OA19529A

OA19529A - Compositions and methods for treating aberrant inflammation in peri - ocular secretory glands or at the ocular surface.

Info

Publication number: OA19529A
Application number: OA1202000181
Authority: OA
Inventors: Charles F. Bosworth; H. Krauss Achim
Original assignee: Axerovision, Inc
Priority date: 2017-11-21
Filing date: 2018-11-21
Publication date: 2020-11-13

Abstract

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

Description

[0047] Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a lipophilie compound, and a pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of the lipophilie compound to one or more peri-orbital glands (e.g., the meibomian, lacrimal, and/or accessory lacrimal glands) of a subject. In some embodiments, the pharmaceutical composition is specifically formulated for peri-ocular delivery in accordance with the teachings herein. Also provided herein are methods of providing prophylactic, palliative, and/or therapeutic relief of one or more signs or symptoms of an ocular disease (e.g., an ocular inflammatory condition, bacterial infection, or glaucoma) comprising administering a therapeutically effective amount of any of the pharmaceutical compositions ofthe présent disclosure to a subject in need thereof. Also provided herein are articles of manufacture or kits comprising one or more of the pharmaceutical compositions described herein.

[0048] Topical drops hâve become the delivery method of choice for eye-care practitioners especially for diseases like dry eye, uveitis, bacterial conjunctivitis, and glaucoma because the ocular surface is seen as the primary target tissue for drug delivery. However, the eye’s rapid turnover of tears créâtes a significant problem for an ocular drop. The tear film is only about 7 pL in volume. An eye drop is about 30 to 50 pL, depending on the surface tension characteristics of the drug; therefore, only up to 1 to 3 percent of an active pharmaceutical ingrédient (API) in a topical drop pénétrâtes to the intended target tissues in the eye. The remainder of the drop drains from the tear film through the nasolacrimal System. Finally, the contact time of a drug with the ocular tissues is only around one minute due to the constant production of lacrimal fluid (0.5 to 2.2 pl/min.) and drainage (Abelson et al, 2012). Methods that increase a drug’s rétention time on the treated eye include highviscosity solutions (e.g., Tobradex ST) and novel technologies such as mucous membrane . penetrating technologies (e.g., Kala Pharmaceuticals, KPI-121), bioadhesive gels and fibrin sealant-based approaches (Gaudana R et al, 2010). Peri-ocular routes of delivery for ocular conditions include subconjunctival, subtenon, retrobulbar, and peribulbar administration (See Figure 1 in Gaudana R et al, 2010).

[0049] Applying a drug directly to the eyelids has been envisioned as a route of drug ’ delivery for lid conditions such as Meibomian Gland Dysfunction (MGD) and blepharitis.

Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian glands (which résidé in the eyelids), commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in the glandular sécrétion (Nichols et al, 2011). Blepharitis is inflammation of the eyelids. Local lid delivery has been envisioned for diseases impacting the lids because as Abelson and colleagues (2012) stated, “When you want to treat a local condition, the more local the delivery, the better the resuit will be. What better example of this need is there than the delivery of therapeutics for blepharitis directly to the affected lids?”

[0050] MacKeen et al (1995) reported on a unique drug delivery System that consists of applying petrolatum ointment vehicle to the lower eyelid. The ointment melts at skin température and gradually moves over the skin onto the ocular surface. The movement of the petrolatum ointment was termed supracutaneous. For this method to work, the musculature of the lower lid must move the drug toward and over the lid margin. Thus, this method of drug delivery envisions that the applied drug does not penetrate the skin of the lower lid, but instead travels on the surface of the skin around the eyelid where it physically mixes with the tear film (see also Tsubota et al, 1999).

[0051] The pharmaceutical compositions and méthodologies of the présent invention are based upon the unexpected finding that, when properly formulated in a suitable vehicle that, following topical peri-ocular application to one or both eyelids of an eye, does not melt and flow or move onto the ocular surface, but, instead, pénétrâtes into the eyelid along with its API payload, lipophilie drugs delivered topically to the lids in such a manner can access the meibomian glands, meibum and other fatty structures within the eyelids which themselves can act as a drug depot resulting in sustained delivery to the ocular surface. Thus, “the more local the delivery, the better the resuit will be” is not an accurate way to conceive of . delivering a lipophilie compound to the ocular surface. The current method of drug delivery also relies upon pénétration of the eyelid skin, which is inconsistent with prior art that envisions the eyelid skin as a barrier to successful ocular surface drug delivery.

[0052] Commonly used lipophilie, topical, ocular therapeutics that could benefit from this new delivery method include treatments for inflammatory eye diseases, which include dry eye disease (e.g., RESTASIS® and corticosteroids), glaucoma (e.g., latanoprost), and bacterial conjunctivitis (e.g., AzaSite).

[0053] Pflugfelder and colleagues (2004) demonstrated that a topical corticosteroid may achieve the objective of a short-term treatment of acute exacerbations of DED signs or symptoms. They evaluated loteprednol etabonate ophthalmic suspension (0.5%) dosed 4 times daily versus placebo for the treatment of DED in patients with delayed tear clearance. In patients with at least moderate clinical inflammation, significant différences in clinical signs (nasal and tarsal hyperemia) between groups were observed as early as week 2 and persisted through week 4 of the study. In addition, the improvement in the redness visual analog scale (VAS) score was consistently 20% better in the loteprednol-treated patients compared with the vehicle-treated patients.

[0054] Capitalizing on the known safety profile of loteprednol etabonate, Kala Pharmaceuticals, Inc is developing KPI-121 as a novel nanoparticle formulation of loteprednol etabonate using mucus-penetrating particle (MPP) technology. In October of 2017, Kala filed an IND for KPI-121 1% as a treatment for inflammation and pain following ocular surgery. In January of 2018, they announced top line results for KPI-121 0.25% for ‘ the temporary relief of the signs and symptoms of DED. Their two Phase 3 DED studies (STRIDE 1 and STRIDE 2) demonstrated that KPI-121 0.25% dosed four-times-daily (QID) could provide statistically significant réductions in conjunctival hyperemia and marginal réductions in ocular discomfort severity at Day 15. Their topical ocular route of delivery results in several significant challenges for the introduction of a successful treatment: 1) QID dosing is inconvénient for patients and likely to resuit in poor compliance; 2) the need for frequent administration to maintain therapeutically active drug levels for anti-inflammatory efficacy; 3) potential safety concems related to frequent administration; and 4) the need for a vehicle that can itself alter the functional characteristics of a normal tear film.

[0055] In addition to seeking sustained release formulations for inflammatory eye conditions to improve patient adhérence by reducing dosing frequency and increasing efficacy by establishing more sustained suppression of inflammation, sustained release formulations are being developed in glaucoma to additionally remove preservatives such as benzalkonium chloride (BAK) and for bacterial conjunctivitis to prevent periods of regrowth. Thus, there is a need across ophthalmic conditions for a sustained release formulation that is less invasive, reduces dosing frequency, maintains constant therapeutic exposures at the site of action, minimizes disruption of the pre-comeal tear film, and reduces ocular exposure to formulation excipients.

L Pharmaceutical Compositions

[0056] Certain aspects of the présent disclosure relate to a pharmaceutical composition comprising a therapeutically effective amount of a lipophilie compound, and a . pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of the lipophilie compound to one or more peri-orbital glands (e.g., the meibomian, lacrimal, and/or accessory lacrimal glands) of a subject. The terni “peri-ocular” refers to the area surrounding the eyeball but within the orbit, including eyelids and latéral régions of the orbit. The periorbital glands are the glands in the area around the eyeball including, for example, the meibomian, lacrimal, and/or accessory lacrimal glands. In some embodiments, the pharmaceutical composition is specifically formulated for peri-ocular delivery. In some embodiments, the pharmaceutically acceptable carrier is adapted for peri-ocular transdermal delivery by: 1) decreasing the concentration of the perméation enhancer in the carrier relative ’ to the concentration used in a standard ointment/cream or ophthalmic formulation; 2) using a perméation enhancer (not typically found in topical steroid ointment/cream formulations) that is suitable for transdermal delivery of the compound into the eyelid (e.g., Tween-80); 3) formulating the pharmaceutical composition to achieve improved spreadability on the periocular surface relative to an ointment base; and/or 4) formulating the pharmaceutical composition to avoid flow from the peri-ocular surface onto the comeal surface. In some embodiments, the pharmaceutical compositions are adapted for peri-ocular transdermal delivery to significantly enhance the ocular safety of the delivered lipophilie compound by: 1) decreasing the concentration of the perméation enhancer in the pharmaceutical composition relative to the concentration used in a standard ointment/cream or ophthalmic formulation; 2) using a perméation enhancer (not typically found in topical steroid ointment/cream formulations) that is suitable for transdermal delivery of the compound into the eyelid (e.g., Tween-80); 3) formulating the pharmaceutical composition to achieve improved spreadability on the peri-ocular surface relative to an ointment base; 4) formulating the pharmaceutical composition to avoid flow from the peri-ocular surface onto the comeal surface; 5) using a novel steroid such as the compound of Formula I (which has been specifically developed with an ability to enable the glucocorticoid receptor to transrepress • gene activation with less or little transactivation) in an effort to reduce the side effects of glucocorticoids that are thought to be mediated through transactivation; 6) using the Meibomian glands, meibum, and other fatty structures in the eyelids as a drug depot of a lipophilie compound for sustained delivery to the ocular surface; and/or 7) use of the Meibomian glands and meibum as a novel drug delivery System for a pharmaceutical formulation of a lipophilie compound applied peri-ocularly to the outside of the upper and/or lower eyelid(s).

[0057] In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of at least one additional steroid, antibiotic, immunomodulatory drug, integrin antagonist, anti-inflammatory agent, and/or anti-glaucoma or ocular anti-hypertension agent, in any combination. In some embodiments comprising a lipophilie compound and further comprising at least one additional steroid, antibiotic, immunomodulatory drug, integrin antagonist, anti-inflammatory agent, and/or anti-glaucoma or ocular anti-hypertension agent, the lipophilie compound is different from the at least one additional steroid, antibiotic, immunomodulatory drug, integrin antagonist, anti-inflammatory agent, and/or anti-glaucoma or ocular anti-hypertension agent. In some embodiments, the pharmaceutical composition is specifically formulated for peri-ocular delivery in accordance with the teachings herein.

[0058] In some embodiments, the lipophilie compound is not delivered systemically when the pharmaceutical composition is administered to the subject. In some embodiments, the lipophilie compound is not delivered by direct application into the tears and/or tear ducts of the subject. In some embodiments, the lipophilie compound is not delivered by direct • application to an ocular surface of the subject (e.g., the comea, conjunctiva). In some embodiments, the pharmaceutical composition is not a liquid topical ocular suspension, émulsion, or suspension (i.e., eye drops). In some embodiments, the lipophilie compound is a steroid. In some embodiments, the lipophilie compound is an antibiotic. In some embodiments, the lipophilie compound is an immunomodulatory drug. In some embodiments, the lipophilie compound is an integrin antagonist. In some embodiments, the lipophilie compound is an anti-inflammatory agent. In some embodiments, the lipophilie compound is an anti-glaucoma or ocular anti-hypertension agent.

Steroids

[0059] In some aspects, the présent disclosure relates to a pharmaceutical composition comprising a steroid as the lipophilie compound. Accordingly, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a steroid, and a pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of the steroid to one or more peri-orbital (e.g., oil-secreting peri-orbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for peri-ocular delivery. Any suitable steroid known in the art may be used in a pharmaceutical composition of the présent disclosure, including, for example, the compound of Formula I, fluocinolone, medrysone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, and testosterone, or any ester dérivatives thereof. In some embodiments, the steroid is a glucocorticoid. In some embodiments, the steroid is the compound of Formula I, difluprednate, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, or any ester dérivative thereof. In some embodiments, the steroid is the compound of Formula I. As used herein, “the compound of Formula I” refers to the compound 6a,9a-difluoro-l 1 βhydroxy-16a-methyl-3 -oxo-17a-(2,2,3,3 - tetramethycyclopropylcarbonyl)oxy-androsta-1,4diene-17β-carboxylic acid cyanomethyl ester. See e.g., US Pat. No. 7,291,609, including for methods of making the same. A structure of the compound of Formula I is shown below:

(Formula I)

[0060] In some embodiments, the pharmaceutical composition comprises the steroid at a concentration between 0.001% and 10% weight per weight (w/w). For example, the pharmaceutical composition may comprise the steroid at a concentration from about 0.001% 23 to about 10%, from about 0.001% to about 9%, from about 0.001% to about 8%, from about 0.001% to about 7%, from about 0.001% to about 6%, from about 0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.01% to about 10%, from about 0.01% to about 9%, from about 0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% to about 6%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 10%, from about 0.05% to about 9%, from about 0.05% to about f

8%, from about 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% to about 10%, from about 0.1% to about 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, from about 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from . about 0.5% to about 10%, from about 0.5% to about 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, from about 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 10%, from about 1% to about 9%, from about 1% to about 8%, from about 1% to about 7%, from about 1% to about 6%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 10%, from about 2% to about 9%, from about 2% to about 8%, from about 2% to about 7%, from about 2% to about 6%, from about 2% to about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 10%, from ' about 3% to about 9%, from about 3% to about 8%, from about 3% to about 7%, from about

3% to about 6%, from about 3% to about 5%, from about 3% to about 4%, from about 4% to about 10%, from about 4% to about 9%, from about 4% to about 8%, from about 4% to about 7%, from about 4% to about 6%, from about 4% to about 5%, from about 5% to about 10%, from about 5% to about 9%, from about 5% to about 8%, from about 5% to about 7%, from about 5% to about 6%, from about 6% to about 10%, from about 6% to about 9%, from about

6% to about 8%, from about 6% to about 7%, from about 7% to about 10%, from about 7% to about 9%, from about 7% to about 8%, from about 8% to about 10%, from about 8% to about 9%, or from about 9% to about 10% w/w. In some embodiments, the pharmaceutical composition comprises the steroid from about 0.01% to about 2% w/w. In some embodiments, the pharmaceutical composition comprises the steroid at any of a concentration of about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w/w.

Antibiotics

[0061] In some aspects, the présent disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an antibiotic as the lipophilie 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.) antibiotics. Accordingly, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an antibiotic, and a pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of the antibiotic to one or more peri-orbital (e.g., oil-secreting peri-orbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for peri-ocular delivery. Any suitable antibiotic known in the art may be used in the pharmaceutical compositions of the présent disclosure, including, for example, sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, tetracyclines, and any combinations thereof. Examples of such antibiotics include, without limitation, azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxifloxacin, chloramphenicol, doxycycline, tetracyclin, gramicidin, mupirocin, polymyxin B, sulfacetamide.

[0062] In some embodiments, the pharmaceutical composition comprises the antibiotic at a concentration between 0.0001% and 10% weight per weight (w/w). For example, the pharmaceutical composition may comprise the antibiotic at a concentration from about from about 0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to 25 about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 10%, from about 0.0005% to about 9%, from about 0.0005% to about 8%, from about 0.0005% to about 7%, from about 0.0005% to about 6%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about 3%, from about 0.0005% to about 2%, from about . 0.0005% to about 1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about 0.001% to about 10%, from about 0.001% to about 9%, from about 0.001% to about 8%, from about 0.001% to about 7%, from about 0.001% to about 6%, from about 0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.01% to about 10%, from about 0.01% to about 9%, ’ from about 0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% to about 6%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 10%, from about 0.05% to about 9%, from about 0.05% to about 8%, from about 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% to about 10%, from about 0.1% to about 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, from about 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5% to about 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, from about 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 10%, from about 1% to about 9%, from about 1% to about 8%, from about 1% to about 7%, from about 1% to about 6%, from about

-1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to 26 about 2%, from about 2% to about 10%, from about 2% to about 9%, from about 2% to about 8%, from about 2% to about 7%, from about 2% to about 6%, from about 2% to about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 10%, from about 3% to about 9%, from about 3% to about 8%, from about 3% to about 7%, from about 3% to about 6%, from about 3% to about 5%, from about 3% to about 4%, from about 4% to about 10%, from about 4% to about 9%, from about 4% to about 8%, from about 4% to about 7%, from about 4% to about 6%, from about 4% to about 5%, from about 5% to about 10%, from about 5% to about 9%, from about 5% to about 8%, from about 5% to about 7%, from about 5% to about 6%, from about 6% to about 10%, from about 6% to about 9%, from about 6% to about 8%, from about 6% to about 7%, from about 7% to about 10%, from about 7% to about 9%, from about 7% to about 8%, from about 8% to about 10%, from about 8% to about 9%, or from about 9% to about 10% w/w. In some embodiments, the pharmaceutical composition comprises the antibiotic at a concentration between 0.0001% and 5% weight per . weight (w/w). In some embodiments, the pharmaceutical composition comprises the antibiotic at any of a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 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.

Immunomodulatory drugs • [0063] In some aspects, the présent disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an immunomodulatory drug as the lipophilie compound. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, fïve or more, etc.) immunomodulatory drugs. Accordingly, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an immunomodulatory drug, and a pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of the immunomodulatory drug to one or more peri-orbital (e.g., oil-secreting peri-orbital) glands of a subject, wherein the pharmaceutical composition is specifïcally formulated for peri-ocular delivery. Any suitable immunomodulatory drug known in the art may be used in the pharmaceutical compositions of the présent disclosure, including, for example, calcineurin inhibitors, thalidomide analogues, and any combinations thereof. Examples of such immunomodulatory drugs include, without limitation, cyclosporine A, voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide. In some embodiments, the ’ immunomodulatory drug is cyclosporine A.

[0064] In some embodiments, the pharmaceutical composition comprises the immunomodulatory drug at a concentration between 0.0001% and 5% weight per weight (w/w). For example, the pharmaceutical composition may comprise the immunomodulatory drug at a concentration from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to . about 0.005%, from about 0.0001% to about 0.001%, from about 0.0001% to about 0.0005%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about 3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% to about 0.005%, from about 0.0005% to about 0.001%, from about 0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.005% to about 5%, from about 0.005% to about 4%, from about 0.005% to about 3%, from about 0.005% to about 2%, from about 0.005% to about 1%, from about 0.005% to about 0.5%, from about 0.005% to about 0.1%, from about 0.005% to about 0.05%, from about 0.005% to about 0.01%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to . about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 5%, from about 3% to about 4%, or from about 4% to about 5% w/w. In some embodiments, the pharmaceutical composition comprises the immunomodulatory drug at any of a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, or 5% w/w.

Integrin antagonists ’ [0065] In some aspects, the présent disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an integrin antagonist as the lipophilie 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. Accordingly, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an integrin antagonist, and a pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of the integrin antagonist to one or more peri-orbital (e.g., oil-secreting peri-orbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for peri-ocular delivery. Any suitable integrin antagonist known in the art may be used in the pharmaceutical compositions of the présent disclosure, including, for example, lifitegrast, GW559090, ester dérivatives thereof, and any combinations thereof. In some embodiments, the pharmaceutical composition comprises GW559090 (See Krauss et al. Invest. Ophthalmol. Vis. Sci. 2015;56(10):5888-95).

[0066] In some embodiments, the pharmaceutical composition comprises the integrin antagonist at a concentration between 0.0001% and 10% weight per weight (w/w). For example, the pharmaceutical composition may comprise the integrin antagonist at a concentration from about 0.0001% to about 10%, from about 0.0001% to about 9%, from ’ about 0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 29

10%, from about 0.0005% to about 9%, from about 0.0005% to about 8%, from about 0.0005% to about 7%, from about 0.0005% to about 6%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about 3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about 0.001% to about 10%, from about 0.001% to about 9%, from about 0.001% to about 8%, from about 0.001% to about 7%, from about 0.001% to about 6%, from about 0.001% to about 5%, from • about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.01% to about 10%, from about 0.01% to about 9%, from about 0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% to about 6%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 10%, from about 0.05% to about 9%, from about 0.05% to about 8%, from about 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% to about 10%, from about 0.1% to about 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, from about 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5% to about 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, from about 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 10%, from about 1% to about 9%, from about 1% to about 8%, from about 1% to about 7%, from about 1% to about 6%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 10%, from about 2% to about 9%, from about 2% to about 8%, from about 2% to about 7%, from about 2% to about 6%, from about 2% to about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 10%, from about 3% to about 9%, from about 3% to about 8%, from about 3% to about 7%, from about 3% to about 6%, from about 3% to about 5%, from about 3% to about 4%, from about 4% to about 10%, from about 4% to about 9%, from about 4% to about 8%, from about 4% to about 7%, from about 4% to about 6%, from about 4% to about 5%, from about 5% to about 10%, from about 5% to about 9%, from about 5% to about 8%, from about 5% to about 7%, from about 5% to about 6%, from about 6% to about 10%, from about 6% to about 9%, from about 6% to about 8%, from about 6% to about 7%, from about 7% to about 10%, from about 7% to about 9%, from about 7% to about 8%, from about 8% to about 10%, from about 8% to about 9%, or from about 9% to about 10% w/w. In some embodiments, the pharmaceutical composition comprises the integrin antagonist at any of a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 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.

Anti-inflammatory agents

[0067] In some aspects, the présent disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an anti-inflammatory agent as the lipophilie 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. Accordingly, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an anti-inflammatory agent, and a pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of the anti-inflammatory agent to one or more peri-orbital (e.g., oil-secreting peri-orbital) glands of a subject, wherein the pharmaceutical composition is specifically formulated for peri-ocular delivery. Any suitable anti-inflammatory agent known in the art may be used in the pharmaceutical compositions of the présent disclosure, including, for example, oméga 3 fatty acids, non-steroidal antiinflammatory drugs (NSAIDS), and any combinations thereof. Examples of suitable oméga 3 fatty acids may include, without limitation, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combinations thereof. Examples of suitable NSAIDS may include, without limitation, bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and any combinations thereof.

[0068] In some embodiments, the pharmaceutical composition comprises the antiinflammatory agent at a concentration between 0.0001% and 5% weight per weight (w/w). For example, the pharmaceutical composition may comprise the anti-inflammatory agent at a concentration from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, from about 0.0001% to about 0.001%, from about 0.0001% to about 0.0005%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about 3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% to about 0.005%, from about 0.0005% to about 0.001%, from about 0.001% to about 5%, from about 0.001% to . about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.005% to about 5%, from about 0.005% to about 4%, from about 0.005% to about 3%, from about 0.005% to about 2%, from about 0.005% to about 1%, from about 0.005% to about 0.5%, from about 0.005% to about 0.1%, from about 0.005% to about 0.05%, from about 0.005% to about 0.01%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, ' from about 0.01% to about 0.05%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 5%, from about 3% to about 4%, or from about 4% to about 5% w/w. In some embodiments, the pharmaceutical composition comprises the anti-inflammatory agent at any of a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, or 5% w/w.

Anti-glaucoma drugs or ocular anti-hypertension agents

[0069] In some aspects, the présent disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an anti-glaucoma drug or ocular antihypertension agent as the lipophilie 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-glaucoma drugs or ocular anti-hypertension agents. Accordingly, in some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an anti-glaucoma drug or ocular anti-hypertension agent, and a pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of the anti-glaucoma drug or ocular anti-hypertension agents to one or more peri-orbital (e.g., oil-secreting peri-orbital) glands of a subject, wherein the pharmaceutical composition is specifïcally formulated for peri-ocular delivery. Any suitable anti-glaucoma drug or ocular anti-hypertension agent known in the art may be used in the pharmaceutical compositions of the présent disclosure, including, for example, prostaglandin analogs, beta blockers, alpha-2 agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and any combinations thereof. Examples of suitable prostaglandin analogs may include, without limitiation, bimatoprost, latanoprost, travoprost, tafluprost, latanoprostene-bunod, and any combinations thereof. Examples of suitable beta blockers may include, without limitiation, timolol, betaxolol, levobunolol, metipranolol, and any combinations thereof. Examples of suitable alpha-2 agonists may include brimonidine, clonidine, apraclonidine, and any combinations thereof. Examples of suitable carbonic anhydrase inhibitors may include, without limitiation, dorzolamide, brinzolamide, acetazolamide, methazolamide, and any combinations thereof. Examples of suitable Rho kinase inhibitors may include, without limitiation, netarsudil, and any combinations thereof.

[0070] In some embodiments, the pharmaceutical composition comprises the antiglaucoma drug or ocular anti-hypertension agent at a concentration between 0.0001% and 10% weight per weight (w/w). For example, the pharmaceutical composition may comprise the anti-glaucoma drug or ocular anti-hypertension agent at a concentration from about

0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%, . from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 10%, from about 0.0005% to about 9%, from about 0.0005% to about 8%, from about 0.0005% to about 7%, from about 0.0005% to about 6%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about 3%, from about 0.0005% to about 2%, from about ‘ 0.0005% to about 1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about 0.001% to about 10%, from about 0.001% to about 9%, from about 0.001% to about 8%, from about 0.001% to about 7%, from about 0.001% to about 6%, from about 0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.01% to about 10%, from about 0.01% to about 9%, from about 0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% to about 6%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 10%, from about 0.05% to about 9%, from about 0.05% to about 8%, from about 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about

0.05% to about 0.1%, from about 0.1% to about 10%, from about 0.1% to about 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, from about 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5% to about 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, from about 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 10%, from about 1% to about 9%, from · about 1% to about 8%, from about 1% to about 7%, from about 1% to about 6%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 10%, from about 2% to about 9%, from about 2% to about 8%, from about 2% to about 7%, from about 2% to about 6%, from about 2% to about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 10%, from about 3% to about 9%, from about 3% to about 8%, from about 3% to about 7%, from about . 3% to about 6%, from about 3% to about 5%, from about 3% to about 4%, from about 4% to about 10%, from about 4% to about 9%, from about 4% to about 8%, from about 4% to about 7%, from about 4% to about 6%, from about 4% to about 5%, from about 5% to about 10%, from about 5% to about 9%, from about 5% to about 8%, from about 5% to about 7%, from about 5% to about 6%, from about 6% to about 10%, from about 6% to about 9%, from about 6% to about 8%, from about 6% to about 7%, from about 7% to about 10%, from about 7% to about 9%, from about 7% to about 8%, from about 8% to about 10%, from about 8% to about 9%, or from about 9% to about 10% w/w. In some embodiments, the pharmaceutical composition comprises the anti-glaucoma drug or ocular anti-hypertension agent at any of a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 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.

Pharmaceutically acceptable carrier

[0071] In some aspects, the présent disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of a steroid to one or more peri-orbital glands of a subject. In some embodiments, the pharmaceutically acceptable carrier is adapted for peri-ocular transdermal delivery by: 1) decreasing the concentration of the perméation enhancer in the carrier relative to the concentration used in a standard steroid ointment/cream formulation; 2) using a perméation enhancer (not typically found in topical steroid ointment/cream formulations) that is suitable for transdermal delivery of the steroid into the eyelid (e.g., Tween-80); 3) formulating the pharmaceutical composition to achieve improved spreadability on the peri-ocular surface relative to an ointment base; and/or 4) formulating the pharmaceutical composition to avoid flow from the peri-ocular surface onto the comeal surface.

[0072] In some embodiments, the pharmaceutically acceptable carrier comprises one or more (e.g., one or more, two or more, three or more, four or more, five or more, etc.) perméation enhancers. As used herein, a “perméation enhancer” or “pénétration enhancer” may refer to a compound or mixture of compounds that interact with one or more skin . constituents to promote drug pénétration into and/or through the skin. Any suitable perméation enhancer known in the art may be used in the pharmaceutical compositions described herein, including, for example, surfactants (e.g., ionic (anionic, cationic, zwittcrionic) surfactants (such as sodium lauryl sulfate, sodium lauréate, etc.) non-ionic surfactants (such as Tween-80, other polysorbates, etc.), and any combinations thereof), bile salts and dérivatives thereof (e.g., sodium glyacolate, sodium deoxycholate, etc.), fatty acids and dérivatives thereof (e.g., oleic acid, caprylic acid, esters of fatty acids such as isopropyl myrisate, etc.), chelating agents (e.g., EDTA, citric acid, etc.), sulphoxides (e.g., DMSO, DMA, DMF, etc.), polyols (e.g., diethylene glycol monoethyl ether, PG, polyethylene glycols ’ (PEGs), glycerol, polyglycols, etc.), alcohols (e.g., alkanols, alkenols, glycols, etc.), hydrocarbons (e.g., alkanes, alkenes, halogenated alkanes, squalene, squalene, minerai oil, etc.), amines, amides (e.g., cyclic amides, acyclic amides, azones, pyrrolidones, urea and dérivatives thereof, etc.), others (e.g., terpenes and terpenoids, essential oils (such as eucalyptus oil, peppermint oil, turpentine oil, etc.), phospholipids, cyclic oligosaccharides (such as cyclodextrins), amino acids and thioacyl dérivatives of amino acids, alkyl amino esters and oxazolidinones, enzymes, ketones (such as macrocyclic ketones), etc.), hyaluronic acid, benzalkonium chloride, and any combinations thereof.

[0073] In some embodiments, the pharmaceutically acceptable carrier is adapted for periocular transdermal delivery by comprising a decreased concentration of the perméation enhancer relative to the concentration of perméation enhancer used in a typical steroid ointment/cream formulation. In some embodiments, the pharmaceutically acceptable carrier comprises about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 35%, about 20%, about 15%, about 10%, about 5%, about 1%, about 0.1%, or about 0.01% of the concentration of the perméation enhancer as compared to the concentration of the perméation enhanced used in a typical steroid ointment/cream formulation for dermal application. In some embodiments, the pharmaceutically acceptable carrier comprises about 1-fold, about 2-fold about 3-fold about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold or about 100-fold less perméation enhancer as compared to the concentration of the perméation enhanced used in a typical steroid ointment/cream formulation for dermal application. For example, if a typical steroid ointment comprises a given perméation enhancer (e.g., hydroxypropyl methylcellulose) at 3% w/w, then the pharmaceutical compositions of the présent disclosure may include the same perméation enhancer at about 2.85%, about 2.7%, about 2.55%, about 2.4%, about 2.25%, about 2.1%, about 1.95%, abouti.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.

[0074] In some embodiments, the pharmaceutically acceptable carrier is adapted for periocular transdermal delivery by comprising a perméation enhancer that is suitable for • transdermal delivery of a steroid into the eyelid (e.g., but not completely through to the topical surface) of a subject. In some embodiments, the perméation enhancer that is suitable for transdermal delivery into the eyelid is a perméation enhancer specifically suitable for transdermal delivery adjacent to the eye and/or not typically found in topical steroid ointment/cream formulations (for use on other areas of the body of a subject like the hands or feet). Examples of suitable perméation enhancers for delivery into the eyelid of the subject may include, without limitation, Tween-80, polyethylene glycols (PEGs), diethylene glycol monoethyl ether, essential oils, hyaluronic acid, benzalkonium chloride (BAK), and/or any combinations thereof.

[0075] In some embodiments, the pharmaceutically acceptable carrier is adapted for periocular transdermal delivery by formulating the carrier to 1) achieve improved spreadability on the peri-ocular surface relative to an ointment base; and/or 2) avoid flow from the periocular surface onto the comeal surface. After application of a typical steroid ointment or cream to the skin, body beat absorbed by the cream or ointment leads to a decrease in viscosity and/or yield stress, causing a decrease in cohesiveness on contact surfaces, such as the peri-ocular skin. Decreasing cohesiveness after beat absorption is problematic for an ointment or cream being applied to the eyelids, as decreased cohesiveness can lead to the • cream or ointment spreading/flowing onto the ocular surface. In some embodiments, the pharmaceutically acceptable carrier comprises characteristics and rheological features of improved spreadability, resulting in easier administration and spreading onto the eyelid surface, and absence of flow at the body température of a subject (e.g., 31°C, 33°C, 35°C, 37°C, etc.), particularly after being applied to the skin of a subject. In some embodiments, • pharmaceutical compositions of the présent disclosure are fonnulated such that the cohesiveness of the formulation does not significantly change after application to the skin (e.g., eyelids) of a subject. Examples of suitable additives that convey a suitable cohesiveness of the formulation may include, for example, additives that increase viscosity of the formulation such as waxes, paraffins, and elastomers. In some embodiments, the viscosity of the pharmaceutically acceptable carrier does not significantly change when heated from room température (e.g., 25°C) to a température doser to the body température of a subject (e.g., 31°C, 33°C, 35°C, 37°C, etc.). In some embodiments, the viscosity of the pharmaceutically acceptable carrier does not change by more than about 10%, more than about 9%, more than about 8%, more than about 7%, more than about 6%, more than about 5%, more than about 4%, more than about 3%, more than about 2%, more than about 1%, more than about 0.5%, more than about 0.1%, or more than about 0.01% when heated from room température (e.g., approximately 20°C, 21 °C, 22°C, 23°, C24°C, or 25°C) to a température (e.g., approximately 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, or 37°C) doser to the body température of the subject.

[0076] In some embodiments, the pharmaceutically acceptable carrier is an ointment, cream, lotion, gel, émulsion, suspension, oil, foam, transdermal patch, spray, or any • combination thereof. In some embodiments, the pharmaceutically acceptable carrier is an ointment. In some embodiments, the pharmaceutically acceptable carrier is a cream. In some embodiments, the pharmaceutically acceptable carrier comprises one or more of buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and méthionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexaméthonium chloride; benzalkonium chloride; benzéthonium chloride; phénol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as sérum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; polyols such as glycerol (e.g., formulations including 38

10% glycerol) or propylene glycol; salt-forming counter-ions such as sodium; métal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). A thorough discussion of pharmaceutically acceptable carriers is available in REMINGTON’S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J. 1991).

[0077] In some embodiments, the pharmaceutically acceptable carrier further comprises one or more additional components. Examples of additional components may include, but are not limited to, binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnésium stéarate, talc, silica, colloïdal Silicon dioxide, stearic acid, metallic stéarates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); wetting agents (e.g., sodium lauryl sulphate, etc.); sait solutions; alcohols; polyethylene glycols; gelatin; lactose; amylase; magnésium stéarate; talc; silicic acid; viscous paraffin; hydroxymethylcellulose; polyvinylpyrrolidone; perfuming agents; colorants; moisturizers; sunscreens; and the like.

[0078] 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., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight of more, or ail nine) of white soft paraffin, minerai 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, minerai 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 minerai oil, about 8% w/w propylene glycol, about 5% w/w of ST cyclomethicone-5NF, about 5% w/w of labrasol, about 5% w/w of propylene carbonate, about 2.5% w/w of steareth 2, about 2.5% w/w of St. emulsifier 10, and about 2.5% w/w of St. elastomer-10.

[0079] 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., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, or ail 13) of white soft paraffin/petrolatum, minerai oil, propylene glycol, cyclomethicone, ST-cyclomethicone-5NF, emulsifïer 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, minerai 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 minerai 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 q.s. purified water. In some embodiments, the cream comprises white soft paraffin/petrolatum, minerai oil, propylene glycol, cyclomethicone, emulsifïer 10, ST-elastomer-10, methylparaben, sodium phosphate dibasic anhydrous, citric acid anhydrous, propylparaben, and purified water. In some embodiments, the cream ' comprises about 48% w/w white soft paraffin/petrolatum, about 8% w/w minerai oil, about 8% w/w propylene glycol, about 6.6% w/w cyclomethicone, about 3.3% w/w emulsifïer 10, about 2% w/w ST-elastomer-10, about 0.08% w/w methylparaben, about 0.06% w/w sodium phosphate dibasic anhydrous, about 0.046% w/w citric acid anhydrous, about 0.02% w/w propylparaben, and q.s. purified water.

[0080] In some embodiments, the cream is preservative-free comprising white soft paraffin/petrolatum, minerai oil, propylene glycol, ST-cyclomethicone-5NF, ST-emulsifier10, ST-elastomer-10, dibasic sodium phosphate, citric acid, and purified water. In some . embodiments, the cream is preservative-free comprising 48% w/w white petrolatum, 8% w/w minerai oil, 8% w/w propylene glycol, 6.6% w/w ST-cyclomethicone-5NF, 3.3% w/w emulsifïer 10, 2% w/w ST-elastomer-10, 0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous, and q.s. purified water.

[0081] Pharmaceutical compositions and formulations of the présent disclosure may be prepared by mixing the steroid with one or more pharmaceutically acceptable carriers. The formulations to be used for in vivo administration are generally stérile. Sterility may be readily accomplished, e.g., by filtration through stérile filtration membranes, by heat exposure, and/or by gamma irradiation.

Additional Lipophilie Compounds

[0082] In some embodiments, a pharmaceutical composition of the présent disclosure further comprises at least one (e.g., at least one, at least two, at least three, at least four, or at least five, etc.) additional lipophilie compound. Thus, in some embodiments, the pharmaceutical composition provided herein further comprises one or more lipophilie compounds selected from the group consisting of steroids, antibiotics, immunomodulatory drugs, integrin antagonists, anti-inflammatory agents, anti-glaucoma agents, and ocular antihypertension agents, and combinations thereof.

Steroids as Additional Lipophilie Compounds

[0083] In some embodiments, a pharmaceutical composition of the présent disclosure further comprises at least one additional steroid. In some embodiments, the pharmaceutical composition comprises at least two (e.g., at least two, at least three, at least four, at least five, etc.) additional steroids. Any suitable steroid known in the art may be used as the one or more additional steroids in the pharmaceutical composition, including, for example, the compound of Formula I, fluocinolone, medrysone, difluprednate, fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, and testosterone, or any ester dérivatives thereof. In some embodiments, the additional steroid is a glucocorticoid. In some embodiments, the at least one additional steroid is a different steroid than the first steroid in the pharmaceutical composition. For example, the first steroid may be the compound of • Formula I and the additional steroid may be triamcinolone acetonide, dexamethasone, and/or loteprednol etabonate.

[0084] In some embodiments, the pharmaceutical composition comprises one or more additional steroids each at a concentration between 0.001% and 10% weight per weight (w/w). For example, the pharmaceutical composition may comprise the additional steroid at a concentration from about 0.001% to about 10%, from about 0.001% to about 9%, from about 0.001% to about 8%, from about 0.001% to about 7%, from about 0.001% to about 6%, from about 0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about

0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.01% to about 10%, from about 0.01% to about 9%, from about 0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% to about 6%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about ’ 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 10%, from about 0.05% to about 9%, from about 0.05% to about 8%, from about 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% to about 10%, from about 0.1% to about 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, from about 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5% to about 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, from about 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 10%, from about 1% to about 9%, from about 1% to about 8%, from about 1% to about 7%, from about 1% to about 6%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 10%, from about 2% to about 9%, from about 2% to about 8%, from about 2% to about 7%, from about • 2% to about 6%, from about 2% to about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 10%, from about 3% to about 9%, from about 3% to about 8%, from about 3% to about 7%, from about 3% to about 6%, from about 3% to about 5%, from about 3% to about 4%, from about 4% to about 10%, from about 4% to about 9%, from about 4% to about 8%, from about 4% to about 7%, from about 4% to about 6%, from about 4% to about 5%, from about 5% to about 10%, from about 5% to about 9%, from about 5% to about 8%, from about 5% to about 7%, from about 5% to about 6%, from about 6% to about 10%, from about 6% to about 9%, from about 6% to about 8%, from about 6% to about 7%, from about 7% to about 10%, from about 7% to about 9%, from about 7% to about 8%, from about 8% to about 10%, from about 8% to about 9%, or from about 9% to about 10% w/w. In some embodiments, the pharmaceutical composition comprises the additional steroid at any of a concentration of about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w/w.

’ [0085] In some embodiments, the pharmaceutically acceptable steroid or its formulation has the additional advantage of not inducing thinning of the skin.

Antibiotics as Additional Lipophilie Compounds

[0086] In some embodiments, a pharmaceutical composition of the présent disclosure further comprises a therapeutically effective amount of one or more antibiotics. 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.) antibiotics. Any suitable antibiotic known in the art may be used in the pharmaceutical compositions of the présent disclosure, including, for example, sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, tetracyclines, and any combinations thereof. Examples of such antibiotics include, without limitation, azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxifloxacin, chloramphenicol, doxycycline, tetracyclin, gramicidin, mupirocin, polymyxin B, sulfacetamide.

[0087] In some embodiments, the pharmaceutical composition comprises the one or more antibiotics at a concentration between 0.0001% and 10% weight per weight (w/w). For • example, the pharmaceutical composition may comprise the one or more antibiotics at a concentration from about from about 0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 10%, from about 0.0005% to about 9%, from about 0.0005% to about 8%, from about 0.0005% to about 7%, from about 0.0005% to about 6%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about 3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about 0.001% to about 10%, from about 0.001% to about 9%, from about 0.001% to about 8%, from about 0.001% to about 7%, from about 0.001% to about 6%, from about 0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.01% to about 10%, from about 0.01% to about 9%, from about 0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% to about 6%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 10%, from about 0.05% to about 9%, from about 0.05% to about 8%, from about 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% to about 10%, from about 0.1% to about 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, from about 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5% to about 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, from about 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 10%, from about 1% to about 9%, from about 1% to about 8%, from about 1% to about 7%, from about 1% to about 6%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 10%, from about 2% to about 9%, from about 2% to about 8%, from about 2% to about 7%, from about 2% to about 6%, from about 2% to about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 10%, from about 3% to about 9%, from about 3% to about 8%, from about 3% to about 7%, from about 3% to about 6%, from about 3% to about 5%, from about 3% to about 4%, from about 4% to about 10%, from about 4% to about 9%, from about 4% to about 8%, from about 4% to about 7%, from about 4% to about 6%, from about 4% to about ' 5%, from about 5% to about 10%, from about 5% to about 9%, from about 5% to about 8%, from about 5% to about 7%, from about 5% to about 6%, from about 6% to about 10%, from about 6% to about 9%, from about 6% to about 8%, from about 6% to about 7%, from about 7% to about 10%, from about 7% to about 9%, from about 7% to about 8%, from about 8% to about 10%, from about 8% to about 9%, or from about 9% to about 10% w/w. In some embodiments, the pharmaceutical composition comprises the one or more antibiotics at a concentration between 0.0001% and 5% weight per weight (w/w). In some embodiments, the pharmaceutical composition comprises the one or more antibiotics at any of a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 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.

Immunomodulatory Drugs as Additional Lipophilie Compounds

[0088] In some embodiments, a pharmaceutical composition of the présent disclosure further comprises a therapeutically effective amount of one or more immunomodulatory . drugs. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) immunomodulatory drugs. Any suitable immunomodulatory drug known in the art may be used in the pharmaceutical compositions of the présent disclosure, including, for example, calcineurin inhibitors, thalidomide analogues, and any combinations thereof. Examples of such immunomodulatory drugs include, without limitation, cyclosporine A, voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide.

[0089] In some embodiments, the pharmaceutical composition comprises the one or more immunomodulatory drugs at a concentration between 0.0001% and 5% weight per weight (w/w). For example, the pharmaceutical composition may comprise the one or more immunomodulatory drugs at a concentration from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, from about 0.0001% to about 0.001%, from about 0.0001% to about 0.0005%, from about 0.0005% to about 5%, from about 0.0005% to about 45

4%, from about 0.0005% to about 3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% to about 0.005%, from about 0.0005% to about 0.001%, from about 0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.005% to about 5%, from about 0.005% to about 4%, from about 0.005% to about 3%, from about 0.005% to about 2%, from about 0.005% to about 1%, from about 0.005% to about 0.5%, from about 0.005% to about 0.1%, from about 0.005% to about 0.05%, from about 0.005% to about 0.01%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%,’ from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 5%, from about 3% to about 4%, or from about 4% to about 5% w/w. In some embodiments, the pharmaceutical composition comprises the one • or more immunomodulatory drugs at any of a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, or 5% w/w.

Integrin Antagonists as Additional Lipophilie Compounds

[0090] In some embodiments, a pharmaceutical composition of the présent disclosure further comprises a therapeutically effective amount of one or more integrin antagonists. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) integrin antagonists. Any suitable integrin antagonist known in the art may be used in the pharmaceutical compositions of the présent disclosure, including, for example, lifitegrast, GW559090, ester dérivatives thereof, and any combinations thereof. In some embodiments, the pharmaceutical composition • comprises GW559090 (See Krauss et al. Invest. Ophthalmol. Vis. Sci. 2015;56(10):5888-95).

[0091] In some embodiments, the pharmaceutical composition comprises the one or more integrin antagonists at a concentration between 0.0001% and 10% weight per weight (w/w). For example, the pharmaceutical composition may comprise the one or more integrin antagonists at a concentration from about 0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 10%, from about 0.0005% to about 9%, from about 0.0005% to about 8%, from about 0.0005% to about 7%, from about 0.0005% to about 6%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about 3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% to about 0.005%, about 0.0005% to about • 0.001%, about 0.001% to about 10%, from about 0.001% to about 9%, from about 0.001% to about 8%, from about 0.001% to about 7%, from about 0.001% to about 6%, from about 0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.01% to about 10%, from about 0.01% to about 9%, from about 0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% to about 6%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 10%, from about 0.05% to about

9%, from about 0.05% to about 8%, from about 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% to about 10%, from about 0.1% to about 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, from about 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5% to about 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, from about 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 10%, from about 1% to about 9%, from about 1% to about 8%, from about 1% to about 7%, from • about 1% to about 6%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 10%, from about 2% to about 9%, from about 2% to about 8%, from about 2% to about 7%, from about 2% to about 6%, from about 2% to about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 10%, from about 3% to about 9%, from about 3% to about 8%, from about 3% to about 7%, from about 3% to about 6%, from about 3% to about 5%, from about 3% to about 4%, from about 4% to about 10%, from about 4% to about 9%, from about 4% to about 8%, from about 4% to about 7%, from about 4% to about 6%, from about 4% to about 5%, from about 5% to about 10%, from about 5% to about 9%, from about 5% to about 8%, from about 5% to about 7%, from about 5% to about 6%, from about 6% to about 10%, from about 6% to about 9%, from about 6% to about 8%, from about 6% to about 7%, from about 7% to about 10%, from about 7% to about 9%, from about 7% to about 8%, from about 8% to about 10%, from about 8% to about 9%, or from about 9% to about 10% w/w. In some embodiments, the pharmaceutical composition comprises the one or more integrin antagonists at any of a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, . 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 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.

Anti-inflammatory Agents as Additional Lipophilie Compounds

[0092] In some embodiments, a pharmaceutical composition of the présent disclosure further comprises a therapeutically effective amount of one or more anti-inflammatory agents. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) anti-inflammatory agents. Any suitable anti-inflammatory agent known in the art may be used in the pharmaceutical compositions of the présent disclosure, including, for example, oméga 3 fatty acids, nonsteroidal anti-inflammatory drugs (NSAIDS), and any combinations thereof. Examples of suitable oméga 3 fatty acids may include, without limitation, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combinations thereof. Examples of suitable NSAIDS may include, without limitation, bromfenac, diclofenac, . indomethacin, flurbiprofen, ketorolac, nepafenac, and any combinations thereof.

[0093] In some embodiments, the pharmaceutical composition comprises the one or more anti-inflammatory agents at a concentration between 0.0001% and 5% weight per weight (w/w). For example, the pharmaceutical composition may comprise the one or more antiinflammatory agents at a concentration from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, from about 0.0001% to about 0.001%, from about 0.0001% to about 0.0005%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about 3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% to about 0.005%, from about 0.0005% to about 0.001%, from about 0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to . about 0.01%, from about 0.001% to about 0.005%, from about 0.005% to about 5%, from about 0.005% to about 4%, from about 0.005% to about 3%, from about 0.005% to about 2%, from about 0.005% to about 1%, from about 0.005% to about 0.5%, from about 0.005% to about 0.1%, from about 0.005% to about 0.05%, from about 0.005% to about 0.01%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 49

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

Anti-glaucoma Drugs and Ocular Anti-hypertension Agents and as Additional ’ Lipophilie Compounds

[0094] In some embodiments, a pharmaceutical composition of the présent disclosure further comprises a therapeutically effective amount of one or more anti-glaucoma drugs or ocular anti-hypertension agents. In some embodiments, the pharmaceutical composition comprises two or more (e.g., two or more, three or more, four or more, five or more, etc.) anti-glaucoma drugs or ocular anti-hypertension agents. Any suitable anti-glaucoma drug or ocular anti-hypertension agent known in the art may be used in the pharmaceutical compositions of the présent disclosure, including, for example, prostaglandin analogs, beta blockers, alpha-2 agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and any combinations thereof. Examples of suitable prostaglandin analogs may include, without limitiation, bimatoprost, latanoprost, travoprost, tafluprost, latanoprostene-bunod, and any combinations thereof. Examples of suitable beta blockers may include, without limitiation, timolol, betaxolol, levobunolol, metipranolol, and any combinations thereof. Examples of suitable alpha-2 agonists may include brimonidine, clonidine, apraclonidine, and any combinations thereof. Examples of suitable carbonic anhydrase inhibitors may include, without limitiation, dorzolamide, brinzolamide, acetazolamide, methazolamide, and any combinations thereof. Examples of suitable Rho kinase inhibitors may include, without limitiation, netarsudil, and any combinations thereof.

[0095] In some embodiments, the pharmaceutical composition comprises the one or more anti-glaucoma drug or ocular anti-hypertension agent at a concentration between 0.0001% and 10% weight per weight (w/w). For example, the pharmaceutical composition may comprise the one or more anti-glaucoma drug or ocular anti-hypertension agent at a concentration from about 0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%, about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 10%, from about 0.0005% to about 9%, from about 0.0005% to about 8%, from about . 0.0005% to about 7%, from about 0.0005% to about 6%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about 3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about 0.001% to about 10%, from about 0.001% to about 9%, from about 0.001% to about 8%, from about 0.001% to about 7%, from about 0.001% to about 6%, from about 0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% to about 0.5%, from about 0.001% to ' about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.01% to about 10%, from about 0.01% to about 9%, from about 0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% to about 6%, from about 0.01% to about 5%, from about 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about 10%, from about 0.05% to about 9%, from about 0.05% to about 8%, from about 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%, from about 0.05% ’ 51 to about 2%, from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% to about 10%, from about 0.1% to about 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, from about 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from . about 0.5% to about 10%, from about 0.5% to about 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, from about 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 10%, from about 1% to about 9%, from about 1% to about 8%, from about 1% to about 7%, from about 1% to about 6%, from about 1% to about 5%, from about 1% to about 4%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 10%, from about 2% to about 9%, from about 2% to about 8%, from about 2% to about 7%, from about 2% to about 6%, from about 2% to about 5%, from about 2% to about 4%, from about 2% to about 3%, from about 3% to about 10%, from about 3% to about 9%, from about 3% to about 8%, from about 3% to about 7%, from about 3% to about 6%, from about 3% to about 5%, from about 3% to about 4%, from about 4% to about 10%, from about 4% to about 9%, from about 4% to about 8%, from about 4% to about 7%, from about 4% to about 6%, from about 4% to about 5%, from about 5% to about 10%, from about 5% to about 9%, from about 5% to about 8%, from about 5% to about 7%, from about 5% to about 6%, from about 6% to about 10%, from about 6% to about 9%, from about 6% to about 8%, from about 6% to about 7%, from about 7% to about 10%, from about 7% to about 9%, from about 7% to about 8%, from about 8% to about 10%, from about 8% to about 9%, or from about 9% to about 10% w/w. In some embodiments, the pharmaceutical composition comprises the one or more anti-glaucoma drug or ocular anti-hypertension agent at any of a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 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.

IL Methods . [0096] Certain aspects of the présent disclosure relate to methods of providing prophylactic, palliative, and/or therapeutic relief of one or more signs or symptoms of an ocular disease (e.g., an ocular inflammatory condition, bacterial infection, or glaucoma) comprising administering a therapeutically effective amount of any of the pharmaceutical compositions of the présent disclosure to a subject in need thereof. In some embodiments, the présent disclosure relates to methods of treating an ocular disease (e.g., an ocular inflammatory condition, bacterial infection, or glaucoma) comprising administering a therapeutically effective amount of any of the pharmaceutical compositions of the présent disclosure to a subject in need thereof. In some embodiments, the subject has, or is at risk of developing an ocular disease (e.g., an ocular inflammatory condition, bacterial infection, or glaucoma).

[0097] In some embodiments, the lipid structures of the eyelid (e.g., meibomian glands, meibum, other fatty tissues) serve as drug depots for the peri-ocularly delivered pharmaceutical compositions provided herein with the meibum becoming a drug delivery ’ vehicle.

[0098] In some embodiments, the subject is a non-human animal, including, without limitation, domesticated animais (e.g., cows, sheep, cats, dogs, horses, etc.), non-human primates (e.g., monkeys), rabbits, and rodents (e.g., mice, hamsters, rats, etc.). In some embodiments, the subject is a human. In some embodiments, the subject suffers from one or more (e.g., one or more, two or more, three or more, four or more, five or more, etc.) ocular diseases and/or conditions. Examples of ocular diseases and/or conditions may include, without limitation, inflammation of the peri-ocular glands, meibomitis, dry eye disease, allergie eye disease, topical preservative toxicity, xerophthalmia, loss of homeostasis of the tear film, tear film instability and hyperosmolarity, ocular surface inflammation and damage, neuronal sensoiy abnormalities, meibomian gland dysfunction, exacerbated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combinations thereof.

[0099] In some embodiments, a pharmaceutical composition of the présent disclosure is topically administered to the subject. As used herein, “topically administered”, “topical administration”, or “topically administering” refers to the delivery of a composition to a subject by contacting, directly or otherwise, a formulation comprising the composition to a portion of the skin of a subject. The term may encompass several routes of administration including, but not limited to, topical and transdermal. Topical administration may be used as a means to deliver a composition to the epidermis or dermis of a subject, or to spécifie strata thereof.

[0100] In some embodiments, a pharmaceutical composition of the présent disclosure is topically administered to an extemal portion of one or ail eyelids of a subject (including the upper latéral région of one or both orbits of the subject). In some embodiments, the pharmaceutical composition is topically administered to the extemal portion of the upper and/or lower eyelid 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.

[0101] In some embodiments, a pharmaceutical composition of the présent disclosure is ’ topically administered to an extemal portion of one or ail eyelids of a subject (including the upper latéral région of one or both orbits of the subject) in order to deliver lipophilie compounds (e.g., steroids) to one or more meibomian glands of the subject. In some embodiments, one or more components (e.g., a steroid) in the pharmaceutical composition are delivered to the ocular surface of a subject via the one or more meibomian glands. In some embodiments, one or more components (e.g., a steroid) in the pharmaceutical composition are delivered to the ocular surface of a subject via the meibum.

[0102] In some embodiments, a pharmaceutical composition of the présent disclosure is . administered one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, etc.) times per day. In some embodiments, a pharmaceutical composition of the présent disclosure is administered for one, two, three, four, five, six, seven or more consecutive days. In some embodiments, a pharmaceutical composition of the présent disclosure is administered for one, two, three, four, five, six, seven or more non-consecutive days. In some embodiments, a pharmaceutical composition of the présent disclosure is administered for one, two, three, four, five, six, seven, eight, nine, 10,11,12 or more consecutive weeks. In some embodiments, a pharmaceutical composition of the présent disclosure is administered for one, two, three, four, five, six, seven, eight, nine, 10, 11, 12 or more non-consecutive weeks. In some embodiments, a pharmaceutical composition of the présent disclosure is administered for one, two, three, four, five, six, seven, eight, nine, 10, 11, 12 or more consecutive months. In some embodiments, a pharmaceutical composition of the présent disclosure is administered for one, two, three, four, five, six, seven, eight, nine, 10, 11,12 or more non54 • consecutive months. In some embodiments, treatment is initiated with a loading dose followed by dose tapering. In some embodiments, treatment is initiated with a loading dose, followed by sustained treatment with a lower dose.

[0103] In some embodiments, the exposure level of the lipophilie compound in the eyelids, bulbar conjunctiva, comea, iris/ciliary body (ICB), and/or aqueous humor (AQH) remains constant or substantially constant for up to 24 hours after the final peri-ocular dose application. In some embodiments, the concentration of the lipophilie compound in one or more compartments selected from the group consisting of the eyelids, bulbar conjunctiva, comea, iris/ciliary body (ICB), and aqueous humor (AQH) differ by less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% when comparing the concentration at 2 hours and 24 hours after the final peri-ocular dose application. In some embodiments, the concentration of the lipophilie compound in one or more compartments selected from the group consisting of the eyelids, bulbar conjunctiva, comea, iris/ciliary body (ICB), and aqueous humor (AQH) at 24 hours after the final peri-ocular dose application is within 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the concentration of the lipophilie compound at 2 hours after the final peri-ocular dose application. In some embodiments, the concentration of the lipophilie compound in the eyelids at 24 hours after the final peri-ocular dose application is within 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the concentration of the lipophilie compound at 2 hours after the final periocular dose application. In some embodiments, the concentration of the lipophilie compound in the eyelids at 24 hours after the final peri-ocular dose application is not less than 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the concentration of the lipophilie compound at 2 hours after the final peri-ocular dose application. In some embodiments, the concentration of the lipophilie compound in one or more compartments selected from the group consisting of the eyelids, bulbar conjunctiva, comea, iris/ciliary body (ICB), and aqueous humor (AQH) at 24 hours after the final periocular dose application is not less than 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the concentration of the lipophilie compound at 2 hours after the final peri-ocular dose application. In some embodiments, the concentration of the lipophilie compound in the eyelids at 24 hours after the final peri-ocular dose application is not less than 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the concentration of the lipophilie compound at 2 hours after the final peri-ocular dose application.

[0104] In some embodiments, topical administration of the pharmaceutical composition as described herein provides prophylactic, palliative, and/or therapeutic relief of one or more signs of an ocular disease in a subject. In some embodiments, topical administration of the pharmaceutical composition as described herein reduces or éliminâtes one or more signs of an ocular disease in a subject. Examples of signs or symptoms of an ocular disease may include, without limitation, eye and/or eyelid margin redness, watery eyes, dry eyes, itching, stinging, or buming sensation of the eyes or orbits, bluny vision, difficulty with nighttime driving, night blindness, conjunctival xerosis, comeal xerosis, comeal ulcers, Bitot’s spots, eye fatigue, foreign body sensation in the eye, light sensitivity, stringy mucus in or around the eyes, swelling of the conjunctiva and/or eyelids, dry, flaky, and/or damaged skin of the eyelids and/or orbits, eyelids that appear greasy, eyelid sticking, abnormal eyelash growth, loss of eyelashes, discomfort or pain of the eyes, eyelids, and/or orbits, chronic and episodic punctate keratopathy, filamentary keratopathy, récurrent comeal érosion, persistent épithélial defect, comeal melt, ocular surface failure, blepharospasm, mucopurulent discharge, appearance of a chalazion, and any combinations thereof.

[0105] In some embodiments, topical administration of the pharmaceutical composition as described herein reduces inflammation in one or more peri-orbital glands (e.g., one or more, two or more, or ail three of the Meibomian, lacrimal, and/or accessory lacrimal glands) of a subject. In some embodiments, topical administration of the pharmaceutical composition as described herein reduces inflammation in one or more peri-orbital 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% relative to the inflammation observed prior to administration of the pharmaceutical composition. In some embodiments, topical administration of the pharmaceutical composition reduces inflammation in one or more periorbital glands by about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 100-fold, or about 1000fold relative to the inflammation observed prior to administration of the pharmaceutical composition. In some embodiments, topical administration of the pharmaceutical composition as described herein éliminâtes inflammation in one or more peri-orbital glands of the subject. Methods of measuring peri-orbital gland inflammation are known in the art, including, for example, using laser in vivo confocal microscopy (IVCM) (See Qazi et al. Investigative Ophthalmology & Visual Science March 2012, Vol.53, 593).

[0106] In some embodiments, topical administration (e.g., prolonged/protracted administration) of the pharmaceutical composition as described herein does not resuit in an • adverse event in the subject. Examples of adverse events may include, but are not limited to, elevated intraocular pressure, the formation or worsening of cataracts, ocular infection, and any combinations there. In some embodiments, topical administration of the pharmaceutical composition does not increase/elevate intraocular pressure in the subject.

[0107] In some embodiments, the lipophilie compound is not delivered systemically to the subject by the administration of the pharmaceutical composition. In some embodiments, the lipophilie compound is not delivered to a tear or tear duct of the subject by the administration of the pharmaceutical composition. In some embodiments, the lipophilie compound is not delivered directly to an ocular surface of the subject by the administration of the pharmaceutical composition.

III. Article of Manufacture or Kit

[0108] Certain aspects of the présent disclosure relate to an article of manufacture or kit comprising one or more of the pharmaceutical compositions described herein. In some embodiments, the article of manufacture or kit comprises a label and/or package insert comprising instructions for use of the one or more pharmaceutical compositions. In some embodiments, the one or more pharmaceutical compositions are provided in a container. In - some embodiments, the components of the pharmaceutical composition are provided in a single container, or in two or more separate containers. In some embodiments, the article of manufacture or kit comprises the container(s) and a label or package insert on or associated with the container(s). Suitable containers may include, for example, tubes, bottles, vials, bags, etc. The container may be formed from a variety of suitable materials such as glass, plastic (such as polyvinyl chloride, polyolefin, or polyethylene), métal, and/or métal alloy (such as stainless Steel). The article of manufacture or kit may further include other materials désirable from a commercial and user standpoint, including buffers, diluents, filters, syringes, applicators, and the like.

[0109] The foregoing written description is considered to be sufficient to enable one skilled in the art to practice the présent disclosure. The following Examples are offered for illustrative purposes only, and are not intended to limit the scope of the présent disclosure in any way. Indeed, varions modifications of the présent disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended daims.

IV. Définitions

[0110] Before describing the présent disclosure in detail, it is to be understood that this présent disclosure is not limited to particular compositions or biological Systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0111] As used herein, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly indicates otherwise. Thus, for example, reference to “a molécule” optionally includes a combination of two or more such molécules, and the like.

[0112] As used herein, the term “about” refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.

[0113] As used herein, the term “and/or”, as in a phrase such as “A and/or B”, is intended . to include both A and B; A or B; A (alone); and B (alone). Likewise, as used herein, the term “and/or”, as in a phrase such as “A, B, and/or C”, is intended to encompass each of the following embodiments: A, B, and C; A; B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0114] As used herein, the terms “individual”, “patient”, or “subject” refer to a mammal. Mammals include, but are not limited to, domesticated animais (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice, hamsters, and rats). In some embodiments, the individual, patient, or subject is a human.

[0115] As used herein, the term “pharmaceutical formulation” refers to a préparation which is in such form as to permit the biological activity of an active ingrédient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0116] As used herein, the term “pharmaceutically acceptable carrier” refers to an ingrédient in a pharmaceutical formulation, other than an active ingrédient, which is nontoxic to a subject.

[0117] As used herein, the term “prévention” includes providing prophylaxis with respect to occurrence or récurrence of one or more signs or symptoms of a disorder in an individual. An individual may be predisposed to a disorder, susceptible to a disorder, or at risk of developing a disorder, but has not yet been diagnosed with the disorder.

[0118] As used herein, an individual “at risk” of developing a disorder may or may not hâve détectable disease or symptoms of disease, and may or may not hâve displayed détectable disease or symptoms of disease prior to the treatment methods described herein. “At risk” dénotés that an individual has one or more risk factors, which are measurable parameters that correlate with development of the disorder, as known in the art. An individual having one or more of these risk factors has a higher probability of developing the disorder than an individual without one or more of these risk factors.

[0119] As used herein, the term “treatment” refers to clinical intervention designed to alter the naturel course of the individual or cell being treated during the course of clinical

- pathology. Désirable effects of treatment include, for example, decreasing the rate of disease progression, ameliorating or palliating the disease State, and improved prognosis. An individual is successfully “treated”, for example, if one or more signs or symptoms associated with the disorder are mitigated or eliminated. For example, an individual is successfully “treated” if one or more symptoms associated with an inflammatory disease are mitigated or eliminated, including, but are not limited to, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other médications required to treat the disease, and/or delaying the progression of the disease.

[0120] An “effective amount” refers to at least an amount effective, at dosages and for periods of time necessary, to achieve the desired or indicated effect, including a therapeutic or prophylactic resuit. An effective amount can be provided in one or more administrations.

[0121] A “therapeutically effective amount” is at least the minimum concentration required to effect a measurable improvement of one or more signs or symptoms of a . particular disorder. A therapeutically effective amount herein may vary according to factors such as the disease State, âge, sex, and weight of the patient. A therapeutically effective amount is also one in which any detrimental effects of the treatment are outweighed by the therapeutically bénéficiai effects.

[0122] The term “peri-ocular” refers to the area surrounding the eyeball but within the orbit, including eyelids and latéral régions of the orbit.

[0123] The “peri-orbital glands” are the glands in the area around the eyeball including, for example, the meibomian, lacrimal, and/or accessory lacrimal glands.

EXAMPLES

Example 1: Effect of treatment with the compound of Formula I on intraocular pressure (IOP) and tear formation

[0124] The compound of Formula I is a fluorinated glucocorticoid with antiinflammatory activity (See US Pat. No. 7,288,536). The compound of Formula I showed close to full agonism in a variety of human in vitro assays of glucocorticoid receptor‘ mediated transrepression activity, and showed a partial response in a number of assays of glucocorticoid receptor-mediated transactivation. In vivo, the compound of Formula I displayed potent anti-inflammatory activity following intratracheal dosing in models of lung inflammation in the mouse and rat, and showed similar activity to fluticasone propionate (FP) in topical delayed type hypersensitivity ear inflammation, tyrosine aminotransferase induction, and chronic house dust mite models in the mouse. Interleukin-ΐβ (IL-Ιβ) and Tumour Necrosis Factor a (TNFa) stimulate the release of the pro-inflammatory cytokines Interleukin-6 (IL-6) and Interleukin-8 (IL-8) from a variety of cell types through activation of the NFkB pathway. FP and the compound of Formula I are able to potently and efïïciently transrepress this activation across a number of Systems (A549, HeLa, MG63, 16HBE, and H9 cell lines). These are the same inflammatory markers elevated in patients with aberrant inflammation of the peri-ocular glands (DEWS, 2007).

[0125] To test the effect of the compound of Formula I on intraocular pressure (IOP), eight female cynomolgus monkeys with unilatéral (OS) ocular hypertension induced by prior photocoagulation (laser) procedure to the trabecular meshwork (TM) were used at an âge between 11 and 14 years at the start of the study. Laser induced ocular hypertension had been created at least 9 years earlier in the study animais. Animais and treatments were randomized according to a 4x4 réplications Williams-type Latin Square design layout. Following random assignment of a number between 1 and 8, the eight primates were randomized two each into four treatment groups (A-D), with treatments masked for the investigators until ail data had been collected and entered into a database. The treatment groups A-D were as follows: the compound of Formula I (10 mg/mL suspension in placebo vehicle), mapracorat (10 mg/mL . suspension in placebo vehicle), Maxidex® (1 mg/mL), and placebo control.

[0126] Topical bilateral treatment occurred in a randomized, masked crossover format. Ail four treatments were investigated in parallel in two animais per treatment group during each 4-week treatment period. The assigned, masked formulation (A, B, C, or D) was administered to both eyes (OU) in a 25 pL volume three times daily (TID; at 8:30 am, 1 pm, and 5 pm). Treatment periods were separated by a 4-week washout/recovery period without topical treatment. The first period (period 1) was preceded by a 2-week run-in period during which ail animais received placebo topically TID.

. [0127] Conscious animais were seated in custom-designed chairs, and IOP was measured with a pneumatonometer (Classic 30, Reichert Depew) after topical application of proparacaine hydrochloride (0.13%) in both eyes (FIG. 1). Two to three measurements were taken for each eye and averaged. Data was stored and archived. During run-in and treatment periods, diumal IOP was determined two times per week at approximately 8:30 am, 1 pm, and 5 pm. For each animal bilateral tonometry was followed immediately by topical instillation of the appropriate drug formulation A, B, C, or D. During washout periods, diumal IOP was measured once per week in both eyes at approximately 8:30 am, 1 pm, and 5 pm. Surprisingly, topical treatment with the compound of Formula I over 4 weeks did not ' resuit in increased IOP in primates (FIG. 1). In fact, IOP in eyes treated with the compound of Formula I was similar to eyes treated with vehicle alone, and was significantly lower than dexamethasone treatment, demonstrating that the compound of Formula I does not produce the IOP increase typically associated with topical corticosteroids (e.g., dexamethasone).

[0128] Next, the effect on tear formation of treatment with the compound of Formula I was examined. Rabbits were placed in a restraining device, and atropine sulfate 1% ophthalmic solution (30 pL) was instilled into the lower conjunctival sac of each eye four times per day. Fifteen minutes after the administration of each dose of atropine sulfate, each eye received 30 pL of eye drops containing the active ingrédient, vehicle, or saline. Tear volume was then evaluated by the Schirmer test (FIG. 2). Schirmer strips were carefully placed in the posterior (i.e., temporal) lower fomix for 60 seconds, and the wetted area was read in millimeters as an index of tear volume. Surprisingly, when administered to the ocular surface in vivo for seven days, the compound of Formula I prevented a decrease in tear formation similar to topical dexamethasone in a model of dry eye disease (FIG. 2).

[0129] Taken together, the data presented herein demonstrate that the compound of Formula I is equally effective at treating dry eye disease as topical corticosteroids, such as dexamethasone, but does not induce the négative side effect of increased IOP typically associated with administration of corticosteroid compounds to the eye. The absence of effect on IOP indicates an improved, désirable safety profile of the compound of Formula I, as compared to other steroids such as dexamethasone.

Example 2: Determining characteristics of a peri-ocular cream formulation ' [0130] The following active pharmaceutical ingrédients (API) were mixed with cream vehicle for the préparation of creams containing 2% API by weight for this study and allowed to rest at room température for 24 hours before testing. Cyclosporin A (Sample A), loteprednol etabonate (Sample B), dexamethasone (Sample C), ketorolac tromethamine (Sample D), gatifloxacin,, USP (Sample E), gentamicin sulfate (Sample F), prednisolone (Sample G), flurbiprofen (Sample H), azithromycin dihydrated (Sample J), triamcinolone acetonide (Sample K), and doxycycline hydrochloride (Sample L). Vehicle cream comprised 48% w/w white soft petrolatum, 8% w/w minerai oil, 8% w/w propylene glycol, 6.6% w/w STcyclomethicone-5NF, 3.3% w/w emulsifier 10,2% w/w ST-elastomer-10, 0.08% w/w methylparaben, 0.06% w/w sodium phosphate dibasic anhydrous, 0.0546% w/w citric acid anhydrous, 0.02% w/w propylparaben, and q.s. purified water. The compound ofFormula I was incorporated into a cream with the following final composition: 2% w/w compound of Formula 1,46% w/w white petrolatum, 8% w/w minerai 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 sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/w propylparaben, and q.s. purified water.

[0131] Results of the flow visualization study are qualitative and were recorded by • photograph, for each sample and each test condition. Using a wide mouth disposable pipette, a small aliquot of 2% API-containing cream at approximately 1 ml was placed into Kimble 1-dram 62 glass vials, 15x45mm. The vial was capped and labeled on the glass vial, A through L, as referenced in the preceding paragraph. For each test, sample vials were placed into the thermostatted couette rheometer cup at 37°C, in sets of 2 or 3 vials, and equilibrated at 37°C for a minimum of 10 minutes. After 10 minutes, sample glass vials were removed, marked with a red • line at the fluid surface or meniscus, inverted and retumed to the 37°C rheometer cup. At two time periods, 2 minutes and 5 minutes, vials were removed and photographed to document any movement of the cream.

[0132] Preliminary measurements with the vehicle cream and the 2% compound of Formula I cream were made in comparison to a high viscosity polybutene standard, N62000. The vehicle cream and the 2% compound of Formula I cream showed no discemible flow at 37°C at the 2 and 5 minute time points in contrast to the N62000 high viscosity polymer standard where bulk flow was observed (FIG. 3A). The same procedure was used for the 2% API-containing experimental cream samples prepared from the eleven compounds listed above and also tested at 37°C. This simple test shows that none of the eleven prepared 2% API-containing creams exhibited any discemible flow under the prescribed test conditions, as shown for three of the creams in FIG. 3B. In summary, the yield stress at 37°C is apparently strong enough to prevent flow under the influence of gravity under the test conditions.

[0133] The stress relaxation yield stress test employed a rheometer and a 10% Step Strain Stress Relaxation measurement on a 25 mm cône and plate. This test applies an instantaneous motion as a step strain to the samples at t=0 and subsequently measures the shear stress relaxation. For Newtonian fluids, the relaxation is immédiate. For non-Newtonian fluids, there . can be a delayed stress relaxation with distribution of relaxation times with relaxation to zéro.

Non-Newtonian materials with yield stress will show a distribution of relaxation times with a non-zero stress relaxation - or infinité relaxation time. This is the équivalent of the yield stress. Testing was performed at both 25 and 37°C.

[0134] Measurements with Ultima white petrolatum were compared with vehicle cream and 2% API-containing creams of the compound of Formula I and the eleven APIs described above. Ail prepared 2% API creams, vehicle cream 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 the insufïicient mixing of the API in each vehicle cream, air ’ entrapment during mixing, particle size of the API used in this study, and other factors. Regardless of the source of variance, each 2% API-containing cream exhibited a yield stress. So did vehicle cream and white petrolatum. Curves (some examples in FIG. 4A-D) very consistently show stress relaxation to a non-zero shear stress value. Noting that the creams are quite shear sensitive, results are summarized in the following table (Table 1) for each sample in . each test at both 25 and 37°C, including Ultima petrolatum; 1-5 replicates.

Table 1

Sample ID	T°C	Yield Stress Values in Units of Pa
A	25	10.1	3.0	10.0	9.5
A	37	3.0	2.3
B	25	15.5	14.6
B	37	3.0	2.0	1.9
C	25	4.2	2.9
C	37	3.4	1.8
D	25	8.5	3.1	10.5
D	37	2.9	114
E	25	17.6	16.9	3.9
E	37	5.0	4.0
F	25	4.1	3.1
F	37	3.6	3.5
G	25	3.9	3.2
G	37	1.4	2.7	4.1
H	25	18.5	18.9	5.9
H	37	2.0	2.3
J	25	8.5	9.7	4.9
J	37	1.8	2.1
K	25	11.6	7.5	7.2	7.1	19.9
K	37	6.9	7.1
L	25	12.9	10.3	4.4
L	37	1.5	1.6
Ultima	25	35.2	30.8
Ultima	37	14.7

[0135] For comparison, yield stress values (in units of Pa) for the vehicle cream were 4.1, 3.3, 2.9 and 1.0, 1.0, 1.5 at 25 and 37°C, respectively (3 replicates each). Yield stress values (in . units of Pa) for the 2% compound of Formula I cream were 2.2,2.8 and 1.0, 0.9, 0.9 at 25 and

37°C, respectively (2-3 replicates each). For comparison, the stress relaxation function for the high viscosity polybutene N62000 standard showed a rapid decay to zéro in less than 1 second at room température.

[0136] For ail samples, except Samples F and G, the yield stress decreases with increasing température from 25°C to 37°C. The yield stress of the Ultima petrolatum is much higher than the 2% API-containing or vehicle cream samples indicating a more difïicult spreadability of the Ultima petrolatum onto contact surfaces, such as the eyelid. Ail 2% API creams show extensional viscosity behavior and may be strain thickening. This is a material property that may contribute to increased cohesiveness on contact surfaces, further counteracting the influence of gravity and limiting flow. More importantly, the extensional viscosity may enhance physical stability preventing sédimentation of active ingrédients. These data suggest that ail of the cream formulations will facilitate application to the intended surfaces (eyelids) compared to an ointment. Because of the lower yield stress of the API-containing creams and the vehicle cream, these formulations will be easier for the consumer to use and apply relative to petrolatum alone. In contrast, a high viscosity polymer such as N62000 is not likely to be suitable for the présent invention. The data clearly show that the goal to develop a cream formulation that is easy to apply to a contact surface, such as the eyelid, and that does not flow following eyelid application, so as to prevent formulation flowing onto the ocular surface, has been achieved with the formulations of this invention.

Example 3: Skin pénétration of a peri-ocular cream

[0137] An in vitro skin pénétration model using human cadaver skin mounted in Franztype diffusion cells (FDC) was chosen to détermine the skin perméation of the compound of Formula I applied as a 2% cream to the epidermal surface. Transdermal flux into a receptor fluid was measured over a period of 46 hours after application of the formulations. At the end of the 46-hour incubation period, the skin was tape-stripped and heat separated based on an established method and the concentration of the compound of Formula I was measured in the residual epidermis and dermis. The applied formulations comprised of 2% w/w compound of Formula I, 46% w/w white petrolatum, 8% w/w minerai oil, 8% w/w propylene glycol, 6.6% w/w ST-cyclomethicone-5NF, 3.3% w/w emulsifïer 10, 2% w/w ST-elastomer• 10, 0.08% w/w methylparaben, 0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/w propylparaben, and q.s. purified water. Vehicle cream comprised of 48% w/w white petrolatum, 8% w/w minerai oil, 8% w/w propylene glycol, 6.6% w/w ST-cyclomethicone-5NF, 3.3% w/w emulsifïer 10, 2% w/w ST-elastomer-10, 0.08% w/w methylparaben, 0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/w propylparaben, and q.s. purified water was also tested as a négative control.

[0138] Human cadaver skin from the posterior leg of a single donor, dermatomed to a thickness of approximately 250 pm, was obtained from a commercial source, eut into pièces of approximately 2 cm x 2 cm with each such piece mounted in an FDC with a 0.55 cm²diffusional area and 3.3 mL receiver volume. The stratum comeum and the dermis were in contact with the donor and receptor compartments, respectively. Following an integrity check (impédance analysis), 10 pL of cream sample was applied to the epidermal surface of each FDC. An aliquot of the receptor fluid (comprised of phosphate-buffered saline pH 7.4 . containing 0.01wt% Na azide and lwt% Brij 020) was sampled 4, 8,24 and 46 hours after application of test article and stored refrigerated until sample analysis. At the end of the 46hour period, the epidermal surface of each skin sample was wiped clean, washed twice using 200 pL of a 1:1 volume water/ethanol mixture. The skin was then tapped dry using KimWipes, tape-stripped thrice with cellophane tape to remove the outer-most layers of the stratum comeum. The remaining skin was then split into epidermal and dermal compartments. The compound of Formula I was extracted with 3 mL of a 1:1 volume DMSO/isopropanol mixture at 40°C for 24 hours.

[0139] A high performance liquid chromatography UV (“HPLC-UV”) analytical method and an LC-MS/MS method for detecting the compound of Formula I in the skin and in the receptor fluid samples, respectively, was implemented and employed mobile phases A (0.05 mL trifluoroacetic acid (TFA) in 1000 mL LC-MS grade water) and B (0.05 mL TFA in 1000 mL LC-MS grade acetonitrile). The lower level of quantification (LLOQ) for the compound of Formula I for the LC-MS/MS method was determined to be in the 6-10 ng/mL range.

[0140] The accumulated amount of compound of Formula I in the epidermis and dermis and at each of the time points in the receptor fluid are shown in FIG. 5. A négative control using vehicle cream is also shown. The compound of Formula I was only detected in the ’ epidermis, at 2.89+/-0.32 pg/cm², and dermis, at 0.73+/-0.21 pg/cm², but not in the transdermal receptor fluid. With the compound of Formula I being lipophilie with low aqueous solubility (the solubility limit of the compound of Formula I in the receptor fluid was determined to be approximately 35.8 pg/mL, sufficient to maintain sink conditions throughout the experiment), the data very clearly demonstrate the much preferred partitioning of the compound of Formula I into lipid containing compartments, such as tissues, over hydrophilic compartments, such as the receptor fluid. This characteristic most likely translates to lipid containing compartments in the eyelid in general, such as Meibomian glands, meibum, and other fatty structures tuming them into drug depot and “extended release” delivery mechanisms (via meibum) to the ocular surface for lipophilie compounds administered peri-ocularly.

Example 4: Ocular and systemic exposure following peri-ocular cream administration

[0141] To détermine the maximal tolerated dose amount first, two Hanford minipigs were dosed twice-daily (BID) approximately 6 hours apart topically with a cream (comprised of 2% w/w compound of Formula 1,46% w/w white petrolatum, 8% w/w minerai oil, 8% w/w propylene glycol, 6.6% w/w ST-cyclomethicone-5NF, 3.3% w/w emulsifier 10, 2% w/w STelastomer-10, 0.08% w/w methylparaben, 0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/w propylparaben, and q.s. purified water) to the upper and lower eyelids of one eye, with ascending doses (25, 50, 75, 100 pL) over 4 days to détermine ocular and dermal tolerability and the maximal feasible amount of the cream formulation on each eyelid. Study variables assessed were mortality, clinical observations of illness or reaction to treatment, ocular observations using a modified Hackett McDonald grading System, and dermal Draize scoring. The cream was generally well tolerated at ail four doses administered BID. A dose amount of 75 pL per eyelid was determined to be the maximal feasible dose amount, because of ease of application and minimal risk of cream transfer to the ocular surface, which covered the entire minipig eyelid with a thin layer of the test article formulation with no dripping, flowing or running down of the formulation onto the ocular surface. The dose amount of 75 pL was then used for subséquent studies.

[0142] To détermine the ocular exposure and pharmacokinetics following topical cream administration to the eyelids, the cream containing 2% of compound of Formula I was applied BID to eyelids of 8 Hanford minipigs for 7 days and one additional application on day 8 for a total of 15 topical doses. After the last dose on day 8, two animais each were euthanized at 2,4, 8, and 24 hours after the final dose, and eyes were collected for dissection into the following tissues and fluids: eyelids (including palpébral conjunctiva), bulbar conjunctiva, comea, iris/ciliary body (ICB), and aqueous humor (AQH). Plasma was also collected (prior to dose application on Days 1 and 8, and prior to euthanasia). A decision was made not to attempt to collect meibum, since the amounts expressable from the lid margin were found to be minimal and the procedure of meibum expression through . manipulation/rubbing/squeezing of the eyelids would hâve rendered the eyelid tissues compromised and unusable for further analysis. Meibum was believed to be only one lipid 67 compartment in the eyelids that could act as a depot for lipophilie compounds. Meibomian glands and other fatty tissues were others. Attempts to express meibum from the ducts, thereby rendering the eyelid itself unusable for further analysis, would hâve not permitted assessment of drug content in other potential lipid structures in the eyelids. Thus, the ’ decision was made to assess drug exposure in the eyelid as an intact tissue to capture ail potential drug depots.

[0143] Three different extraction and analytical methods were developed for the détermination of the compound of Formula I in i) plasma and aqueous humor; iï) bulbar conjunctiva, comea, ICB; iii) eyelids. Assay ranges were 0.1 — 100 ng/mL, 1-1000 ng/g, and 1-1000 ng/g, respectively. Briefly, analytical methods were as follows: i) plasma and aqueous humor standards were from minipig and rabbit, respectively; ü) bulbar conjunctiva, comea, ICB standard was rabbit comea; iii) eyelid standard was pig skin. The internai . standard working solution for analytical purposes was comprised of 20.0 ng/mL ¹³C2,¹⁵Nlabeled compound of Formula I in acetonitrile with 1% formic acid (v/v) which was being added to each sample. The tissue/fluid sample extraction procedure involved i) plasma/aqueous humor sample; ii) bulbar conjunctiva, comea, ICB homogenization in acetonitrile; iii) eyelid digestion in 1:1 acetonitrile: ammonium hydroxide solution for 1.5 hours at 37°C foliowed by acetonitrile addition, homogenization, and neutralization with formic acid; in ail cases followed by addition of internai standard working solution, vortexing and centrifugation. Analysis of the samples was then carried out with LC-MS/MS, employing mobile phases A (Water with 0.1% formic acid) and B (acetonitrile with 0.1% ' formic acid).

[0144] 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 (highest mean concentration of 30613 ng/g at 4 hours post final dose), followed by bulbar conjunctiva (mean of 1931 ng/g at 4 hours post final dose), comea (mean of452 ng/g at 8 hours post final dose), ICB (mean of 20.48 ng/g at 24 hours post final dose), and aqueous humor (mean of 5.81 ng/g at 8 hours post final dose) (FIG. 6). In ail tissues, these concentration ranges represent pharmacologically active concentrations of the compound of Formula I even when . taking high protein binding of approximately 99% into account resulting in “free” drug concentrations that are approximately l/100^th ofthe total measured concentration.

Unexpectedly, in each compartment the exposure levels remained almost constant for up to hours post final peri-ocular dose application. This exposure profile is very different from that of a typical eyedrop application and highly suggestive of a drug depot in the eyelids that . “feeds” the downstream compartments (conjunctiva, comea, ICB, aqueous humor) over at least a 24-hour period. Since lipophilie compounds preferentially partition into lipid compartments and not into aqueous, hydrophilic compartments as evidenced for the compound of Formula I by the aforementioned skin perméation study it can be concluded that the lipid structures of the eyelid (e.g., meibomian glands, meibum, other fatty tissues) serve as drug depots for peri-ocularly delivered drugs with the meibum becoming a drug delivery vehicle since it is constantly produced by the meibomian glands and secreted onto the comeal surface. These conclusions are related to, and consistent with, the lipophilie properties of the compound of Formula I and, as such, are expected to generally translate to ail other lipophilie compounds similarly if not equally.

[0145] Furthermore, this 24-hour exposure profile following peri-ocular administration of a lipophilie compound, such as the compound of Formula I, translates to a once-daily application regimen representing a major benefit for patients who are often required to administer steroid or other eyedrops up to 4 to 6 or more times each day. A once-daily application regimen provides for improved safety and convenience for patients over eyedrops that hâve to be administered more frequently.

[0146] A further significant benefit of peri-ocular application is the larger dosing volume ' which allows much greater flexibility with respect to delivery of a wide range of drug doses compared to eyedrop application, making it possible that many more drugs may be applied once-daily than with eyedrops, translating to the aforementioned patient benefit. The volume of eyedrops is typically limited to approximately a 30 pL volume, or up to approximately a 40 pL volume in some cases, per administration per eye. A 75 pL peri-ocular dosing volume for each eyelid, or 150 pL per eye, equates to at least a 4-fold greater dose volume per administration.

[0147] Yet a further benefit of peri-ocular application, aside from the larger dosing . volume as described above, is that a greater percentage of drug is available for delivery to the target tissues at the ocular surface. Eyedrop application is particularly known for delivering only a small fraction of the API that is applied as part of the eyedrop formulation. The reason is that an eyedrop applied to the ocular surface rapidly drains away from the ocular surface via the nasolacrimal duct and is thus understood to deliver only about up to 1% of its API “payload” contained in the delivered eyedrop to the ocular surface tissues (comea and conjunctiva). In contrast, peri-ocular administration delivers essentially 100% or close to 100% of the API contained in the peri-ocular formulation to the eyelid tissue. Taken together with the larger delivery volume of a peri-ocularly applied formulation compared to a topically applied eyedrop, the peri-ocular route represents an enormous dosing advantage of API to ocular surface tissues over the topical eyedrop route.

[0148] Plasma exposure to the compound of Formula I in this study (for up to 24 hours after the last peri-ocular application) was variable but generally low or below the lower limit of quantification of 0.1 ng/mL (FIG. 6). The highest plasma concentration, 2.22 ng/mL, was ’ observed 24 hours following the final Day 8 dose. The results indicated that there was no or very low systemic accumulation after 7.5 days of multiple topical eyelid application.

[0149] Plasma exposure was also detennined in another 7-day study in minipigs. The compound of Formula I was formulated in a cream at 4% w/w and 6% w/w additionally comprised of 44% w/w or 42% w/w White Petrolatum, respectively, and 8% w/w minerai oil, 8% w/wpropylene glycol, 6.6% w/w ST-cyclomethicone-5NF, 3.3% w/w emulsifîer 10,2% w/w ST-elastomer-10,0.08% w/w methylparaben, 0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/w propylparaben, and q.s. purified . water. The cream formulation was applied peri-ocularly at a dose volume of 75 pL per eyelid to the upper and lower eyelids of the right eye of 3 minipigs for each concentration 3 times daily (TID) at an 8-hour interval for 6 days and once in the moming on day 7. Plasmas levels of the compound of Formula I were then assessed for up to 7 days post final dosing.

[0150] Dennal administration of 4%. (18 mg/eye/day) and 6% (27 mg/eye/day) compound of Formula I cream to the upper and lower eyelids of one eye of Hanford minipigs was well tolerated. There were no test article-related effects on body weights, clinical observations, tonometry (intraocular pressure), hematology, or sérum chemistry.

. [0151] In female minipigs receiving multiple doses of compound of Formula I cream at 18 mg/eye/day and 27 mg/eye/day, plasma TK parameters (C_max, T_max, AUCiast, AUC0-24) for the compound of Formula I were low and variable. Plasma concentrations persisted for at least 2 to 7 days after the last administered dose.

[0152] This is an intriguing and unexpected finding as the data suggest that the ocular drug depot (established following peri-ocular cream application for 7 days) released drug over an extended period of time such that, in some animais, systemic levels of the compound of Formula I could be measured for up to 7 days after the final peri-ocular cream application. Conceptually, these finding are entirely consistent with extended delivery from a Meibomian gland/meibum drug depot to the systemic circulation and, presumably, ocular surface.

Example 5: Manufacturing process

[0153] Peri-ocular application requires a stérile manufacturing process for ophthalmic drug products, regardless of the presence or absence of preservatives in the formulation. The manufacturing process, as outlined in FIG. 7, is based on the combination under aseptie conditions of hydrophilic and lipophilie components, each presterilized separately by an appropriate sterilization process, such as filtration, heat, gamma or beta or alpha irradiation, or otherwise. The presterilized API (heat, gamma or beta or alpha irradiation, or otherwise) is incorporated into the presterilized lipophilie component at an appropriate température using an appropriate mixing process. Then, this lipophilie component is mixed with the presterilized hydrophilic component at an appropriate température using an appropriate process, such as stirring, shaking, vortexing, sonication, etc. at a predetermined mixing rate.

. The final mixture is then allowed to cool to an appropriate température necessary for the filling process into appropriate containers for the final drug product, whether for clinical or commercial use.

[0154] As one embodiment, the manufacturing process of a cream comprising the compound of Formula I, as described in this application and in FIG. 7, requires a high-speed homogenization procedure to incorporate the API and a gentle mixing/stirring procedure for combining the lipophilie and hydrophilic components. In the same embodiment, the lipophilie component is heated to 55-60°C for the incorporation of the API, such as the compound of Formula I, and the mixing process with the hydrophilic component. The final product is then slowly cooled to under 30°C prior to filling into the final containers for a clinical study or commercial use.

[0155] In other embodiments, the lipophilie component is heated to a température necessary to liquefy this component to make it suitable to a sterilization procedure by filtration, or not heated at ail. This includes température ranges of 1-10°C, 10-20°C, 2030°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, 110120°C, 120-130°C, 130-140°C, 140-150°C, 150-160°C, and 160-170°C,.

[0156] In other embodiments, incorporation of the API requires a slow, high, or intermediate mixing speed at a spécifie température within a range of l-10°C, 10-20°C, 2030°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, 110120°C, 120-130°C, 130-140°C, 140-150°C, 150-160°C, and 160-170°C. Thisprocess includes mixing, shaking, stirring, vortexing, sonication, etc.

[0157] In other embodiments, mixing of the hydrophilic and lipophilie components is achieved at room température or température ranges of l-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, 120130°C, 130-140°C, 140-150°C, 150-160°C, and 160-170°C.

[0158] In other embodiments, the final product is then slowly or rapidly cooled to a température necessary for the filling into the final containers for a clinical study or commercial use. This cooling process requires mixing at a slow, rapid or intermediate speed, or no mixing at ail.

Claims

1. A pharmaceutical composition comprising:

a) a therapeutically effective amount of a lipophilie compound; and

b) a pharmaceutically acceptable carrier adapted for peri-ocular transdermal delivery of the lipophilie compound to one or more peri-orbital glands;

for use in treating an ocular disease in a subject, wherein the pharmaceutical composition is specifïcally formulated for peri-ocular delivery.

2. The pharmaceutical composition for its use according to claim 1, wherein the ocular disease is selected from the group consisting of inflammation of the peri-ocular glands, meibomitis, dry eye disease, allergie eye disease, topical preservative toxicity, xerophthalmia, loss of homeostasis of the tear film, tear film instability and hyperosmolarity, ocular surface inflammation and damage, neuronal sensory abnormalities, Meibomian gland dysfimetion, exacerbated inflammatory ocular surface disease, phlyctenular keratitis, chalazion, anterior blepharitis, posterior blepharitis, bacterial infection, glaucoma, ocular hypertension, and any combinations thereof.

3. The pharmaceutical composition for its use according to any one of daims 1-2, wherein the pharmaceutical composition is for topical administration to an extemal portion of an eyelid of the subject, including the upper latéral région of an orbit of the subject, advantageously to the extemal portion of the upper and/or lower eyelid of the subject.

4. The pharmaceutical composition for its use according to any one of daims 1-3, wherein the pharmaceutical composition is for administration one, two, three, four, five, six or more times per day, advantageously 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, 10 weeks, 11 weeks, 12 weeks or more, 24 weeks, 36 weeks, 48 weeks or more.

5. The pharmaceutical composition for its use according to any one of daims 1-4, wherein the lipophilie compound is selected in the group consisting of:

- a steroid, advantageously a compound of Formula I, fluocinolone, difluprednate, . fluticasone, fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and ester dérivatives thereof; .

wherein the compound of Formula I comprises the structure:

(Formula I)

F more advantageously the compound of Formula I;

- an antibiotic, advantageously selected from the group consisting of sulfonamides, macrolides, chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin, and tetracyclines, more advantageously selected from the group consisting of azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, oxifloxacin, chloramphenicol, doxycycline, tetracyclin, gramicidin, mupirocin, polymyxin B, and sulfacetamide;

- an immunomodulatory drug, advantageously selected from the group consisting of calcineurin inhibitors and thalidomide analogues, more advantageously selected from the group consisting of cyclosporine A, voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, and pomalidomide;

- an integrin antagonist, advantageously selected from the group consisting of lifitegrast, GW559090, and ester dérivatives thereof.

an anti-inflammatory agent, advantageously selected from the group consisting of oméga 3 fatty acids and non-steroidal anti-inflammatory drugs (NSAIDs), more advantageously selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and any combinations thereof or selected from the group consisting of bromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac, and ' any combinations thereof;

- an anti-glaucoma or ocular anti-hypertension agent, advantageously 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 combinations thereof.

6. The pharmaceutical composition for its use according to any one of daims 1-5, wherein the pharmaceutical composition comprises the lipophilie compound at a concentration between about 0.001% and about 10% weight per weight (w/w), between about 0.0001% and about 10% weight per weight (w/w), or between about 0.0001% and about 5% weight per weight (w/w), advantageously the pharmaceutical composition comprises a steroid at a concentration between about 0.01% and about 2% w/w.

7. The pharmaceutical composition for its use according to any one of daims 1-6, wherein the pharmaceutically acceptable carrier is selected from the group consisting of an ointment, cream, lotion, gel, émulsion, suspension, oil, foam, transdermal patch, spray, and any combinations thereof.

8. The pharmaceutical composition for its use according to daim 7, wherein the ointment comprises a paraffinic or a water-miscible ointment base, advantageously the ointment comprises 61.5% w/w white soft paraffin, 8% w/w minerai oil, 8% w/w propylene glycol, 5% w/w of St. cyclomethicone-5NF, 5% w/w of labrasol, 5% w/w of propylene carbonate, 2.5% w/w of steareth 2, 2.5% w/w of St. emulsifier 10, and 2.5% w/w of St. elastomer-10.

9. The pharmaceutical composition for its use according to daim 7, wherein the cream, preferably preservative-free, comprises an oil-in-water base or a water-in-oil base, advantageously the cream comprises 48% w/w white soft paraffin, 8% w/w minerai 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 or the cream comprises 48% w/w white soft paraffin, 8% w/w minerai 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 sodium phosphate dibasic anhydrous, 0.046% w/w citric acid . anhydrous, 0.02% w/w propylparaben, and purified water or the cream comprises 48% w/w white petrolatum, 8% w/w minerai oil, 8% w/w propylene glycol, 6.6% w/w STcyclomethicone-5NF, 3.3% w/w emulsifier 10, 2% w/w ST-elastomer-10, 0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/w benzalkonium chloride, and purified water, more advantageously the cream is preservative-free and comprises white soft paraffin/petrolatum, minerai oil, propylene glycol, ST-cyclomethicone-5NF, emulsifier-10, ST-elastomer-10, dibasic sodium phosphate, citric acid, and purified water or comprises 48% 75 w/w white petrolatum, 8% w/w minerai oil, 8% w/w propylene glycol, 6.6% w/w STcyclomethicone-5NF, 3.3% w/w emulsifier 10, 2% w/w ST-elastomer-10, 0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous, and purified water.

10. A pharmaceutical composition as defined in any one of daims 1-9