Thiol- and disulfide-containing agents for increasing lipid secretion from the meibomian glands

Abstract

Described herein are compositions and methods for increasing the amount of lipids secreted by the meibomian glands. Such compositions and methods can be used to treat meibomian gland dysfunction and conditions resulting therefrom.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of September 28, 2016, application number 201680069405.8, and invention name “Agents containing thiols and disulfides for increasing lipid secretion of meibomian glands” (the application date of the corresponding PCT application is September 28, 2016, and application number PCT / IB2016 / 001510).

[0002] Cross-references

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 233,906, filed September 28, 2015, and U.S. Provisional Application No. 62 / 233,941, filed September 28, 2015, both of which are incorporated herein by reference in their entirety. Background Art

[0004] Meibomian glands are glands arranged vertically within the eyelids near the eyelashes. The force of blinking the eyelids causes oil to be secreted into the posterior eyelid margin. This oil is the "staying power" of the tears, which helps prevent the tears from evaporating quickly. In patients with Meibomian Gland Dysfunction (MGD), vision is affected due to too much or too little oil in the tear film.

[0005] Meibomian glands are large sebaceous glands located in the eyelids, and they are different from the skin and are not connected to hair. Meibomian glands produce a lipid layer of tear film, which protects the tear film from evaporation of the aqueous phase. Meibomian gland holes are located on the epithelial side of the eyelid margin, and are only a few hundred microns away from the mucosal side. The glands are located on both the upper and lower eyelids, and the amount of glands on the upper eyelid is more. A single meibomian gland is composed of clusters of secretory alveoli, which are arranged in a circular pattern around the long central duct and are connected to the meibomian glands by short small ducts. The terminal part of the central duct is filled with ingrowing epithelium, which covers the free eyelid margin and forms a short excretory duct, which opens in the shape of a hole in front of the mucosae skin junction near the inner eyelid border at the rear of the eyelid margin. The oily secretion composed of lipids is synthesized in the secretory alveoli. Lipid secretions are liquids close to body temperature and are delivered to the skin of the eyelid margin as a clear fluid (called "meibum"). They form shallow reservoirs on the upper and lower eyelid margins and consist of a complex mixture of cholesterol, waxes, cholesterol esters, phospholipids, and smaller amounts of triglycerides, triacylglycerols, and hydrocarbons. The individual meibomian glands are arranged in parallel in the upper and lower eyelids and in a single row throughout the length of the tarsal plate. The extent of the glands roughly corresponds to the size of the tarsal plate.

[0006] The eyelid margin is the source of a physiologically important lipid secretion (meibum). Secretions from the eyelid meibomian glands form the outer layer of the tear film. Functions attributed to this tear film lipid layer are: (1) a lubricant that facilitates eyelid movement during blinking, (2) a barrier to prevent evaporation of aqueous tears, and (3) a barrier to the entry of microorganisms and organic matter such as pollen.

[0007] The moving eyelids spread meibum across the ocular surface and mix it with tears (AT) produced by the lacrimal glands. The mixing and diffusion of meibum and AT produce a nearly continuous structure called the tear film (TF), which covers the entire ocular surface and is used for a variety of purposes, including protection, lubrication, nutrition, and antimicrobial, etc. TF is also related to visual acuity because it provides a smoother ocular surface, which improves the optical properties of the eye. However, TF is not uniform, which is not surprising given that lipids do not easily form aqueous solutions and tend to separate by forming a lipid-rich subphase that is significantly hydrophobic. The classical view of TF structure assumes a three-layer organization of TF. Since lipids are generally less dense than water, they accumulate on the surface of the aqueous subphase, thereby forming a lipid-rich TF outermost layer (also called the tear film lipid layer or TFLL). Below the TFLL is a more hydrophilic aqueous layer rich in water-soluble proteins, carbohydrates, salts, and other more or less hydrophilic compounds. It is believed that closest to the corneal epithelium is a relatively hydrophilic, mucin-rich glycocalyx layer, which is primarily formed by membrane-bound mucins. Using interferometry, the depth of the TFLL was estimated to be about 40-90 nanometers, while the aqueous layer was found to be thicker at about 4 microns. It is important to recognize that all three layers are soft, dynamic structures in which changes occur due to many factors that occur simultaneously, such as mechanical movement of the eyelids, the continuous secretion of meibum, tears, and mucins, and evaporation of AT and its drainage through the nasal cannula. If the eye is forced to remain open without blinking, the human TF will rapidly deteriorate, thin, and break apart - a phenomenon known as tear breakup.

[0008] The human tear breakup time (TBUT) is measured in seconds. It has long been considered an important and objective diagnostic parameter to assess the health of the ocular surface. TBUT is widely used in ophthalmology to diagnose dry eye - a multifactorial condition (or disease) whose onset and progression are often associated with the deterioration of TF, especially TFLL. When breakup occurs, the cornea is exposed to air, causing discomfort to the patient. Incomplete coverage of the ocular surface by TF also increases the chances of damage to the corneal epithelial cells due to excessive dehydration, abrasions, irritation, inflammation, infection, etc. Another reason for TF instability is the inability of the meibomian glands to secrete enough necessary quality of meibum, for example due to MGD associated with meibomian gland inflammation and / or obstruction.

[0009] Lipids produced by the meibomian glands are the main components of the lipid layer on the tear film surface, which protects the tear film from evaporation of the aqueous phase and is also believed to stabilize the tear film by reducing surface tension. As described by Heiligenhaus et al. (Heiligenhaus et al., Therapie. von Klin. Monatsbl. Augenheilkd., 1994, Vol. 204, pages 162–168) reported that changes in the lipid phase are more indicative of MGD than changes in the separate aqueous phase, where lipid deficiency was observed in 76.7% of dry eye patients, while only 11.1% of patients had changes in the aqueous phase alone. Therefore, meibum lipids are essential for maintaining the health and integrity of the ocular surface.

[0010] Lipids are the major components of meibum (also known as "meibomian gland secretions"). The biochemical composition of meibum is very complex and very different from sebum. It is generally believed that lipids are the major components of human and animal meibum. In humans, more than 90 different proteins have been identified in meibum secretions. A large number of researchers have attempted to characterize meibum, and the amount of lipids recovered by researchers ranges widely (Table 1), probably due to the different collection and analysis techniques used.

[0011] Table 1. Type and amount of each lipid present in meibum.

[0012]

[0013]

[0014] In subjects without MGD, meibum lipids are a pool of clear oil. In MGD, the amount, nature, and composition of secreted material are altered. Thus, MGD is characterized by lipid deficiency. Furthermore, in MGD, the nature of the extruded lipids changes in appearance from a clear fluid to a viscous fluid containing particulate matter and a thick, opaque, toothpaste-like substance. The meibum aperture may appear elevated above the level of the eyelid surface, referred to as tamponade or bulge, and is caused by obstruction of the terminal duct and extrusion of meibum lipids of increased viscosity.

[0015] Lipid deficiency and increased viscosity of meibum are important pathogenic factors in MGD and are seen in most cases of obstructive MGD. Therefore, it is highly desirable to enhance lipogenesis and lipid secretion of the meibomian glands to overcome lipid deficiency and to reduce the viscosity of the meibum oil composition to dissolve any meibomian gland obstruction.

[0016] As demonstrated by molecular biology and immunohistochemistry, high viscosity meibum is mixed with hyperkeratotic cellular material, as seen in extruded pathological human meibum prepared as smears or in impression cytology and histopathology. Increased viscosity is also observed within obstructed glands in animal models. Therefore, softening and dissolving the obstructing lipids is required to unclog the ducts and restore the normal flow of excreted lipids.

[0017] Meibomian gland dysfunction, or MGD, is the leading cause of dry eye syndrome and is often characterized by inadequate lipid delivery from the meibomian glands to the surface of the eye. Also known as posterior blepharitis, MGD is the most common form of eyelid margin disease. In its early stages, patients are often asymptomatic, but if left unmanaged, MGD can cause or worsen dry eye symptoms and eyelid inflammation. The oil glands become blocked due to thickening of their secretions. Chronically blocked glands eventually become unable to produce oil, leading to permanent changes in the tear film and dry eyes. Symptoms of MGD include dry eyes, burning sensations, itching, stickiness, tearing, sensitivity to light, red eyes, and blurred vision.

[0018] MGD is the main cause of dry eye syndrome. The occurrence of dry eye syndrome is widespread and affects approximately 20 million patients in the United States alone. Dry eye syndrome is an ocular surface disorder caused by insufficient tear production or excessive evaporation of water from the surface of the eye. Tears are essential for corneal health because the cornea does not contain blood vessels and relies on tears to provide oxygen and nutrients. Tears and tear film are composed of lipids, water and mucus, and disruption of any of them may cause dry eye disease. 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 always be associated with inflammation or posterior blepharitis. Clinical signs of MGD include meibomian gland detachment (dropout), changes in meibomian gland secretion, and changes in eyelid morphology.

[0019] 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, irregularity of the eyelid margin), and 3) obstruction or changes in the quality or amount of glandular secretion (reduced meibum extrusion with moderate digital pressure).

[0020] Currently, standard treatments for MGD are limited in part to heating the eyelids to increase oil production and melt oil that has solidified in the glands with warm compresses, applying gentle pressure to the eyelid margins near the eyeline, and manually removing thickened secretions as well as pharmacological treatments such as antibiotics and anti-inflammatory agents. However, these treatments can be frustrating for patients and ophthalmologists. Massaging the eyelids can only partially and temporarily relieve obstruction of the meibomian glands, which can be painful. Traditional warm compress methods apply heat to the outer surface of the eyelid; therefore, heat is generally of limited effectiveness. Topical use of antibiotics and corticosteroids to inhibit bacterial colonization and inflammation of the eyelid margin associated with MGD has been shown to be effective in relieving the symptoms and signs of MGD, however, the success of this treatment may not be related to altered meibum. Antibiotics, particularly tetracyclines (including doxycycline, tetracycline, and minocycline) and azithromycin, are used to inhibit bacterial colonization and reduce eyelid margin inflammation; however, drug intolerance and long-term treatment limit the clinical use of oral antibiotics.

[0021] Eyelid care is considered the primary treatment for MGD and consists of three parts: 1) application of heat; 2) mechanical massage of the eyelids; and 3) cleaning the eyelids. The eyelid warming process improves meibomian gland secretion by melting pathologically altered meibomian lipids. Warming is achieved by warm compresses or devices. Mechanical eyelid care includes the use of wipes, mechanical compression, and cleaning with a variety of eyelash and eyelid margin solutions. Optionally, the eyelid margins are also cleaned with hypoallergenic bar soap, diluted baby shampoo, or commercially available eyelid wipes. Physical compression of the meibomian glands is performed in the physician's office or by the patient at home. The technique varies from gently massaging the eyelids against the eyeball to forcefully pushing the eyelids against each other or between a rigid object on the inner surface of the eyelid and a finger, thumb, or rigid object on the outer surface of the eyelid (such as a glass rod, cotton swab (Q-tip) or metal paddle). The rigid object on the inner surface of the eyelid protects the eyeball from the forces transmitted through the eyelid during compression and provides a stable resistance to increase the force applied to the gland.

[0022] Eyelid warming has limitations because warming melts lipids but cannot address the movement of keratinized material. In addition, eyelid warming causes transient visual degradation due to corneal deformation. Mechanical eyelid care also has limitations because the force required to remove the obstruction can be large, causing significant pain to the patient. The effectiveness of mechanical eyelid care is limited by the patient's ability to tolerate the associated pain during the procedure. Other treatments for MGD also have limitations.

[0023] Physical dredging of meibomian gland obstruction by meibomian gland squeezing is an acceptable method for improving meibomian gland secretion and dry eye syndrome. In addition, probing of the meibomian gland duct has been used to dredge the obstructed duct. However, both methods (squeezing and probing) are limited by the pain caused by the process, the possible physical damage to the gland and duct structure, and their short-term effects estimated to be days and weeks.

[0024] In summary, each of these treatments has different disadvantages, and the treatment of MGD remains challenging. Therefore, there is a need for methods to improve patient comfort that will not cause damage to the meibomian glands and ducts, will reduce dependence on frequent visits to the clinic, and improve meibum secretion.

[0025] Emerging treatments for MGD include the use of mucolytics and / or keratolytics. Mucolytic therapies aim to promote physiological clearance by optimizing the viscoelastic properties of mucus, whereas keratolytic therapies aim to soften keratin, the main component of the skin.

[0026] Acetylcysteine, also known as N-acetylcysteine ​​or N-acetyl-L-cysteine ​​(abbreviated as NAC), is a drug and nutritional supplement mainly used as a mucolytic agent. Acetylcysteine ​​is an acetylated derivative of L-cysteine, in which an acetyl group is attached to a nitrogen atom known to have mucolytic, anti-collagen and antioxidant properties. It is used as a cough suppressant because it breaks disulfide bonds in mucus and liquefies it, making it easier to cough up. It is also the effect of breaking disulfide bonds that makes it useful for thinning abnormally thickened mucus in patients with cystic and pulmonary fibrosis. Akyol-Salman et al. (J.Ocul.Pharmacol.Ther., 2010, Vol.26(4), pp.329-33) evaluated the local efficacy of N-acetylcysteine ​​(NAC) therapy for patients with meibomian gland dysfunction (MGD). Qiao and Yan (Clinical Ophthalmology 2013, Vol. 7, pages 1797–1803) reviewed several emerging treatment options for MGD, including NAC.

[0027] Despite the possible treatment options for MGD, it remains difficult to achieve complete relief of signs and symptoms. Summary of the invention

[0028] The present invention provides methods for increasing lipogenesis and / or lipid secretion from the meibomian glands of the eyelids. Without wishing to be bound by any theory or mechanism, it is hypothesized that enhanced lubrication of the eyelid margin by natural lipids that are the major component of meibum will improve MGD and / or related symptoms.

[0029] The present invention is based on the unexpected discovery that drugs containing thiol, -SeH and / or disulfide can increase lipid production in the meibomian glands and / or increase lipid secretion from the meibomian glands of the eyelids. This ability can effectively prevent, treat and / or improve certain adverse eyelid conditions, such as MGD.

[0030] In one aspect, the present invention provides a method for increasing lipid secretion of meibomian glands, comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent comprises a sulfhydryl group or a disulfide.

[0031] In another aspect, the present invention further provides a method for treating meibomian gland dysfunction (MGD), comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent, wherein the agent is selected from Captopril, Zofenopril, Tiopronin, Penicillamine, Gluthatione, Dithiothreitol, Thiofen, Cysteamine, Bucillamine, 2,3-Dimercaptopropanol, 1,1-ethanedithiol, Dimercaptosuccinic acid, Furan-2-ylmethanethiol, Omatrilat, Ovothiol A, Pantethiol, Lenzopril, Thiosalicylic acid, Thioctadecanoic acid, Mycothiol, Coenzyme A and Coenzyme B, or wherein the agent comprises a disulfide.

[0032] In another aspect, the present invention further provides a method for lowering the melting point of lipids secreted by meibomian glands, comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent comprises a sulfhydryl group or a disulfide.

[0033] In another aspect, the present invention further provides a method for reducing the viscosity of lipids secreted by meibomian glands, comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent comprises a sulfhydryl group or a disulfide.

[0034] In certain embodiments, the agent comprises a thiol group. In certain embodiments, the agent is selected from captopril, zofenopril, tiopronin, penicillamine, L-cysteine, selenocysteine, glutathione, dithiothreitol, thiophene, cysteamine, bucillamine, 2,3-dimercaptopropanol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethylthiol, omapatrilat, ovothiol A, pantetheine, lenzopril, thiosalicylic acid, thiocortisone, fungal thiols, coenzyme A and coenzyme B. In certain embodiments, the agent is selected from the group consisting of captopril, zofenopril, tiopronin, penicillamine, glutathione, dithiothreitol, thiophene, cysteamine, bucillamine, 2,3-dimercaptopropanol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovathiol A, pantetheine, lenzopril, thiosalicylic acid, thiocortisone, fungal mercaptan, coenzyme A and coenzyme B. Each possibility represents a separate embodiment of the present invention.

[0035] In certain embodiments, the agent comprises a disulfide bond. In certain embodiments, the agent is selected from Disulfiram, Psammaplin A, Dixanthate, Pantethine, Fursultiamine, Octothiamine, Sulbutiamine, Prosultiamine, Thiram, Lipoic Acid, Mushroom Essence, Ajoene, Allicin, Gemopatrilat and Sulfanegen. Each possible scheme represents a separate embodiment of the present invention.

[0036] In certain embodiments, the ophthalmologically acceptable carrier comprises at least one ophthalmologically acceptable excipient.

[0037] In certain embodiments, the above method further comprises the step of administering a keratolytic agent to the patient. In certain embodiments, the keratolytic agent is selected from benzoyl peroxide, coal tar, anthralin, salicylic acid, selenium sulfide, alpha-hydroxy acid, urea, boric acid, retinoic acid, lactic acid, sodium thioglycolate or allantoin.

[0038] In certain embodiments, the meibomian gland dysfunction is characterized by obstruction of the meibomian glands. In certain embodiments, the topical application of the agent to the eyelid margin of the patient is repeated until the meibomian gland obstruction is substantially eliminated. In certain embodiments, the topical application of the agent to the eyelid margin of the patient is repeated periodically to prevent the formation of meibomian gland obstruction. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The novel features of the present invention are particularly set forth in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by referring to the following detailed description of illustrative embodiments utilizing the principles of the present invention and the accompanying drawings, in which:

[0040] Figure 1 Graph showing Oil Red-0 staining in control 3D sebocyte epithelial cells.

[0041] Figure 2 Graph showing Oil Red-0 staining in 3D sebocyte epithelial cells for 1.0 μM 12-mercaptododecanoic acid.

[0042] Figure 3 Graph showing Oil Red-0 staining in 3D sebocyte epithelial cells for 0.1 micromolar 12-mercaptododecanoic acid.

[0043] Figure 4 Illustrative synthetic methods for preparing thiol- and disulfide-containing lipids used in the methods described herein are provided.

[0044] Figure 5 Illustrative synthetic methods for preparing thiol- and disulfide-containing lipids used in the methods described herein are provided.

[0045] Figure 6 Illustrative synthetic methods for preparing thiol- and disulfide-containing lipids used in the methods described herein are provided.

[0046] Figure 7 Illustrative synthetic methods for preparing thiol- and disulfide-containing lipids used in the methods described herein are provided.

[0047] Figure 8 Illustrative synthetic methods for preparing thiol- and disulfide-containing lipids used in the methods described herein are provided. DETAILED DESCRIPTION

[0048] The present invention provides, for the first time, non-hormonal agents for enhancing meibum lipid secretion in vivo.

[0049] More specifically, methods of enhancing lipogenesis and / or lipid secretion by administering thiol-, -SeH-, or disulfide-containing agents that increase lipid production in the meibomian glands, increase the amount of lipids secreted by the meibomian glands, and / or alter the composition of lipids secreted by the meibomian glands are described herein. The agents described herein include agents for acute treatment, for example, by a physician or other trained professional, and agents for chronic treatment, for example, by a physician or other trained professional or by a patient. Certain agents that enhance lipogenesis and lipid secretion are described herein; methods for preparing compositions comprising thiol-, -SeH-, or disulfide-containing agents that enhance lipogenesis and lipid secretion and their use in methods for treating patients are further provided herein.

[0050] The terms "meibomian gland dysfunction" and "MGD", which are used interchangeably herein, refer to a chronic, diffuse abnormality of the meibomian glands characterized by obstruction of the terminal ducts or changes in the quality or quantity of glandular secretion, or both. MGD can result in changes in tear film viscosity, symptoms of eye irritation, inflammation, or ocular surface disease. The most prominent aspects of MGD are obstruction of the meibomian gland orifices and terminal ducts and changes in meibomian gland secretions. MGD also involves abnormal function of the meibomian glands, while "meibomian gland disease" describes a wide range of meibomian gland disorders, including neoplasia and congenital diseases.

[0051] According to the principles of the present invention, thiol-, -SeH- or disulfide-containing drugs or agents that induce adipogenesis and membranous lipid secretion can be used, for example, to treat MGD via a thiol-mediated lipid hypersecretion mechanism. According to the principles of the present invention, disulfide-containing drugs such as disulfiram provide thiol or sulfhydryl groups once their disulfide bonds are broken in vivo by enzymes or chemical reactions.

[0052] Drug-induced activation of cellular lipogenesis therefore represents a novel approach to therapeutically manage meibomian gland dysfunction by enhancing cholesterol synthesis and increasing the production of fatty acids and triglycerides, which results in alterations in the meibum lipid composition by lowering the melting point and viscosity of meibum lipids, thereby causing a more fluid appearance of meibum lipids.

[0053] Thiol-, -SeH- or disulfide-containing agents that enhance adipogenesis and lipid secretion as described herein are useful as acute treatments (e.g., by a trained professional or physician) or as chronic treatments (e.g., by the patient, or by a trained professional or physician). In certain embodiments, agents are tested using the assays and methods described herein (e.g., as described in the Examples).

[0054] Drugs with thiol or sulfhydryl groups have been previously reported to cause excess sebum production. Drugs containing thiol or sulfhydryl groups have also been reported to cause pemphigus, a seborrheic dermatitis-like skin disease characterized by oily skin. Xanthine oxidoreductase (XOR) is an essential enzyme for milk lipid droplet secretion, and two distinct, interchangeable enzyme forms are known to exist, the thiol-reduced form (XD) and the thiol-oxidized form (XO), which differ in their enzymatic properties and conformations. Mammary tissue and the milk fat globule membrane (MFGM) have been shown to contain thiol oxidases capable of converting XD to XO. The association of XOR with the apical plasma membrane is mediated by a thiol-dependent process involving disulfide cross-link formation with butyrophilin (the most abundant protein in the MFGM essential for lipid droplet secretion in the mammary gland), ADPH or other membrane proteins, and / or conformational changes of XOR. The expression level and apical membrane localization of XOR are key properties of secretory mammary epithelial cells, and membrane binding of XOR regulates the coupling of cytoplasmic lipid droplets to the apical plasma membrane during lipid secretion.

[0055] In one aspect, the present invention provides a method for increasing lipid secretion of meibomian glands, comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide.

[0056] In one aspect, the present invention provides a method for increasing lipid secretion of meibomian glands, comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of an agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide.

[0057] In one aspect, the present invention provides a method for increasing lipid secretion of meibomian glands, comprising topically applying an ophthalmic composition to the eyelid margin of a patient in need thereof, the ophthalmic composition consisting of an ophthalmologically acceptable carrier and a therapeutically effective amount of an agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide.

[0058] In one aspect, the present invention provides a method for increasing lipid secretion of meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition consisting of an ophthalmically acceptable carrier and a therapeutically effective amount of an agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent comprises a thiol group, a -SeH group or a disulfide, and wherein the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable excipient.

[0059] In one aspect, the present invention provides a method for increasing lipid secretion of meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition consisting of an ophthalmically acceptable carrier and a therapeutically effective amount of an agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide, and wherein the ophthalmically acceptable carrier comprises no more than two ophthalmically acceptable excipients.

[0060] In one aspect, the present invention provides a method for increasing lipid secretion of meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition consisting of an ophthalmically acceptable carrier and a therapeutically effective amount of an agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide, and wherein the ophthalmically acceptable carrier comprises no more than three ophthalmically acceptable excipients.

[0061] In one aspect, the present invention provides a method for increasing lipid secretion of meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition consisting of an ophthalmically acceptable carrier and a therapeutically effective amount of an agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide, and wherein the ophthalmically acceptable carrier comprises no more than four ophthalmically acceptable excipients.

[0062] In another aspect, the present invention further provides a method for treating meibomian gland dysfunction (MGD), comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent, wherein the agent is selected from captopril, zofenopril, tiopronin, penicillamine, glutathione, dithiothreitol, thiophene, cysteamine, bucillamine, 2,3-dimercaptopropanol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovalthiolate A, pantetheine, lenzopril, thiosalicylic acid, thiocortisone, fungal thiols, coenzyme A and coenzyme B, or wherein the agent comprises a disulfide.

[0063] In another aspect, the present invention further provides a method for lowering the melting point of lipids secreted by meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide.

[0064] In another aspect, the present invention further provides a method for reducing the viscosity of lipids secreted by meibomian glands, comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide.

[0065] In certain embodiments, the agent comprises a thiol group or a -SeH group. In certain embodiments, the agent is selected from captopril, zofenopril, tiopronin, penicillamine, L-cysteine, selenocysteine, glutathione, dithiothreitol, thiophene, cysteamine, bucillamine, 2,3-dimercaptopropanol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethylthiol, omapatrilat, egg mercaptan A, pantetheine, lenzopril, thiosalicylic acid, thiocortisone, fungal mercaptan, coenzyme A and coenzyme B. In certain embodiments, the agent is selected from the group consisting of captopril, zofenopril, tiopronin, penicillamine, glutathione, dithiothreitol, thiophene, cysteamine, bucillamine, 2,3-dimercaptopropanol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovathiol A, pantetheine, lenzopril, thiosalicylic acid, thiocortisone, fungal thiols, coenzyme A and coenzyme B. Each possible scenario represents a separate embodiment of the present invention.

[0066] In certain embodiments, the agent is an amino acid, peptide or peptidomimetic containing -SH or -SeH. In certain embodiments, the amino acid, peptide or peptidomimetic containing -SH or -SeH is selected from captopril, zofenopril, tiopronin, penicillamine, L-cysteine, selenocysteine, glutathione, thiophene, bucillamine, omapatrilat, pantetheine or fungal mercaptan.

[0067] In certain embodiments, the agent is an aryl or heteroaryl compound containing -SH or -SeH. In certain embodiments, the aryl or heteroaryl compound containing -SH or -SeH is selected from furan-2-ylmethanethiol, ovothiol A, lenzopril or thiosalicylic acid.

[0068] In certain embodiments, the agent comprises a disulfide bond. In certain embodiments, the agent is selected from Disulfiram, Psammaplin A, Dixanthate, Pantethine, Fursultiamine, Octothiamine, Sulbutiamine, Prosultiamine, Thiram, Lipoic Acid, Mushroom Essence, Ajoene, Allicin, Gemopatrilat and Sulfanegen. Each possible scheme represents a separate embodiment of the present invention.

[0069] In certain embodiments, the ophthalmically acceptable carrier comprises at least one ophthalmologically acceptable excipient.

[0070] In certain embodiments, the above method further comprises the step of administering a keratolytic agent to the patient. In certain embodiments, the keratolytic agent is selected from benzoyl peroxide, coal tar, anthralin, salicylic acid, selenium sulfide, alpha-hydroxy acid, urea, boric acid, retinoic acid, lactic acid, sodium thioglycolate or allantoin.

[0071] In certain embodiments, the meibomian gland dysfunction is characterized by obstruction of the meibomian glands. In certain embodiments, the topical application of the agent to the eyelid margin of the patient is repeated until the meibomian gland obstruction is substantially eliminated. In certain embodiments, the topical application of the agent to the eyelid margin of the patient is repeated periodically to prevent the formation of meibomian gland obstruction.

[0072] In certain embodiments, the above methods result in a therapeutically effective increase in the amount of lipids produced by the meibomian glands. In certain embodiments, the above methods result in a therapeutically effective increase in the amount of lipids secreted by the meibomian glands. In certain embodiments, the above methods result in a change in the composition of lipids secreted by the meibomian glands. In certain embodiments, the above methods result in a change, preferably a decrease, in the viscosity of lipids secreted by the meibomian glands.

[0073] In some embodiments, active agents are formulated and applied so that they are acceptable to the ocular surface (ie, do not cause undue irritation or damage to the ocular epithelial surface) and do not damage lipid-producing cells that come in contact with the composition.

[0074] In some embodiments, the composition is applied for a duration and frequency that is acceptable and practical to the physician or patient administering the medicament. For example, the physician applies the composition described herein once a week or twice a week for several weeks to induce an increase in the amount of lipid secreted by the meibomian glands, and the patient applies a different composition every day, or the patient uses a more potent composition every day for several weeks, and then, uses a less potent composition every day thereafter. In some embodiments, the patient applies the composition once or several times a day.

[0075] In some embodiments, the coating method varies according to the concentration of the medicament and / or the lack of lipid. In other embodiments, the method of applying the composition is adjusted to increase the penetration or residence time on the target tissue to enhance the therapeutic effect. In other embodiments, the method of applying the composition is changed to increase the penetration or residence time on the target tissue to minimize the necessary amount of coating time. In other embodiments, the composition is formulated (e.g., by adjusting viscosity and / or skin adhesion) to increase contact with the target tissue while minimizing contact with non-target tissues (including eyes), and thus limiting or reducing any undesirable incidental activity.

[0076] In certain embodiments, the concentrations of the agent and excipients are optimized to deliver the lowest effective concentration of the agent to achieve therapeutic benefit while minimizing any irritation or damage to the eye or surrounding ocular tissue.

[0077] The methods and compositions described herein are means for increasing the amount of lipids secreted by the meibomian glands, altering the composition of lipids secreted by the meibomian glands, and / or reducing the viscosity of lipids secreted by the meibomian glands, thereby enhancing dissolution of any meibomian gland obstruction and improving tear breakup time (TBUT).

[0078] The composition used in the method of the present invention includes at least one thiol-containing, -SeH-containing or disulfide-containing agent that enhances lipogenesis and lipid secretion. In some embodiments, the agent is a thiol-containing, -SeH-containing drug that causes increased meibum production. In some embodiments, the agent is a thiol-containing, -SeH-containing drug, such as captopril, zofenopril, tiopronin, penicillamine, L-cysteine, selenocysteine, glutathione, dithiothreitol, thiophene, cysteamine, bucillamine, 2,3-dimercaptopropanol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethylthiol, omapatra, egg mercaptan A, pantetheine, lenzopril, thiosalicylic acid, thiocortisone, fungal mercaptan, coenzyme A and coenzyme B. Their chemical structures are listed in Table 2.

[0079] Table 2. Chemical structures of some thiol- or -SeH-containing drugs.

[0080]

[0081]

[0082]

[0083]

[0084] In certain embodiments, the agent is a disulfide-containing drug, such as disulfiram, Psammaplin A, dixanthate, pantethine, fursultiamine, octotiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, mushroom flavor, ajoene, allicin, Gemopatrilat and Sulfanegen. Their chemical structures are listed in Table 3.

[0085] Table 3. Chemical structures of disulfide-containing drugs.

[0086]

[0087]

[0088] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is captopril.

[0089] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is zofenopril.

[0090] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is tiopronin.

[0091] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is penicillamine.

[0092] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is L-cysteine.

[0093] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is selenocysteine.

[0094] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is glutathione.

[0095] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is dithiothreitol.

[0096] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is thiophene.

[0097] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is cysteamine.

[0098] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is bucillamine.

[0099] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is 2,3-dimercaptopropanol.

[0100] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is 1,1-ethanedithiol.

[0101] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is dimercaptosuccinic acid.

[0102] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is furan-2-ylmethylthiol.

[0103] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is omapatrilat.

[0104] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is ovalthiol A.

[0105] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is pantetheine.

[0106] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is lenzopril.

[0107] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is thiosalicylic acid.

[0108] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is thiocortisone.

[0109] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is a fungal thiol.

[0110] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is coenzyme A.

[0111] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is coenzyme B.

[0112] A method for increasing lipid secretion of meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent is Gemopatrilat.

[0113] A method for increasing lipid secretion from the meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in the meibomian glands or increases lipid secretion from the meibomian glands, wherein the agent is Sulfanegen.

[0114] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is seleno D-methionine.

[0115] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is disulfiram.

[0116] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is Psammaplin A.

[0117] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is dixanthogenic acid.

[0118] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is pantethine.

[0119] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is fursultiamine.

[0120] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is octotiamine.

[0121] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is sulbutiamine.

[0122] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is prosultiamine.

[0123] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is thiram.

[0124] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is lipoic acid.

[0125] A method for increasing lipid secretion of meibomian glands, comprising topically applying an ophthalmic composition to the eyelid margin of a patient in need thereof, the ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent is shiitake mushroom essence.

[0126] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is ajoene.

[0127] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is allicin.

[0128] A method for increasing lipid secretion of meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion of meibomian glands, wherein the agent is Gemopatrilat.

[0129] A method for increasing lipid secretion from the meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in the meibomian glands or increases lipid secretion from the meibomian glands, wherein the agent is Sulfanegen.

[0130] The present invention provides for the first time thiol-group-containing and / or disulfide-containing lipid derivatives for enhancing the secretion of meibum lipids in vivo and for treating meibomian gland dysfunction (MGD).

[0131] In particular, methods of enhancing lipogenesis in the meibomian glands, reducing the melting point of lipids secreted by the meibomian glands, reducing the viscosity of lipids secreted by the meibomian glands, and reducing the viscosity of lipids in the eyelid margins by administering thiol- or disulfide-containing lipid derivatives are also described herein. The lipid derivatives described herein include lipid derivatives for acute treatment, such as used by a physician or other trained professional, and lipid derivatives for chronic treatment, such as used by a physician or other trained professional or by a patient. Certain lipid derivatives are described herein; methods of preparing the lipid derivatives and their use in methods of treating a patient are further provided herein.

[0132] According to the principles of the present invention, thiol- or disulfide-containing lipid derivatives that induce adipogenesis and meibum lipid secretion can be used, for example, to treat MGD via a thiol-mediated lipid hypersecretion mechanism. Further according to the principles of the present invention, once the disulfide bonds of the disulfide-containing lipid derivatives are broken in vivo by an enzyme or chemical reaction, they provide thiol or sulfhydryl groups.

[0133] Lipid derivative-induced activation of cellular lipogenesis therefore represents a novel approach to treat MGD by enhancing cholesterol synthesis and increasing the production of fatty acids and triglycerides, which results in a change in the composition of meibum lipids by lowering their melting point and viscosity, thereby causing a more fluid appearance.

[0134] The lipid derivatives that enhance adipogenesis and lipid secretion described herein are useful as acute treatment (e.g., by a trained professional or physician) or as chronic treatment (e.g., by the patient, or by a trained professional or physician). In certain embodiments, the agents are tested using the assays and methods described herein (e.g., as described in the Examples).

[0135] In one aspect, the present invention provides a method for increasing lipid secretion of meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmically acceptable carrier and an effective amount of at least one lipid derivative containing a thiol group or a disulfide.

[0136] In another aspect, the present invention further provides a method for treating MGD comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one lipid derivative containing a thiol group or a disulfide.

[0137] In another aspect, the present invention further provides a method for increasing lipid production in meibomian glands, comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmically acceptable carrier and an effective amount of at least one lipid derivative comprising a thiol group or a disulfide.

[0138] In another aspect, the present invention further provides a method for lowering the melting point of lipids secreted by meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmically acceptable carrier and an effective amount of at least one lipid derivative containing a thiol group or a disulfide.

[0139] In another aspect, the present invention further provides a method for reducing the viscosity of lipids secreted by meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmically acceptable carrier and an effective amount of at least one lipid derivative containing a thiol group or a disulfide.

[0140] In another aspect, the present invention further provides a method for reducing lipid viscosity in the eyelid margin, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmically acceptable carrier and an effective amount of at least one lipid derivative containing a thiol group or a disulfide.

[0141] In certain embodiments, the lipid derivative is a derivative of a lipid selected from fatty acids, glycerides, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, glycolipids, polyketides, and any combination thereof. Each possible scheme represents a separate embodiment of the present invention. In certain embodiments, the lipid derivative is a lipid derivative naturally present in meibum.

[0142] In some embodiments, the lipid derivative is a lipid containing -SH or a disulfide, such as a thiophospholipid, thiocholesterol, 12-mercaptododecanoic acid, or 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatetricosanoic acid.

[0143] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is a thiophospholipid.

[0144] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is sulfocholesterol.

[0145] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is 12-mercaptododecanoic acid.

[0146] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatetricosanoic acid.

[0147] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is thioethanol.

[0148] A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent is selenium disulfide.

[0149] In certain embodiments, the lipid is selected from fatty acids, wax esters, cholesterol esters, triglycerides, diglycerides, monoglycerides, phospholipids, diesters, fatty acid amides, squalene, ceramides, sphingolipids, ω-hydroxy fatty acids, cholesterol and epoxides thereof. Each possible embodiment represents a separate embodiment of the present invention.

[0150] In certain embodiments, the fatty acid has a molecular formula selected from the group consisting of: (i) C n H 2n O2, wherein n is any integer selected from 12, 14-18 and 20-29; (ii) C n H 2n-2 O2, wherein n is any integer selected from 16-18, 20, 22, 24, 26, 28, 30 and 32; and (iii) Cn H 2n-4 O2, wherein n is 18. In certain embodiments, the fatty acid is selected from myristic acid, palmitic acid, stearic acid and oleic acid. Each possible embodiment represents a separate embodiment of the present invention.

[0151] In certain embodiments, the wax ester is a saturated C 18-30 In certain embodiments, the cholesterol ester is C 16-34 Cholesteryl esters of fatty acids. Each possibility represents a separate embodiment of the present invention.

[0152] In certain embodiments, the triglyceride has a molecular formula selected from the group consisting of: (i) C n H 2n-8 O6, wherein n is any integer selected from 55 and 57; (ii) C n H 2n-10 O6, wherein n is any integer selected from 55 and 57; and (iii) fatty acid chains associated with triglycerides: C14:0, C15:0, C16:0, C16:1, C17:0, C18:0, C18:1, C18:2.9. Each possible scheme represents a separate embodiment of the present invention.

[0153] In certain embodiments, the phospholipid is selected from phosphatidylcholine (PC), phosphatidylethanolamine (PE), alkylacylphosphatidylcholine, sphingomyelin, dihydrosphingomyelin, dimethylphosphatidylethanolamine, diphosphatidylglycerol (cardiolipin), ethanolamine plasmalogen, lysoethanolamine plasmalogen, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol and phosphatidylserine. Each possible scheme represents a separate embodiment of the present invention.

[0154] In certain embodiments, the fatty acid amide is selected from oleamide, myristamide, palmitamide, stearamide, and erucamide.Each possibility represents a separate embodiment of the present invention.

[0155] In certain embodiments, the ω-hydroxy fatty acid has a molecular formula selected from the group consisting of: (i) C n H 2n-7 O4, wherein n is any integer selected from 46-52; (ii) C n H 2n-4 O4, wherein n is any integer selected from 42-50; (iii) C n H 2n-6 O4, wherein n is any integer selected from 42, 44, 46 and 48-52; (iv) C n H 2n-8O4, wherein n is any integer selected from 48, 50 and 52; and (v) C n H 2n-10 O4, wherein n is any integer selected from 50 and 52. Each possibility represents a separate embodiment of the present invention.

[0156] In certain embodiments, the lipid derivative is polar. In certain embodiments, the lipid derivative is non-polar. In certain embodiments, the lipid derivative comprises a sulfhydryl group. In certain embodiments, the lipid derivative comprises a disulfide.

[0157] In certain embodiments, the above method further comprises the step of administering a keratolytic agent to the patient. In certain embodiments, the keratolytic agent is selected from benzoyl peroxide, coal tar, anthralin, salicylic acid, selenium sulfide, alpha-hydroxy acid, urea, boric acid, retinoic acid, lactic acid, sodium thioglycolate or allantoin. Each possible scheme represents a separate embodiment of the present invention.

[0158] In certain embodiments, the meibomian gland dysfunction is characterized by obstruction of the meibomian glands. In certain embodiments, the topical application of the lipid derivative to the eyelid margin of the patient is repeated until the meibomian gland obstruction is substantially eliminated. In certain embodiments, the topical application of the lipid derivative to the eyelid margin of the patient is repeated periodically to prevent the formation of meibomian gland obstruction.

[0159] One embodiment provides a method for increasing lipid secretion of meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmically acceptable carrier and an effective amount of at least one lipid derivative containing a thiol group or a disulfide.

[0160] Another embodiment provides a method for increasing lipid secretion of meibomian glands, wherein the lipid derivative is a derivative of a lipid selected from the group consisting of fatty acids, glycerides, glycerophospholipids, sphingolipids, sterol lipids, pregnenolone lipids, glycolipids, polyketides, and any combination thereof.

[0161] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipid derivative is a lipid derivative naturally occurring in meibum.

[0162] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipids are selected from the group consisting of fatty acids, wax esters, cholesterol esters, triglycerides, diglycerides, monoglycerides, phospholipids, diesters, fatty acid amides, squalene, ceramides, sphingolipids, ω-hydroxy fatty acids, cholesterol and epoxides thereof.

[0163] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipid is a fatty acid, and the fatty acid has a molecular formula selected from the group consisting of: (i) C n H 2n O2, wherein n is any integer selected from 12, 14-18 and 20-29; (ii) C n H 2n-2 O2, wherein n is any integer selected from 16-18, 20, 22, 24, 26, 28, 30 and 32; and (iii) C n H 2n-4 O2, where n is 18.

[0164] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipid is a fatty acid, and the fatty acid is selected from the group consisting of myristic acid, palmitic acid, stearic acid, and oleic acid.

[0165] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipid is a wax ester, and the wax ester is a saturated C 18-30 Oleic acid esters.

[0166] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipid is a cholesterol ester, and the cholesterol ester is C 16-34 Cholesterol esters of fatty acids.

[0167] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipid is a triglyceride, and the triglyceride has a molecular formula selected from the group consisting of: (i) C n H 2n-8 O6, wherein n is any integer selected from 55 and 57; (ii) C n H 2n-10 O6, wherein n is any integer selected from 55 and 57; and (iii) fatty acid chains associated with triglycerides: C14:0, C15:0, C16:0, C16:1, C17:0, C18:0, C18:1, C18:2.9.

[0168] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipid is a phospholipid and the phospholipid is selected from the group consisting of phosphatidylcholine (PC), phosphatidylethanolamine (PE), alkylacylphosphatidylcholine, sphingomyelin, dihydrosphingomyelin, dimethylphosphatidylethanolamine, diphosphatidylglycerol (cardiolipin), ethanolamine acetal phospholipids, lysoethanolamine acetal phospholipids, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol and phosphatidylserine.

[0169] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipid is a fatty acid amide, and the fatty acid amide is selected from the group consisting of oleamide, myristicamide, palmitamide, stearamide, erucamide, and ceramide.

[0170] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipid is an ω-hydroxy fatty acid, and the ω-hydroxy fatty acid has a molecular formula selected from the group consisting of: (i) C n H 2n-7 O4, wherein n is any integer selected from 46-52; (ii) C n H 2n-4 O4, wherein n is any integer selected from 42-50; (iii) C n H 2n-6 O4, wherein n is any integer selected from 42, 44, 46 and 48-52; (iv) C n H 2n-8 O4, wherein n is any integer selected from 48, 50 and 52; and (v) C n H 2n-10 O4, wherein n is any integer selected from 50 and 52.

[0171] Another embodiment provides a method for increasing lipid secretion of the meibomian glands, wherein the lipid derivative is polar. Another embodiment provides such a method, wherein the lipid derivative is non-polar. Another embodiment provides such a method, wherein the lipid derivative comprises a sulfhydryl group. Another embodiment provides such a method, wherein the lipid derivative comprises a disulfide.

[0172] Another embodiment provides a method for increasing lipid secretion of meibomian glands, wherein the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable excipient.

[0173] One embodiment provides a method for increasing lipid secretion of the meibomian glands, comprising topically applying an ophthalmic composition to the eyelid margin of a patient in need thereof, the ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one lipid derivative containing a sulfhydryl group or a disulfide, wherein the method further comprises the step of administering a keratolytic agent to the patient. Another embodiment provides such a method, wherein the keratolytic agent is selected from selenium sulfide, anthralin, benzoyl peroxide, urea, salicylic acid, boric acid, lactic acid, retinoic acid, and alpha-hydroxy acids.

[0174] One embodiment provides a method for treating Meibomian Gland Dysfunction (MGD) comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one lipid derivative containing a thiol group or a disulfide.

[0175] Another embodiment provides a method for treating Meibomian Gland Dysfunction (MGD), wherein the lipid derivative is a derivative of a lipid selected from the group consisting of fatty acids, glycerides, glycerophospholipids, sphingolipids, sterol lipids, pregnenolone lipids, glycolipids, polyketides, and any combination thereof.

[0176] Another embodiment provides a method for treating Meibomian Gland Dysfunction (MGD), wherein the lipid derivative is a lipid derivative naturally occurring in meibum.

[0177] One embodiment provides a method for treating meibomian gland dysfunction (MGD), comprising topically applying an ophthalmic composition to the eyelid margin of a patient in need thereof, the ophthalmic composition comprising an ophthalmically acceptable carrier and a therapeutically effective amount of at least one lipid derivative containing a thiol group or a disulfide, wherein the method further comprises the step of administering a keratolytic agent to the patient. One embodiment provides a method for treating meibomian gland dysfunction (MGD), wherein the keratolytic agent is selected from selenium sulfide, anthralin, benzoyl peroxide, urea, salicylic acid, boric acid, lactic acid, retinoic acid, and alpha-hydroxy acids. Another embodiment provides a method for treating meibomian gland dysfunction (MGD), wherein the meibomian gland dysfunction is characterized by obstruction of the meibomian glands. Another embodiment provides a method for treating meibomian gland dysfunction (MGD), wherein the lipid derivative is topically applied to the eyelid margin of the patient repeatedly until the meibomian gland obstruction is substantially eliminated. Another embodiment provides a method for treating Meibomian Gland Dysfunction (MGD), wherein the topical application of a lipid derivative to the eyelid margin of a patient is repeated periodically to prevent the formation of Meibomian gland obstruction. Another embodiment provides a method for treating Meibomian Gland Dysfunction (MGD), wherein the ophthalmically acceptable carrier comprises at least one ophthalmically acceptable excipient.

[0178] In certain embodiments, the above methods result in a significant increase, preferably a statistically significant increase, in the amount of lipids produced by the meibomian glands. In certain embodiments, the above methods result in a significant increase, preferably a statistically significant increase, in the amount of lipids secreted by the meibomian glands. In certain embodiments, the above methods result in a significant change, preferably a statistically significant change, in the composition of lipids secreted by the meibomian glands. In certain embodiments, the above methods result in a significant change, preferably a statistically significant change, preferably a decrease, in the melting point of lipids secreted by the meibomian glands. In certain embodiments, the above methods result in a significant change, preferably a statistically significant change, preferably a decrease, in the viscosity of lipids secreted by the meibomian glands. In certain embodiments, the above methods result in a significant change, preferably a statistically significant change, preferably a decrease, in the viscosity of lipids in the eyelid margin.

[0179] In certain embodiments, the above methods result in a therapeutically effective increase in the amount of lipids produced by the meibomian glands. In certain embodiments, the above methods result in a therapeutically effective increase in the amount of lipids secreted by the meibomian glands. In certain embodiments, the above methods result in a therapeutically effective change in the composition of lipids secreted by the meibomian glands. In certain embodiments, the above methods result in a therapeutically effective change, preferably a decrease, in the melting point of lipids secreted by the meibomian glands. In certain embodiments, the above methods result in a therapeutically effective change, preferably a decrease, in the viscosity of lipids secreted by the meibomian glands. In certain embodiments, the above methods result in a therapeutically effective change, preferably a decrease, in the viscosity of lipids in the eyelid margin.

[0180] In some embodiments, active agents are formulated and applied so that they are acceptable to the ocular surface (ie, do not cause undue irritation or damage to the ocular epithelial surface) and do not damage lipid-producing cells in contact with the composition.

[0181] In some embodiments, the composition is applied for a duration and frequency that is acceptable and practical to the physician or patient administering the medicament. For example, the physician applies the composition described herein once a week or twice a week for several weeks to induce an increase in the amount of lipid secreted by the meibomian glands, and the patient applies a different composition every day, or the patient uses a more potent composition every day for several weeks, and then, uses a less potent composition every day thereafter. In some embodiments, the patient applies the composition once or several times a day.

[0182] In some embodiments, the coating method varies according to the concentration of lipid derivatives and / or the lack of lipids. In other embodiments, the method of applying the composition is adjusted to improve the penetration or residence time on the target tissue to enhance the therapeutic effect. In other embodiments, the method of applying the composition is changed to increase the penetration or residence time on the target tissue to minimize the amount of the necessary coating time. In other embodiments, (for example, by adjusting viscosity and / or skin adhesion) the composition is formulated to increase contact with the target tissue while minimizing contact with non-target tissues (including eyes), and therefore limiting or reducing any undesirable incidental activity.

[0183] In certain embodiments, the concentrations of the lipid derivative and excipient are optimized to deliver the lowest effective concentration of the lipid derivative to achieve therapeutic benefit while minimizing any ocular irritation or damage or irritation or damage to surrounding ocular tissue.

[0184] The methods and compositions described herein are means for increasing the amount of lipids secreted by the meibomian glands, altering the composition of lipids secreted by the meibomian glands, and / or reducing the viscosity of lipids secreted by the meibomian glands, thereby enhancing dissolution of any meibomian gland obstruction and improving tear breakup time (TBUT).

[0185] In some embodiments, topical application of at least one lipid derivative is performed twice a week. In some embodiments, topical application of at least one lipid derivative is performed every other day. In some embodiments, topical application of at least one lipid derivative is performed once a day. In some embodiments, topical application of at least one lipid derivative is performed several times a day.

[0186] In some embodiments, the composition for topical administration is a liquid or semisolid. In some embodiments, the composition for topical administration is a semisolid emulsion. In some embodiments, the composition for topical administration is a cream. In some embodiments, the composition for topical administration is an ointment. In some embodiments, the lipid derivative is suspended or dispersed in the composition. In some embodiments, the composition for topical administration is a lotion. In some embodiments, the composition for topical administration is a gel.

[0187] One embodiment provides a method of treating MGD in a patient in need thereof by topically administering a composition comprising at least one lipid derivative, wherein the treatment results in a therapeutically relevant increase in the amount of lipids produced by the meibomian glands. One embodiment provides a method of treating MGD in a patient in need thereof by topically administering a composition comprising at least one lipid derivative, wherein the treatment results in a therapeutically relevant increase in the amount of lipids secreted by the meibomian glands. Another embodiment provides a method of treating MGD in a patient in need thereof by topically administering a composition comprising a lipid derivative, wherein the treatment results in a therapeutically relevant increase in meibum production. Another embodiment provides a method of treating MGD in a patient in need thereof by topically administering a composition comprising a lipid derivative, wherein the treatment results in a therapeutically relevant change in meibum lipid composition. Another embodiment provides a method of treating MGD in a patient in need thereof by topically administering a composition comprising a lipid derivative, wherein the treatment results in a therapeutically relevant decrease in the melting point of lipids secreted by the meibomian glands. Another embodiment provides a method of treating MGD in a patient in need thereof by topically administering a composition comprising a lipid derivative, wherein the treatment results in a therapeutically relevant decrease in the viscosity of lipids secreted by the meibomian glands. Another embodiment provides a method of treating MGD in a patient in need thereof by topically administering a composition comprising a lipid derivative, wherein the treatment results in a therapeutically relevant decrease in lipid viscosity in the eyelid margin.

[0188] In any of the above embodiments, the composition further comprises an ophthalmologically acceptable carrier. In a further embodiment, the ophthalmologically acceptable carrier comprises an ophthalmologically acceptable excipient. In certain embodiments, the ophthalmologically acceptable carrier comprises a plurality of ophthalmologically acceptable excipients. Such excipients are described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005)).

[0189] One embodiment provides a method for enhancing the lipogenesis and lipid secretion of the meibomian glands of patients in need by applying a topical composition comprising a lipid derivative, wherein the composition comprises 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%, 2.5%, 5% or 10% of the lipid derivative. In some embodiments, the composition is formulated as a suspension, emulsion, cream, lotion, gel or ointment. In some embodiments, the composition is applied to clean skin as a thin layer, initially once every other day, and then gradually increased to a maximum of twice a day as tolerance develops. In some embodiments, the composition is an ointment or paste. In some embodiments, the composition starts as a 0.1% ointment. After 7 days, the concentration can be increased to 0.25%, and then doubled weekly (if necessary) to a maximum strength of 2%. In some embodiments, a thin layer of the ointment is applied to the affected area once a day for 2-4 weeks. In some embodiments, the ointment is left in place for 10-20 minutes, after which the area is thoroughly rinsed. In some embodiments, the concentration of the thiol- or disulfide-containing drug or pharmaceutical agent that enhances adipogenesis and lipid secretion is gradually increased to a maximum of 5%, and treatment is continued as long as necessary.

[0190] In some embodiments, topical application of a composition comprising a lipid derivative is performed once a week. In some embodiments, topical application of a composition comprising a lipid derivative is performed twice a week. In some embodiments, topical application of a composition comprising a lipid derivative is performed once every other day. In some embodiments, topical application of a composition comprising a lipid derivative is performed once a day. In some embodiments, topical application of a composition comprising a lipid derivative is performed several times a day.

[0191] In some embodiments, the method includes treatment in an acute treatment setting. In another embodiment, the method includes similar or identical treatment for a patient who has no prior treatment experience. In another embodiment, the method includes treatment in a chronic treatment setting. In another embodiment, the method includes treatment in a maintenance treatment setting. In an acute treatment setting, the administration dose of the lipid derivative may be higher than the administration dose of the lipid derivative used in a chronic treatment setting or a maintenance treatment setting. In an acute treatment setting, the lipid derivative may be different from the lipid derivative used in a chronic treatment setting. In some embodiments, the course of treatment begins with an acute treatment setting in the initial stage of treatment, followed by a transition to a chronic treatment setting or a maintenance treatment setting.

[0192] In some embodiments, the agent is an active agent for increasing the amount of lipids secreted by the meibomian glands, altering the composition of lipids secreted by the meibomian glands, and / or reducing the viscosity of lipids secreted by the meibomian glands, thereby enhancing dissolution of any meibomian gland obstruction.

[0193] In some embodiments, topical application of at least one agent is performed twice a week. In some embodiments, topical application of at least one agent is performed every other day. In some embodiments, topical application of at least one agent is performed once a day. In some embodiments, topical application of at least one agent is performed several times a day.

[0194] In some embodiments, the composition for topical administration is a liquid or semisolid. In some embodiments, the composition for topical administration is a semisolid emulsion. In some embodiments, the composition for topical administration is a cream. In some embodiments, the composition for topical administration is an ointment. In some embodiments, the agent is suspended or dispersed in the composition. In some embodiments, the composition for topical administration is a lotion.

[0195] In some embodiments, the composition for topical administration is a gel.

[0196] Pharmaceutically acceptable topical compositions containing thiol-containing, -SeH-containing or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion are prepared. The gel is mainly hydrophilic and optionally contains suspending agents, dispersants, solubilizing agents, emulsifiers, thickening agents, preservatives, antioxidants in acceptable concentrations required for ophthalmic preparations. Ophthalmic ointments are mainly anhydrous and contain mineral oil and white petrolatum as base ingredients. By adding lanolin, the petrolatum base can be more miscible with the aqueous component. The exemplary formulations described herein that enhance adipogenesis and lipid secretion also include suspending agents, emulsifying agents, solubilizing agents or thickening agents.

[0197] Suspending agents: Suspending agents help to reduce the sedimentation rate of suspended particles. These are insoluble particles dispersed in a liquid vehicle. Suspending agents work by increasing the viscosity of the liquid vehicle, thereby slowing down sedimentation according to Stokes Law. Most suspending agents perform two functions. In addition to acting as suspending agents, they also give the solution viscosity. Suspending agents form a film around the particles and reduce the attraction between particles. Suspending agents can also act as thickeners. They increase the viscosity of the solution, which is necessary to prevent the suspended particles from settling and thus causing the particles to aggregate or agglomerate. Examples of suspending agents are cellulose derivatives (CMC, HPMC, HEC), carbomer (carbomer, polycarophil), gums, alginates, gelatin or colloidal silicon dioxide.

[0198] Emulsifiers: Emulsifiers help keep finely divided droplets dispersed in a liquid vehicle. Emulsions consist of two or more immiscible liquids such as water and oil, which can be liquid or semisolid, such as creams or lotions. Emulsifiers can be of natural origin such as lecithin (phospholipids) or synthetic origin such as ionic (SLS) or nonionic surfactants (polyoxyethylene castor oil, polysorbates, poloxamers).

[0199] Solubilizers: Solubilizers are used to improve the solubility of slightly soluble drugs and increase their bioavailability. Solubilizers can be water-soluble alcohol solvents (such as polyethylene glycol, propylene glycol, glycerol), complexing agents such as cyclodextrins, or water-soluble synthetic polymers such as povidone (PVP) or polyvinyl alcohol (PVA).

[0200] Thickener: Thickener is added to increase the viscosity of the suspension. All ingredients are mixed by mechanical shaking to obtain a stable and uniform dispersion / suspension / solution of the thiol-, -SeH- or disulfide-containing active drug or pharmaceutical agent in an ointment or gel for enhancing adipogenesis and lipid secretion with the aid of suspending agents, solubilizing agents, emulsifiers or thickening agents.

[0201] The pharmaceutical compositions described herein comprise about 0.2% to about 10% of thiol-containing, -SeH-containing or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 0.2% to about 1.0% of thiol-containing, -SeH-containing or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 1.0% to about 3.0% of thiol-containing, -SeH-containing or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 3.0% to about 5.0% of thiol-containing, -SeH-containing or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 5.0% to about 10.0% of thiol-containing, -SeH-containing or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 1.0% of thiol-containing, -SeH-containing, or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 1.5% of thiol-containing, -SeH-containing, or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 2.0% of thiol-containing, -SeH-containing, or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 2.5% of thiol-containing, -SeH-containing, or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 3.0% of thiol-containing, -SeH-containing, or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 3.5% of thiol-containing, -SeH-containing, or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 4.0% of thiol-containing, -SeH-containing, or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 4.5% of thiol-containing, -SeH-containing, or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion. In some embodiments, the pharmaceutical compositions described herein comprise about 5.0% of thiol-containing, -SeH-containing, or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion.

[0202] One embodiment provides a method of treating meibomian gland dysfunction in a patient in need thereof by topical administration of a composition comprising at least one thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion results in a treatment-related increase in the amount of lipids secreted by the meibomian glands. Another embodiment provides a method of treating meibomian gland dysfunction in a patient in need thereof by topical administration of a composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the pharmaceutical agent that enhances lipogenesis and lipid secretion is a pharmaceutical composition comprising selenium sulfide. Another embodiment provides a method of treating meibomian gland dysfunction in a patient in need thereof by topical administration of a composition comprising a pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the pharmaceutical agent that enhances lipogenesis and lipid secretion is a pharmaceutical composition comprising a thiol-, -SeH-, or disulfide-containing drug. Another embodiment provides a method of treating meibomian gland dysfunction in a patient in need thereof by topically administering a composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion results in increased meibum production. Another embodiment provides a method of treating meibomian gland dysfunction in a patient in need thereof by topically administering a composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion is an agent that causes pemphigus. Another embodiment provides a method of treating meibomian gland dysfunction in a patient in need thereof by topically administering a composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the drug or pharmaceutical agent that enhances lipogenesis and lipid secretion is capable of increasing the amount of meibum lipids secreted by the meibomian glands and altering the meibum lipid composition, thereby dissolving meibomian gland obstruction. Another embodiment provides a method of treating meibomian gland dysfunction in a patient in need thereof by topically administering a composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion is capable of increasing the amount of meibum lipids secreted by the meibomian glands due to contact with the contents of the meibomian gland orifices when applied to the eyelid margin.

[0203] One embodiment provides a method for treating meibomian gland dysfunction by topical administration of a composition comprising a thiol-containing, -SeH-containing, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the pharmaceutical agent that enhances lipogenesis and lipid secretion is a pharmaceutical composition in which at least one agent is capable of increasing the amount of meibum lipids secreted by the meibomian glands. Another embodiment provides a method for treating meibomian gland dysfunction in a patient in need by topical administration of a composition comprising a pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the pharmaceutical agent that enhances lipogenesis and lipid secretion is a pharmaceutical composition comprising selenium sulfide. Another embodiment provides a method for treating meibomian gland dysfunction by topical administration of a composition comprising a pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the pharmaceutical agent that enhances lipogenesis and lipid secretion is a pharmaceutical composition in which at least one agent capable of increasing the amount of meibum lipids secreted by the meibomian glands is a thiol-containing, -SeH-containing, or disulfide-containing drug. Another embodiment provides a method of treating meibomian gland dysfunction by topically administering a composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion is a pharmaceutical composition in which at least one agent capable of increasing the amount of meibum lipids secreted by the meibomian glands causes cortical overproduction. Another embodiment provides a method of treating meibomian gland dysfunction by topically administering a composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion is a pharmaceutical composition in which at least one agent capable of increasing the amount of meibum lipids secreted by the meibomian glands is an agent that causes pemphigus. Another embodiment provides a method of treating meibomian gland dysfunction by topically administering a composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion is a pharmaceutical composition in which at least one agent capable of increasing the amount of meibum lipid secreted by the meibomian glands lowers the melting point of the meibum lipids, thereby reducing the viscosity of the meibum lipids and allowing dissolution of any meibomian gland obstruction. Another embodiment provides a method of treating meibomian gland dysfunction by topically administering a composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion is a pharmaceutical composition in which at least one agent is capable of increasing the amount of meibum lipid secreted by the meibomian glands due to contact with the contents of the meibomian gland orifices when applied to the eyelid margin.

[0204] One embodiment provides a method for treating meibomian gland dysfunction by topical administration of a composition comprising a pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the pharmaceutical agent that enhances lipogenesis and lipid secretion is a drug containing a thiol or disulfide group. Another embodiment provides a method for treating meibomian gland dysfunction by topical administration of a composition comprising a pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the thiol-containing drug is selected from captopril, zofenopril, tiopronin, penicillamine, L-cysteine, selenocysteine, glutathione, dithiothreitol, thiophene, cysteamine, bucillamine, 2,3-dimercaptopropanol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethylthiol, omapatrilat, egg mercaptan A, pantetheine, lenzopril, thiosalicylic acid, thiocortisone, fungal mercaptan, coenzyme A and coenzyme B.

[0205] Another embodiment provides a method of treating meibomian gland dysfunction by topically administering a composition comprising a pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the disulfide-containing drug is selected from the group consisting of Disulfiram, Psammaplin A, Dixanthate, Pantethine, Fursultiamine, Octothiamine, Sulbutiamine, Prosultiamine, Thiram, Lipoic Acid, Lentinan, Ajoene, Allicin, Gemopatrilat, and Sulfanegen.

[0206] In any of the above embodiments, the composition further comprises an ophthalmologically acceptable carrier. In a further embodiment, the ophthalmologically acceptable carrier comprises an ophthalmologically acceptable excipient.

[0207] In certain embodiments, the thiol-containing, -SeH-containing or disulfide-containing drugs or pharmaceutical agents for enhancing lipogenesis and lipid secretion of the methods and compositions described herein are optionally used to maintain a therapeutic environment. In certain embodiments, the thiol-containing, -SeH-containing or disulfide-containing drugs or pharmaceutical agents for enhancing lipogenesis and lipid secretion for maintaining a therapeutic environment include low concentrations of pharmaceutical agents for enhancing lipogenesis and lipid secretion.

[0208] The term "maintenance therapy" or "maintenance dosage regimen" refers to a treatment regimen for a subject or patient diagnosed with a disorder / disease (eg, MGD) to enable them to maintain a given state of health, eg, remission.

[0209] In one embodiment, the thiol-containing, -SeH-containing drug or pharmaceutical agent for enhancing adipogenesis and lipid secretion for maintaining a therapeutic environment is selected from captopril, zofenopril, tiopronin, penicillamine, L-cysteine, selenocysteine, glutathione, dithiothreitol, thiophene, cysteamine, bucillamine, 2,3-dimercaptopropanol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiolate A, pantetheine, lenzopril, thiosalicylic acid, thiocortisone, fungal thiols, coenzyme A and coenzyme B.

[0210] In one embodiment, the disulfide-containing drug or pharmaceutical agent for enhancing adipogenesis and lipid secretion for maintaining a therapeutic environment is selected from Disulfiram, Psammaplin A, Dixanthate, Pantethine, Fursultiamine, Octothiamine, Sulbutiamine, Prosultiamine, Thiram, Lipoic Acid, Lentinan, Ajoene, Allicin, Gemopatrilat and Sulfanegen.

[0211] One embodiment provides a method of enhancing the lipogenesis and lipid secretion of the meibomian glands of a patient in need thereof by administering a topical composition comprising a thiol-, -SeH- or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, wherein the composition comprises 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%, 2.5%, 5% or 10% of a thiol-, -SeH- or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion. In some embodiments, the composition is formulated as a suspension, emulsion, cream, lotion, gel or ointment. In some embodiments, the composition is applied to clean skin as a thin layer, initially once every other day, and then gradually increased to a maximum of twice a day as tolerance develops. In some embodiments, the composition is an ointment or paste. In some embodiments, the composition is initially a 0.1% ointment. After 7 days, the concentration can be increased to 0.25%, then doubled weekly (if necessary) to a maximum strength of 2%. In some embodiments, a thin layer of ointment is applied to the affected area once a day for 2-4 weeks. In some embodiments, the ointment is retained in place for 10-20 minutes, and then the area is thoroughly rinsed. In some embodiments, the concentration of thiol-containing, -SeH-containing or disulfide-containing drugs or pharmaceutical agents that enhance adipogenesis and lipid secretion is gradually increased to a maximum of 5%, and treatment will continue as long as necessary.

[0212] 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)).

[0213] One embodiment provides a method of treating meibomian gland dysfunction by administering a topical composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion. One embodiment provides a method of treating meibomian gland dysfunction by administering a topical composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion in combination with a keratolytic agent.

[0214] In some embodiments, the topical application of a composition comprising a thiol-containing, -SeH-containing or disulfide-containing drug or pharmaceutical agent that enhances adipogenesis and lipid secretion is performed once a week. In some embodiments, the topical application of a composition comprising a thiol-containing, -SeH-containing or disulfide-containing drug or pharmaceutical agent that enhances adipogenesis and lipid secretion is performed twice a week. In some embodiments, the topical application of a composition comprising a thiol-containing, -SeH-containing or disulfide-containing drug or pharmaceutical agent that enhances adipogenesis and lipid secretion is performed once every other day. In some embodiments, the topical application of a composition comprising a thiol-containing, -SeH-containing or disulfide-containing drug or pharmaceutical agent that enhances adipogenesis and lipid secretion is performed once a day. In some embodiments, the topical application of a composition comprising a thiol-containing, -SeH-containing or disulfide-containing drug or pharmaceutical agent that enhances adipogenesis and lipid secretion is performed several times a day.

[0215] In some embodiments, the method includes treatment in an acute treatment scenario. In another embodiment, the method includes similar or identical treatment for patients without treatment experience. In another embodiment, the method includes treatment in a chronic treatment scenario. In another embodiment, the method includes treatment in a maintenance treatment scenario. In the acute treatment scenario, the dosage of the drug or pharmaceutical agent containing thiol, -SeH or disulfide that enhances adipogenesis and lipid secretion may be higher than the dosage of the drug or pharmaceutical agent containing thiol, -SeH or disulfide that enhances adipogenesis and lipid secretion used in a chronic treatment scenario or a maintenance treatment scenario. In the acute treatment scenario, the drug or pharmaceutical agent containing thiol, -SeH or disulfide that enhances adipogenesis and lipid secretion may be different from the drug or pharmaceutical agent containing thiol, -SeH or disulfide that enhances adipogenesis and lipid secretion used in a chronic treatment scenario. In some embodiments, the course of treatment begins with an acute treatment scenario in the initial stage of treatment, followed by a transition to a chronic treatment scenario or a maintenance treatment scenario.

[0216] In certain clinical presentations, the patient may require initial treatment administered by a physician or healthcare professional by placing a higher concentration composition of one of the therapeutic agents described herein. Where a higher concentration composition is required, its application may require eye protection or other measures to minimize the effects of irritation or damage to the ocular surface or surrounding tissues. Following such a procedure, the patient may be given a different composition of the active agent to take home for periodic application to the eyelid margins to maintain patency of the meibomian glands. Such application may be performed twice a day, once a day, once a week, or once a month, depending on the activity of the composition and the desired therapeutic outcome profile.

[0217] One aspect of the methods of treatment described herein is the location of topical administration of the composition. In one embodiment, administration of the composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion does not irritate the eye. In one embodiment, the composition comprising a thiol-, -SeH-, or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion is applied to the eyelid margin.

[0218] Another embodiment of the treatment methods described herein is to use a protective element provided for the eye to avoid irritation to the eye. Although the compositions described herein are generally non-irritating, in some embodiments (e.g., high concentrations of agents or when used for sensitive eyes), protective elements provide additional layers of safety and comfort for patients. In one embodiment, while applying a composition comprising a thiol-containing, -SeH-containing or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, an eye protector is placed on the eye to reduce the contact of the agent with the cornea and / or conjunctiva, so that the irritation to the eye is reduced. In some embodiments, the eye protector is a contact lens or an eye covering. In some embodiments, the eye covering comprises a self-adhesive. In one embodiment, while applying a composition comprising a thiol-containing, -SeH-containing or disulfide-containing drug or pharmaceutical agent that enhances lipogenesis and lipid secretion, the eyelid is pulled away from the eyeball to reduce the contact of the agent with the cornea and / or conjunctiva, so as to reduce the irritation to the eye.

[0219] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, etc. When a range is used herein for a physical property such as molecular weight, or a chemical property such as a chemical formula, all combinations and subcombinations of the range and specific embodiments thereof are intended to be included. When the term "about" refers to a numerical value or a numerical range, it means that the numerical value or numerical range referred to is an approximation within the experimental variability (or within the statistical experimental error), and thus the numerical value or numerical range may vary between 1% and 15% of the specified numerical value or numerical range. The term "comprising" (and related terms such as "containing" or "having" or "including" are not intended to exclude the following situations: in other certain embodiments, for example, embodiments of any part of the substances, compositions, methods or processes described herein, etc. may be "consisting of" or "essentially consisting of" the features.

[0220] As used herein, the term "ophthalmologically acceptable carrier" refers to a carrier that, when applied according to the teachings of the present invention, does not cause significant irritation to the eye of an organism and does not abrogate the pharmacological activity and properties of the agent carried thereby.

[0221] Ophthalmologically acceptable carriers are generally sterile, substantially free of foreign particles, and generally have a pH in the range of 5-8. Preferably, the pH is as close as possible to the pH of tear fluid (7.4). Ophthalmologically acceptable carriers are, for example, sterile isotonic solutions, such as isotonic sodium chloride or boric acid solutions. Such carriers are generally aqueous solutions containing sodium chloride or boric acid. Phosphate buffered saline (PBS) solutions may also be used.

[0222] As used herein, the term "effective amount" refers to the amount required to achieve a particular condition, such as increasing lipid secretion from the meibomian glands, lowering the melting point of lipids secreted by the meibomian glands, or lowering the viscosity of lipids secreted by the meibomian glands.

[0223] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutically effective compound or a pharmaceutically acceptable salt thereof that is effective in treating, preventing, alleviating or ameliorating symptoms of a disease. The term "therapeutically effective compound" refers to a compound that is effective in treating, preventing, alleviating or ameliorating symptoms of a disease.

[0224] As used herein, the term "thiol group" refers to a -SH functional group.

[0225] As used herein, the term "thiol group" refers to a -C-SH or R-SH group, wherein R represents an alkane, an alkene or other carbon-containing atom group.

[0226] As used herein, the term "disulfide" refers to a linked pair of sulfur atoms.

[0227] As used herein, the term "disulfide bond" refers to a covalent bond, usually resulting from the coupling of two thiol groups, so that the overall connection is -SS-. This connection is also called an SS bond or a disulfide bridge.

[0228] As used herein, the term "ophthalmologically acceptable excipient" refers to a carrier that does not cause significant irritation to the eye of an organism and does not abrogate the pharmacological activity and properties of the agent carried thereby when applied according to the teachings of the present invention.

[0229] As used herein, the term "keratolytic agent" refers to compounds that loosen and remove the stratum corneum of the skin or change the structure of the keratin layer of the skin.

[0230] As used herein, the terms "treat" or "treatment" include reducing, alleviating, reducing, ameliorating, alleviating or reducing symptoms associated with MGD in chronic or acute treatment settings. In one embodiment, treatment includes increasing lipid production. In one embodiment, treatment includes increasing lipid secretion. In one embodiment, treatment includes reducing the viscosity of secreted lipids.

[0231] The terms "relapse" or "reduction of relapse" refer to the return of MGD symptoms in the setting of chronic treatment.

[0232] The term "unclogging" refers to (at least partially) clearing a blocked meibomian gland duct or orifice and / or maintaining the patency of a meibomian gland duct or orifice.

[0233] As used herein, the term "thiol-, -SeH- or disulfide-containing drug or pharmaceutical agent that enhances adipogenesis and lipid secretion" refers to a thiol-, -SeH- or disulfide-containing drug or pharmaceutical agent that causes increased meibomian cell differentiation or increased meibomian cell proliferation or increases the amount of lipids secreted by the meibomian glands or changes the lipid composition of meibum.

[0234] As used herein, the term "meibum lipid" refers to lipids secreted by the meibomian glands.

[0235] The term "lotion" describes an emulsion liquid dosage form. Such dosage forms are typically intended for external application to the skin (US FDA Drug Nomenclature Monograph, No. C-DRG-00201).

[0236] The term "cream" describes an emulsion semisolid dosage form, usually containing >20% water and volatiles and / or <50% hydrocarbons, waxes or polyols as vehicles. Creams are more viscous than lotions. This dosage form is usually used for external application to the skin (USFDA Drug Nomenclature Monograph, No. C-DRG-00201).

[0237] The term "ointment" describes a semisolid dosage form, usually containing <20% water and volatiles and / or >50% hydrocarbons, waxes or polyols as a vehicle. This dosage form is usually used for external application to the skin or mucous membranes (US FDA Drug Nomenclature Monograph, No. C-DRG-00201).

[0238] The term "solution" describes a clear, homogeneous liquid dosage form containing one or more chemical substances dissolved in a solvent or a mutually miscible mixture of solvents (US FDA Drug Nomenclature Monograph, No. C-DRG-00201).

[0239] The term "suspension" refers to a heterogeneous mixture containing solid particles large enough to settle.

[0240] As used herein, the term "lipid derivative" generally refers to a hydrophobic or amphipathic molecule comprising at least one sulfhydryl group or at least one disulfide. The term "lipid derivative" further refers to a hydrophobic or amphipathic molecule comprising at least one sulfhydryl group and at least one disulfide. The term "lipid derivative" further refers to combinations and mixtures of lipid derivatives.

[0241] The thiol- and / or disulfide-containing lipids or "lipid derivatives" described herein are highly diverse in structure and level of derivatization. For example, a lipid such as cholesterol can have a variety of different thiol-containing derivatives ( Figure 4 Methods for synthesizing fatty thiol compounds have been previously described (J. Org. Chem., 1958, Vol. 23, pp. 525-1530), producing a variety of lipids linked by disulfide bonds ( Figure 5 ). The above also describes methods for synthesizing disulfide-containing lipids ( Figure 6 ) and a method for synthesizing a lipid containing multiple thiols such as squalene ( Figure 7 ). Mono-, di-, and triglycerides are also converted to their thiol-containing derivatives ( Figure 8 ). In summary, lipids can be derivatized to produce a variety of thiol-containing and / or disulfide-containing derivatives by methods well known in the art.

[0242] The present invention provides embodiments including but not limited to the following:

[0243] 1. A method for increasing lipid secretion of meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in the meibomian glands or increases lipid secretion of the meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide.

[0244] 2. The method of embodiment 1, wherein the agent comprises a thiol group.

[0245] 3. A method as described in embodiment 1 or embodiment 2, wherein the agent is selected from captopril, zofenopril, tiopronin, penicillamine, L-cysteine, selenocysteine, glutathione, dithiothreitol, thiophene, cysteamine, bucillamine, 2,3-dimercaptopropanol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethylthiol, omapatrilat, egg mercaptan A, pantetheine, lenzopril, thiosalicylic acid, thiocortisone, fungal mercaptan, coenzyme A and coenzyme B.

[0246] 4. The method of embodiment 1, wherein the agent comprises a disulfide bond.

[0247] 5. A method as described in embodiment 1 or embodiment 4, wherein the agent is selected from disulfiram, Psammaplin A, dixanthate, pantethine, fursultiamine, octothiamine, sulbutiamine, prosultiamine, thiram, lipoic acid, mushroom flavor, ajoene, allicin, gemopatrilat and sulfanegen.

[0248] 6. The method of any one of embodiments 1-5, wherein the ophthalmologically acceptable carrier comprises at least one ophthalmologically acceptable excipient.

[0249] 7. The method of any one of embodiments 1-6, further comprising the step of administering a keratolytic agent to the patient.

[0250] 8. The method of embodiment 7, wherein the keratolytic agent is selected from benzoyl peroxide, coal tar, anthralin, salicylic acid, selenium disulfide, α-hydroxy acid, urea, boric acid, retinoic acid, lactic acid, sodium thioglycolate or allantoin.

[0251] 9. A method for treating meibomian gland dysfunction (MGD) comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent, wherein the agent is selected from captopril, zofenopril, tiopronin, penicillamine, glutathione, dithiothreitol, thiophene, cysteamine, bucillamine, 2,3-dimercaptopropanol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovalthiol A, pantetheine, lenzopril, thiosalicylic acid, thiocortisone, fungal thiols, coenzyme A and coenzyme B, or wherein the agent comprises a disulfide.

[0252] 10. The method of embodiment 9, wherein the agent comprises a disulfide bond.

[0253] 11. The method of embodiment 9 or 10, wherein the agent is selected from the group consisting of Disulfiram, Psammaplin A, Dixanthate, Pantethine, Fursultiamine, Octothiamine, Sulbutiamine, Prosultiamine, Thiram, Lipoic Acid, Shiitake Essence, Ajoene, Allicin, Gemopatrilat, and Sulfanegen.

[0254] 12. The method of any one of embodiments 9-11, wherein the ophthalmologically acceptable carrier comprises at least one ophthalmologically acceptable excipient.

[0255] 13. The method of any one of embodiments 9-11, further comprising the step of administering a keratolytic agent to the patient.

[0256] 14. The method of embodiment 13, wherein the keratolytic agent is selected from benzoyl peroxide, coal tar, anthralin, salicylic acid, selenium disulfide, α-hydroxy acid, urea, boric acid, retinoic acid, lactic acid, sodium thioglycolate or allantoin.

[0257] 15. The method of any one of embodiments 9-11, wherein the meibomian gland dysfunction is characterized by obstruction of the meibomian glands.

[0258] 16. The method of embodiment 15, wherein the topical application of the agent to the eyelid margin of the patient is repeated until the meibomian gland obstruction is substantially eliminated.

[0259] 17. The method of embodiment 15, wherein topical application of the agent to the eyelid margin of the patient is repeated periodically to prevent the formation of meibomian gland obstruction.

[0260] 18. A method for lowering the melting point of lipids secreted by meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide.

[0261] 19. A method for reducing the viscosity of lipids secreted by meibomian glands, comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion from meibomian glands, wherein the agent comprises a thiol group, a -SeH group, or a disulfide.

[0262] 20. A method for increasing lipid secretion from meibomian glands comprising topically applying to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one lipid derivative containing a thiol group or a disulfide.

[0263] 21. A method as described in embodiment 20, wherein the lipid derivative is a derivative of a lipid selected from fatty acids, glycerides, glycerophospholipids, sphingolipids, sterol lipids, pregnenolone lipids, glycolipids, polyketides and any combination thereof.

[0264] 22. A method as described in embodiment 20, wherein the lipid is selected from fatty acids, wax esters, cholesterol esters, triglycerides, diglycerides, monoglycerides, phospholipids, diesters, fatty acid amides, squalene, ceramides, sphingolipids, ω-hydroxy fatty acids, cholesterol and its epoxides.

[0265] 23. A method as described in embodiment 21 or 22, wherein the fatty acid has a molecular formula selected from the following items: (i) C n H 2n O2, wherein n is any integer selected from 12, 14-18 and 20-29; (ii) C n H 2n-2 O2, wherein n is any integer selected from 16-18, 20, 22, 24, 26, 28, 30 and 32; and (iii) C n H 2n-4 O2, where n is 18.

[0266] 24. The method of embodiment 21, wherein the fatty acid is selected from the group consisting of myristic acid, palmitic acid, stearic acid, and oleic acid.

[0267] 25. The method according to embodiment 22, wherein the wax ester is a saturated C 18-30 Oleic acid esters.

[0268] 26. The method of embodiment 22, wherein the cholesterol ester is C 16-34 Cholesterol esters of fatty acids.

[0269] 27. The method of embodiment 22, wherein the triglyceride has a molecular formula selected from the group consisting of: (i) C n H 2n-8 O6, wherein n is any integer selected from 55 and 57; (ii) C n H 2n-10 O6, wherein n is any integer selected from 55 and 57; and (iii) fatty acid chains associated with triglycerides: C14:0, C15:0, C16:0, C16:1, C17:0, C18:0, C18:1, C18:2.9.

[0270] 28. A method as described in embodiment 22, wherein the phospholipid is selected from phosphatidylcholine (PC), phosphatidylethanolamine (PE), alkylacylphosphatidylcholine, sphingomyelin, dihydrosphingomyelin, dimethylphosphatidylethanolamine, diphosphatidylglycerol (cardiolipin), ethanolamine acetal phospholipids, lysoethanolamine acetal phospholipids, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol and phosphatidylserine.

[0271] 29. The method of embodiment 22, wherein the fatty acid amide is selected from the group consisting of oleamide, myristicamide, palmitamide, stearamide, erucamide and ceramide.

[0272] 30. The method of embodiment 22, wherein the ω-hydroxy fatty acid has a molecular formula selected from the group consisting of: (i) C n H 2n-7 O4, wherein n is any integer selected from 46-52; (ii) C n H 2n-4 O4, wherein n is any integer selected from 42-50; (iii) C n H 2n-6 O4, wherein n is any integer selected from 42, 44, 46 and 48-52; (iv) C n H 2n-8 O4, wherein n is any integer selected from 48, 50 and 52; and (v) C n H 2n-10O4, wherein n is any integer selected from 50 and 52.

[0273] Example

[0274] Example 1: In vivo evaluation of the effects of thiol- or disulfide-containing compounds on lipid synthesis in a 3D model culture of sebocytes.

[0275] Since the secretory cells of the meibomian glands (meibocytes) have similarities with the secretory cells of the sebaceous glands (sebocytes), which can be verified by their similar structures, similar functions and their joint embryonic development (Knop 2011_IOVS), the effects of thiol-containing lipids on lipid production can be evaluated in 3D model cultures of sebocytes. See also: Barrault 2012, Immortalized sebocytes can spontaneously differentiate into asebaceous-like phenotype when cultured as a 3D epithelium, Exp. Derm, 21: 299-319.

[0276] The effects of different compounds on lipid synthesis were evaluated in 3D model cultures of sebocytes. Candidate drugs were drugs containing SH or disulfide: selenium disulfide (SeS2 dispersed in carboxymethylcellulose-CMC) as a positive control, selenocysteine, captopril, disulfiram and lipids containing SH or disulfide: thioethanol, 12-mercaptododecanoic acid. Since sebocyte differentiation is associated with increased lipid synthesis and accumulation, proliferation and differentiation were evaluated by quantifying lipid accumulation in 3D sebocyte cultures (human cell line-SEBO662). Lipid staining was performed by oil red staining to evaluate lipid accumulation.

[0277] Sebocytes SEBO662 were cultured into three-dimensional (3D) epithelial cells and differentiated into sebaceous phenotypes. Sebocytes were treated with or without (control) test compounds and incubated for 14 days. All experiments were performed 3 times. After incubation, the tissues were snap-frozen. Formaldehyde-fixed frozen sections were stained with Oil Red-O solution and counterstained with hematoxylin. For each test condition, sections were observed using an optical microscope equipped with a camera. Five photos were taken repeatedly, and 15 values ​​were obtained under each treatment condition. The lipid content in each sample was quantified by calculating the lipid droplet surface area. All data points between the lipid droplet surface area of ​​the test compound and the control were quantitatively compared.

[0278] result:

[0279] Figure 1 Graph showing Oil Red-0 staining in control 3D sebocyte epithelial cells.

[0280] Figure 2 Graph showing Oil Red-0 staining in 3D sebocyte epithelial cells for 1.0 μM 12-mercaptododecanoic acid.

[0281] Figure 3 Graph showing Oil Red-0 staining in 3D sebocyte epithelial cells for 0.1 micromolar 12-mercaptododecanoic acid.

[0282] Quantitative comparison

[0283] At both tested concentrations, 0.01 μM and 0.1 μM selenium disulfide (SeS2) induced a statistically significant increase in lipid accumulation in the upper region of 3D sebocytes (282% and 348% of control, respectively).

[0284] Selenocysteine ​​was tested at 1 μM and 10 μM. At a concentration of 1 μM, this compound induced a statistically significant increase in lipid accumulation in 3D sebocytes (296% of control). At 10 μM, no stimulatory effect was found.

[0285] Captopril induced a statistically significant increase in lipid accumulation at both concentrations tested (240% and 173% of control, respectively).

[0286] Disulfiram was tested at 100 μM and 1000 μM. At a concentration of 100 μM, it stimulated a statistically significant increase in lipid accumulation in 3D sebocytes (199% of control). At 1000 μM, no stimulatory effect was found.

[0287] When tested at 0.1 [mu]M and 1 [mu]M, thioethanol stimulated lipid accumulation with statistically significant increases at both concentrations tested (251% and 228% of control, respectively).

[0288] 12-Mercaptododecanoic acid induced a statistically significant increase in lipid accumulation in 3D sebocytes when tested at 0.1 μM and 1 μM. The effects were similar at both concentrations (385% and 349% relative to control, respectively)

[0289] in conclusion:

[0290] Selenium disulfide, selenocysteine, thioethanol, captopril, disulfiram, and 12-mercaptododecanoic acid, which are SH- or disulfide-containing compounds, have a significant stimulatory effect on lipid synthesis in a 3D sebocyte model.

[0291] Example 2: Preparation of a pharmaceutical composition comprising a thiol-, -SeH- or disulfide-containing drug or pharmaceutical agent that enhances adipogenesis and lipid secretion.

[0292] 2.5 g of 12-mercaptododecanoic acid are mixed with 10 g of liquid paraffin and 87.5 g of white soft vaseline and heated to about 60° C. with constant stirring until a homogeneous mixture is obtained and cooled to room temperature.

[0293] 2.5 g of 12-mercaptododecanoic acid was mixed with 2.5 g of cholesterol, 10 g of liquid petrolatum and 85 g of petrolatum. The mixture was heated while mixing until all ingredients melted at about 80°C and homogeneity was achieved, and then cooled to room temperature.

[0294] 2.5 g of 12-mercaptododecanoic acid was mixed with 5 g of squalene and 97.5 g of petrolatum and heated to about 60°C while mixed to obtain homogeneity and then cooled to room temperature.

[0295] 2.5 g of 12-mercaptododecanoic acid was mixed with 10 g of mineral oil, 10 g of squalene, 10 g of capric / caprylic triglyceride, 10 g of microcrystalline wax, 10 g of hydrogenated vegetable oil, and 3 g of lanolin plus petrolatum for a total of 100 g. The mixture was heated to about 80°C-90°C while mixing until homogeneity was achieved and cooled to room temperature.

[0296] 2.5 g of thiocholesterol was mixed with 10 g of mineral oil, 10 g of squalene, 10 g of capric / caprylic triglyceride, 10 g of microcrystalline wax, 10 g of hydrogenated vegetable oil and 3 g of lanolin plus petrolatum for a total of 100 g. The mixture was heated to about 80°C-90°C while mixing until homogeneity was achieved and cooled to room temperature.

[0297] 2.5 g of thiophospholipids were mixed with 10 g of mineral oil, 10 g of squalene, 10 g of capric / caprylic triglyceride, 10 g of microcrystalline wax, 10 g of hydrogenated vegetable oil and 3 g of lanolin plus petrolatum for a total of 100 g. The mixture was heated to about 80°C-90°C while mixing until homogeneity was achieved and cooled to room temperature.

[0298] 2.5 g of 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatricosanoic acid was mixed with 10 g of mineral oil, 10 g of squalene, 10 g of capric / caprylic triglyceride, 10 g of microcrystalline wax,

[0299] 10 grams of hydrogenated vegetable oil and 3 grams of lanolin plus petrolatum, a total of 100 grams, are mixed. The mixture is heated to about 80°C-90°C while mixing until homogeneity is achieved and cooled to room temperature.

[0300] 2.5 g of disulfiram was mixed with 10 g of mineral oil, 10 g of squalene, 10 g of capric / caprylic triglyceride, 10 g of microcrystalline wax, 10 g of hydrogenated vegetable oil and 3 g of lanolin plus petrolatum for a total of 100 g. The mixture was heated to about 80°C-90°C while mixing until homogeneity was achieved and cooled to room temperature.

[0301] 2.5 g of thiophospholipids were mixed with 3 g of cholesterol and 10 g of phospholipids and dissolved in an ethanol-acetone mixture. The mixture was dried under vacuum and mixed with 1000 ml of saline solution under vigorous stirring and then homogenized under high pressure to produce a very fine liposome dispersion.

[0302] 2.5 g of disulfiram was mixed with 5 g of hydrogenated vegetable oil and 5 g of mineral oil and heated to about 80°C under stirring until all ingredients were melted. 87.5 g of an aqueous solution preheated to 80°C containing 1% Tween 80 and 2% phospholipids was added under vigorous mixing and high shear homogenization. 0.8 g of xanthan gum was added under vigorous mixing.

[0303] 3000 TM ), and the mixture was cooled to room temperature to obtain a solid lipid dispersion.

[0304] 2.5 g of captopril was dissolved in sterile water for injection, 1.2 g of xanthan gum and 0.8 g of sodium chloride were added, and the mixture was stirred to produce a transparent gel.

[0305] Example 3: Increasing lipid production in the meibomian glands.

[0306] The aim of this study was to evaluate the effects of agents that enhance lipogenesis and lipid secretion on increasing the amount of lipid produced by the meibomian glands.

[0307] A light layer of a thiol-, -SeH-, or disulfide-containing drug or agent that enhances adipogenesis and lipid secretion is applied to the lower eyelid of a subject, and the amount of lipid produced by the meibomian glands is measured before and after application of the drug or agent. An exemplary method for determining the level of lipid production in the meibomian glands is to culture human meibomian gland epithelial cells with or without a thiol-, -SeH-, or disulfide-containing drug or agent for 1 day, 3 days, 5 days, and 7 days, and then stain the cells by staining with LipidTOX Green Neutral Lipid Stain and Red DND-99 (fluorescence technology designed for labeling lysosomes) stains cells to determine the magnitude of cell lipid and lysosome accumulation. In addition, check whether thiol-containing, -SeH-containing or disulfide-containing drugs increase the synthesis of polar and neutral lipid substances in human meibomian gland epithelial cells, culture cells in culture medium with or without thiol-containing, -SeH-containing or disulfide-containing drugs, continue 7 days, then process cells to identify phospholipids, and wax esters and cholesterol esters. The latter two are the main lipids in human meibum. Analysis includes using high performance thin layer chromatography and quantitative staining intensity with ImageJ dye. Another known alternative method utilizes Oil Red O and Nile Red dyeing. Determine the degree of lipid accumulation by using Nile Red dye. The dye will produce a fluorescent signal proportional to the amount of lipid that has accumulated.

[0308] Example 4: Increasing lipid secretion of the meibomian glands.

[0309] The aim of this study was to evaluate the effects of agents that enhance lipogenesis and lipid secretion on increasing the amount of lipid secreted by the meibomian glands.

[0310] A light layer of a thiol-, -SeH-, or disulfide-containing drug or agent that enhances lipogenesis and lipid secretion is applied to the lower eyelid of a subject, and the amount of lipid secreted by the meibomian glands is measured before and after the application of the drug or agent. An exemplary method for determining the level of lipid secretion by the meibomian glands is to quantify meibomian lipids on the eyelid margin using a "meibometry" instrument, which is an optical spectrophotometer with a tape attached to the eyelid margin to measure the amount of secreted meibum (Chew et al., Current Eye Research, Vol. 12(3), pages 247-254, 1993).

[0311] Example 5: Lowering the melting point of lipids secreted by the meibomian glands.

[0312] The aim of this study was to evaluate the effects of agents that enhance lipogenesis and lipid secretion on lowering the melting point of lipids secreted by the meibomian glands.

[0313] A light layer of a thiol-, -SeH- or disulfide-containing drug or agent that enhances lipogenesis and lipid secretion is applied to the lower eyelid of the subject, and the melting point of lipids secreted by the meibomian glands is determined before and after the application of the drug or agent. An exemplary method for determining the melting point of lipid secretions of the meibomian glands is to weigh 100 mg of meibum lipids and dissolve them in a chloroform-methanol (3:1) solvent mixture. A small portion of the above mixture is taken out and placed on a pre-weighed differential scanning calorimeter (DSC) plate. Subsequently, the solvent is evaporated under a nitrogen stream to obtain a uniformly mixed sample. The DSC plate is weighed again to determine the exact weight of the lipid. The sample is then analyzed using DSC in triplicate and run from -50°C to 100°C at a rate of 5°C / min. Single components are also run under similar conditions as a reference to identify them from the mixture. Individual components are run as is, as well as after being dissolved in a chloroform-methanol mixture and after the solvent is evaporated. Melting points are recorded as peaks in the DSC thermogram.

[0314] Example 6: Reducing the viscosity of lipids secreted by the meibomian glands.

[0315] The aim of this study was to evaluate the effects of agents that enhance lipogenesis and lipid secretion on reducing the viscosity of lipids secreted by the meibomian glands.

[0316] A light layer of a thiol-, -SeH- or disulfide-containing drug or agent that enhances lipogenesis and lipid secretion is applied to the lower eyelid of the subject, and the viscosity of the lipids secreted by the meibomian glands is measured before and after the application of the drug or agent. An exemplary method for measuring the viscosity of meibomian gland lipid secretions is to provide researchers with a complex instrument for routinely measuring the absolute viscosity of small sample amounts of fluids by using a Brookfield Cone / Plate viscometer with a special geometry. The Brookfield Cone / Plate viscometer provides multiple shear rates and viscosity ranges, which can be further expanded by using interchangeable cone shafts. Different models can be selected to meet the specific range of required viscosity and shear rate. The required small sample amount allows rheological evaluations to be performed on materials with limited sample availability, such as biological fluids and meibum samples.

[0317] Example 7: Treatment of MGD patients.

[0318] The aim of this study was to evaluate the effects of agents that enhance lipogenesis and lipid secretion for the treatment of MGD or at least one of its symptoms.

[0319] A light layer of a thiol-, -SeH-, or disulfide-containing drug or agent that enhances lipogenesis and lipid secretion is applied to the lower eyelid of a MGD patient, and the severity of MGD or at least one symptom thereof is determined before and after application of the drug or agent. Exemplary methods for assessing and monitoring the severity of MGD or at least one symptom thereof include, but are not limited to, patient questionnaires, meibomian gland squeezing, tear stability breakup time, and determining the number of patent glands visible by finger squeezing. Other methods for assessing MGD symptoms include, but are not limited to, Shirmer's test, ocular surface staining, eyelid morphology analysis, meibomian gland imaging, meibomian gland meibometry, interferometry, evaporometry, tear lipid composition analysis, fluorophotometry, meiscometry, osmolarity analysis, tear film dynamics index, evaporation, and tear turnover.

Claims

1. Use of an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent that increases fat production in meibomian glands or increases lipid secretion of said meibomian glands in the preparation of a medicament for increasing fat production in meibomian glands or increasing lipid secretion of said meibomian glands, wherein said medicament is formulated for topical administration to the eyelid margin of a patient in need thereof, wherein said agent is selected from the group consisting of captopril, bucillamine and disulfiram.

2. The use according to claim 1, wherein the pharmaceutical agent is captopril.

3. The use according to claim 1, wherein the pharmaceutical agent is bucillamine.

4. The use according to claim 1, wherein the agent is disulfiram.

5. The use according to any one of claims 1 to 4, wherein the medicament is in the form of an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of the at least one pharmaceutical agent.

6. The use according to claim 5, wherein the ophthalmologically acceptable carrier comprises at least one ophthalmologically acceptable excipient.

7. Use of an ophthalmic composition comprising an ophthalmologically acceptable carrier and an effective amount of at least one agent in the preparation of a medicament for treating meibomian gland dysfunction, wherein the medicament is formulated for topical administration to the eyelid margin of a patient in need thereof, wherein the agent is selected from the group consisting of captopril, bucillamine and disulfiram.

8. The use according to claim 7, wherein the pharmaceutical agent is captopril.

9. The use of claim 7, wherein the pharmaceutical agent is Bucillamine.

10. The use of claim 7, wherein the agent is disulfiram.

11. The use according to any one of claims 7 to 10, wherein the medicament is in the form of an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of the at least one pharmaceutical agent.

12. The use according to claim 11, wherein the ophthalmologically acceptable carrier comprises at least one ophthalmologically acceptable excipient.

13. The use of any one of claims 7-10, wherein the meibomian gland dysfunction is characterized by obstruction of the meibomian glands.

14. The use of claim 13, wherein the topical application of the medicament to the eyelid margin of the patient is repeated until the meibomian gland obstruction is substantially eliminated.

15. The use of claim 13, wherein topical application of the medicament to the eyelid margin of the patient is repeated periodically to prevent the formation of meibomian gland obstruction.

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