurements on a 25 mm cone and plate. This test applies instantaneous motion as step strain to the sample at t=0, and then measures shear stress relaxation. For Newtonian fluids, relaxation is immediate. For non-Newtonian fluids, delayed stress relaxation may exist, accompanied by a distribution of relaxation times with relaxation to zero. Non-Newtonian fluids with yield stress exhibit a distribution of relaxation times (or infinite relaxation time) with non-zero stress relaxation. This is the equivalent of the yield stress. The test was performed at both 25°C and 37°C.

[0128] Measurements in Ultima white petrolatum were compared with those in vehicle cream, as well as 2% API-containing creams of the compound of Formula I and the 11 APIs mentioned above. All prepared 2% API creams, vehicle creams, and Ultima white petrolatum exhibited yield stresses 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 APIs in each vehicle cream, air trapping during mixing, the particle size of the APIs used in this study, and other factors. Regardless of the source of variability, each 2% API-containing cream exhibited a yield stress. This was also true for vehicle cream and white petrolatum. The curves (some examples in Figures 4A-D) show very consistent stress relaxation to non-zero shear stress values. Note that the creams are highly shear-sensitive, and the results for each sample in each test at both 25°C and 37°C, including Ultima petrolatum, are summarized in the following table (Table 1); 1-5 replicates.

[0129] (Table 1) TIFF2026048951000004.tif143128

[0130] For comparison, the yield stress values ​​(in Pa) for vehicle cream were 4.1, 3.3, 2.9, and 1.0, 1.0, and 1.5 at 25 and 37°C, respectively (3 replicates each). The yield stress values ​​(in Pa) for 2% of the compound of formula I were 2.2, 2.8, and 1.0, 0.9, and 0.9 at 25 and 37°C, respectively (2-3 replicates each). For comparison, the stress relaxation function for high-viscosity polybutene N62000 standard showed a rapid decrease to 0 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 spreadability of Ultima Vaseline on contact surfaces such as eyelids. All 2% API creams exhibited extensional viscosity behavior and may be strain thickening. This is a material property that can contribute to increased adhesion on contact surfaces, further counteracting the effects of gravity and limiting flow. More importantly, extensional viscosity can enhance physical stability, preventing sedimentation of the active ingredient. These data suggest that all cream formulations are easier to apply to the intended surface (eyelids) compared to ointments. Due to the lower yield stress of the API-containing creams and vehicle creams, these formulations are easier for consumers to use and apply compared to Vaseline alone. In contrast, high-viscosity polymers such as N62000 are less likely to be suitable for the present invention. These data clearly demonstrate that the goal of developing a cream formulation that is easy to apply to contact surfaces such as eyelids and does not flow after application to the eyelids to prevent the formulation from flowing 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 penetration model using human cadaver skin placed on a Franz-type diffusion cell (FDC) was selected, and skin permeability of the compound of formula I applied as a 2% cream to the epidermal surface was determined. Transdermal efflux into the receptor fluid was measured over a period of 46 hours after application of the formulation. At the end of the 46-hour incubation period, the skin was tape-removed and thermally separated according to an established method, 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 dibasic sodium phosphate, 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 dibasic sodium phosphate, 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 cadaveric skin, harvested to a thickness of approximately 250 μm from the hind limb of a single donor, was obtained from a commercial source, cut into approximately 2 cm x 2 cm fragments, and each such fragment was cut to 0.55 cm. 2The samples were placed in FDCs with a diffusion area and a receiver volume of 3.3 mL. The stratum corneum and dermis were brought into contact with the donor and receptor compartments, respectively. After integrity checks (impedance analysis), 10 μL of cream sample was applied to the epidermal surface of each FDC. Aliquots of the receptor fluid (consisting of phosphate-buffered saline pH 7.4 containing 0.01 wt% sodium azide and 1 wt% Brij O20) were sampled 4, 8, 24, and 46 hours after application of the test material and stored refrigerated until sample 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 1:1 volume water / ethanol mixture. The skin was then dried by lightly patting it with a Kimwipe and the outermost layer of the stratum corneum was removed by peeling the tape three times with cellophane tape. The remaining skin was then divided into epidermal and dermal compartments. The compound of formula I was extracted using 3 mL of a 1:1 volume DMSO / isopropanol mixture at 40°C for 24 hours.

[0134] High-performance liquid chromatography-UV (HPLC-UV) and LC-MS / MS 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 limit of quantification (LLOQ) for the compound of formula I by LC-MS / MS was determined to be in the range of 6–10 ng / mL.

[0135] Figure 5 shows the accumulation of the compound of formula I in the epidermis and dermis, as well as in the receptor fluid, at each time point. A negative control using vehicle cream is also shown. The compound of formula I was 2.89 ± 0.32 μg / cm³ in the epidermis. 2 In the dermis, the concentration was 0.73 ± 0.21 μg / cm³. 2It was detected only in the receptor fluid and not in the transdermal receptor fluid. Compound I is lipophilic with low water solubility (the solubility limit of compound I in the receptor fluid was determined to be approximately 35.8 μg / mL, which was sufficient to maintain a settled state throughout the experiment), and the data very clearly demonstrate a far more favorable distribution of compound I into lipid-containing compartments, such as tissue, compared to hydrophilic compartments, such as the receptor fluid. This feature likely leads to lipid-containing compartments in the eyelids in general, such as meibomian glands, meibums, and other fatty structures, altering them for drug depot (via meibums) and "sustained-release" delivery mechanisms to the ocular surface for lipophilic compounds administered periorbitally.

[0136] Example 4: Eye and systemic exposure after administration of periocular cream First, to determine the maximum tolerable dose, two Hanford miniature pigs were administered a cream (composed of 2% w / w compound 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 dibasic sodium phosphate, 0.05% w / w anhydrous citric acid, 0.02% w / w propylparaben, and an appropriate amount of purified water) topically to the upper and lower eyelids of one eye over four days in gradually increasing doses (25, 50, 75, 100 μL), approximately 6 hours apart, twice daily (BID). This allowed for the determination of ocular and skin tolerance and the maximum practicable amount of the cream formulation on each eyelid. The evaluated study variables were mortality, clinical observation of response to disease or treatment, eye observation using a modified Hackett-McDonald grading system, and skin Draize scoring. The cream was generally well tolerated at all four doses administered as BID. Due to ease of application and minimal risk of cream migration onto the ocular surface, a dosage of 75 μL per eyelid was determined to be the maximum viable dosage, which covered the entire miniature pig eyelid with a thin layer of the test formulation without dripping, flowing, or runoff of the formulation onto the ocular surface. The 75 μL dosage 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 compound I was applied as a BID to the eyelids of eight Hanford miniature pigs over seven days in a total of 15 topical doses, with one additional dose on day eight. After the final dose on day eight, two animals were euthanized 2, 4, 8, and 24 hours after the final dose, and their eyes were collected for dissection of the following tissues and fluids: eyelids (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. This was because the amount that could be extracted from the eyelid margin was found to be minimal, and the procedure of extracting meibomian glands through eyelid manipulation / friction / compression appeared to jeopardize the eyelid tissue, making it unusable for further analysis. Meibomian glands were considered to be the only lipid compartment in the eyelid that could act as a depot for lipophilic compounds. Meibomian glands and other adipose tissues were others. Attempts to extract meibomian glands from the ducts, thereby rendering the eyelid itself unusable for further analysis, would not have allowed for the assessment of drug content in other potential lipid structures within the eyelid. Therefore, the decision was made to assess drug exposure in the eyelid as intact tissue in order 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) conjunctiva, cornea, and ICB; and (iii) eyelids. 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 derived from miniature pigs and rabbits, respectively; (ii) conjunctiva, cornea, and ICB standards were rabbit corneas; and (iii) eyelid standards were porcine skin. The internal standard working solution for analytical purposes was 20.0 ng / mL in acetonitrile with 1% formic acid (v / v). 13 C2 15The compound consisted of an N-labeled compound of formula I, which was added to each sample. The tissue / fluid sample extraction procedure was as follows: (i) plasma / aqueous humor samples; (ii) conjunctival, corneal, and ICB homogenization in acetonitrile; (iii) eyelid digestion in a 1:1 acetonitrile:ammonium hydroxide solution at 37°C for 1.5 hours, followed by acetonitrile addition, homogenization, and neutralization with formic acid; in all cases, this was followed by the addition of an internal standard working solution, vortexing, and centrifugation. The samples were then analyzed by LC-MS / MS using mobile phases A (water containing 0.1% formic acid) and B (acetonitrile containing 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 eyelid tissue (peak mean concentration of 30613 ng / g 4 hours after the final dose), followed by conjunctiva (mean value of 1931 ng / g 4 hours after the final dose), cornea (mean value of 452 ng / g 8 hours after the final dose), ICB (mean value of 20.48 ng / g 24 hours after the final dose), and aqueous humor (mean value of 5.81 ng / g 8 hours after the final dose) (Figure 6). In all tissues, even when considering high protein binding of approximately 99%, which results in a "free" drug concentration of approximately 1 / 100 of the total measured concentration, these concentration ranges represent pharmacologically active concentrations of the compound of formula I. Unexpectedly, within each compartment, exposure levels remained nearly constant for up to 24 hours after the application of the final periorbital dose. This exposure profile is quite different from that of typical eye drop applications and strongly suggests a drug depot in the eyelid that "supplies" the downstream compartments (conjunctiva, cornea, ICB, aqueous humor) for at least a 24-hour period. As demonstrated for the compound of formula I by the aforementioned skin permeability test, lipophilic compounds are preferentially distributed into the lipid compartment rather than the aqueous hydrophilic compartment. Therefore, it can be concluded that the lipid structures of the eyelid (e.g., meibomian glands, meibum, and other adipose tissue) serve as drug depots for drugs delivered periocularly, and meibum becomes a 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 are therefore expected to be generally interchangeable with all other lipophilic compounds, if not equally so.

[0140] Furthermore, this 24-hour exposure profile after periorbital administration of lipophilic compounds, such as the compound of formula I, leads to a once-daily application regimen, which represents a significant benefit for patients who are often required to receive steroids or other eye drops up to 4-6 times or more daily. The once-daily application regimen offers improved safety and patient convenience compared to eye drops that must be administered more frequently.

[0141] A further significant advantage of periorbital application is the larger dosage volume, which allows for far greater flexibility in delivering a wide range of drug doses compared to eye drop application, enabling more medication to be administered once daily than with eye drops, leading to the aforementioned patient benefits. The volume of eye drops is typically limited to approximately 30 μL per eye per dose, or in some cases up to approximately 40 μL. A periorbital dosage volume of 75 μL per eyelid, or 150 μL per eye, is equivalent to a dosage volume at least four times greater per dose.

[0142] In addition to the larger delivery volume described above, a further benefit of periorbital application is that a larger percentage of the drug is available for delivery to target tissues on the ocular surface. It is well known that eye drop application, in particular, delivers only a small fraction of the API applied as part of an eye drop formulation. This is because eye drops applied to the ocular surface rapidly drain from the ocular surface via the nasolacrimal duct, and therefore, it is understood that only about 1% of the API "payload" contained in the eye drops delivered to the ocular surface tissues (cornea and conjunctiva). In contrast, periorbital administration delivers essentially 100% or nearly 100% of the API contained in the periorbital formulation to the eyelid tissue. Combined with the larger delivery volume of periorbital formulations compared to topical eye drops, the periorbital route demonstrates a very significant drug delivery advantage of the 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 periorbital application) was variable but generally low or below the lower limit of quantification of 0.1 ng / mL (Figure 6). The peak plasma concentration of 2.22 ng / mL was observed 24 hours after the final day 8 dose. The results indicated no or very low systemic accumulation after 7.5 days of multiple topical eyelid applications.

[0144] Plasma exposure was also determined in another 7-day study in minipigs. The compound of formula I was formulated in a cream composed of 4% w / w and 6% w / w, and further 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 dibasic sodium phosphate anhydrous, 0.05% w / w citric acid anhydrous, 0.02% w / w propylparaben, and an appropriate amount of purified water. The cream formulation was applied periorbitally to the upper and lower eyelids of the right eye of 3 minipigs at a dose volume of 75 μL per eyelid, three times a day (TID) for each concentration at 8-hour intervals for 6 days, and once on the morning of the 7th day. Plasma levels of the compound of formula I were then evaluated for up to 7 days after the final dosing.

[0145] Dermal administration of 4% (18 mg / eye / day) and 6% (27 mg / eye / day) of the cream of the compound of formula I 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, intraocular pressure measurement (IOP), hematology, or serum chemistry.

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

[0147] This is an interesting and unexpected finding because the data show that the ocular drug depot (established after 7 days of periorbital cream application) releases the drug over a long period, and as a result, in some animals, the systemic levels of the compound of formula I are after the final periorbital cream application rearThis suggests that measurements could be taken for up to 7 days. Conceptually, these findings are perfectly consistent with extended delivery from the meibomian gland / meibomian drug depot to the systemic circulation and possibly the ocular surface.

[0148] Example 5: Manufacturing Process Periocular applications require 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 a combination of hydrophilic and lipophilic components under sterile conditions, each separately pre-sterilized by an appropriate sterilization process such as filtration, heating, gamma or beta or alpha irradiation, or other methods. The pre-sterilized API (heating, gamma or 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 at an appropriate temperature using an appropriate process such as stirring, shaking, vortexing, or sonication. The final mixture is then cooled to an appropriate temperature required for the filling process into appropriate containers for the final drug product, whether for clinical or commercial use.

[0149] In one embodiment, a process for producing a cream containing a compound of formula I, as described in this application and Figure 7, requires a rapid homogenization procedure for incorporating the API, as well as a gentle mixing / stirring procedure for combining the lipophilic and hydrophilic components. In the same embodiment, the lipophilic component, such as the compound of formula I, is heated to 55-60°C for the process of incorporating the API and mixing with the hydrophilic component. The final product is then gradually cooled to below 30°C and subsequently filled into final containers for clinical research or commercial use.

[0150] In other embodiments, the lipophilic component is heated to a temperature necessary to liquefy it and make it suitable for sterilization by filtration, or it is not heated at all. This includes 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 intermediate mixing rates 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. This process includes mixing, shaking, stirring, vortexing, sonication, etc.

[0152] In other embodiments, the mixing of hydrophilic and lipophilic components is achieved at room temperature or in the 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.

[0153] In other embodiments, the final product is then gradually or rapidly cooled to the temperature required for filling into final containers for clinical research or commercial use. This cooling process may require mixing at a low, rapid, or intermediate rate, or may not require mixing at all.

Claims

1. A method for providing preventive, mitigating, or therapeutic relief of one or more signs or symptoms of an eye disease in a subject, comprising the step of administering a pharmaceutical composition according to any one of claims 14 to 76 to the subject.

2. The method according to claim 1, wherein the subject is a human or a non-human animal.

3. The method according to claim 1 or 2, wherein the eye disease is selected from the group consisting of inflammation of the periocular glands, meibomian gland inflammation, dry eye disease, allergic eye disease, topical preservative toxicity, xerophthalmos, loss of tear film homeostasis, tear film instability and hyperosmolarity, ocular surface inflammation and injury, neuronal paresthesia, meibomian gland dysfunction, aggravated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof.

4. The method according to any one of claims 1 to 3, comprising topically administering the pharmaceutical composition to the lateral portion of the eyelid of the subject, including the superior lateral portion of the orbit of the subject.

5. The method according to claim 4, comprising topically administering the pharmaceutical composition to the outer portion of the upper and / or lower eyelid of the target.

6. The method according to any one of claims 1 to 5, wherein a lipophilic compound is delivered to the ocular surface of a target via the meibomian glands.

7. The method according to any one of claims 1 to 6, wherein the pharmaceutical composition is administered once, twice, three, four, five, six times, or more times per day.

8. The method according to any one of claims 1 to 7, 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.

9. A method according to any one of claims 1 to 8, wherein long-term administration of the pharmaceutical composition does not cause ocular adverse events in the target population.

10. The method according to claim 9, wherein the ocular adverse event is selected from the group consisting of increased intraocular pressure, cataract, ocular infection, and any combination thereof.

11. The method according to any one of claims 1 to 10, wherein the lipophilic compound is not delivered systemically to the subject.

12. The method according to any one of claims 1 to 11, wherein the lipophilic compound is not delivered to the target tear or lacrimal duct.

13. The method according to any one of claims 1 to 12, wherein the lipophilic compound is not directly delivered to the target ocular surface.

14. (a) therapeutically effective amounts of lipophilic compounds; and (b) A pharmaceutically acceptable carrier adapted for periocular transdermal delivery of a lipophilic compound to one or more periorbital glands of a target; A pharmaceutical composition containing, A pharmaceutical composition specifically formulated for periorbital delivery.

15. The pharmaceutical composition according to claim 14, wherein the lipophilic compound is not delivered systemically to the subject.

16. The pharmaceutical composition according to claim 14 or claim 15, wherein the lipophilic compound is not delivered to the target tear or lacrimal duct.

17. The pharmaceutical composition according to any one of claims 14 to 16, wherein the lipophilic compound is not directly delivered to the target ocular surface.

18. A pharmaceutical composition according to any one of claims 14 to 17, which is not a liquid topical ophthalmic suspension, emulsion, or solution.

19. The pharmaceutical composition according to any one of claims 14 to 18, wherein one or more periorbital glands are selected from the group consisting of meibomian glands, lacrimal glands, accessory lacrimal glands, and any combination thereof.

20. A pharmaceutical composition according to any one of claims 14 to 19, wherein a lipophilic compound is delivered to the ocular surface of a target via the meibomian glands.

21. The pharmaceutical composition according to any one of claims 14 to 20, wherein the lipophilic compound is a steroid.

22. The steroid is selected from the group consisting of compounds of formula I, fluocinolone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and their ester derivatives; The compound of formula I has the following structure: The pharmaceutical composition according to claim 21, comprising:

23. The pharmaceutical composition according to claim 21 or claim 22, wherein the steroid is selected from the group consisting of compounds of formula I, difluprednate, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, and ester derivatives thereof.

24. The pharmaceutical composition according to any one of claims 21 to 23, wherein the steroid is a compound of formula I.

25. A pharmaceutical composition according to any one of claims 14 to 20, wherein the lipophilic compound is an antibiotic.

26. The pharmaceutical composition according to claim 25, wherein the antibiotic is selected from the group consisting of sulfonamide drugs, macrolide drugs, chloramphenicol, aminoglycoside drugs, fluoroquinolone drugs, vancomycin, and tetracycline drugs.

27. The pharmaceutical composition according to claim 25 or 26, wherein the antibiotic is selected from the group consisting of azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxyfloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, and sulfacetamide.

28. A pharmaceutical composition according to any one of claims 14 to 20, wherein the lipophilic compound is an immunomodulator.

29. The pharmaceutical composition according to claim 28, wherein the immunomodulator is selected from the group consisting of calcineurin inhibitors and thalidomide analogs.

30. The pharmaceutical composition according to claim 28 or claim 29, wherein the immunomodulator is selected from the group consisting of cyclosporine A, voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide.

31. A pharmaceutical composition according to any one of claims 14 to 20, wherein the lipophilic compound is an integrin antagonist.

32. The pharmaceutical composition according to claim 31, wherein the integrin antagonist is selected from the group consisting of rifitegrast, GW559090, and its ester derivatives.

33. A pharmaceutical composition according to any one of claims 14 to 20, wherein the lipophilic compound is an anti-inflammatory agent.

34. The pharmaceutical composition according to claim 33, wherein the anti-inflammatory agent is selected from the group consisting of omega-3 fatty acids and nonsteroidal anti-inflammatory drugs (NSAIDs).

35. The pharmaceutical composition according to claim 34, 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.

36. The pharmaceutical composition according to claim 34, wherein the NSAID is selected from the group consisting of bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and any combination thereof.

37. The pharmaceutical composition according to any one of claims 14 to 20, wherein the lipophilic compound is an antiglaucoma agent or an ocular anti-hypertension agent.

38. The pharmaceutical composition according to claim 37, wherein the antiglaucoma agent or antihypertensive agent is selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, latanoprostenbunod, timolol, betaxolol, levobunolol, metipranolol, brimonidine, clonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, metazolamide, netalusdil, and any combination thereof.

39. A pharmaceutical composition according to any one of claims 14 to 38, comprising a lipophilic compound at a concentration of approximately 0.001% to approximately 10% by weight / weight (w / w), approximately 0.0001% to approximately 10% by weight / weight (w / w), or approximately 0.0001% to approximately 5% by weight / weight (w / w).

40. A pharmaceutical composition according to any one of claims 14 to 39, comprising a steroid at a concentration of approximately 0.01% to approximately 2% w / w.

41. The pharmaceutical composition according to any one of claims 14 to 40, further comprising a therapeutically effective amount of additional steroids.

42. The pharmaceutical composition according to claim 41, wherein the additional steroid is selected from the group consisting of compounds of formula I, fluocinolone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and their ester derivatives.

43. The pharmaceutical composition according to claim 41 or claim 42, wherein the lipophilic compound and additional steroids are different.

44. A pharmaceutical composition according to any one of claims 14 to 43, further comprising a therapeutically effective amount of one or more antibiotics.

45. The pharmaceutical composition according to claim 44, wherein one or more antibiotics are selected from the group consisting of sulfonamide drugs, macrolide drugs, chloramphenicol, aminoglycoside drugs, fluoroquinolone drugs, vancomycin, tetracycline drugs, and any combination thereof.

46. The pharmaceutical composition according to claim 44 or claim 45, wherein one or more antibiotics are selected from the group consisting of azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxyfloxacin, chloramphenicol, doxycycline, tetracycline, gramicidin, mupirocin, polymyxin B, sulfacetamide, and any combination thereof.

47. A pharmaceutical composition according to any one of claims 44 to 46, wherein the lipophilic compound and one or more antibiotics are different.

48. A pharmaceutical composition according to any one of claims 14 to 47, further comprising a therapeutically effective amount of one or more immunomodulators.

49. The pharmaceutical composition according to claim 48, wherein one or more immunomodulatory agents are selected from the group consisting of calcineurin inhibitors, thalidomide analogs, and any combination thereof.

50. The pharmaceutical composition according to claim 48 or claim 49, wherein one or more immunomodulatory agents are selected from the group consisting of cyclosporine A, voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, pomalidomide, and any combination thereof.

51. A pharmaceutical composition according to any one of claims 48 to 50, wherein the lipophilic compound and one or more immunomodulators are different.

52. A pharmaceutical composition according to any one of claims 14 to 51, further comprising a therapeutically effective amount of one or more integrin antagonists.

53. The pharmaceutical composition according to claim 52, wherein one or more integrin antagonists are selected from the group consisting of rifitegrast, GW559090, its ester derivatives, and any combination thereof.

54. The pharmaceutical composition according to claim 52 or claim 53, wherein the lipophilic compound and one or more integrin antagonists are different.

55. A pharmaceutical composition according to any one of claims 14 to 54, further comprising one or more anti-inflammatory agents in a therapeutically effective amount.

56. The pharmaceutical composition according to claim 55, wherein 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.

57. The pharmaceutical composition according to claim 56, 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.

58. The pharmaceutical composition according to claim 56, wherein the NSAID is selected from the group consisting of bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and any combination thereof.

59. A pharmaceutical composition according to any one of claims 55 to 58, wherein the lipophilic compound and one or more anti-inflammatory agents are different.

60. A pharmaceutical composition according to any one of claims 14 to 59, further comprising one or more antiglaucoma agents or antihypertensive agents in a therapeutically effective amount.

61. The pharmaceutical composition according to claim 60, wherein one or more antiglaucoma agents or antihypertensive agents are selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, latanoprostenbunod, timolol, betaxolol, levobunolol, metipranolol, brimonidine, clonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, metazolamide, netalusdil, and any combination thereof.

62. The pharmaceutical composition according to claim 60 or claim 61, wherein the lipophilic compound and one or more antiglaucoma agents or anti-ocular hypertension agents are different.

63. The pharmaceutical composition according to any one of claims 14 to 62, wherein the pharmaceutically acceptable carrier is selected from the group consisting of ointments, creams, lotions, gels, emulsions, suspensions, oils, foams, transdermal patches, sprays, and any combination thereof.

64. The pharmaceutical composition according to claim 63, wherein the ointment comprises a paraffin-based or water-miscible ointment base.

65. The pharmaceutical composition according to claim 63 or claim 64, 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.

66. The pharmaceutical composition according to claim 63, wherein the cream comprises an oil-in-water base or a water-in-oil base.

67. The pharmaceutical composition according to claim 63 or claim 66, 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.

68. The pharmaceutical composition according to claim 63 or claim 66, 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 dibasic sodium phosphate, 0.046% w / w anhydrous citric acid, 0.02% w / w propylparaben, and purified water.

69. A pharmaceutical composition according to any one of claims 63 and 66-68, wherein the cream contains benzalkonium chloride (BAK).

70. The pharmaceutical composition according to any one of claims 63 and 66-69, 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.

71. The pharmaceutical composition according to any one of claims 63 and 66-70, wherein the cream is preservative-free.

72. The pharmaceutical composition according to claim 71, 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.

73. The pharmaceutical composition according to claim 71 or claim 72, 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.

74. A pharmaceutical composition according to any one of claims 14 to 73, wherein the subject is a human or a non-human animal.

75. A pharmaceutical composition according to any one of claims 14 to 74, wherein the subject is suffering from an eye disease.

76. The pharmaceutical composition according to claim 75, wherein the eye disease is selected from the group consisting of inflammation of the periocular glands, meibomian gland inflammation, dry eye disease, allergic eye disease, topical preservative toxicity, xerophthalmos, loss of homeostasis of the tear film, tear film instability and hyperosmolarity, inflammation and injury of the ocular surface, neuronal paresthesia, meibomian gland dysfunction, aggravated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combination thereof.

77. (a) the pharmaceutical composition according to any one of claims 14 to 76; and (b) Package insert containing instructions for administering the pharmaceutical composition A kit that includes this.

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