Compositions and methods for treating meibomian gland dysfunction

Abstract

Compositions and methods for the treatment of dry eye disease (DED) or meibomian gland dysfunction are provided. Use of a composition in the manufacture of a formulation for treating dry eye disease (DED) or meibomian gland dysfunction in a patient in need thereof, the composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier, the treatment comprising topically administering the formulation to the patient so that it reaches the patient's eyelid margin. The keratolytic agent is preferably selenium disulfide, and the concentration of selenium disulfide in the composition is preferably from about 0.1% to about 10%.

Description

[Technical Field]

[0001] <Cross reference> This application claims the benefit of U.S. Provisional Patent Application No. 62 / 065,716, filed October 19, 2014, and U.S. Patent Application No. 14 / 732,622, filed June 5, 2015, which are incorporated herein by their entireties. [Background technology]

[0002] Meibomian gland dysfunction, or MGD, is a major cause of dry eye syndrome and is most often characterized by keratinized obstruction of the terminal ducts of the meibomian glands. Summary of the Invention

[0003] Prior to the methods and formulations described herein, there were no agents useful for treating MGD, including removing keratinized blockages of the meibomian glands or preventing further keratinized blockages of the meibomian glands. Current techniques for removing keratinized blockages of the meibomian glands are limited to physical removal methods, some of which can cause significant discomfort to the patient.

[0004] Thus, methods and formulations for treating MGD are described herein. In one embodiment, a method for treating meibomian gland dysfunction in a patient in need thereof is provided, the method comprising topically administering to the patient a composition that reaches the patient's eyelid margin, the composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier. In some embodiments, the keratolytic agent is benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, an alpha hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidone carboxylic acid. In some embodiments, the keratolytic agent is salicylic acid or selenium disulfide. In some embodiments, the keratolytic agent is selenium disulfide. In some embodiments, the concentration of selenium disulfide in the composition is between about 0.1% and about 10%. In some embodiments, the keratolytic agent is salicylic acid. In some embodiments, the composition is topically administered to the patient until keratinization obstruction is relieved. In some embodiments, the composition is topically administered to a patient periodically after keratinization obstruction has been alleviated. In some embodiments, the topical administration is a single administration. In some embodiments, the topical administration is periodic administration. In some embodiments, the periodic administration is once daily. In some embodiments, the periodic administration is twice daily. In some embodiments, the composition for topical administration is semi-solid. In some embodiments, the composition for topical administration is homogenous. In some embodiments, the composition for topical administration is a dispersion. In some embodiments, the composition for topical administration is hydrophilic. In some embodiments, the composition for topical administration has a fatty base. In some embodiments, the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable excipient. In some embodiments, administration of the composition results in enhanced meibomian production.

[0005] In one embodiment, a method of treating meibomian gland dysfunction in a patient in need thereof is provided, the method comprising topically administering to the patient a composition that reaches the patient's eyelid margin, the composition comprising a therapeutically effective amount of a keratolytic agent in an ophthalmically acceptable carrier. In some embodiments, the keratolytic agent is salicylic acid or selenium disulfide. In some embodiments, the keratolytic agent is selenium disulfide. In some embodiments, the concentration of selenium disulfide in the composition is between about 0.1% and about 10%. In some embodiments, administration of the composition results in enhanced meibomian production. In some embodiments, the topical composition is homogeneous. In some embodiments, the topical composition is a dispersion. In some embodiments, the topical composition is hydrophilic. In some embodiments, the topical composition has a fatty base. In some embodiments, the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable excipient.

[0006] In one embodiment, there is a method of treating MGD by administering a meibomian gland opening agent that allows (at least partial) opening of meibomian glands, (at least partial) opening of keratin obstructions, and / or prevention of subsequent keratin obstructions in the meibomian glands (at least to the extent such obstructions are due to meibomian gland dysfunction). In one embodiment, the formulation includes a therapeutically effective amount of a meibomian gland opening agent. In a further or alternative embodiment, the formulation includes an additional therapeutic agent that is not a meibomian gland opening agent. In a further or alternative embodiment, the formulation includes an additional meibomian gland opening agent. In an alternative embodiment, the formulation does not include any additional therapeutic agents other than the additional meibomian gland opening agent. In an alternative embodiment, the formulation consists solely of a meibomian gland opening agent and does not include any other therapeutic agents. In any of the foregoing embodiments, the formulation optionally includes an ophthalmically acceptable carrier. In a further embodiment, the ophthalmically acceptable carrier comprises an ophthalmically acceptable excipient.

[0007] In one aspect, the methods and formulations described herein include an agent useful for treating MGD in a subject in need thereof. In some embodiments, the formulations described herein are applied to the eyelid margin of a patient in need thereof. In some embodiments, multiple applications of the formulation are required.

[0008] In some embodiments, the eye is at least partially shielded to prevent the agent from contacting the eye of a subject in need thereof. Further described are kits comprising the formulations described herein along with a device that shields the eye from contact with the formulation.

[0009] The methods and formulations described herein include therapeutically active agents that act alone or in combination with other components to (at least partially) open blocked meibomian glands or (at least partially) prevent further blockage of the meibomian glands. Furthermore, such active agents are formulated or applied so as to be applicable to the ocular surface (i.e., not to cause undue irritation or disruption to the epithelial surface of the eye) and without damaging lipid-producing cells upon contact with the formulation.

[0010] In some embodiments, the formulations are applied for a period and frequency that is acceptable and practical for the physician or patient administering the drug, e.g., the physician applies a formulation described herein weekly or twice weekly for several weeks to induce (at least partial) opening of the obstruction, and the patient applies a different formulation on a daily basis, or uses a stronger formulation on a daily basis for several weeks, followed by a less strong formulation on a daily basis.

[0011] In some embodiments, the application method varies depending on the concentration of the active agent and / or the severity of the MGD being treated, including, but not limited to, ocular surface occlusion. In other embodiments, the application method or formulation is modified to enhance penetration or residence time on the target tissue to enhance treatment efficacy. In other embodiments, the application method or formulation is modified to enhance penetration or residence time on the target tissue to minimize the time required. In other embodiments, the application method or formulation is formulated (e.g., viscosity enhancement and / or skin adhesion) to increase contact with the target tissue while minimizing contact with non-target tissues, including the eye, thereby limiting or reducing unwanted collateral activity.

[0012] In certain embodiments of the methods and formulations described herein, the concentration of the active agent and the components of the co-formulation are optimized to deliver the minimum effective concentration of the active agent to achieve a therapeutic effect while minimizing any ocular irritation or disruption, or irritation or disruption to surrounding ocular tissues. The methods and formulations described herein are a means for the (at least partial) removal of keratinized obstruction of the meibomian glands or the (at least partial) prevention of further keratinized obstruction of the meibomian glands.

[0013] The formulation includes at least one meibomian gland opening agent. In some embodiments, the meibomian gland opening agent is a keratolytic and / or keratoplastic agent. In some embodiments, the keratolytic and / or keratoplastic agent in the formulation is an active agent that results in opening or maintaining patency of the ducts of the meibomian glands.

[0014] In some embodiments, an agent having a primarily keratolytic effect is used. In some embodiments, an agent having a primarily keratolytic effect is used. In some embodiments, an agent having both keratolytic and keratolytic effects is used. In some embodiments, the keratolytic and / or keratolytic agent enhances lipid production in the meibomian glands. In some embodiments, the meibomian gland opening agent is an anesthetic. In some embodiments, the meibomian gland opening agent is an anti-inflammatory agent. In some embodiments, the meibomian gland opening agent is an antioxidant. In some embodiments, the meibomian gland opening agent is a prostaglandin synthetase inhibitor. In some embodiments, the meibomian gland opening agent is a lipoxygenase or cyclooxygenase enzyme.

[0015] In one embodiment, described herein is a method of treating meibomian gland dysfunction in a patient in need thereof, the method comprising topically administering a composition to at least the non-mucosal epithelial side of the patient's eyelid margin, the composition comprising a therapeutically effective amount of at least one meibomian gland opening agent applied in an ophthalmically acceptable manner or formulation. In one embodiment of the methods and formulations described herein, the formulation comprises a pharmaceutical excipient.

[0016] In some embodiments, the meibomian gland opening agent is a keratolytic and / or keratomellowing agent selected from benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, inorganic selenium compounds such as selenium disulfide, organic selenium compounds such as SeCl, NaSeO, ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) or analogs thereof, alpha hydroxy acids, urea, lactic acid, or sodium thioglycolate. In some embodiments, the keratolytic and / or keratomellowing agent is selected from benzoyl peroxide, coal tar, dithranol, salicylic acid, or selenium disulfide. In some embodiments, the keratolytic and / or keratomellowing agent is salicylic acid or selenium disulfide. In some embodiments, the keratolytic and / or keratomellowing agent is salicylic acid. In some embodiments, the keratolytic and / or keratolytic agent is selenium disulfide. In some embodiments, at least one keratolytic and / or keratolytic agent is salicylic acid. In some embodiments, at least one keratolytic and / or keratolytic agent is selenium disulfide. In some embodiments, salicylic acid is present at about 0.1% to about 30%. In some embodiments, selenium disulfide is present at about 0.1% to about 10%.

[0017] In some embodiments, the meibomian gland opening agent is an anesthetic selected from an aminoamide local anesthetic and / or an aminoester local anesthetic. In one embodiment, the aminoamide local anesthetic or aminoester local anesthetic is present in a concentration between about 4% and about 80%. In one embodiment, the aminoamide local anesthetic or aminoester local anesthetic is present in a concentration between about 6% and about 60%. In one embodiment, the aminoamide local anesthetic or aminoester local anesthetic is present in a concentration between about 8% and about 50%. In one embodiment, the aminoamide local anesthetic or aminoester local anesthetic is present in a concentration between about 10% and about 40%. In one embodiment, the aminoamide local anesthetic or aminoester local anesthetic is present in a concentration between about 12% and about 45%. In one embodiment, the aminoamide local anesthetic or aminoester local anesthetic is present in a concentration between about 14% and about 40%. In one embodiment, the formulation includes more than one local anesthetic.

[0018] In some embodiments, topical administration of a composition comprising at least one meibomian gland opening agent is performed twice a week. In some embodiments, topical administration of a composition comprising at least one meibomian gland opening agent is performed every other day. In some embodiments, topical administration of a composition comprising at least one meibomian gland opening agent is performed daily. In some embodiments, topical administration of a composition comprising at least one meibomian gland opening agent is performed several times a day.

[0019] In some embodiments, the topical composition is a liquid or semi-solid. In some embodiments, the topical composition is an emulsion semi-solid. In some embodiments, the topical composition is a cream. In some embodiments, the topical composition is an ointment. In some embodiments, the meibomian gland opening agent is suspended in the composition. In some embodiments, the topical composition is a lotion. In some embodiments, the topical composition is a gel. DETAILED DESCRIPTION OF THE INVENTION

[0020] Prior to the methods and formulations described herein, there were no drugs useful for treating MGD, including removing keratinized obstruction of the meibomian glands or preventing further keratinized obstruction of the meibomian glands.

[0021] Current techniques for removing keratinized blockages in meibomian glands are limited to painful physical removal. Therefore, described herein are methods for treating MGD by administering a meibomian gland opening agent that allows the keratinized blockage to open, while preventing subsequent buildup of keratinized blockages within the meibomian glands. The meibomian gland opening agents described herein include agents for acute treatment, e.g., for use by a physician or other trained professional, and agents for chronic treatment, e.g., by a physician, other trained professional, or patient. Specific meibomian gland opening agents are provided herein, and further provided herein are methods and assays for identifying additional meibomian gland opening agents (e.g., by testing the relative keratolytic activity of potent agents, such as those described in Examples 1 and 2).

[0022] <Meibomian glands> Meibomian glands are large sebaceous glands located within the eyelids. Unlike skin, they are not attached to hair. They produce the lipid layer of the tear film, protecting them from evaporation of the aqueous phase. The meibomian gland orifices are located on the epithelial side of the eyelid margin, only a few hundred microns from the mucosal side. These glands are present in both the upper and lower eyelids, with the upper eyelid having a greater number of glands. A single meibomian gland consists of a collection of secretory acini arranged in a ring around a long central duct and connected to it by short ductules. The distal end of the central duct is covered by an epithelial ingrowth that covers the distal eyelid margin and forms a short excretory duct that opens at the posterior edge of the eyelid margin, just anterior to the mucocutaneous junction near the inner lid margin. Lipid oil secretions are synthesized within the secretory acini. Lipid secretions are liquid near body temperature and are delivered to the skin of the eyelid margin as a clear fluid called "meibom." The lipid secretions form shallow reservoirs on the upper and lower eyelid margins and consist of a complex mixture of cholesterol, waxes, cholesterol esters, phospholipids, and small amounts of triglycerides, triacylglycerols, and hydrocarbons. Separate meibomian glands are arranged parallel and in a line along the length of the tarsal cartilage on the upper and lower lids. The extent of the glands corresponds approximately to the dimensions of the tarsal cartilage.

[0023] As used herein, the term "keratinized obstruction" refers to blockage of the meibomian gland, regardless of the location of the blockage. In some embodiments, the blockage is complete, while in other embodiments, the blockage is partial. Regardless of the degree of blockage, such keratinized obstruction contributes to meibomian gland dysfunction. In some embodiments, the keratinized obstruction is composed of keratinized material and lipids. In some embodiments, the keratinized obstruction is a blockage at the orifice and drainage duct of the meibomian gland. In some embodiments, the keratinized obstruction is caused by keratinized epithelium at the lid margin and meibomian gland. In certain instances, the keratinized obstruction is affected by stem cell migration or abnormal differentiation. In some embodiments, the keratinized obstruction results in stagnation within the meibomian gland, which reduces oil delivery to the lid margin and tear film, resulting in increased pressure, resulting in enlargement, acinar atrophy, and reduced secretion. In certain instances, keratinization of the meibomian gland leads to degenerative gland enlargement and atrophy.

[0024] <Meibomian gland dysfunction (MGD)> As used herein, the term "meibomian gland dysfunction" refers to a chronic, diffuse abnormality of the meibomian glands, characterized by blockage of the end ducts, qualitative or quantitative changes in the gland's secretions, or both. MGD can result in alterations in the tear film, ocular irritation, inflammation, or ocular surface disease. The most prominent aspects of MGD are blockage of the orifices and end ducts of the meibomian glands and changes in the meibomian gland secretions.

[0025] MGD is primarily caused by dry eye syndrome, which is widespread and affects approximately 20 million patients in the United States alone. Dry eye syndrome is a disorder of the ocular surface that results in inadequate tear production or excessive evaporation of moisture from the ocular surface. Tears are important for corneal health because the cornea does not contain blood vessels and relies on tears to provide oxygen and nutrients. Tears and the tear film are composed of lipids, water, and mucus, and disruptions to any of these can cause dry eye. Inadequate lipid flow from the meibomian glands, such as caused by keratinization obstruction, can cause excessive evaporation, thereby resulting in dry eye syndrome.

[0026] MGD is not synonymous with posterior blepharitis, which describes an inflammatory condition of the posterior eyelid margin. MGD can cause posterior blepharitis, but MGD may not necessarily be associated with inflammation or posterior blepharitis. MGD also refers to functional abnormalities of the meibomian glands, while "meibomian gland disease" describes a wide range of disorders of the meibomian glands, including neoplasms and congenital disorders. Clinical signs of MGD include meibomian gland shedding, changes in meibomian gland secretions, and changes in eyelid morphology.

[0027] In some embodiments, alterations in meibomian gland secretions are detected by physically expressing the meibomian glands by applying digital pressure to the tarsal cartilage. In subjects without MGD, meibum is a clear, oily pool. In MGD, both the nature and compressibility of the expressed material are altered. Altered meibum, also known as meibomian excreta, is composed of a mixture of altered secretions and keratinized epithelial material. In MGD, the nature of the expressed lipids varies in appearance from a clear fluid to a viscous fluid containing particulate matter and a thick, opaque, toothpaste-like substance. The meibomian orifice exhibits elevation above the surface level of the eyelid, referred to as plugging or pouting, due to blockage of the terminal duct and protrusion of a mixture of meibomian lipids and keratinized material.

[0028] Obstructive MGD is characterized by all or some of the following: 1) chronic ocular discomfort, 2) anatomical abnormalities around the meibomian gland orifices (one or more of the following: vascular congestion, anterior or posterior displacement of the mucocutaneous junction, or eyelid margin irregularity), and 3) meibomian gland obstruction (finding of an obstructive gland orifice (bulging, plug, or bulge) on slit-lamp biomicroscopy and decreased meibomian expression with moderate digital pressure).

[0029] Current methods for assessing and monitoring MGD symptoms include, but are not limited to, patient questionnaires, meibomian gland expression, tear stability breakdown time, and determination of the number of patent glands as seen on digital expression.

[0030] In some embodiments, the patient's symptoms are assessed by asking the patient a series of questions. The questionnaire allows for the assessment of various symptoms related to ocular discomfort. In some embodiments, the questionnaire is the SPEED questionnaire. The SPEED questionnaire assesses the frequency and severity of the patient's dry eye symptoms. It examines the onset of symptoms on the same day, after 72 hours, and after three months. A SPEED score is compiled based on the patient's answers to the questions to provide a range of severity for the patient's symptoms. The SPEED questionnaire includes questions such as: 1) Have you ever experienced eye symptoms and when did they occur? 2) How often do you experience dryness, grittiness, or scratchiness in your eyes? 3) How often do you experience eye pain or irritation? 4) How often do you experience burning or watery eyes? 5) How often do you experience eye strain? and 6) What is the severity of your symptoms?

[0031] The compressibility of the meibomian glands is optionally determined to assess meibomian gland function. In normal patients, meibum is a clear to pale yellow oil. Meibum is expelled from the glands when digital pressure is applied to the glands. Changes in the compressibility of the meibomian glands are a potential indicator of MGD. In some embodiments, quantification of the amount of physical force applied during expression is monitored in addition to assessing lipid volume and lipid content during expression.

[0032] Tear film breakdown time (TBUT) is a surrogate marker for tear stability. Tear film instability is a central mechanism in dry eye and MGD. A low TBUT indicates lipid layer compromise and possible MGD. TBUT is optionally measured by fluorescein breakup time testing, defined as the time to the first tear film breakdown after blinking. Fluorescein is optionally applied by wetting commercially available fluorescein-impregnated strips with saline and applying them to the inferior fornix or bulbar conjunctiva. The patient is then asked to blink several times and move their eyes. Breakdown is then analyzed using a slit lamp, a cobalt blue filter, and a 4-mm beam width. The patient is instructed to blink, and the time from the upward movement of the last blink to the first tear film breakup or dry spot formation is recorded as a measurement.

[0033] Other methods for assessing MGD symptoms include, but are not limited to, Schirmer's test, ocular surface staining, eyelid morphology analysis, meibography, meibometry, interferometry, evaporometry, tear lipid composition analysis, fluorescence analysis, meniscometry, osmolality analysis, indices of tear film dynamics, evaporation, and tear turnover.

[0034] Current treatments for MGD include eyelid warming, eyelid massage, preventative eyelid hygiene, eyelid expression, and meibomian gland probing. No pharmacological methods have been used prior to those described herein.

[0035] Preventive eyelid hygiene is considered the primary treatment for MGD and consists of three components: 1) application of heat, 2) mechanical massage of the eyelids, and 3) eyelid cleansing. Eyelid warming procedures improve meibomian gland secretions by dissolving pathologically altered meibomian lipids. Warming is achieved with warm compresses or devices. Mechanical eyelid hygiene involves the use of scrubs, mechanical expression, and cleaning of the eyelashes and eyelid margins with various solutions. The eyelid margins are also optionally cleansed with hypoallergenic bar soap, diluted baby shampoo, or commercial eyelid scrubs. Physical expression of the meibomian glands can be performed in the doctor's office or by the patient at home. The techniques vary from gentle massaging of the eyelids against the eyeball to forceful squeezing of the eyelids against each other or between a hard object on the inner eyelid surface and a finger (thumb) or a hard object on the outer eyelid surface (such as a glass rod, Q-tip, or metal paddle). The hard object on the inner eyelid surface protects the eyeball from the force transmitted through the eyelid during squeezing, thereby providing a steady resistance and increasing the amount of force applied to the gland.

[0036] Eyelid heating has limited efficacy because it dissolves lipids but does not address the movement of keratinized material. Furthermore, eyelid heating induces temporary visual deterioration due to corneal distortion. Mechanical eyelid hygiene is also limited because the force required to remove the occlusion can be substantial, resulting in considerable pain for the patient. The effectiveness of mechanical eyelid hygiene is limited to patients who can tolerate the pain associated with the procedure. Other treatments for MGD are limited.

[0037] Physical opening of blocked meibomian glands by expression of the meibomian glands is an acceptable method for improving meibomian gland secretion and dry eye symptoms. In addition, probing of the meibomian gland ducts has been used to open blocked ducts. However, both methods, expression and probing, are limited by procedural pain, i.e., potential physical damage to the gland and duct structures, and their short-lived effects, estimated at several days and weeks. Therefore, such methods are needed to improve patient comfort, i.e., not harm the meibomian glands and ducts, reduce dependency on frequent office visits, and improve meibomian secretion.

[0038] <Meibomian gland opening agent> <Keratolytics and / or keratolytics> The keratolytic and keratoemollient agents described herein are useful for acute treatment (e.g., by a trained professional or physician) or chronic treatment (e.g., at the patient's hand, or alternatively, by a trained professional or physician), and are tested in certain embodiments using the assays and methods described herein (e.g., as described in the Examples).

[0039] One embodiment provides a method of treating MGD in a patient in need thereof, the method comprising topically administering a composition comprising a meibomian gland opening agent, wherein the meibomian gland opening agent is a keratolytic or keratosoftening agent. In some embodiments, the meibomian gland opening agent is a keratolytic selected from allantoin, benzoyl peroxide, inorganic selenium compounds such as selenium disulfide, SeCl, NaSeO, organic selenium compounds such as ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) or analogs thereof, coal tar, dithranol, salicylic acid, selenium disulfide, alpha hydroxy acids, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolodione carboxylate. In some embodiments, the keratolytic agent is not retinoic acid.

[0040] It is important that agents used to open the meibomian glands have minimal undesirable side effects, such as atrophy and / or blockage of the glands due to lipid production within the glands. Thus, in some embodiments, agents with such undesirable side effects are not included within the scope of the formulations described herein. As an example, retinoic acid or retinoic acid derivatives may cause atrophy and / or blockage of the glands due to lipid production in certain patients or at certain concentrations or frequencies of use; therefore, in some embodiments, retinoic acid or retinoic acid derivatives are not used in the formulations and methods described herein.

[0041] In certain embodiments, mild or weak keratolytics and / or keratomellowers are used in the methods and formulations described herein, e.g., by subjects who produce low levels of keratin. Such mild or weak keratolytics and / or keratomellowers are optionally used in a maintenance therapy setting. Mild or weak keratolytics and / or keratomellowers include less active keratolytics and / or keratomellowers at lower concentrations, as well as keratolytics and / or keratomellowers with lower inherent activity (e.g., as determined by the methods described herein). In certain embodiments, the mild or weak keratolytics and / or keratomellowers are not boric acid.

[0042] In one embodiment, a method of treating meibomian gland dysfunction in a patient in need thereof is provided, the method comprising topically administering to the patient a composition that reaches the patient's eyelid margin, the composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier. In one embodiment, the keratolytic agent is benzoyl peroxide. In another embodiment, the keratolytic agent is coal tar. In another embodiment, the keratolytic agent is dithranol. In another embodiment, the keratolytic agent is salicylic acid. In another embodiment, the keratolytic agent is selenium disulfide. In another embodiment, the keratolytic agent is selenium sulfide. As used herein, the terms "selenium sulfide" and "selenium disulfide" are used interchangeably to refer to a compound having the formula SeS2, in which the ratio of selenium to sulfur is about 1:2. In another embodiment, the keratolytic agent is zinc pyrithione. In another embodiment, the keratolytic agent is zinc L-pyrrolidone carboxylate.

[0043] In some embodiments, more than one keratolytic agent is used.

[0044] In some embodiments, administration of a keratolytic agent to a keratinocyte obstruction results in proteolysis of desmosomes, which form the tight bonds between keratinocytes. In some embodiments, administration of a keratolytic agent results in dissolution, including hydrolysis of disulfide bonds. In some embodiments, administration of a keratolytic agent reduces keratin production.

[0045] One embodiment provides a method of treating MGD in a patient in need thereof by administering a topical composition comprising a keratolytic agent, wherein the keratolytic agent comprises benzoyl peroxide. In some embodiments, the composition comprises 2.5%, 5%, or 10% benzoyl peroxide. In some embodiments, the benzoyl peroxide-containing composition is a suspension, emulsion, cream, lotion, gel, or ointment. In some embodiments, the benzoyl peroxide-containing composition is applied as a thin layer to clean skin once daily, every other day, initially, and then gradually increased to twice daily as tolerance develops.

[0046] One embodiment provides a method of treating MGD in a patient in need thereof by administering a topical composition comprising a keratolytic agent, wherein the keratolytic agent comprises coal tar. In some embodiments, the composition comprises a 5% to 10% solution of coal tar. In some embodiments, the composition comprising coal tar is a solution of at least 5%, 6%, 7%, 8%, 9%, 10%, or more of coal tar. In one embodiment, the composition comprising coal tar is a 1% crude coal tar ointment. In some embodiments, coal tar inhibits hyperproliferation of epithelial cells by reducing DNA synthesis and mitotic activity to normal levels.

[0047] One embodiment provides a method for treating MGD in a patient in need thereof by administering a topical composition comprising a keratolytic agent, wherein the keratolytic agent comprises dithranol. In some embodiments, the composition comprises a 0.1% to 2.0% ointment of dithranol. In some embodiments, the dithranol-containing composition is at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, or more dithranol. In some embodiments, the dithranol-containing composition begins as a 0.1% ointment. After 7 days, the concentration is increased to 0.25%, and can then be doubled, if necessary, to a maximum strength of 2% at weekly intervals. In some embodiments, a thin layer of the ointment is applied to the affected area once daily for 2-4 weeks. In some embodiments, the ointment is left in place for 10-20 minutes before the area is thoroughly rinsed. In some embodiments, dithranol slows epithelial cell division and inhibits excessive proliferation and keratinization of epithelial cells in patients.

[0048] One embodiment provides a method of treating MGD in a patient in need thereof by administering a topical composition comprising a keratolytic agent, wherein the keratolytic agent comprises salicylic acid. In some embodiments, the composition comprises 0.1% to 6% salicylic acid. In some embodiments, the composition comprises at least 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, or more salicylic acid. In some embodiments, the salicylic acid-containing composition is an ointment or paste. In some embodiments, the salicylic acid-containing composition is initially applied as a thin layer of a 2% ointment or paste and applied daily. In some embodiments, the concentration is gradually increased to a maximum of 5%, and treatment is continued for as long as needed.

[0049] One embodiment provides a method for treating MGD in a patient in need thereof by administering a topical composition comprising a keratolytic agent, wherein the keratolytic agent comprises selenium disulfide. In some embodiments, the composition comprises 0.1% to 10% selenium disulfide. In some embodiments, the composition comprises at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, or more selenium disulfide. In some embodiments, the selenium disulfide-containing composition is a semi-solid. In some embodiments, the selenium disulfide-containing composition is a lotion. In some embodiments, the selenium disulfide-containing composition is a cream. In some embodiments, the composition comprising selenium disulfide is an ointment. In some embodiments, the composition comprising selenium disulfide is a suspension. In some embodiments, the composition comprising selenium disulfide is a solution. In some embodiments, the composition comprising selenium disulfide enhances lipid production from the meibomian glands.

[0050] In some embodiments, the compositions contain inorganic selenium compounds that are inhibitors of prostaglandin synthase, an enzyme involved in the production of prostaglandins. Selenium compounds that demonstrate this inhibitory effect include SeCl4 and Na2SeO3. The pro-inflammatory effects of prostaglandins enhance keratinization, and therefore, water-soluble inorganic selenium compounds that interfere with prostaglandin production may be useful in reducing keratinization.

[0051] In some embodiments, the composition includes an organic selenium compound. Organoselenium compounds, such as ebselen, are antioxidants and anti-inflammatory agents that inhibit cyclooxygenase and lipoxygenase enzymes and act as scavengers of hydrogen peroxide, as well as hydroperoxides, including membrane-bound phospholipids and cholesterol esters. Anti-inflammatory agents are known to inhibit keratinization, and therefore ebselen and other organic selenium analogs may act as keratolytic agents through this antioxidant / anti-inflammatory effect.

[0052] In some embodiments, the formulation comprising a keratolytic and / or keratolytic agent further comprises an additional therapeutic agent that is not a meibomian gland opening agent. In some embodiments, the formulation does not comprise jojoba wax or jojoba extract. In some embodiments, the formulation does not comprise boric acid. In some embodiments, the formulation does not comprise retinoic acid. Alternatively, in some embodiments, the formulation comprising a keratolytic and / or keratolytic agent excludes any additional therapeutic agent other than any additional meibomian gland opening agent.

[0053] <Local anesthetic> One embodiment provides a method of treating MGD in a patient in need thereof, the method comprising topical administration of a composition comprising a meibomian gland opening agent, wherein the meibomian gland opening agent is a local anesthetic. In some embodiments, the meibomian gland opening agent is a local anesthetic selected from an aminoamide local anesthetic or an aminoester local anesthetic.

[0054] The term "local anesthetic" as used herein refers to an agent that induces a reversible loss of pain sensation. In some embodiments, the local anesthetic may also induce temporary muscle paralysis in addition to inducing a reversible loss of pain sensation.

[0055] The local anesthetic agents described herein are useful primarily as emergency treatments, e.g., under the guidance of a physician or other trained professional, and are tested in certain embodiments using the assays and methods described herein (e.g., as described in the Examples).

[0056] In some embodiments, the local anesthetic is an aminoamide. In some embodiments, the local anesthetic is an aminoester. In some embodiments, the local anesthetic comprises a combination of two or more local anesthetics. In some embodiments, the combination comprises an aminoamide local anesthetic and an aminoester local anesthetic.

[0057] In some embodiments, the local anesthetic is an aminoester selected from the group consisting of: benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine, tetracaine, and amethocaine.

[0058] In some embodiments, the local anesthetic is an aminoamide selected from the group consisting of: articaine, bupicaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, prilocaine, ropivacaine, trimecaine.

[0059] In some embodiments, the local anesthetic is a combination of lidocaine and prilocaine, or a combination of lidocaine and tetracaine.

[0060] In some embodiments, the local anesthetic is a naturally occurring local anesthetic, hi some embodiments, the naturally occurring local anesthetic is selected from the group consisting of saxitoxin, neosaxitoxin, tetrodotoxin, menthol, eugenol, and cocaine.

[0061] In some embodiments, the local anesthetic is mixed with a vasoconstrictor to constrict blood vessels and thereby increase the duration of local anesthesia. In some embodiments, prilocaine hydrochloride is mixed with epinephrine. In some embodiments, lidocaine or bupivacaine is mixed with epinephrine. In some embodiments, iontocaine is mixed with lidocaine and epinephrine. In some embodiments, septocaine is mixed with a combination of articaine and epinephrine. In some embodiments, the local anesthetics bupicaine or lidocaine are mixed in combination with a steroid.

[0062] <Pharmaceutical excipients> In other embodiments, the topical compositions described herein are combined with a pharmaceutically suitable or acceptable carrier (e.g., a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier). Exemplary excipients are described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0063] <Treatment method using meibomian gland opening agents> Described herein are methods for treating MGD in a patient in need thereof, comprising topical administration of a meibomian gland opening agent to the eyelid margin of a patient in need thereof. Two potential administration categories exist. One occurs with the assistance of a healthcare professional; this category includes acute and maintenance use of the meibomian gland opening agent. Acute use, in one embodiment, requires a more potent meibomian gland opening agent (either in drug concentration or intrinsic activity). Maintenance use, in one embodiment, allows for the use of a lower drug concentration or a drug with less inherent activity. Maintenance use, in one embodiment, involves the patient during regular visits to a healthcare professional. Both acute and maintenance use optionally include the use of an eye protection device or appliance. In one embodiment, acute use is administered by a healthcare professional, and maintenance use is administered by the patient or a non-healthcare professional. A second potential administration category does not occur with the active assistance of a healthcare professional, but rather involves the patient applying the meibomian gland opening agent to their own eyelid margin. In one embodiment, such administration occurs over an extended period of time; one way to describe this form of multiple administration to the patient is chronic use. Typically, a different or second formulation of the meibomian gland opening agent is recommended for chronic or patient-administered use. In one embodiment, the different or second formulation uses a lower concentration of the meibomian gland opening agent. In another embodiment, the second or different formulation uses a meibomian gland opening agent that is less active than the first formulation.

[0064] It should be understood that the methods of the present invention also include the physical removal of blockages in the meibomian glands, followed by chronic and / or sustained administration of a meibomian gland opening agent as described herein.

[0065] One embodiment provides a method of treating meibomian gland dysfunction in a patient in need thereof, the method comprising topically administering to the patient a composition that reaches the patient's eyelid margin, wherein the composition comprises a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier results in enhanced meibomian production.

[0066] In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed until keratinization occlusion is relieved. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed periodically after keratinization occlusion is relieved. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed in a single dose. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed in a cyclical dose. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed once daily. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is performed twice daily.

[0067] In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is semi-solid. In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is homogeneous. In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is a dispersion. In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier is hydrophilic. In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier has an oleaginous base. In some embodiments, the topical composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier has at least one ophthalmically acceptable excipient.

[0068] One embodiment provides a method of treating MGD in a patient in need thereof, the method comprising topically administering a composition comprising a meibomian gland opening agent. In some embodiments, the topical administration of the composition comprising a meibomian gland opening agent is performed once a week. In some embodiments, the topical administration of the composition comprising a meibomian gland opening agent is performed twice a week. In some embodiments, the topical administration of the composition comprising a meibomian gland opening agent is performed every other day. In some embodiments, the topical administration of the composition comprising a meibomian gland opening agent is performed daily. In some embodiments, the topical administration of the composition comprising a meibomian gland opening agent is performed several times a day.

[0069] In some embodiments, the method includes treatment in an acute treatment scenario. In another embodiment, the method includes treatment of a treatment-naive patient. In another embodiment, the method includes treatment in a chronic treatment scenario. In another embodiment, the method includes treatment in a maintenance therapy scenario. In an acute treatment scenario, the dose of meibomian gland opening agent administered may be higher than the dose of meibomian gland opening agent utilized in a chronic treatment scenario or a maintenance therapy scenario. In an acute treatment scenario, the meibomian gland opening agent may be different from the meibomian gland opening agent utilized in a chronic treatment scenario. In some embodiments, the course of treatment begins in an early stage of treatment as an acute treatment scenario and later progresses to a chronic treatment scenario or a maintenance therapy scenario. In some embodiments, the meibomian gland opening agent administered in the acute treatment scenario is a local anesthetic, and the meibomian gland opening agent administered in the chronic treatment scenario or a maintenance therapy scenario is a keratolytic and / or keratoemollient. In some embodiments, the meibomian gland opening agent administered in an acute treatment scenario is a keratolytic and / or keratolytic agent, and the meibomian gland opening agent administered in a chronic treatment scenario or maintenance therapy scenario is a keratolytic and / or keratolytic agent.

[0070] In certain clinical conditions, patients may require initial treatment by a physician or healthcare professional to initially open the blockage of the meibomian glands by administering a more concentrated formulation of one of the therapeutic agents described herein. In this event, a more concentrated formulation is required, and its application may require ocular shielding or other activities to minimize the effects of irritation or disruption of the ocular surface or surrounding tissues. Following such a procedure, patients may be provided with a different formulation of the active agent to take home and periodically apply to the eyelid margin to maintain patency of the meibomian glands. Such application may be twice daily, once daily, weekly, or monthly, depending on the activity of the formulation and the characteristics of the desired outcome of the treatment.

[0071] One aspect of the treatment methods described herein is the location of topical administration of the composition. In one embodiment, the composition containing the meibomian gland opening agent is administered so as not to cause irritation to the eye. In one embodiment, the composition containing the meibomian gland opening agent is administered to the eyelid margin.

[0072] An additional embodiment of the treatment methods described herein is the use of a protective element provided to the eye to avoid eye irritation. While the formulations described herein are generally non-irritating, in some embodiments (e.g., when used with high concentrations of the drug or sensitive eyes), the protective element provides an additional layer of safety and comfort for the patient. In one embodiment, an eye shield is placed on the eye while a composition containing a meibomian gland opening agent is administered to reduce contact of the drug with the cornea and / or conjunctiva, thereby reducing eye irritation. In some embodiments, the eye shield is a contact lens or an eye cover. In some embodiments, the eye cover is self-adhesive. In one embodiment, the eyelid is pulled away from the eyeball while a composition containing a meibomian gland opening agent is administered to reduce contact of the drug with the cornea and / or conjunctiva, thereby reducing eye irritation.

[0073] <Specific definition> As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents; a reference to a "cell" includes a reference to one or more cells (or cells), and equivalents known to those of skill in the art, and so forth. When ranges for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, are used herein, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about," when used in reference to a number or numerical range, means that the referenced number or numerical range is an approximation within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises," or "having" or "including") is not intended to exclude that in other specific embodiments, for example, any compound, composition, method, or process embodiment described herein may "consist of" or "consist essentially of" the recited features.

[0074] The terms "treat," "treating," or "treatment" as used herein include decreasing, reducing, alleviating, ameliorating, or alleviating symptoms associated with MGD in chronic or acute treatment scenarios. In one embodiment, treating includes reducing end duct obstruction.

[0075] The terms "relapse" or "reduction of relapse" refer to the return of MGD symptoms in a chronic treatment scenario.

[0076] The term "opening" refers to (at least partially) cleansing a blocked meibomian gland duct or orifice and / or maintaining the patency of the meibomian gland duct or orifice.

[0077] The terms "keratolytic" and / or "keratomellowing agent" as used herein refer to agents that soften, disrupt, dissolve, solubilize, or loosen keratinized blockages, or prevent the formation of keratinized blockages. Specifically, the term "keratolytic" refers to agents used to promote the softening and dissolution of keratin, and the term "keratomellowing agent" refers to agents used to reduce keratin production.

[0078] The term "lotion" describes a liquid emulsion formulation, usually intended for external application to the skin (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0079] The term "cream" describes a semi-solid dosage form of an emulsion, usually containing >20% water and volatile materials and / or <50% hydrocarbons, waxes, or polyols as a vehicle. Creams are more viscous than lotions. This dosage form is usually intended for external application to the skin (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0080] The term "ointment" describes a semi-solid dosage form, usually containing <20% water and volatile substances and / or >50% hydrocarbons, waxes or polyols as a vehicle, which is usually intended for external application to the skin or mucous membranes (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0081] The term "solution" describes a clear, homogeneous liquid dosage form containing one or more chemicals dissolved in a solvent or mixture of miscible solvents (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0082] The term "suspension" refers to a heterogeneous mixture containing solid particles large enough to settle. [Example]

[0083] Example 1: Effect of selenium disulfide and salicylic acid on exfoliation of the forearm and eyelid The purpose of this study was to evaluate the effect of potential keratolytic agents on keratin removal as detected by removal of lissamine green, which stains keratin.

[0084] The following reagents were used for this study: 1% salicylic acid (SA), 2.5% selenium disulfide (SD), selenium disulfide diluted 1:10 (SD / 10), soap containing citric acid and salicylic acid (SK), tearless shampoo (SS), and Lissamine Green (LG).

[0085] <Study #1: Forearm A> LG stains keratin, and therefore was used to evaluate the effectiveness of various agents on the ability of LG to remove five keratin spots (2.5 cm x 2.5 cm). LG was applied to each arm of two subjects. Each spot was compared with the opposite spot on the opposite forearm. Different substances were administered across the LG spots.

[0086] The following comparison spots were analyzed: SA vs. control; SA vs. SK; SA vs. SD; SD vs. control; SD vs. SK.

[0087] Ten minutes after application, each spot was gently scrubbed (x10) with a golf club spud to assess LG removal. The color intensity of Lissamine was compared between each pair to assess the degree of LG removal (better removal = fewer LG remnants was defined as better).

[0088] The results were identical in both subjects and exfoliation superiority: SA > control; SA <SK;SA<SD;SD> Control; SD is approximately equal to SK.

[0089] <Study #2: Forearm B> Three spots (2.5 cm x 2.5 cm) of Lissamine Green (LG) application were performed on each forearm of one subject. Each spot was compared with the opposite spot on the opposite forearm. Different substances were administered across the LG spots. The following comparisons were analyzed: SS vs. SK; SD vs. SD / 10.

[0090] Ten minutes after application, each spot was gently scrubbed (x10) with a golf club-shaped spud to assess the extent of LG removal.

[0091] The results were as follows: SS<SK;SD> SD / 10

[0092] <Research #3: Forearm C> Four spots (2.5 cm x 2.5 cm) of Lissamine Green (LG) application were applied to the forearm of one subject. SK was applied for 10 minutes, 5 minutes, 3 minutes, 2 minutes, and 1 minute.

[0093] At the end of each period, the substance was scraped off using a gold club (x10).

[0094] After 10 and 5 minutes of application, SK nearly completely removed exfoliant. A 3 minute application of SK resulted in excellent exfoliant removal. A 2 minute application of SK was suboptimal in removing exfoliant. A 1 minute application was inadequate in removing exfoliant.

[0095] <Study #4: Eyelid A> The purpose of this study was to investigate the tolerability of SD applied to the eyes of subjects. A light layer of SD was applied to the lower eyelid of one subject. Application of SD resulted in immediate and severe irritation. The eye was immediately washed. The irritated and reddened eye persisted for approximately 30 minutes and then subsided.

[0096] <Study #5: Eyelid B> LG was applied to the lower eyelid of one subject. Because SD is irritating to the eyes, safety precautions were taken. The anterior surface of the eye was protected by placing a contact lens on the cornea, followed by anesthetic drops, and by separating the eyelid from the eyeball while the SD was on the eyelid. SD was applied to the central area of ​​the eyelid, while the nose and ear areas remained stained with LG only. Ten minutes after application, the entire lower eyelid was gently scrubbed (x2) with a sponge tip.

[0097] The LG staining was completely removed in the central area treated with SD, but not in the untreated ear or nose areas. Some stinging was felt during the procedure, but was tolerated by the subject. No adverse events occurred.

[0098] <Study #6: Eyelid C> LG was applied to the lower eyelid. SD was applied to the nasal third of the eyelid, SD / 10 to the temporal third, and the central third remained stained with LG only. Ten minutes after application, the lower eyelid was gently scrubbed (x2) with a sponge tip.

[0099] LG staining was completely removed in the nasal third treated with SD. LG staining was not removed in the untreated central third. LG staining was slightly removed in the temporal third treated with SD / 10. The procedure was uneventful, with a slight burn felt on the nasal side (undiluted SD) but not on the temporal side (diluted SD).

[0100] <Conclusions of Studies 1-6> The results demonstrated the following:

[0101] 1) Selenium disulfide (2.5% preparation) is highly irritating to the eye and cannot be applied without substantial precautions to avoid contact with mucous membranes and the cornea, and the use of topical anesthetics.

[0102] 2) The estimated effectiveness scale was as follows (from most effective to least effective): (SD=SK)>(SD / 10)=(SA)>(SS)>(control).

[0103] 3) Soap (cleaning agent) alone is not enough to remove dead skin cells.

[0104] 4) Selenium disulfide and SK soap were found to have similar effectiveness in exfoliating the skin. Note that SK soap contains a few keratolytic agents (salicylic acid and possibly citric acid) in unknown concentrations.

[0105] 5) The duration of application of SK is important in determining its effectiveness.

[0106] 6) Selenium disulfide is very effective in removing dead skin cells from the eyelids.

[0107] 7) Selenium disulfide diluted 1:10 was found to be less effective in exfoliating forearm skin than undiluted SD (2.5%).

[0108] 8) Selenium disulfide diluted 1:10 was found to be less effective at exfoliating the eyelids than undiluted SD (2.5%), but was superior to the control.

[0109] Example 2: A 17-day study of treatment with 2.5% selenium disulfide over the eyelid margin in patients with MGD New observations regarding the use of selenium disulfide have also been made, giving rise to a new hypothesis that at least one active agent may be effective in pharmacologically treating obstructions in the meibomian glands without the need for additional mechanical intervention.

[0110] One eye of eight patients with meibomian gland disease and signs and symptoms of dry eye was treated twice weekly for 17 days (five total applications) with a commercially available suspension containing 2.5% selenium disulfide. The suspension was placed on the treated eyelid margin for five minutes. The fellow eye was untreated and served as a control. After five treatment sessions in which the 2.5% selenium disulfide suspension was applied to the eyelid margin, the signs and symptoms of dry eye were significantly improved compared to the fellow control eye. The results of the eight patients treated with 2.5% selenium disulfide are shown in Table 1.

[0111] [Table 1]

[0112] Example 3: Effect of treatment with high-concentration local anesthetic cream (23% lidocaine and 7% tetracaine ointment) A study comparing mechanical expression and probing was conducted. Because both methods are painful for patients, high-dose topical anesthetics (lidocaine 23% and tetracaine 7% ointment), not indicated for ophthalmic use, were applied to the eyelids before either procedure. The topical anesthetic was not removed from the eye after application. New observations regarding the additional mechanisms of anesthetics were also made, giving rise to a new hypothesis that at least one active agent may be effective in pharmacologically treating blockages in the meibomian glands. In a specific set of cases, it was observed that the local anesthetic had a complete therapeutic effect in relieving glandular blockage, without the need for further mechanical intervention, and apart from providing nominal comfort to aid in the mechanical extraction of the gland contents, it also had a complete therapeutic effect in relieving glandular blockage.

[0113] The lower eyelids of both eyes of two patients with MGD were treated topically with 2-3 applications of 23% lidocaine and 7% tetracaine cream. The cream was not removed from the eyelids. Probing was performed on one eye, while expression was performed on the other. Probing was successful in both patients. Expression was partially successful in one patient (expressible material produced from approximately 50% of the glands), and no expressible material produced from the other patient's eye (e.g., the glands were completely blocked). A few hours after this procedure, both patients exhibited corneal abrasions, likely caused by the anesthetic cream.

[0114] Both patients were re-examined 48 hours later. The patient with complete blockage (Patient #2) demonstrated a dramatic (50%) improvement in his meibomian gland function (a combination of the number of open glands and the quality of the meibum) (MG score improved from 96 to 52), and clear meibum was evident in many glands after gentle digital squeezing. The other patient (Patient #1) showed approximately a 25% improvement (score improved from 46 to 36). The results for Patients 1 and 2 are shown in Table 2.

[0115] The other nine patients were treated with ophthalmic gel containing 4% lidocaine. In the presence of such meibomian gland blockage, no improvement in meibomian gland function was observed.

[0116] [Table 2]

[0117] Example 4: Effect of treatment with a high-concentration local anesthetic cream (lidocaine 23% and tetracaine 7% ointment) on meibomian gland patency Four patients with MGD were treated with a high-dose topical anesthetic (lidocaine 23% and tetracaine 7% ointment) not indicated for ophthalmic use on the lower eyelid margin only. The eyelids were separated from the eyeball and taped to the lower cheek for 15 minutes to avoid direct contact between the medication and the anterior surface of the eye. A contact lens was also placed as a barrier for the medication in case of any leakage toward the eyeball, and a thin layer of highly concentrated topical anesthetic cream was applied and wiped off after 15 minutes. This procedure caused no adverse events. The results are shown in Table 3 below. In patient #6, a significant improvement in meibomian gland function was observed. The doubling of the tear meniscus height was measured using an Oculus M5 Kertometer in the study eye, and no change was observed in the fellow eye. In all other patients, no change in the MG score of the tear meniscus in either eye was observed. Note that in Example 5, a high concentration of topical anesthetic remained on the eyelid and was not wiped off, whereas in this group of patients it was wiped off after 15 minutes.

[0118] [Table 3]

Claims

1. 1. A method for treating meibomian gland dysfunction in a patient in need thereof, comprising the step of topically administering to the patient a composition that reaches the patient's eyelid margin, the composition comprising a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier.

2. 10. The method of claim 1, wherein the keratolytic agent is benzoyl peroxide, coal tar, dithranol, salicylic acid, selenium disulfide, an alpha hydroxy acid, urea, lactic acid, sodium thioglycolate, zinc pyrithione, or zinc L-pyrrolidone carboxylic acid.

3. 3. The method of claim 2, wherein the keratolytic agent is salicylic acid or selenium disulfide.

4. 4. The method of claim 3, wherein the keratolytic agent is selenium disulfide.

5. 5. The method of claim 4, wherein the concentration of selenium disulfide in the composition is between about 0.1% and about 10%.

6. 4. The method of claim 3, wherein the keratolytic agent is salicylic acid.

7. 7. The method of claim 6, wherein the concentration of salicylic acid in the composition is between about 0.1% and about 10%.

8. 10. The method of claim 1, wherein the composition is topically administered to the patient until the keratinization obstruction is relieved.

9. 10. The method of claim 1, wherein the composition is topically administered to the patient periodically after the keratinization obstruction has been alleviated.

10. 10. The method of claim 1, wherein the topical administration is a single dose.

11. 10. The method of claim 1, wherein the topical administration is periodic administration.

12. 12. The method of claim 11, wherein the periodic administration is once daily.

13. 12. The method of claim 11, wherein the periodic administration is twice daily.

14. 10. The method of claim 1, wherein the composition for topical administration is semi-solid.

15. The method of claim 1, wherein the composition for topical administration is homogeneous.

16. 10. The method of claim 1, wherein the composition for topical administration is a dispersion.

17. 10. The method of claim 1, wherein the composition for topical administration is hydrophilic.

18. 10. The method of claim 1, wherein the composition for topical administration is an oleaginous base.

19. 10. The method of claim 1, wherein the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable excipient.

20. 10. The method of claim 1, wherein administration of the composition results in enhanced meibomian production.

21. 1. A method for treating meibomian gland dysfunction in a patient in need thereof, comprising the step of topically administering to the patient a composition that reaches the patient's eyelid margin, the composition comprising a therapeutically effective amount of a keratolytic agent in an ophthalmically acceptable carrier.

22. 22. The method of claim 21, wherein the keratolytic agent is salicylic acid or selenium disulfide.

23. 23. The method of claim 22, wherein the keratolytic agent is selenium disulfide.

24. 24. The method of claim 23, wherein the concentration of selenium disulfide in the composition is between about 0.1% and about 10%.

25. 22. The method of claim 21, wherein administration of the composition results in enhanced meibomian production.

26. 22. The method of claim 21, wherein the composition for topical administration is homogeneous.

27. 22. The method of claim 21, wherein the composition for topical administration is a dispersion.

28. 22. The method of claim 21, wherein the composition for topical administration is hydrophilic.

29. 22. The method of claim 21, wherein the composition for topical administration is oleaginous-based.

30. 22. The method of claim 21, wherein the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable excipient.

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