Methods for Treating Ocular Inflammatory Diseases

Abstract

The present invention relates to a method of treating ocular inflammatory diseases by administering an ophthalmic pharmaceutical composition of roflumilast, which may provide significant immunomodulatory and anti-inflammatory activity compared to existing immunomodulatory, immunosuppressive, or non-steroidal anti-inflammatory treatments, including corticosteroids and antihistamines, while also providing an improved safety and convenience profile compared to one or both agents.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 247,174, filed September 22, 2021, and U.S. Provisional Application No. 63 / 251,874, filed October 4, 2021. Each of these applications is incorporated by reference herein.

[0002]

[0002] The present invention includes a method for treating ocular inflammatory diseases by administering an ophthalmic pharmaceutical composition of roflumilast. The inventors of the present application have surprisingly discovered that administration of an ophthalmic pharmaceutical suspension of roflumilast can provide significant anti-inflammatory activity compared to existing immunosuppressive and immunomodulatory treatments, including corticosteroids and antihistamines, while also providing an improved safety profile and convenience compared to one or both of the agents. [Background technology]

[0003] Roflumilast is a potent, selective, long-acting inhibitor of phosphodiesterase (PDE) type 4, with anti-inflammatory and potential antineoplastic activity. It is known that roflumilast is suitable as a bronchotherapeutic agent as well as for the treatment of inflammatory disorders. Compositions containing roflumilast are used in human and veterinary medicine and have been proposed for the treatment and prevention of diseases including, but not limited to, inflammatory and allergen-induced airway disorders (e.g., bronchitis, asthma, COPD), skin diseases (e.g., proliferative, inflammatory, and allergen-induced skin disorders), and systemic inflammation in the gastrointestinal region (Crohn's disease and ulcerative colitis). Oral pharmaceutical compositions of roflumilast are currently sold under the trade names Daliresp® (USA) and Daxas® (Europe) for COPD, and topical compositions of roflumilast cream are currently sold for dermatological use under the trade name Zoryve® (USA) for psoriasis.

[0004] Roflumilast and its synthesis are described in US Patent No. 5,712,298. It has been recognized that pharmaceutical compounds with phosphodiesterase (PDE)-4 inhibitory properties, such as roflumilast, are therapeutically effective and useful in the treatment of inflammatory disorders, such as psoriasis and atopic dermatitis. Although the therapeutic effectiveness of oral and transdermal pharmaceutical compositions has been studied, there is a need for ophthalmic pharmaceutical compositions of roflumilast suitable for treating ocular inflammatory or immune-mediated disorders. Today, the majority of the market for anti-inflammatory ophthalmic drugs is based on antibiotics / antimicrobials (in the context of infectious / inflammatory indications), immunosuppressants (including corticosteroids), immunomodulators (including antihistamines), and nonsteroidal anti-inflammatory agents. These major types of drugs typically do not meet the clinical needs of medium- to long-term inflammatory or immune-mediated diseases or have significant comorbidities and safety issues. Thus, there is a high unmet need for anti-inflammatory ophthalmic formulations of roflumilast in a convenient and acceptable form.

[0005]

[0005] Pharmaceutical ophthalmic agents must balance tolerability, sterility, safety, and efficacy, making delivery of drugs to the eye very challenging. Priyanka Agarwal et al., Formulation Considerations for the Management of Dry Eye Disease, Pharmaceutics, 13, 207 (February 3, 2021) discusses formulation challenges for ophthalmic pharmaceutical formulations. For example, there may be poor tolerability of the formulation excipients. In addition, low patient compliance is a frequent challenge with ophthalmic pharmaceutical formulations. It is very difficult to develop a stable ophthalmic formulation that can be made under sterile conditions and delivered to the eye in effective doses while retaining the physicochemical properties of the active agent and falling within a narrow range of pH and inactive ingredients that are acceptable to the eye. Delivery to the eye is focused on either the ocular surface, the anterior segment, or the posterior segment. Ocular surface formulations are often delivered by the patient one to four or more times per day, with the added challenge of requiring consistency of dosing and the versatility to deliver an effective amount despite common operator errors found in home patient delivery: sterility challenges, variability in delivered volume, and location accuracy. Patients with long-term ocular disease also have increased sensitivity to active and inactive ingredients and preservatives, presenting additional formulation challenges.

[0006] Ocular surface diseases (OSD) are preferentially treated with three major classes of therapeutic ophthalmic pharmaceutical agents: immunomodulators, immunosuppressants (including corticosteroids), antimicrobials, and nonsteroidal anti-inflammatory drugs (NSAIDs). Each has its place, and all have their challenges. Corticosteroids, an immunosuppressive therapeutic approach to ocular diseases, are effective in attenuating inflammatory activity, but whether used systemically, topically, or in intraocular ophthalmic treatments, have long been known for their side effects and often must be administered frequently. Antibiotics are highly effective against bacterial infections that may lead to certain OSDs, but inflammatory diseases are often misdiagnosed as purely bacterial in nature, and therefore antibacterial drugs are often overused, leading to antibiotic and antimicrobial resistance, a long-term public health challenge, as well as inadequate treatment of inflammation or underlying autoimmune or immune-mediated ocular conditions. Nonsteroidal immunomodulators or immunosuppressants (including antihistamines, antiintegrins, and calcineurin inhibitors) and nonsteroidal anti-inflammatory agents (including bromfenac, diclofenac, and others) also play a role in the treatment of inflammatory or immune-driven eye diseases, but they are often recognized as having limited usefulness due to either limited efficacy or difficult safety or tolerability profiles due to a small group of immune targets (based on cellular or intraocular location). The challenge with all current standard of care immune and inflammatory focused therapeutics is that there remains a large unmet need for alternative classes of drugs that directly address the underlying drivers of eye diseases, with high efficacy but also lower patient- or population-based side effects, and greater convenience. In particular, prior to the present invention, there was a large unmet need for anti-inflammatory pharmaceutical agents with a broad mechanism of action that targets the most frequent but multifaceted underlying drivers of inflammatory and immune-mediated eye diseases, but with few systemic or ocular side effects and less frequent dosing. Summary of the Invention [Problem to be solved by the invention]

[0007]

[0007] Corticosteroids are one of the most frequently used types of ophthalmic pharmaceutical agents, administered as first and last resort drugs in inflammatory eye diseases with non-infectious etiology, or often in combination with antibacterial agents in diseases with suspected infectious etiology. Corticosteroids are typically relatively effective, have a relatively short onset of action, and can be administered in many formulations: topical suspensions, gels, ointments, injections or depots; and can be administered in co-formulations with antibiotics or other targeted pharmaceutical agents. However, as with their use in dermatological, immunological, autoimmune, and many other disease conditions; corticosteroids are associated with a variety of serious side effects, both local and systemic, even over a short period of time. Corticosteroid use in the eye can locally decrease wound healing, increase or reactivate susceptibility to fungal or viral infections (indeed, if delivered improperly in a nonsterile state, may even increase the risk of direct endophthalmitis or other infections), and have tissue-specific side effects such as epithelial thinning in the cornea, sclera, and other tissues, perhaps best known for their effect on increasing intraocular pressure that can result in glaucoma, optic nerve damage, cataracts, or central serous chorioretinopathy (Fung 2020). Effects associated with instillation can include site-related pain, burning or stinging, allergic reactions, foreign body sensation, visual disturbances, pruritus, urticaria, and rash; as well as keratitis, conjunctivitis, corneal ulcers, mydriasis, hyperemia, reduced accommodation amplitude, ptosis, acute anterior uveitis, and globe perforation (Pred Forte Label, 2017). Systemic side effects may include headache, hyperglycemia, and susceptibility to systemic microbial infections. In the eye, these side effects may occur even after a short period of medication (e.g., several weeks). For example, corticosteroids are a suboptimal solution for inflammatory or immune-mediated eye diseases, and often require mid- or long-term anti-inflammatory management.Antihistamines and cyclosporines are also frequently used in large populations of OSD to address allergic, immune-mediated, or inflammatory diseases of the eye, but these agents can also have severe side effects, including irritation to ocular tissues, cold symptoms, pharyngitis, and systemic side effects ranging from delayed wound healing to sulfite-related anaphylaxis. All of these commonly used immunomodulator / immunosuppressant classes (including corticosteroids, antihistamines, and cyclosporines) can cause localized side effects, particularly those that directly affect the patient's quality of life (pain, discomfort, itching), exacerbated by the fact that these products are often given 4-8 times a day or more and often need to be reduced to lower doses due to these side effects, particularly at the beginning of their use. In clinical practice, it is not uncommon to use corticosteroids every 1-2 hours for indications such as anterior uveitis to try to get the appropriate effect against the underlying inflammation inherent in this immune-mediated disease. [Means for solving the problem]

[0008]

[0008] The present invention relates to a method for treating ocular inflammatory or immune-mediated diseases by administering an ophthalmic pharmaceutical composition of roflumilast. The inventors of the present application have surprisingly discovered that administration of an ophthalmic pharmaceutical composition of roflumilast can provide clinically meaningful immunomodulatory and anti-inflammatory activity compared to existing standard of care treatments including corticosteroids and antihistamines, while also providing an improved safety and convenience profile compared to one or both types of drugs. The present invention addresses the high unmet need for alternative types of drugs to address immune and inflammatory-driven factors of ocular surface and anterior / posterior segment disorders with clinically meaningful efficacy and even lower patient- or population-based side effects. With strong efficacy and low levels of side effects, the present invention can provide short-, medium-, or long-term therapeutic solutions for many ocular diseases with inflammatory or immune-mediated components.

[0009]

[0009] One embodiment of the present invention provides a method of treating a patient with an ocular inflammatory disorder. The method includes administering to the ocular surface of the patient an ophthalmic pharmaceutical suspension comprising a therapeutically effective amount of roflumilast or a pharma- ceutically acceptable salt or metabolite thereof. The administration results in a reduction in at least one side effect compared to administration of an immunosuppressant, an immunomodulator, or a nonsteroidal anti-inflammatory agent. In certain embodiments, administration of the roflumilast composition results in a reduction in at least one side effect compared to administration of an ophthalmic prednisolone suspension or an antihistamine olopatadine suspension.

[0010]

[0010] In certain embodiments, the reduced side effect is an ocular side effect selected from the group consisting of: increased intraocular pressure, thinning of the cornea, sclera and epithelial tissue, perforation of the cornea, sclera and epithelial tissue, delayed or decreased wound or epithelial healing, hyperemia, eyelid edema, pain, ocular pruritus, hives, rash, allergic reactions, keratitis, conjunctivitis, posterior subcapsular cataract formation, glaucoma, optic nerve damage, corneal ulcer, pupillary dilation, visual defects, burning sensation, stinging sensation, foreign body sensation, increased susceptibility to fungal, bacterial, or viral infections, reactivation of fungal or viral infections, masking of acute suppurative infections, increased postoperative blebbing, dry eye, punctate keratopathy, central serous chorioretinopathy, and ophthalmicus medicamentosa, reduced accommodative amplitude, ptosis, acute anterior uveitis, or ocular perforation.

[0011]

[0011] In certain embodiments, the reduced side effects are systemic side effects selected from the group consisting of: changes in blood glucose levels, weight gain or loss, decreased systemic wound healing, susceptibility to systemic microbial infections, irritation to tissues around the eyes, cold symptoms, pharyngitis, asthenia, back pain, headache, cough, nausea, rhinitis, sinusitis, osteoporosis, and taste inversion or dysgeusia, or sulfite-related anaphylaxis.

[0012]

[0012] In certain embodiments, the administration downregulates inflammatory stress-driven cytokine or chemokine activity, particularly Th17, Th1, and / or Th2 cytokine activity, in at least one ocular tissue selected from the group consisting of corneal and conjunctival tissues.

[0013] In certain embodiments, roflumilast more strongly downregulates cytokine activity, including Th1, Th2, and / or Th17-associated cytokines, compared to cytokine downregulation by immunosuppressants, immunomodulators, or nonsteroidal anti-inflammatory drugs. Furthermore, in certain embodiments, cytokine downregulation by roflumilast is more robust in the conjunctiva than downregulation by steroids or antihistamines.

[0014]

[0014] In certain embodiments, the administration results in disease-modifying activity in at least one supporting tissue or gland selected from the group consisting of the cornea, conjunctiva, meibomian gland, iris, uvea, retina, and choroid.

[0015] In certain embodiments, the ocular inflammatory disorder is: post-operative pain and inflammation from cataract or other ophthalmic surgery or laser treatment, blurred vision after corneal refractive surgery, post-operative full or partial thickness corneal transplant, dry eye syndrome associated with Sjogren's syndrome or other autoimmune or inflammatory disease, evaporative or desiccant dry eye disease, ocular graft-versus-host disease, ocular rosacea, allergic conjunctivitis or keratoconjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, keratitis, herpetic or viral stromal keratitis / herpetic or viral blepharitis or conjunctivitis, inflammation associated with varicella zoster, bacterial In one embodiment, the ocular surface disease is selected from the group consisting of inflammation secondary to other infectious agents such as ocular, viral, or fungal infections, inflammation secondary to ocular chemical burns, ocular Stevens-Johnson syndrome / toxic epidermolysis, uveitis including juvenile idiopathic arthritic uveitis, seborrheic or other forms of blepharitis, limbal stem cell deficiency, meibomian gland dysfunction, episcleritis, pingueculitis, and pterygium, phlyctenular conjunctivitis, staphylococcal hypersensitivity, Mooren's ulcer, endotheliitis, superior limbal keratoconjunctivitis, or other ocular conditions traditionally treated with steroids where the patient is contraindicated due to intraocular pressure, wound healing, or a history of fungal or other microbial infection.

[0016] In certain embodiments, the ocular inflammatory disorder is an anterior or posterior ocular disease selected from the group consisting of anterior uveitis, panuveitis and posterior uveitis (infectious or non-infectious), diabetic retinopathy, diabetic macular edema, geographic atrophy, dry or wet age-related macular degeneration, retinal vein occlusion, drug-related / iatrogenic, non-infectious / sterile, or idiopathic retinal vasculitis, endophthalmitis, or retinitis, ocular Behcet's disease, and other inflammatory diseases of the anterior and posterior tissues of the eye. In preferred embodiments, the ocular inflammatory disorder is dry eye disease, uveitis, or herpetic or viral keratitis.

[0017] Another embodiment of the present invention provides a method of treating a patient with an ocular inflammatory or immune-mediated disorder. The method comprises administering to the ocular surface of the patient an ophthalmic pharmaceutical formulation comprising a therapeutically effective amount of roflumilast or a pharma- ceutically acceptable salt or metabolite thereof. The administration downregulates inflammatory stress-driven cytokine activity in at least one ocular tissue selected from the group consisting of corneal and conjunctival tissues. In certain embodiments, the pharmaceutical formulation is a suspension.

[0018] Another embodiment of the present invention provides a method of treating a patient with an ocular inflammatory or immune-mediated disorder. The method comprises administering to the ocular surface of the patient an ophthalmic pharmaceutical formulation comprising a therapeutically effective amount of roflumilast or a pharma- ceutically acceptable salt or metabolite thereof. The administration downregulates cytokine activity in a manner superior to cytokine downregulation by corticosteroids or other immunosuppressants, immunomodulators, or nonsteroidal anti-inflammatory agents, including antihistamines. In certain embodiments, administration of the roflumilast composition results in downregulation of cytokine activity in a manner superior to cytokine downregulation by administration of ophthalmic prednisolone suspension or antihistamine olopatadine suspension.

[0019]

[0019] The accompanying drawings, which are incorporated herein and form a part of this disclosure, serve to illustrate various embodiments of the invention and, together with the description, further serve to explain the invention so as to enable one skilled in the art to make and use the embodiments disclosed herein. Error bars in the figures are standard deviation values. [Brief description of the drawings]

[0020] [Figure 1]

[0020] This graph provides data on body weight after 7 days of administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%) measured in a mouse preclinical model of systemic and local allergen challenge. [Diagram 2]

[0021] FIG. 1 provides data on the clinical response of hyperemia following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%) as measured in a mouse preclinical model of systemic and local allergen challenge. [Diagram 3]

[0022] FIG. 1 provides data on the clinical response of eyelid swelling following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%) as measured in a mouse preclinical model. [Figure 4]

[0023] FIG. 1 is a graph providing data regarding the clinical response of ocular discharge following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%) as measured in a mouse preclinical model. [Diagram 5]

[0024] FIG. 1 is a graph providing data on the clinical response of strabismus following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%) as measured in a mouse preclinical model. [Figure 6]

[0025] FIG. 1 is a graph providing data on Th2 cytokine responses following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%) as measured in a mouse preclinical model. [Figure 7]

[0026] FIG. 13 provides data on Th17 (IL-6) and Th1 (IL-12p70 and TNF-a) cytokine responses following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%) as measured in a mouse preclinical model. [Figure 8]

[0027] FIG. 13 provides data on Th1 cytokine and chemokine responses following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%) as measured in a mouse preclinical model. [Figure 9]

[0028] 1 is a graph providing the results of a 13-week GLP toxicology study of body weight following administration of roflumilast topical ophthalmic suspension (0.1%, 0.3%, 1.0%) and placebo / vehicle. [Figure 10]

[0029] 1 is a graph providing the results of a 13-week GLP toxicology study of intraocular pressure (IOP) following administration of roflumilast topical ophthalmic suspension (0.1%, 0.3%, 1.0%) and placebo / vehicle. [Figure 11]

[0030] 1 is a graph providing the results of a 13-week GLP toxicology study of central corneal thickness (pachymetry) following administration of roflumilast topical ophthalmic suspension (0.1%, 0.3%, 1.0%) and placebo / vehicle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021]

[0031] It is to be understood that the present invention is not limited to the specific methodology, protocols, and reagents described herein, as they may vary. It is also to be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.

[0022]

[0032] All publications, patents and patent applications cited herein are incorporated herein in their entirety by reference unless otherwise stated.When the same term is defined in a publication, patent, or patent application and in this disclosure incorporated herein by reference, the definition in this disclosure represents the controlling definition.For publications, patents, patent applications that are referenced to describe a particular type of compound, chemistry, etc., the portion that relates to such compound, chemistry, etc. is the portion of the document that is incorporated herein by reference.

[0023]

[0033] It should be noted that as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, "an active ingredient" includes both a single ingredient and two or more distinct ingredients.

[0024]

[0034] The term "about," when used in connection with a numerical value, is intended to encompass numerical values ​​in a range having a lower limit of 5% less than the stated numerical value and an upper limit of 5% greater than the stated numerical value.

[0025]

[0035] The term "effective" refers to an amount of a compound, drug, substance, preparation or composition that is sufficient to reduce the severity of disease symptoms, increase the frequency and duration of disease symptom-free periods, or prevent functional impairment or disability due to disease affliction. The amount may be administered alone or in combination with other compounds, drugs or substances, either as a single dose or in a multiple dose regimen. Those skilled in the art can determine such amounts based on factors such as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0026]

[0036] The terms "eye disorder," "eye condition," or "ocular disorder" refer to an eye disease / condition(s) that may threaten vision, result in eye discomfort, and may be indicative of general health. The ocular surface is composed of the cornea, conjunctiva, eyelids, lacrimal and meibomian glands, and interconnecting nerves.

[0027]

[0037] "Pharmaceutically acceptable" means generally safe for administration to humans or animals. Preferably, a pharmaceutically acceptable ingredient is one that has been approved by a federal or state government regulatory agency for use in animals, more particularly humans, or is listed in the United States Pharmacopeia, published by the United States Pharmacopeia, Inc., Rockville Md., or other generally recognized pharmacopoeias.

[0028]

[0038] A "pharmaceutical composition" according to the invention may be in the form of a composition in which the different active ingredients and the diluents and / or carriers are mixed with one another, or it may take the form of a combined preparation in which the active ingredients are partially or wholly present in different forms. An example of such a combination or combined preparation is a kit-of-parts.

[0029]

[0039] The term "roflumilast," as used in this application, refers to roflumilast, its salts, the N-oxide of roflumilast and its salts, as well as other hydrolyzable or amide metabolites, unless otherwise specified or clear from the context that reference is to roflumilast itself.

[0030]

[0040] As used herein, the term "subject" or "patient" most preferably refers to a human. The term "subject" or "patient" may include any mammal that may benefit from the compounds described herein.

[0031]

[0041] A "therapeutic amount" or a "therapeutically effective amount" is an amount of a therapeutic agent sufficient to achieve its intended purpose. The effective amount of a given therapeutic agent varies depending on factors such as the nature of the agent, the route of administration, the size of the subject receiving the therapeutic agent, and the purpose of administration. The effective amount in each individual case can be empirically determined by those skilled in the art using methods established in the art.

[0032]

[0042] As used herein, "treat," "treating," or "treatment" of a disease or disorder means accomplishing one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing the recurrence of the disorder(s) in patients who previously had the disorder(s); and (e) limiting or preventing the recurrence of symptoms in patients who previously had symptoms of the disorder(s).

[0033]

[0043] The present invention relates to a method of treating ocular inflammatory disease by administering ophthalmic pharmaceutical suspension of roflumilast.The inventors of the present application have surprisingly discovered that administration of ophthalmic pharmaceutical suspension of roflumilast can provide clinically meaningful anti-inflammatory activity compared to existing immunomodulatory, immunosuppressive and nonsteroidal anti-inflammatory treatments, including corticosteroids and antihistamines, while providing an improved safety profile compared to these drugs and adding the benefit of convenience in a less frequent dosing format.The present invention addresses the high unmet need for alternative classes of drugs to address the inflammatory drivers of OSD, with high efficacy and even less patient- or population-based side effects and inconvenience.The present invention can provide short-term, medium-term, or long-term treatment for ocular diseases with inflammatory or immune-mediated components.

[0034]

[0044] In certain embodiments, the method comprises administering to a patient suffering from an ocular inflammatory disease an ophthalmic pharmaceutical suspension comprising a therapeutically effective amount of a phosphodiesterase-4 inhibitor, roflumilast, or a pharma- ceutical acceptable salt or metabolite thereof. In certain embodiments, the pharmaceutical composition comprises as an active ingredient a metabolite of roflumilast, comprising an N-oxide of the pyridine residue of roflumilast, or a salt thereof.

[0035]

[0045] Roflumilast is a compound of formula (I):

[0036] [ka]

[0037] In the formula, R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyrid-4-yl.

[0046] Roflumilast has the chemical name N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide. The N-oxide of roflumilast has the chemical name 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl 1-oxide)benzamide. Roflumilast and its synthesis, use of roflumilast as a phosphodiesterase (PDE) 4 inhibitor, and roflumilast formulations are described in U.S. Patent No. 5,712,298, which is incorporated herein by reference. The ophthalmic pharmaceutical composition may include roflumilast as a free base or a pharma-ceutical acceptable salt thereof. Exemplary salts of roflumilast are those described in U.S. Patent Application Publication No. 2006 / 0084684, paragraphs

[0012] and

[0013] , the disclosure of which is incorporated herein by reference. In certain embodiments, the pharmaceutical composition comprises a metabolite of roflumilast, including an N-oxide or salt of the pyridine residue of roflumilast, as an active ingredient. In certain embodiments, the pharmaceutical composition comprises a hydrolyzable or amide metabolite of roflumilast.

[0038]

[0047] In certain embodiments of the invention, roflumilast is administered to the ocular surface of a patient having an ocular disorder or condition, including, for example, an ocular inflammatory disorder. In certain embodiments, the ocular inflammatory disorder is: post-operative pain and inflammation from cataract or other ocular surgery or laser treatment, blurred vision after corneal refractive surgery, post-operative full or partial thickness corneal transplant, dry eye syndrome associated with Sjogren's syndrome or other autoimmune or inflammatory disease, evaporative or desiccant dry eye disease, ocular graft versus host disease, ocular rosacea, allergic conjunctivitis or keratoconjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, keratitis, herpetic or viral stromal keratitis / herpetic or viral blepharitis or conjunctivitis, herpes zoster-related inflammation, bacterial, viral, or other inflammatory conditions. In one embodiment, the ocular surface disease is selected from the group consisting of inflammation secondary to other infectious agents such as bacterial, fungal, or mycotic infections, inflammation secondary to ocular chemical burns, ocular Stevens-Johnson syndrome / toxic epidermolysis, uveitis including juvenile idiopathic arthritic uveitis, seborrheic or other forms of blepharitis, limbal stem cell deficiency, meibomian gland dysfunction, episcleritis, pingueculitis, and pterygium, phlyctenular conjunctivitis, staphylococcal hypersensitivity, Mooren's ulcer, endotheliitis, superior limbal keratoconjunctivitis, or other ocular conditions traditionally treated with steroids where the patient is contraindicated due to intraocular pressure, wound healing, or a history of fungal or other microbial infection.

[0039]

[0048] In a particular embodiment of the present invention, roflumilast is administered to the anterior or posterior segment of a patient with an ocular disorder or condition.In a particular embodiment, the ocular inflammatory disorder is an anterior or posterior ocular disease selected from the group consisting of anterior uveitis, panuveitis and posterior uveitis (infectious or non-infectious), diabetic retinopathy, diabetic macular edema, geographic atrophy, dry or wet age-related macular degeneration, retinal vein occlusion, drug-related / iatrogenic, non-infectious / sterile, or idiopathic retinal vasculitis, endophthalmitis, or retinitis, ocular Behcet's disease, and other inflammatory diseases of the anterior and posterior tissues of the eye.In a preferred embodiment, the ocular inflammatory disorder is dry eye disease, uveitis, or herpetic or viral keratitis.

[0040]

[0049] Other examples of eye disorders that can be treated by the methods disclosed herein may include ocular conditions that are traditionally treated with corticosteroids, which are contraindicated for patients due to their history, such as intraocular pressure, wound healing, fungal or other microbial infections, thin or punctate corneal or retinal epithelium, or due to intolerance or non-compliance with the frequency of administration, or intolerance to the drug administration itself. Eye disorders treatable by the methods described herein may be acute or chronic. In certain embodiments, eye disorders originate from infectious or other external antigenic origins, which in turn cause an inflammatory cascade. In a preferred embodiment, the eye inflammatory disorder is dry eye disease, uveitis, or herpetic or viral stromal keratitis.

[0041]

[0050] In certain embodiments, the ophthalmic pharmaceutical formulation is administered as multiple types of injections (including intravitreal, suprachoroidal, sub-Tenon, subconjunctival or other sites) or devices, implanted injections, or depots that can be used to treat anterior or posterior inflammatory eye diseases, such as anterior uveitis, panuveitis and / or posterior uveitis (infectious or non-infectious), diabetic retinopathy, diabetic macular edema, geographic atrophy, dry or wet age-related macular degeneration, retinal vein occlusion, drug-related / iatrogenic, non-infectious / sterile, or idiopathic retinal vasculitis, endophthalmitis, or retinitis, ocular manifestations of Behcet's disease, or other inflammatory diseases of the anterior and posterior tissues of the eye.

[0042]

[0051] In certain embodiments, the pharmaceutical composition is administered according to a regimen, such as at regular intervals. For example, the pharmaceutical composition can be administered directly to the ocular surface once a day, twice a day, three times a day, four times a day, once a week, twice a week, three times a week, or four times a week, monthly, as needed (PRN) or extended treatment. In certain embodiments, the pharmaceutical composition can be administered as part of a maintenance or titration regimen. The pharmaceutical composition can be administered for a prescribed period of time. For example, the pharmaceutical composition can be administered for a period of about 2 days to at least about 6 weeks, or until an improvement in ocular condition or disease is observed. Exemplary periods of treatment regimen include 1 week, 2 weeks, 1 month, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or 1 year. For example, the pharmaceutical composition may be administered as an injection or as an implantable, depot, or adsorbent device, once a week, once a month, once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks, once a quarter, once every 6 months, as needed (PRN), as directed by a physician, or according to some clinical criteria, such as treatment and extension or other criteria. The pharmaceutical composition may be administered as an open-ended continuous treatment.

[0043]

[0052] In certain embodiments, administration of ophthalmic pharmaceutical compositions of roflumilast to patients results in significant immunomodulatory and anti-inflammatory activity.The anti-inflammatory activity achieved as a result of the methods disclosed herein can be similar, comparable, or greater than that achieved through frequently administered, commonly used, and potent corticosteroids and / or antihistamines, including but not limited to ophthalmic prednisolone suspension and ophthalmic olopatadine solution.As a PDE4 inhibitor, roflumilast is known to have a broad range of inhibitory effects on inflammatory mediators, such as cytokines, through the increase of cyclic AMP and other downstream mediators.The methods disclosed herein can downregulate inflammatory stress-driven cytokine disease activity, particularly Th17, Th1, and Th2 cytokines, in both conjunctival and corneal tissues. Furthermore, the methods disclosed herein can extend disease-modifying activity beyond conjunctival and corneal tissues to other ocular and orbital tissues, including supporting tissues such as meibomian glands, and anterior tissues such as iris (including ciliary body) and uvea, and posterior tissues such as retina and choroid. The methods of the present invention can result in reduced inflammatory activity, as well as reduced intracellular trafficking of cytokines and immune cells across cellular tissues, as evidenced by reduced signs of inflammation and / or intracellular trafficking of cytokines in and across the cornea and conjunctiva. Downregulation of cytokines and chemokines is also important in reducing vascular chemotaxis or neovascular growth, macrophage polarization, and the broader infiltrating T-cell and B-cell immune responses across ocular tissues, as well as exchange between the eye and the broader systemic environment. In certain embodiments, downregulation of cytokine activity and associated immune activity by roflumilast is similar to or superior to immunomodulators and immunosuppressants such as corticosteroids or antihistamines.

[0044]

[0053] In addition, the safety profile of the methods disclosed herein may be similar, comparable, or better than that of frequently dosed, commonly used, and potent corticosteroids and / or antihistamines, including, but not limited to, ophthalmic prednisolone suspension and ophthalmic olopatadine solution. In certain embodiments, the methods result in a reduction in at least one side effect compared to administration of ophthalmic prednisolone suspension or other corticosteroids. In certain embodiments, the reduced side effect is an ocular side effect selected from the group consisting of: increased intraocular pressure, thinning of the cornea, sclera and epithelial tissue, perforation of the cornea, sclera and epithelial tissue, delayed or decreased wound or epithelial healing, hyperemia, eyelid edema, pain, ocular pruritus, hives, rash, allergic reactions, keratitis, conjunctivitis, posterior subcapsular cataract formation, glaucoma, optic nerve damage, corneal ulcer, pupil dilation, visual defects, burning sensation, stinging sensation, foreign body sensation, increased susceptibility to fungal, bacterial, or viral infections, reactivation of fungal or viral infections, masking of acute suppurative infections, increased postoperative blebbing, dry eye, punctate keratopathy, central serous chorioretinopathy, and drug-induced eye, diminished accommodative amplitude, ptosis, acute anterior uveitis, and ocular perforation.

[0045]

[0054] In certain embodiments, the reduced side effects are systemic side effects selected from the group consisting of: changes in blood glucose levels, weight gain or loss, decreased systemic wound healing, susceptibility to systemic microbial infections, irritation to tissues around the eye, cold symptoms, sore throat, asthenia, back pain, headache, cough, nausea, rhinitis, sinusitis, osteoporosis, and taste inversion or dysgeusia, and sulfite-related anaphylaxis. Additionally, inactive ingredients and preservatives in these pharmaceutical ingredients may be absorbed by the contact lenses of contact lens wearers.

[0046]

[0055] In addition, in certain embodiments, the use of roflumilast pharmaceutical compositions can provide patients and caregivers with the benefit of less frequent administration, which is both more convenient and allows patients to work, travel, and leave the house without these medications, but also means avoiding the pain and discomfort of applying drugs multiple times a day.The PK profile of this drug is such that in certain embodiments, it can be used once or twice a day (QD or BID), compared to the frequent dosing of corticosteroids, which is 8 times a day or more QID.In some eye diseases, doctors ask patients to use corticosteroid topical ophthalmic preparations once every hour or two hours and stay up at night to instill additional doses, which causes significant burden to patients and caregivers.

[0047]

[0056] In addition, for patients who require moderate to long-term anti-inflammatory medical intervention, the use of corticosteroids entails an increased burden on patients and physician practices, as patients require frequent monitoring for safety concerns, including intraocular pressure, cataract formation, and infection. This is particularly difficult for patients for whom this monitoring is difficult or uncomfortable: young children, the elderly, and patients with sensitive ocular tissues due to long-term illness, all of which frequently overlap with inflammatory eye diseases. In this embodiment, the drug can avoid the need and expense for such frequent monitoring.

[0048]

[0057] In the present invention, a patient who needs to administer an ophthalmic pharmaceutical composition is administered an ophthalmic pharmaceutical composition containing a therapeutically effective amount of roflumilast. The ophthalmic pharmaceutical composition can be formulated into the following preparations using many widely used methods well known to those skilled in the art. For example, the ophthalmic pharmaceutical composition can be a gel, ointment, cream, solution, suspension, or other topical formulation. In certain embodiments, the ophthalmic pharmaceutical composition can be a periocular or subconjunctival implant or injection via various sites (intravitreal, subconjunctival, subtenon, suprachoroidal, etc.), or an intracorneal or intravitreal implant, injection, or depot. In a preferred embodiment, the ophthalmic pharmaceutical composition is administered topically directly to the eye in the form of a suspension.

[0049]

[0058] In certain embodiments, the ophthalmic pharmaceutical composition may contain roflumilast in the range of about 0.01% w / v to about 5.0% w / v, or about 0.01% w / v to about 3.0% w / v, or about 0.01% w / v to about 2.0% w / v, or about 0.01% to about 1.0% w / v, or about 0.01% to about 0.3% w / v. For example, an ophthalmic medication may contain roflumilast in any of the following w / v percentages: 0.01%, 0.05%, 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%, 7%, 1.8%, 1.9%, 1.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, etc.

[0050]

[0059] In certain embodiments, the ophthalmic pharmaceutical composition may be a suspension, a solution, an eye drop, an eye ointment, a gel, a cream, a spray, an intranasal spray, an injectable formulation (intravitreal, subconjunctival, subtenon, suprachoroidal or other injection), or an adsorbent device or an implanted injection or depot, or an adsorbent contact lens. In a preferred embodiment, the pharmaceutical composition is a suspension, and the active ingredient (i.e., roflumilast) is suspended in a pharmaceutical carrier and / or excipient. In certain embodiments, the ophthalmic pharmaceutical composition of roflumilast includes a thickening agent, a surfactant, and a buffering agent. In certain embodiments, the ophthalmic pharmaceutical composition may include one or more additional excipients, including, for example, a stabilizer, a preservative, a wetting agent, a diluent, a pH adjuster, a tonicity agent, or an absorption enhancer. In certain embodiments, the ophthalmic pharmaceutical compositions may also be utilized in the form of injections (intravitreal, suprachoroidal, or other), as depots, implantable adhesive devices for any ophthalmic or peripheral tissue placement, in situ forming gels, or drug / device combinations in anterior or posterior ocular locations, where the active ingredient (i.e., roflumilast) is suspended with one or more excipients as described above, such as, for example, viscosity enhancing agents, surfactants, or buffers; with or without a device or inert depot compound.

[0051]

[0060] In certain embodiments, the thickening agent is at least one selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), polyvinylpyrrolidone or povidone, carboxymethylcellulose, hypromellose, methylcellulose, or polyvinyl alcohol (PVA).In certain embodiments, the thickening agent is dextran or gelatin.In addition, the thickening agent may include carbomer, such as carbomer copolymer type A or carbomer copolymer type B, including those sold under the trade name Carbopol by Lubrizol® in certain embodiments. In certain embodiments, the ophthalmic pharmaceutical formulation may contain a viscosity enhancing agent in the range of about 0.1% w / v to about 5.0% w / v, or about 0.1% w / v to about 4.0% w / v, or about 0.1% w / v to about 3.0% w / v, or about 0.1% w / v to about 2.0% w / v, or about 0.1% to about 1.0% w / v, or about 0.1% to about 0.5% w / v. For example, an ophthalmic medication may contain any of the following w / v percentages of a thickening agent: 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%, 7%, 1.8%, 1.9%, 1.0%, 2.1%, 2.2%. , 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0% etc.

[0052]

[0061] In certain embodiments, the surfactant is at least one selected from the group consisting of polysorbates (including polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80) and tyloxapol. In certain embodiments, the ophthalmic pharmaceutical formulation may contain a surfactant in the range of about 0.05% w / v to about 3.0% w / v, or about 0.05% w / v to about 2.0% w / v, or about 0.05% to about 1.0% w / v, or about 0.1% to about 0.5% w / v. For example, an ophthalmic medication may contain a surfactant in any of the following w / v percentages: 0.05%, 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%, 7%, 1.8%, 1.9%, 1.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, etc.

[0053]

[0062] In certain embodiments, the buffering agent is at least one selected from the group consisting of citrate, phosphate, Tris-HCl (Tris), acetate, and borate buffering agents. In certain embodiments, the ophthalmic pharmaceutical formulation may contain a buffering agent in the range of about 0.5% w / v to about 7.5% w / v, or about 0.5% w / v to about 5.0% w / v, or about 0.5% to about 3.0% w / v, or about 0.5% w / v to about 2.0% w / v, or about 0.5% to about 1.0% w / v. For example, ophthalmic medications may contain any of the following w / v percentages of buffer: 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%, 7%, 1.8%, 1.9%, 1.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 2.10%, 2.12%, 2.14%, 2.16%, 2.18%, 2.19%, 2.26%, 2.28%, 2.29%, 2.30%, 2.31%, 2.32%, 2.33%, 2.34%, 2.35%, 2.36%, 2.37%, 2.38%, 2.39%, 2.40%, 2.41%, 2.42%, 2.43%, 2.44%, 2.45%, 2.46%, 2.47%, 2.48%, 2.49 ... .3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0% etc.

[0054]

[0063] In certain embodiments, the ophthalmic pharmaceutical formulation is an ointment. The ointment may include an inactive ingredient selected from the group consisting of petrolatum, mineral oil, and in such embodiments, the ophthalmic pharmaceutical formulation may include a therapeutically effective amount of roflumilast, petrolatum, and mineral oil. In certain embodiments, the composition includes about 0.1% w / v to about 3.0% w / v, or about 0.1% w / v to about 2.0% w / v, or about 0.1% to about 1.0% w / v of roflumilast. In certain embodiments, the composition includes about 75% to about 85% w / w of petrolatum, or more preferably about 75% to about 80% w / w of petrolatum. In certain embodiments, the composition includes about 15% to about 25% w / w of mineral oil, or more preferably about 15% to about 20% w / w of mineral oil. Ointments can offer advantages compared to suspensions, including, for example, increased contact time and increased soluble drug concentration in the dosage system, which can be important for water-insoluble drugs such as roflumilast.

[0055]

[0064] The inventors of the present application have confirmed that roflumilast undergoes hydrolysis in certain ophthalmic pharmaceutical compositions under certain standard sterile manufacturing processes. In certain embodiments, the pH of the ophthalmic pharmaceutical composition is between 5.5 and 7.5. In a preferred embodiment, the pH of the ophthalmic pharmaceutical composition is between about 6.0 and about 6.7 to reduce the rate of hydrolysis of roflumilast. In certain embodiments, the pH of the ophthalmic pharmaceutical composition is between about 6.2 and about 6.7, or in some embodiments, between 6.3 and 6.6. In certain embodiments, the osmolality of the ophthalmic pharmaceutical composition is about 270 mOsm / kg to 330 mOsm / kg, more preferably about 270 mOsm / kg to about 300 mOsm / kg, and even more preferably 270 mOsm / kg to 280 mOsm / kg.

[0056]

[0065] The ophthalmic pharmaceutical composition of the present invention is stable and exhibits a particle size distribution suitable for delivery to the eye. The particle size of the ophthalmic pharmaceutical composition for suspension can be determined using a laser diffraction method. Laser diffraction is recognized by standards and guidance organizations including ISO and ASTM and is widely used to determine particle size distribution. In performing the determination, the sample passes through a laser beam, which causes the laser light to scatter at a range of angles. A detector placed at a fixed angle measures the intensity of the light scattered at that position. A mathematical model is then applied to generate the particle size distribution.

[0057]

[0066] In particle size determination, the median is defined as the value above which half of the population lies and below which half lies. In terms of particle size distribution, the median is called the D50. The D50 is the size that divides the distribution so that half is above this diameter and half is below this diameter. The distribution width can also be typically characterized by listing one, two, or three values ​​on the x-axis, such as some combination of D10, D50, and D90. The D50 (or median), as discussed above, refers to the diameter below which half of the population lies. Similarly, 90 percent of the distribution is below the D90 and 10 percent of the distribution is below the D10.

[0058]

[0067] In certain embodiments of the present invention, the ophthalmic pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of about 50 μm or less, prior to preferential processing. In certain embodiments, the ophthalmic pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of about 5 μm to about 25 μm. In certain embodiments, the pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of about 5 μm to about 15 μm. In a preferred embodiment, the pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of about 10 μm or less.

[0059]

[0068] In certain embodiments, the pharmaceutical composition of roflumilast is sterilized using slow dry heat sterilization at a temperature below the melting point of roflumilast, gamma irradiation, or other sterilization methods. In certain embodiments, gamma radiation or other end-product sterilization methods can be used to sterilize and ensure sterility of the final drug product in the final packaging by applying low to moderate levels of gamma irradiation, which is a preferred embodiment to maximize patient safety and comfort since the product does not need to contain preservatives that are known to sting when applied. In certain embodiments, the ophthalmic pharmaceutical composition can be characterized by a retention potency of greater than 99% of the original value of the active substance. In certain embodiments, the retention potency is greater than 99.1%, 99.2%, 99.3%, 99.4%, or 99.5% of the original value of the active substance.

[0060]

[0069] The following examples illustrate certain embodiments of the invention without limiting them. EXAMPLES

[0061]

[0070] While various embodiments have been described herein, it should be understood that these are presented by way of example only and not by way of limitation. Thus, the breadth and scope of the present disclosure should not be limited by any of the exemplary embodiments described. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure unless otherwise indicated herein or clearly contradicted by context.

[0062]

[0071] Example 1

[0072] Ophthalmic pharmaceutical compositions containing roflumilast as set forth in Table 1 were prepared.

[0063] [Table 1]

[0064]

[0073] Example 2

[0074] Ophthalmic pharmaceutical compositions containing roflumilast as set forth in Table 2 were prepared.

[0065] [Table 2]

[0066]

[0075] Example 3 Ophthalmic pharmaceutical compositions containing roflumilast as set forth in Table 3 were prepared.

[0067] [Table 3]

[0068]

[0076] Example 4

[0077] Ophthalmic pharmaceutical compositions containing roflumilast as set forth in Table 4 were prepared.

[0069] [Table 4]

[0070]

[0078] Examples 5 and 6

[0079] Pharmaceutical ophthalmic ointments containing roflumilast as set forth in Table 5 were prepared.

[0071] [Table 5]

[0072]

[0080] Example 7

[0081] Ophthalmic pharmaceutical compositions containing roflumilast as set forth in Table 6 were prepared.

[0073] [Table 6]

[0074]

[0082] Example 8

[0083] Two animal studies were carried out to determine the safety and tolerability of roflumilast (Example 7). Roflumilast has been shown to be well tolerated in two animal models, which are highly correlated with human models. The first study is a 3-day pilot study of rabbit tolerability, and the second study is a 5-day rabbit model of tolerability, which found no drug effects on ocular tissues, as well as no adverse effects on animal weight. Animals in these studies maintained or gained normal weight over the study period. Rabbit ocular tolerability is well known as a proxy for human tolerability of ophthalmic preparations, and weight is an indicator of the overall health of the animal.

[0075]

[0084] Example 9

[0085] The safety of roflumilast (Example 7, BID) was compared to that of a corticosteroid (Prednisolone acetate ophthalmic suspension, 1%, QID to BID) and an antihistamine (Olopatadine HCl ophthalmic solution, 0.1%, QID to BID) in a 24-day mouse preclinical model of allergic conjunctivitis with long-term inflammation. In a mouse preclinical model of short-term and long-term inflammation caused by antigen challenge with systemic and local ragweed allergen (SRW), n=70 female Balb C mice in a provocative environment (68-79 dF, 50% + / - 20% humidity, 55-60 air changes / hour) were exposed to SRW systemically by SC injection into both hind legs on days 0 and 11 for 17 days. The mice were then exposed to a local SRW challenge on day 18 (first local challenge - baseline), followed by a first local drug treatment with roflumilast (Example 7), vehicle with no active drug, high dose prednisolone 1% dosed repeatedly (BID-QID), or olopatadine 0.1% dosed repeatedly (BID-QID). On day 18, mice were randomized (10 per group) based on achieving a clinical level of hyperemic response. Mice were then given two days (days 19-20) of prophylactic drug treatment before a twice-daily local challenge of SRW antigen (within 30-90 minutes of drug treatment) on days 21-24, and then the response to drug treatment was followed (roflumilast topical ophthalmic suspension and vehicle BID), (two positive controls (prednisolone and olopatadine) QID, TID, or BID). The results of this study are illustrated in Figures 1-5 and described below. Mouse models are commonly used to compare standard of care corticosteroids and antihistamines with novel agents.

[0076]

[0086] Drug dosing was initiated only on day 18. During the study, the weights of the mice were determined after days 11, 18, and 24 of the study. Figure 1 illustrates the weights of mice following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%) measured in an animal model study. Mice exposed to high frequency, high doses of corticosteroids showed weight loss over 18-24 days, which is a typical response of mice exposed to corticosteroids. Although different from the human response, it is an indication of the overall systemic health risk due to even localized corticosteroid exposure. There were no effects on weight, cage side observation, food intake, or other markers of ocular or overall systemic health in the roflumilast group, suggesting that the drug was well tolerated. The inflammatory clinical responses of hyperemia, eyelid swelling, eye discharge, and strabismus were also examined on days 18, 21 (early phase), and days 22, 23, and 24 (late phase). Figure 2 illustrates the clinical response of hyperemia after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%), as measured in an animal model study. Figure 3 illustrates the clinical response of eyelid swelling after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%), as measured in an animal model study. Figure 4 illustrates the clinical response of ocular discharge measured in an animal model study following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%). Figure 5 illustrates the clinical response of strabismus measured in an animal model study following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%).

[0077]

[0087] As illustrated in Figure 5, both the corticosteroid and antihistamine groups showed an increase in strabismus over the course of the study, which may also be recognized as a marker for local irritation. Strabismus was less frequent in both the roflumilast and vehicle groups, and was significantly less frequent in the early stages. No safety or behavioral challenges in the cage side were observed in either group, other than the weight loss and strabismus mentioned above. Thus, the roflumilast and vehicle groups showed improved tolerability in this preclinical study compared to the active control, which represents the current standard of care in human pharmaceutical topical treatment of most OSDs.

[0078]

[0088] Additionally, as illustrated in Figures 2-5, preclinical mouse models of chronic inflammation caused by both systemic and topical models of allergic conjunctivitis demonstrated that roflumilast was able to improve the inflammatory clinical responses of hyperemia, eyelid swelling, eye discharge, and strabismus compared to baseline. Significance from baseline was not measured in this study. Although the overall baseline inflammation seen in this model was relatively low, the intervention generally performed better than baseline and resulted in clinical improvement, including in the roflumilast group. The corticosteroid group performed better than the other groups for fewer days and in clinical endpoints, but not consistently, suggesting that roflumilast may provide similar levels of efficacy without the safety concerns outlined above.

[0079]

[0089] Example 10

[0090] As part of the mouse preclinical model discussed in Example 9, administration of cytokine upregulation as a marker of pharmaceutical control of inflammation was measured by comparing the levels of cytokines in conjunctival and corneal tissues at the end of the experimental time frame following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%). The results of these cytokine-based inflammation measurements are illustrated in Figures 6-8 and described below. Figure 6 illustrates the Th2 cytokine response measured in an animal model study following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%). Figure 7 illustrates the Th17 cytokine response measured in an animal model study following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%). Figure 8 illustrates the Th1 cytokine response, as well as the response of the chemokine KC / GRO, also known as CXCL1, following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%), and olopatadine HCl ophthalmic solution (0.1%), as measured in an animal model study.

[0080]

[0091] Cellular inflammation, as measured by final cytokine levels, was at higher absolute levels than clinical findings, and more variable between groups, making it a useful indicator of disease response. Systemic and local antigen challenge with SRW, a mediator of long-term inflammation, was initiated on days 1 and 18, respectively, but pharmaceutical treatment in each group was only initiated on day 18 for a total of 24 days in each of these experiments, allowing long-term inflammation to be created over time before any treatment was administered. However, in seven eye samples pooled into four samples (pooled to ensure sufficient cytokine concentrations), only roflumilast-treated animals had undetectable cytokine levels of all four conjunctival cytokines associated with Th2 responses (the primary tissue and mechanism of response to the allergic conjunctivitis disease state underlying the model) - namely, IL2, IL4, IL5, and IL10 in all four samples. In this end value assay, an undetectable level meant that the cytokine was not present in either the model or in its tissues, or that the drug successfully reduced the cytokine below the measurable limit, sufficiently downregulating that particular cytokine. The higher the relative level of the cytokine measured in pg / μg of the relevant tissue, the greater the inflammatory impact that the cytokine has on the ocular tissue. The goal of treatment was to reduce the cytokine to undetectable or as close to undetectable as possible, and understand which inflammatory targets are most relevant in which tissue. The standard of care for treatment of this disease has traditionally been known to have either an immediate response (e.g., olopatadine) or a strong and sustained response (e.g., corticosteroids), and the conjunctival Th2 cytokine sample had a significantly high residual level of cytokines, without controlling their inflammatory impact on the disease.Of the two known primary mechanisms of PDE-4 inhibition, Th17 and Th1 cytokines, roflumilast had a more highly significant effect on IL-6 and IL-12p70 in the conjunctiva (p<0.0005) than steroids and antihistamines (similarly significant against vehicle), but was not statistically different from corticosteroids (TNF-α in the conjunctiva and IL-6 and TNF-α in the cornea, tissues not directly related to the model), suggesting cytokine intracellular transport across ocular tissues. The drug also showed similar levels of cytokine and chemokine regulation as olopatadine and corticosteroids in Th1 cytokines typically associated with early-stage allergic mast cell-driven responses (as evidenced by the robust response of IL-1b to olopatadine in the cornea). Corticosteroids are known for their effects on Th1 pathways and showed a highly significant downregulatory effect on IL-12p70 in corneal tissue, which is associated with Th1 activation.

[0081]

[0092] Th2 cytokines are particularly important for allergic and short- to mid-term inflammatory diseases due to their B cell activation adapted from defense against parasites triggering IgE via IL-4, eosinophil-dependent inflammation typically triggered by IL-5, and mast cell proliferation and degranulation cascade (IL3 / IL4). Th17-driven cytokine responses are important drivers of autoimmune signaling and CD4+ effector responses and are therefore highly relevant in autoimmune and immune-mediated diseases (including many ocular diseases), which typically show upregulation of both Th17 and Th1 cytokines, which are considered to be a particularly inflammatory combination. IL-17, IL-17F, IL6, IL-22, and TNF-α are important T-cell drivers of tissue inflammation and neutrophil activation and recruitment. While Th1 cytokines such as IL-1, INF-γ, and TNF-β are important in diseases of autoimmune origin alone, they are also often upregulated in protecting against infectious agents and macrophage infiltration (Kaiko et al., Immunology 2008). Th2 and Th17 cytokines have been implicated in inflammation-driven diseases, including ocular inflammatory diseases (Sakkas 2017). Both Tan et al. (2014) and Liu et al. (2017) investigated the correlation of Th17 cytokines with various forms of dry eye disease and found increased concordance and good correlation in the pathogenesis of dry eye disease, highly associated with inflammation-driven factors, such as elevated cytokines from the Th17 cell cascade. In addition, they found that higher levels of Th17 cytokine expression correlated with clinical severity markers of dry eye, such as OSDI, Schirmer test, and CFS. Thus, there is widespread support that cytokine upregulation of all Th17, Th1, and Th2 cytokines is a good indicator of inflammation in ocular disease; cytokine-associated inflammation correlates with disease severity; and the ability to downregulate these cytokines may be an effective tool in the management of these diseases.Because cytokine involvement has been linked to worsening disease severity, downregulation of cytokines is a reasonable therapeutic goal and a positive outcome of the studies described in this application. In Example 14, the inventors surprisingly found that cytokine measurements are good endpoints for observing and estimating inflammation and immune activation in mouse models, as well as immune control and anti-inflammatory success of tested drugs, and that the drug roflumilast outperforms corticosteroids and antihistamines in downregulating several key cytokines known to be associated with multiple eye diseases.

[0082]

[0093] In addition, this study was conducted in an allergic conjunctivitis model, but the addition of additional systemic challenge has been adapted to provide observations that mimic longer-term inflammatory and immune-mediated eye stress.Therefore, these cytokine results are applicable to many other diseases.Examples 13 and 14 concern models of allergic conjunctivitis, and thus cytokine upregulation is highest in the conjunctiva with Th2 cytokines, but corneal involvement was also seen in this study.The effects of Th2 and Th17 cytokines observed in this study suggest potential impacts across a wide range of related eye diseases. Many ocular diseases have a wide range of cytokine markers of involvement and severity, including demodicid blepharitis (Th17: IL-7, IL-12, IL-17; Kim et al., 2010), JIA-associated uveitis (Th17; Walschield, 2019), ocular graft-versus-host disease after allogeneic stem cell transplantation (IFN-γ (early), IL-6 (late); Riemens 2012) and recurrent herpes keratitis (Th17 / Th1; Rajasagi 2019).

[0083]

[0094] Surprisingly, the inventors of the present application have found that roflumilast administered locally, not systemically, and in small and convenient doses provides a strong response to the cytokines IL-6 and IL-12 that are important for Th17, and IL-2, IL-4, and IL-5 that are related to Th2-driven inflammation.The results in Example 14 suggest that roflumilast has a wide range of immunomodulatory and anti-inflammatory effects that are relevant to many ocular diseases, and also suggest that this drug may produce similar or more effects than other common immunomodulators, immunosuppressants, and anti-inflammatory agents, and also be accompanied by a better safety and convenience profile.

[0084]

[0095] Example 11

[0096] A study was performed to evaluate the ocular tolerability of repeated topical ocular administration of 1% roflumilast in an ointment formulation (Example 6) or 0.1% roflumilast in two suspension formulations (Examples 1 and 3) at exaggerated dosing concentrations and / or frequencies in male Dutch Belted rabbits (n=3 per group). No vehicle group was included. Test materials were provided ready to use, dosing volume was 40 μL per eye, and suspensions were shaken before dose administration. Cohort A received BID dosing of the ointment (Example 6) or QID dosing of the suspension (Examples 1 and 3) to test the tolerability of exaggerated dosing frequencies, i.e., more frequently than expected clinical dosing frequencies. Parameters evaluated included mortality / morbidity, clinical observations, body weight, ophthalmic examinations including slit lamp biomicroscopy and indirect fundus examination using Hackett-McDonald scoring performed by a veterinary ophthalmology board certified, and ocular histopathology. For each eye, 5 μm thick sections were prepared (5 slides per eye). The central section of each eye, including the optic nerve and optic streak, was stained with hematoxylin and eosin (H&E) and examined using a light microscope. Ophthalmic examinations (OE) were performed at baseline and on days 1, 3, and 5. Approximately 30 minutes to 1 hour after the final dose on day 5, eyes were harvested for histopathology.

[0085]

[0097] Bilateral BID administration of 1% roflumilast ophthalmic ointment (Example 6) for 5 days resulted in findings of mild to moderate blepharitis on day 5. Bilateral QID administration of 0.1% roflumilast ophthalmic suspension in either the HPMC (Example 1) or PVP (Example 3) formulation was well tolerated, and no findings were observed during ophthalmic examination, including hyperemia, chemosis, ocular discharge, opacity, corneal pannus, pupillary reflex, aqueous humor flare or cells, vitreous cells, or choroidal, retinal, or optic nerve lesions. In addition, all animals maintained or gained normal weight over the 5-day period.

[0086]

[0098] Histopathological evaluation showed that 1 / 6 of the eyes receiving 1% ointment (Example 1) and 3 / 6 of the eyes receiving 0.1% roflumilast ophthalmic suspension in PVP formulation (Example 3) showed a mild increase in mononuclear cells in the limbus. No other abnormalities were noted in any of the eyes. Infiltration in the limbus was mild and within normal range; therefore, no test article-related adverse ocular pathology was observed in this cohort. In addition, there were no histopathological signs of cataract, retinal detachment, or retinal degeneration.

[0087]

[0099] These data demonstrate that 1% roflumilast ointment (Example 6) and 0.1% roflumilast suspension (Examples 1 and 3) were well tolerated by Dutch Belted rabbits, even when administered at an exaggerated frequency of twice or four times daily (respectively) for five days. Roflumilast ointment (Example 6) induced mild eyelid irritation, which was not considered adverse.

[0088] [000100] Example 12 [000101] A study was performed to evaluate the ocular tolerability of 0.1% roflumilast ointment (Example 5) in New Zealand White rabbits, or the ocular tolerability of a range of concentrations of roflumilast suspension (0.3%, 1%, or 3%) in Dutch Belted rabbits that were studied in previous studies. Rabbits (n=3 per group) received roflumilast or placebo ointment QD or roflumilast suspension QID. The dosing volume was 40 μL per eye, and the suspension was shaken before dose administration. Parameters evaluated included mortality / morbidity, clinical observations, body weight, ophthalmic examinations including slit lamp biomicroscopy and indirect fundus examinations using Hackett-McDonald scoring performed by a veterinary ophthalmology board certified, and ocular histopathology. 5 μm thick sections were prepared for each eye (5 slides per eye). Central slices of each eye, including the optic nerve and optic streak, were stained with H&E and examined using light microscopy. OEs were performed at baseline and on days 1, 3, and 5. Eyes were harvested for histopathology approximately 45 minutes to 6.5 hours after the last dose on day 5.

[0089] [000102] Unilateral once daily administration of 0.1% roflumilast ophthalmic ointment (Example 5) induced mild blepharitis in 1 / 3 of the eyes on day 5; this finding was not observed in the contralateral placebo eye. Bilateral QID administration of 0.3%, 1%, or 3% roflumilast ophthalmic suspension (Examples 1 and 3) was well tolerated, and no findings were observed during ophthalmic examination, including hyperemia, chemosis, ocular discharge, opacity, corneal pannus, pupillary reflex, aqueous humor flare or cells, vitreous cells, or choroidal, retinal, or optic nerve lesions. In addition, all animals maintained or gained normal weight over the 5-day period.

[0090] [000103] Histopathology evaluation showed mild mononuclear inflammatory cell infiltration in the limbus and ciliary body in one eye treated with 0.1% ointment (Example 5) and one eye receiving placebo ointment. Treatment with 0.3% roflumilast ophthalmic suspension resulted in mild / focal subconjunctival mononuclear cell infiltration in one suspension eye (Example 3) and a few mononuclear cells in the vitreous in one suspension eye (Example 1). Eyes receiving 1% and 3% roflumilast ophthalmic suspension showed mild mononuclear inflammatory cell infiltration in the limbus and subconjunctival area. The severity was low, but the incidence appeared to increase at higher doses. No difference was observed in this mild inflammation between the two suspension vehicles. In addition, no histopathological signs of cataract, retinal detachment, or retinal degeneration were seen. Thus, no test substance-related adverse ocular lesions were observed in this cohort.

[0091] [000104] Example 13 [000105] To further test the tolerability and safety of roflumilast topical ophthalmic suspension over extended dosing ranges and frequencies, as well as extended dosing periods, similar to those used in human clinical trials, the pharmaceutical composition was utilized in a GLP-toxicology study of 13 weeks of treatment in rabbits. Either 0.1%, 0.3%, or 1.0% concentration of roflumilast topical ophthalmic suspension (Example 3, Table 3), or a control (either saline or the same roflumilast topical ophthalmic suspension vehicle (Example 1, Table 1, minus the active drug)) was administered TID (3 times daily) to New Zealand White rabbits for 13 weeks, followed by a 4-week recovery period. Both male and female animals were tested with n=7 animals in each sex / dosing group, for a total of n=56. Animals were assessed for clinical observations, morbidity / mortality, body weight, food intake, intraocular pressure, corneal thickness, ophthalmologic examination using McDonald-Shadduck scoring, electroretinogram (ERG), clinical pathology (hematology, coagulation, clinical chemistry), systemic exposure, organ weights, and ocular and systemic histopathology. The specific objective of the three areas studied was the known human side effects of standard of care anti-inflammatory agents, with some interspecies variability. Animals were evaluated at regular intervals for intraocular pressure (IOP) in both eyes, corneal thickness change, and overall body weight change as a proxy for the animals' general well-being and health. As shown in Figures 9-11, in Example 13, there was no test substance effect on body weight, IOP, or central corneal thickness (pachymetry) throughout the duration of the study. Figure 9 provides the results of the study on body weight. Figure 10 provides the results of the study on IOP. Figure 11 provides the results of the study on central corneal thickness (pachymetry). Of note, no IOP spikes were noted in any of the eyes, and although there were some transient changes in IOP or corneal thickness in certain eye or gender groups, none were considered adverse.

[0092] [000106] The foregoing description has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed. Those skilled in the art will recognize that modifications and substitutions to the basic invention description may be made.

Claims

1. 1. An ophthalmic pharmaceutical suspension comprising roflumilast or a pharmaceutically acceptable salt thereof for use in a method of treating a patient having an ocular inflammatory or immune-mediated disorder, comprising: the method comprising administering an ophthalmic pharmaceutical suspension to the ocular surface of the patient; An ophthalmic pharmaceutical suspension, wherein said administration results in a reduction in at least one side effect compared to administration of an immunosuppressant, an immunomodulator, or a nonsteroidal anti-inflammatory drug.

2. 10. The ophthalmic pharmaceutical suspension of claim 1, wherein the immunosuppressant, immunomodulator, or nonsteroidal anti-inflammatory agent is an ophthalmic prednisolone topical composition or an antihistamine olopatadine topical composition.

3. 2. The ophthalmic pharmaceutical suspension of claim 1, wherein the side effect is an ocular side effect selected from the group consisting of increased intraocular pressure, thinning of the cornea, sclera, and epithelial tissue, perforation of the cornea, sclera, and epithelial tissue, delayed or decreased wound or epithelial healing, visual defects, burning sensation, stinging sensation, foreign body sensation, redness, eyelid edema, pain, ocular pruritus, hives, rash, allergic reaction, keratitis, conjunctivitis, posterior subcapsular cataract formation, glaucoma, optic nerve damage, corneal ulcer, mydriasis, increased susceptibility to fungal, bacterial, or viral infections, reactivation of fungal or viral infections, masking of acute suppurative infections, increased postoperative blebbing, dry eye, punctate keratopathy, central serous chorioretinopathy, drug-induced eye, decreased accommodative amplitude, ptosis, acute anterior uveitis, or ocular perforation.

4. 10. The ophthalmic pharmaceutical suspension of claim 1, wherein the side effect is a systemic side effect selected from the group consisting of: changes in blood glucose levels, weight gain or loss, decreased systemic wound healing, systemic susceptibility to microbial infections, irritation of tissues around the eye, cold symptoms, sore throat, asthenia, back pain, headache, cough, nausea, rhinitis, sinusitis, osteoporosis, and taste perversion or dysgeusia, or sulfite-related anaphylaxis.

5. 3. The ophthalmic pharmaceutical suspension of claim 2, wherein the topical prednisolone or olopatadine composition is a suspension.

6. 10. The ophthalmic pharmaceutical suspension of claim 1, wherein the administration results in reduced dosing frequency or other measures of dosing convenience compared to administration of an immunosuppressant, immunomodulator, or nonsteroidal anti-inflammatory drug.

7. 10. The ophthalmic pharmaceutical suspension of claim 1, wherein said administration downregulates inflammatory stress-driven cytokine or chemokine activity in at least one ocular tissue selected from the group consisting of corneal and conjunctival tissues.

8. 10. The ophthalmic pharmaceutical suspension of claim 1, wherein said administration results in disease-modifying activity in at least one supporting tissue or gland of the patient selected from the group consisting of: the cornea, conjunctiva, meibomian gland, iris, uvea, retina, or choroid.

9. The ocular inflammatory or immune-mediated disorder is: postoperative pain and inflammation from cataract or other ophthalmic surgery or laser treatment, blurred vision after corneal refractive surgery, postoperative full or partial thickness keratoplasty, dry eye syndrome including Sjogren's syndrome or other autoimmune or inflammatory dry eye disease, evaporative or desiccant dry eye disease, ocular graft-versus-host disease, ocular rosacea, allergic conjunctivitis or keratoconjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, keratitis, herpetic or viral stromal keratitis / herpetic or viral blepharitis or conjunctivitis, varicella-zoster-related inflammation, bacterial, viral, or 10. The ophthalmic pharmaceutical suspension of claim 1, wherein the ocular surface disease is selected from the group consisting of inflammation secondary to other infectious agents including fungal infections, inflammation secondary to ocular chemical burns, ocular Stevens-Johnson syndrome / toxic epidermolysis, uveitis including juvenile idiopathic arthritis uveitis, seborrheic or other forms of blepharitis, limbal stem cell deficiency, meibomian gland dysfunction, episcleritis, pingueculitis, and pterygium, phlyctenular conjunctivitis, staphylococcal hypersensitivity, Mooren's ulcer, endotheliitis, superior limbal keratoconjunctivitis, or other ocular conditions traditionally treated with steroids for which the patient is contraindicated due to intraocular pressure, wound healing, or a history of fungal or other microbial infection.

10. 10. The ophthalmic pharmaceutical suspension of claim 1, wherein the ocular inflammatory or immune-mediated disorder is a disease of the anterior or posterior segment of the eye selected from the group consisting of anterior uveitis, panuveitis and posterior uveitis (infectious or non-infectious), diabetic retinopathy, diabetic macular edema, geographic atrophy, dry or wet age-related macular degeneration, retinal vein occlusion, drug-related / iatrogenic, non-infectious / sterile, or idiopathic retinal vasculitis, endophthalmitis, or retinitis, ocular manifestations of Behcet's disease, or other retinal or anterior segment diseases.

11. 10. The ophthalmic pharmaceutical suspension of claim 1, wherein the ocular inflammatory or immune-mediated disorder is dry eye disease, uveitis, or herpetic or viral keratitis.

12. 1. An ophthalmic pharmaceutical suspension comprising roflumilast, or a pharmaceutically acceptable salt or metabolite thereof, for use in a method of treating a patient having an ocular inflammatory or immune-mediated disorder: the method comprising administering to said patient an ophthalmic pharmaceutical suspension; An ophthalmic pharmaceutical suspension, wherein said administering comprises downregulating inflammatory stress-driven cytokine activity in at least one ocular tissue selected from the group consisting of corneal and conjunctival tissues.

13. 13. The ophthalmic pharmaceutical suspension of claim 12, wherein the administration results in disease-modifying activity in at least one supporting tissue or gland of the patient selected from the group consisting of: the cornea, conjunctiva, meibomian gland, sclera, ciliary body, iris, lens, uvea, choroid, retinal pigment epithelium (RPE), or retina.

14. The ocular inflammatory or immune-mediated disorder is: postoperative pain and inflammation from cataract or other ophthalmic surgery or laser treatment, blurred vision after corneal refractive surgery, postoperative full or partial thickness keratoplasty, dry eye syndrome including Sjogren's syndrome or other autoimmune or inflammatory dry eye disease, evaporative or desiccant dry eye disease, ocular graft-versus-host disease, ocular rosacea, allergic conjunctivitis or keratoconjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, keratitis, herpetic or viral stromal keratitis / herpetic or viral blepharitis or conjunctivitis, varicella-zoster-related inflammation, bacterial, viral, or 13. The ophthalmic pharmaceutical suspension of claim 12, wherein the ocular surface disease is selected from the group consisting of inflammation secondary to other infectious agents including fungal infections, inflammation secondary to ocular chemical burns, ocular Stevens-Johnson syndrome / toxic epidermolysis, uveitis including juvenile idiopathic arthritic uveitis, seborrheic or other forms of blepharitis, limbal stem cell deficiency, meibomian gland dysfunction, episcleritis, pingueculitis, and pterygium, phlyctenular conjunctivitis, staphylococcal hypersensitivity, Mooren's ulcer, endotheliitis, superior limbal keratoconjunctivitis, or other ocular conditions traditionally treated with steroids in which the patient is contraindicated due to intraocular pressure, wound healing, or a history of fungal or other microbial infection.

15. 13. The ophthalmic pharmaceutical suspension of claim 12, wherein the ocular inflammatory or immune-mediated disorder is a disease of the anterior or posterior segment of the eye selected from the group consisting of anterior uveitis, panuveitis and posterior uveitis (infectious or non-infectious), diabetic retinopathy, diabetic macular edema, geographic atrophy, dry or wet age-related macular degeneration, retinal vein occlusion, drug-related / iatrogenic, non-infectious / sterile, or idiopathic retinal vasculitis, endophthalmitis, or retinitis, ocular manifestations of Behcet's disease, or other anterior or posterior segment diseases.

16. 13. The ophthalmic pharmaceutical suspension of claim 12, wherein the ocular inflammatory disorder is dry eye disease, uveitis, or herpetic or viral stromal keratitis.

17. 13. The ophthalmic pharmaceutical suspension of claim 12, wherein the administration results in reduced dosing frequency or other indications of dosing convenience compared to administration of an immunosuppressant, immunomodulator, or nonsteroidal anti-inflammatory drug.

18. 1. A method of treating a patient having an ocular inflammatory or immune-mediated disorder, comprising: administering to said patient an ophthalmic pharmaceutical suspension comprising a therapeutically effective amount of roflumilast or a pharmaceutically acceptable salt or metabolite thereof; An ophthalmic pharmaceutical suspension, wherein said administering comprises down-regulating cytokine activity in a manner superior to down-regulation of cytokines by administration of an immunosuppressant, an immunomodulator, or a nonsteroidal anti-inflammatory drug.

19. 20. The ophthalmic pharmaceutical suspension of claim 18, wherein the immunosuppressant, immunomodulator, or nonsteroidal anti-inflammatory agent is an ophthalmic prednisolone topical composition or an antihistamine olopatadine topical composition.

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