CN118284416A - Methods of treating ocular inflammatory diseases - Google Patents
Methods of treating ocular inflammatory diseases Download PDFInfo
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- CN118284416A CN118284416A CN202280075654.3A CN202280075654A CN118284416A CN 118284416 A CN118284416 A CN 118284416A CN 202280075654 A CN202280075654 A CN 202280075654A CN 118284416 A CN118284416 A CN 118284416A
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- ocular
- roflumilast
- inflammatory
- eye
- administration
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Abstract
The present invention relates to methods of treating ocular inflammatory diseases by administering roflumilast ophthalmic pharmaceutical compositions. The administration of roflumilast's ophthalmic pharmaceutical composition provides significant immunomodulatory and anti-inflammatory activity relative to existing immunomodulators, immunosuppressants, or non-steroidal anti-inflammatory therapeutic agents (including corticosteroids and antihistamines), while also providing improved safety and convenience relative to either or both agents.
Description
Cross Reference to Related Applications
The present application claims priority from U.S. provisional application Ser. No.63/247,174 filed on 22 th 9 of 2021 and U.S. provisional application Ser. No.63/251,874 filed on 4 th 10 of 2021. Each of these applications is incorporated herein by reference.
Technical Field
The application includes methods of treating ocular inflammatory diseases by administering an ophthalmic pharmaceutical composition of roflumilast (roflumilast). The inventors of the present application have surprisingly found that administration of a suspension of roflumilast in an ophthalmic drug provides significant anti-inflammatory activity relative to existing immunosuppressive and immunomodulatory therapies (including corticosteroids and antihistamines), while also providing improved safety and convenience relative to either or both agents.
Background
Roflumilast is an effective selective long-acting phosphodiesterase type 4 (PDE) inhibitor with anti-inflammatory and potentially anti-tumor activity. Roflumilast is known to be suitable as a bronchotherapeutic agent and 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 airway diseases and allergen-induced airway diseases (e.g., bronchitis, asthma, COPD), skin diseases (e.g., proliferative, inflammatory and allergen-induced skin disorders), and generalized inflammation of the gastrointestinal tract (crohn's disease and ulcerative colitis). Oral roflumilast pharmaceutical compositions for the treatment of COPD are currently under the trade name(In the United states) andTopical compositions of roflumilast cream for dermatological use are currently marketed under the trade name Zoryve TM (in the united states) for psoriasis (in europe).
Roflumilast and its synthesis are described in U.S. patent 5712298. Pharmaceutical compounds having Phosphodiesterase (PDE) -4 properties, such as roflumilast, have been recognized as having therapeutic effects and are useful in the treatment of inflammatory disorders, such as psoriasis and atopic dermatitis. Although the therapeutic efficacy of oral and dermatological pharmaceutical compositions has been investigated, there remains a need for ophthalmic pharmaceutical compositions of roflumilast suitable for the treatment of inflammatory or immune-mediated conditions of the eye.
Most of the markets for anti-inflammatory ophthalmic drugs today are based on antibiotics/antimicrobials (in the case of infectious/inflammatory indications), immunosuppressives (including corticosteroids), immunomodulators (including antihistamines) and non-steroidal anti-inflammatory agents. These major classes of agents often do not meet the clinical needs of medium-to-long-term inflammatory diseases, or present significant complications and safety issues. Thus, there is a highly unmet need for an anti-inflammatory roflumilast ophthalmic formulation in a convenient and tolerable form.
Delivery of drugs to the eye is very difficult because ophthalmic agents must have balanced tolerability, sterility, safety and efficacy. PRIYANKAAGARWAL et al discuss formulation challenges (Priyanka Agarwal et al.,Formulation Considerations for the Management of Dry Eye Disease,Pharmaceutics,13,207(Feb.3,2021)). of ophthalmic pharmaceutical formulations, e.g., poor tolerability of formulation excipients. In addition, poor patient compliance is often a challenge for ophthalmic pharmaceutical formulations. It is very difficult to develop stable ophthalmic formulations that can be prepared under sterile conditions, while maintaining the physicochemical properties of the active agent, remain within a strict range of eye-tolerable pH and inactive ingredients, and can be delivered to the eye in effective doses. Ocular delivery is focused on the ocular surface, anterior segment, or posterior segment. The ocular surface formulations, which are typically delivered by patients one to four or more times a day, have additional challenges that require dosing consistency and flexibility in delivering effective doses, despite the following common operator errors in home-based patient delivery: sterility problems, delivery volume differences, and placement accuracy. Patients with long-term ocular disease also have increased sensitivity to active and inactive ingredients and preservatives, which creates additional formulation challenges.
Ocular Surface Diseases (OSD) are mainly treated with three classes of therapeutic ophthalmic agents: immunomodulators, immunosuppressants (including corticosteroids), antibacterial agents, and non-steroidal anti-inflammatory agents (NSAIDs). Each agent has its own location, but all face challenges. Corticosteroids are immunosuppressants for the treatment of ocular diseases, which, although effective in inhibiting inflammatory activity, have long been known for their side effects, whether for systemic, topical or intraocular treatment, and often have to be administered frequently. Antibiotics are very effective against bacterial infections, which can lead to certain OSDs, but diseases of inflammatory nature are often misdiagnosed as purely bacterial diseases, and therefore, antibacterial drugs are often overused, resulting in antibiotic and antimicrobial drug resistance, long-term public health challenges, and inadequate treatment of inflammatory or potentially autoimmune or immune-mediated ocular diseases. Non-steroidal immunomodulators or immunosuppressants (including antihistamines, anti-integrins and calcineurin inhibitors) and non-steroidal anti-inflammatory agents (including bromfenac, diclofenac, etc.) also play a role in the treatment of inflammatory or immune-driven diseases, but are generally considered to be of limited utility because a small range of immune targets (cell level or based on intraocular location) results in limited efficacy or is challenging to safety or tolerability. All current challenges facing standard therapies for therapeutic drugs that focus on immunity and inflammation result in an unmet need for alternative classes of agents as described below: the medicament directly solves potential driving factors of eye diseases, has high efficiency, and has fewer side effects and higher convenience for patients or crowds. In particular, there has been a highly unmet need prior to the present invention for anti-inflammatory agents with a broad spectrum of mechanisms of action that target the most common but versatile potential drivers of inflammatory and immune-mediated ocular diseases, but with fewer systemic or ocular side effects and less frequent dosing.
Corticosteroids are one of the most commonly used ophthalmic agents, often as the first and last resort to ocular inflammatory diseases of non-infectious etiology, or in combination with antibacterial agents for suspected infectious etiology diseases. Corticosteroids are generally relatively effective and have a relatively short onset of action, and can be administered in a variety of dosage forms: topical suspensions, gels, ointments, injections or depot formulations; and may be co-formulated with antibiotics or other targeting agents. However, corticosteroids, like their use in dermatological, immunological, autoimmune and many other disease states, can have a variety of serious local and systemic side effects, even in short-term settings. The use of corticosteroids in the eye can locally reduce wound healing, increase susceptibility to or reactivate fungal or viral infections (in fact, if improperly used under non-sterile conditions, even increase the risk of direct endophthalmitis or other infections), leading to tissue specific side effects such as thinning of epithelial tissue in the cornea, sclera and other tissues, most notably its effect on elevated intraocular pressure, which can lead to glaucoma, optic nerve damage, cataracts or central serous chorioretinopathy (Fung 2020). Effects associated with instillation may include pain, burning or stinging, allergic reactions, foreign body sensation, vision disorders, itching, urticaria and rashes associated with the site; and keratitis, conjunctivitis, corneal ulcers, mydriasis, hyperemia, loss of accommodation, ptosis, acute anterior uveitis, and eye perforation (Pred Forte Label, 2017). Systemic side effects may include headache, elevated blood glucose and susceptibility to systemic microbial infection. These side effects can occur in the eye even after short-term (e.g., weeks) administration. Thus, corticosteroids are not optimal solutions for inflammatory or immune-mediated ocular diseases, which often require mid-or long-term anti-inflammatory treatment. Antihistamines and cyclosporins are also frequently used on OSD in large populations to address allergic, immune-mediated or inflammatory eye diseases, but these agents may also produce serious side effects including irritation of eye tissue, cold symptoms, pharyngitis, and systemic side effects from wound healing delay to sulfite-related allergic reactions, etc. All these commonly used immunomodulatory/immunosuppressive agents (including corticosteroids, antihistamines, cyclosporins) cause local side effects, especially those that directly affect the quality of life of the patient (pain, discomfort, itching), which are exacerbated by the fact that: these products are typically administered four to eight times per day, even more frequently, especially at the beginning of use, and typically require gradually decreasing doses due to these side effects. In clinical practice, it is not uncommon to use corticosteroids once every 1 to 2 hours for the treatment of pre-uveitis or like indications in an attempt to produce sufficient effect on the underlying inflammation inherent in such immune-mediated diseases.
Disclosure of Invention
The present application relates to methods of treating ocular inflammatory diseases or immune-mediated diseases by administering an ophthalmic pharmaceutical composition of roflumilast. The inventors of the present application have surprisingly found that administration of roflumilast ophthalmic pharmaceutical compositions provides clinically significant immunomodulatory and anti-inflammatory activity relative to existing standard of care therapies (including corticosteroids and antihistamines), while also providing improved safety and convenience relative to one or both classes of agents. The present application addresses a highly unmet need for alternative classes of agents that address immune and inflammatory drivers of ocular surface and anterior/posterior segment disorders, have clinically significant efficacy, and also have lower patient-based or crowd-based side effects. The application has strong efficacy and low side effect, and can provide short-term, medium-term or long-term treatment scheme for various ocular diseases with inflammation or immune-mediated components.
One embodiment of the invention provides a method for treating a patient suffering from an ocular inflammatory disorder. The method comprises administering an ophthalmic pharmaceutical suspension comprising a therapeutically effective amount of roflumilast or a pharmaceutically acceptable salt or metabolite thereof to the ocular surface of the patient. The administration results in a reduction of at least one side effect relative to administration of an immunosuppressant, immunomodulator or non-steroidal anti-inflammatory agent. In certain embodiments, administration of the roflumilast composition results in a reduction of at least one side effect relative to an ophthalmic prednisolone suspension or an antihistamine olopatadine suspension.
In certain embodiments, the reduced side effect is an ocular side effect selected from the group consisting of: increased intraocular pressure, thinning of cornea, sclera and epithelial tissue, perforation of cornea, sclera and epithelial tissue, delayed or reduced wound or epithelial healing, congestion, eyelid edema, pain, ocular itching, urticaria, rash, allergic reactions, keratitis, conjunctivitis, subcoapsular cataract formation, glaucoma, optic nerve damage, corneal ulceration, mydriasis, vision defects, burning sensations, stinging, foreign body sensation, increased sensitivity to fungal, bacterial or viral infections, reactivation of fungal or viral infections, masking of acute suppurative infections, increased post-operative blister formation, dry eye, punctate keratopathy, central serous chorioretinopathy, drug-induced eye diseases, loss of accommodation, ptosis, acute anterior uveitis or perforation of the eyeball.
In certain embodiments, the reduced side effect is a systemic side effect selected from the group consisting of: blood glucose changes, weight gain or loss, reduced systemic wound healing, susceptibility to systemic microbial infection, irritation to tissues surrounding the eye, cold syndrome, pharyngitis, weakness, back pain, headache, cough, nausea, rhinitis, sinusitis, osteoporosis, dysgeusia or dysgeusia, or sulfite-related allergic reactions.
In certain embodiments, the administration down-regulates cytokine or chemokine activity driven by inflammatory stress, particularly Th17, th1 and/or Th2 cytokine activity, in at least one ocular tissue selected from the group consisting of corneal and conjunctival tissue.
In certain embodiments, roflumilast down-regulates cytokine activity, including Th1, th2, and/or Th 17-related cytokines, more strongly than does immunosuppressants, immunomodulators, or non-steroidal anti-inflammatory agents. Furthermore, in certain embodiments, roflumilast down-regulates cytokines in the conjunctiva more strongly than steroids or antihistamines.
In certain embodiments, the administration results in disease modifying activity (treatment-modifying activity) in at least one supporting tissue or gland selected from the group consisting of cornea, conjunctiva, meibomian gland, iris, uvea, retina and choroid.
In certain embodiments, the ocular inflammatory disorder is an ocular surface disease selected from the group consisting of: postoperative pain and inflammation of cataract or other ocular surgery or laser therapy, corneal refractive postoperative turbidity, postoperative full-thickness or partial thickness corneal transplants, dry eye syndrome associated with Sjogren's syndrome or other autoimmune or inflammatory diseases, evaporative or desiccating dry eye disease, ocular graft versus host disease, ocular rosacea, allergic conjunctivitis or allergic keratoconjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, keratitis, herpetic or viral keratitis, including herpetic or viral stromal keratitis/herpetic or viral blepharitis or conjunctivitis, herpes zoster-related inflammation, inflammation secondary to other infectious agents including bacterial, viral or fungal infections, inflammation secondary to chemical burns of the eye, history-about syndrome/toxic epidermonecrosins, uveitis, including uveitis of juvenile idiopathic arthritis, seborrheic or other forms of blepharitis, limbal stem cell deficiency, meibomian gland dysfunction, episcleritis, blepharitis and pterygium, keratoconjunctivitis bullosa (phlyctenulosis), staphylococcal allergy, moren ulcers, intracorneal dermatitis (endotheleitis), limbal keratoconjunctivitis, or other ophthalmic conditions that are commonly treated with steroids but where patients are contraindicated due to intraocular pressure history, wound healing, or fungal or other microbial infections.
In certain embodiments, the ocular inflammatory disorder is an anterior or posterior segment disease selected from the group consisting of: anterior uveitis, total uveitis, 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, retinitis, ocular behcet disease, and other inflammatory diseases of anterior and posterior segment tissues of the eye. In preferred embodiments, the ocular inflammatory disease is dry eye, uveitis, or herpetic or viral keratitis.
Another embodiment of the invention provides a method for treating a patient suffering from an ocular inflammatory disorder or an immune-mediated disorder. The method comprises administering an ophthalmic pharmaceutical formulation comprising a therapeutically effective amount of roflumilast or a pharmaceutically acceptable salt or metabolite thereof to the ocular surface of the patient. The administration down-regulates cytokine activity driven by inflammatory stress in at least one ocular tissue selected from the group consisting of corneal and conjunctival tissue. In certain embodiments, the pharmaceutical formulation is a suspension.
Another embodiment of the invention provides a method for treating a patient suffering from an ocular inflammatory disorder or an immune-mediated disorder. The method comprises administering an ophthalmic pharmaceutical formulation comprising a therapeutically effective amount of roflumilast or a pharmaceutically acceptable salt or metabolite thereof to the ocular surface of the patient. The administration down-regulates cytokine activity in a manner that is superior to that of corticosteroids or other immunosuppressants, immunomodulators, or non-steroidal anti-inflammatory agents, including antihistamines. In certain embodiments, administration of the roflumilast composition results in down-regulation of cytokine activity in a manner superior to down-regulation of cytokines by administration of an ophthalmic prednisolone suspension or an antihistamine olopatadine suspension.
Drawings
The accompanying drawings, which are incorporated herein and form a part of the disclosure, help illustrate various embodiments of the present invention and, together with the description, further serve to describe the invention to enable a person skilled in the relevant art to make and use the embodiments disclosed herein. Error bars in the figure are standard deviation values.
Figure 1 provides body weight data measured in preclinical models of murine systemic and local allergen irritation (challenge) after 7 days of administration of roflumilast topical ophthalmic suspensions (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%).
Figure 2 provides data of clinical response of hyperemia after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%) measured in preclinical models of murine systemic and topical allergen stimulation.
Fig. 3 provides data of clinical response of eyelid swelling after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%) measured in a murine preclinical model.
Fig. 4 provides data of clinical response of secretion after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%) measured in a murine preclinical model.
Fig. 5 provides data of clinical response of squint (squinting) after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%) measured in a murine preclinical model.
Figure 6 provides data of Th2 cytokine responses measured in a murine preclinical model following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%).
Figure 7 provides data of Th17 (IL-6) and Th1 (IL-12 p70 and TNF-a) cytokine responses following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%) measured in a murine preclinical model.
Figure 8 provides data of Th1 cytokine and chemokine responses after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%) measured in a murine preclinical model.
Figure 9 provides results of GLP toxicology studies on body weight for 13 weeks after administration of roflumilast topical ophthalmic suspensions (0.1%, 0.3%, 1.0%) and placebo/carrier.
Figure 10 provides results of GLP toxicology studies on intraocular pressure (IOP) for 13 weeks after administration of roflumilast topical ophthalmic suspensions (0.1%, 0.3%, 1.0%) and placebo/carrier.
Figure 11 provides results of GLP toxicology studies on central corneal thickness (corneal thickness measurements) for 13 weeks after administration of roflumilast topical ophthalmic suspensions (0.1%, 0.3%, 1.0%) and placebo/carrier.
Detailed Description
It is to be understood that this invention is not limited to the particular methodology, protocols, and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
All publications, patents, and patent applications cited herein are incorporated by reference in their entirety unless otherwise indicated. When the same term is defined in publications, patents, or patent applications, and this disclosure, which are incorporated by reference herein, the definition in this disclosure represents a controlling definition. For publications, patents, and patent applications cited to describe particular types of compounds, chemistry, and the like, the portion of such compounds, chemistry, and the like that is relevant to the literature incorporated herein by reference.
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, reference to "an active ingredient" includes a single ingredient and two or more different ingredients.
The term "about" when used in conjunction with a numerical value is intended to encompass a numerical value within a range having a lower limit of 5% less than the numerical value shown and an upper limit of 5% greater than the numerical value shown.
The term "effective" means that the amount of a compound, agent, substance, formulation or composition is sufficient to result in a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods of symptoms, or prevention of injury or disability due to affliction of the disease. The amounts may be single dose or according to a multi-dose regimen, alone or in combination with other compounds, agents or substances. One of ordinary skill in the art will be able to determine such amounts based on factors such as the size of the individual, the severity of the individual's symptoms, the particular composition or route of administration selected, and the like.
The term "eye disorder", "eye condition" or "eye disorder" refers to an eye disease/disorder that may threaten vision, cause eye discomfort, and may be predictive of general health problems. Ocular surfaces include cornea, conjunctiva, eyelid, lacrimal and meibomian glands, and interconnecting nerves.
By "pharmaceutically acceptable" is meant that administration to a human or animal is generally safe. Preferably, the pharmaceutically acceptable component is a component that has been approved by a regulatory agency of the federal or a state government or listed in the united states pharmacopeia published by the united states pharmacopeia committee (United States Pharmacopeial Convention, inc., rockville Md.), or other generally recognized component in the pharmacopeia for use in animals, and more particularly in humans.
The "pharmaceutical composition" according to the invention may be present in the form of a composition, in which the different active ingredients and diluents and/or carriers are mixed with each other, or may take the form of a combined preparation, in which the active ingredients are present in partially or completely different forms. An example of such a combination or combination formulation is a kit.
The term "roflumilast" as used in the present application refers to roflumilast, salts thereof, N-oxides of roflumilast and salts thereof, as well as other hydrolyzed or amide metabolites, unless otherwise indicated or unless the context clearly indicates otherwise.
As used herein, the term "individual" or "patient" most preferably refers to a human. The term "individual" or "patient" may include any mammal that may benefit from the compounds described herein.
A "therapeutic amount" or "therapeutically effective amount" is an amount of a therapeutic agent sufficient to achieve the intended purpose. The effective amount of a given therapeutic agent will vary depending upon factors such as the nature of the agent, the route of administration, the size of the individual receiving the therapeutic agent, and the purpose of administration. The effective amount in each individual case can be determined empirically by one skilled in the art according to methods established in the art.
As used herein, "treatment" of a disease or disorder means achieving one or more of the following: (a) reducing the severity and/or duration of the condition; (b) Limiting or preventing the occurrence of symptoms characteristic of the disorder being treated; (c) Inhibiting exacerbation of symptoms characteristic of the condition being treated; (d) Limiting or preventing recurrence of a disorder in a patient previously suffering from the disorder; and (e) limiting or preventing recurrence of symptoms in a patient previously suffering from the disorder.
The present application relates to methods of treating ocular inflammatory diseases by administering roflumilast in an ophthalmic pharmaceutical suspension. The inventors of the present application have surprisingly found that administration of ophthalmic drug suspensions of roflumilast can provide clinically significant anti-inflammatory activity relative to existing immunomodulatory, immunosuppressive and non-steroidal anti-inflammatory therapies (including corticosteroids and antihistamines), while also providing improved safety relative to these agents, as well as additional convenience benefits in terms of reduced frequency of administration. The present application addresses a highly unmet need for alternative classes of agents that address inflammatory drivers of OSD that have high efficacy and also have lower patient-based or crowd-based side effects and inconveniences. The present application is capable of providing short-, medium-or long-term therapies for ocular diseases with inflammatory or immune-mediated components.
In certain embodiments, the methods comprise administering to a patient suffering from an ocular inflammatory disease an ophthalmic pharmaceutical suspension comprising a therapeutically effective amount of the phosphodiesterase-4 inhibitor roflumilast or a pharmaceutically acceptable salt or metabolite thereof. In certain embodiments, the pharmaceutical composition comprises a metabolite of roflumilast, including the N-oxide of the pyridyl group of roflumilast or a salt thereof as an active ingredient.
Roflumilast is a compound of the formula (I):
wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy and R3 is 3, 5-dichloropyridin-4-yl.
The chemical name of roflumilast is N- (3, 5-dichloropyridin-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide. The chemical name of the N-oxide of roflumilast is 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloropyridin-4-yl 1-oxide) benzamide. Roflumilast and its synthesis, its use as a Phosphodiesterase (PDE) 4 inhibitor, and roflumilast formulations are described in U.S. patent 5712298, incorporated herein by reference. The ophthalmic pharmaceutical composition may comprise roflumilast in free base or pharmaceutically acceptable salt form. Exemplary salts of roflumilast are those described in paragraphs [0012] and [0013] of U.S. patent application publication No. US2006/0084684, the disclosure of which is incorporated herein by reference. In certain embodiments, the pharmaceutical composition comprises a metabolite of roflumilast, including the N-oxide of the pyridyl group of roflumilast or a salt thereof, as an active ingredient. In certain embodiments, the pharmaceutical composition comprises a hydrolyzed or amide metabolite of roflumilast.
In certain embodiments of the invention, roflumilast is administered to the ocular surface of a patient suffering from an ocular disorder or ocular condition, including, for example, ocular inflammatory disorders. In certain embodiments, the ocular inflammatory disorder is an ocular surface disease selected from the group consisting of: postoperative pain and inflammation of cataract or other ocular surgery or laser therapy, corneal refractive postoperative turbidity, postoperative full-thickness or partial thickness corneal transplants, dry eye associated with Sjogren's syndrome or other autoimmune or inflammatory diseases, evaporative or desiccating dry eye, ocular graft versus host disease, ocular rosacea, allergic conjunctivitis or allergic keratoconjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, keratitis, herpetic or viral keratitis, including herpetic or viral stromal keratitis/herpetic or viral blepharitis or conjunctivitis, herpes zoster-related inflammation, inflammation secondary to other infectious agents, such as bacterial, viral or fungal infections, inflammation secondary to chemical burns of the eye, eye history-about syndrome/toxic epidermolysis, uveitis, including juvenile idiopathic arthritis, blepharitis, seborrheic or other forms of blepharitis, limbal stem cell deficiency, meibomian gland dysfunction, episcleritis, blepharitis, pterygium, keratoconjunctivitis bullosa, staphylococcal allergies, moren ulcers, intracorneal dermatitis, limbal keratoconjunctivitis, or other ophthalmic conditions that are commonly treated with steroids but where patients are contraindicated due to intraocular pressure history, wound healing or fungal or other microbial infections.
In certain embodiments of the invention, roflumilast is administered to the anterior or posterior segment of the eye of a patient suffering from an eye disorder or eye condition. In certain embodiments, the ocular inflammatory disorder is an anterior or posterior segment disease selected from the group consisting of: anterior uveitis, total uveitis, 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 disease, and other inflammatory diseases of anterior and posterior segment tissues of the eye. In preferred embodiments, the ocular inflammatory disease is dry eye, uveitis, or herpetic or viral keratitis.
Other examples of ocular disorders that can be treated by the methods disclosed herein can include ocular disorders that are generally treated with corticosteroids, wherein patients are contraindicated for use of steroids due to history of intraocular pressure, wound healing, fungal or other microbial infection, thin or punctate cornea or retinal epithelial tissue, etc., or intolerance or inability to adhere to frequency of administration, or intolerance to drugs themselves. The ocular disorders treatable by the methods described herein may be acute or chronic. In certain embodiments, the ocular disorder is derived from an infectious or other externally derived antigen, but then produces an inflammatory cascade. In a preferred embodiment, the ocular inflammatory disease is dry eye, uveitis, or herpetic or viral stromal keratitis.
In certain embodiments, the ophthalmic pharmaceutical formulation is administered as various types of injections (including intravitreal, suprachoroidal, sub-tenon, subconjunctival or other sites) or devices, implants or reservoirs useful in the treatment of anterior or posterior segment inflammatory eye diseases such as anterior uveitis, total uveitis 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, or other inflammatory diseases of anterior and posterior segment tissues of the eye.
In certain embodiments, the pharmaceutical composition is administered in a regimen, such as at regular intervals. For example, the pharmaceutical composition may 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, once a month or as needed (PRN), or treated and prolonged. In certain embodiments, the pharmaceutical composition may be administered as part of a maintenance dose or a stepwise dose adjustment regimen. The administration of the pharmaceutical composition may be for a prescribed period of time. For example, the pharmaceutical composition may be administered for a period of about two days to at least about six weeks, or until an improvement in the ocular condition or disease is observed. Exemplary time periods for the treatment regimen include one week, two weeks, one month, six weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, or one year. For example, the pharmaceutical composition may be administered as an injection or as an implantable device, depot or adsorbable device, once a week, once a month, once every 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, once a quarter, once every six months, as needed (PRN), according to physician guidelines, or according to some clinical criteria such as treatment and extension criteria or other criteria. The pharmaceutical composition may be administered as a continuous treatment without an endpoint.
In certain embodiments, administration of an ophthalmic pharmaceutical composition of roflumilast to a patient results in significant immunomodulatory and anti-inflammatory activity. The anti-inflammatory activity achieved by the methods disclosed herein may be similar to, equal to, or greater than that achieved by frequently administered, commonly used and effective corticosteroids and/or antihistamines, including but not limited to, suspensions of prednisolone and ophthalmic solutions of olopatadine. Roflumilast, a PDE4 inhibitor, is known to have a broad spectrum of inhibitory effects on inflammatory mediators such as cytokines by increasing cyclic AMP and other downstream mediators. The methods disclosed herein can down-regulate cytokine disease activity in conjunctival and corneal tissues driven by inflammatory stress, particularly Th17, th1, and Th2 cytokines. In addition, the methods disclosed herein can extend disease modifying activity from conjunctival and corneal tissue to supporting tissue, such as meibomian glands and other ocular and orbital tissues, including anterior segment tissues such as the iris (including ciliary body) and uvea, and posterior segment tissues such as retina and choroid. The methods of the invention can result in reduced inflammatory activity and reduced transport of cytokines and immune cells through the tissue as evidenced by reduced signs of inflammation and/or reduced transport of cytokines in and through the cornea and conjunctiva. Cytokine and chemokine downregulation is also important for reducing vascular chemotaxis or neovascular growth, macrophage polarization, and more extensive infiltrating t-cell and b-cell immune responses in ocular tissues, and exchange between the eye and a broader systemic environment. In certain embodiments, the down-regulation of cytokine activity and related immune activity by roflumilast is similar to or better than immunomodulators and immunosuppressants, such as corticosteroids or antihistamines.
In addition, the safety profile of the methods disclosed herein may be similar to, equal to, or superior to that of frequently administered, commonly used and effective corticosteroids and/or antihistamines, including but not limited to, prednisone longan suspensions and olopatadine ophthalmic solutions. In certain embodiments, the methods result in a reduction of at least one side effect relative to administration of a suspension of prednisolone or other corticosteroid. In certain embodiments, the reduced side effect is an ocular side effect selected from the group consisting of: increased intraocular pressure, thinning of cornea, sclera and epithelial tissue, perforation of cornea, sclera and epithelial tissue, delayed or reduced wound or epithelial healing, congestion, eyelid edema, pain, ocular itching, urticaria, rash, allergic reactions, keratitis, conjunctivitis, subcoapsular cataract formation, glaucoma, optic nerve damage, corneal ulceration, mydriasis, vision defects, burning sensations, stinging, foreign body sensation, increased sensitivity to fungal, bacterial or viral infections, reactivation of fungal or viral infections, masking of acute suppurative infections, increased post-operative blister formation, dry eye, punctate keratopathy, central serous chorioretinopathy, drug-induced eye diseases, loss of accommodation, ptosis, acute anterior uveitis or perforation of the eyeball.
In certain embodiments, the reduced side effect is a systemic side effect selected from the group consisting of: blood glucose changes, weight gain or loss, reduced systemic wound healing, susceptibility to systemic microbial infection, irritation to tissues surrounding the eye, cold syndrome, pharyngitis, weakness, back pain, headache, cough, nausea, rhinitis, sinusitis, osteoporosis, dysgeusia or dysgeusia, and sulfite-related allergic reactions. Furthermore, inactive ingredients and preservatives in these pharmaceutical ingredients may be absorbed by the contact lens of the contact lens wearer.
In addition, in certain embodiments, the use of roflumilast pharmaceutical compositions can provide less frequent administration benefits to patients and caregivers, which is both more convenient, so that patients can work, travel and leave home without the use of a drug, and can also mean avoiding the pain and discomfort of multiple daily administrations of the drug. The PK profile of the agent allows for its use in certain embodiments once or twice daily (QD or BID), in contrast to QID, eight times daily, or even more frequent dosing of corticosteroids. In the case of certain ocular diseases, doctors require the patient to use the topical ophthalmic corticosteroid formulation once every one or two hours and wake up at night to instill additional doses, which places a great burden on the patient and caregivers.
Furthermore, for patients who require anti-inflammatory drug intervention for medium and long periods, the use of corticosteroids results in increased practical burden on the patient and doctors, as frequent monitoring of patient safety issues, including intraocular pressure, cataract formation and infection, is required. This is particularly difficult in patients where such monitoring is aggressive or uncomfortable, such as young children, elderly, patients with ocular tissue sensitivity due to long-term disease, all of which often overlap with inflammatory eye disease. In the current embodiment, such agents may avoid the need and cost of such frequent monitoring.
In the present invention, an ophthalmic pharmaceutical composition comprising a therapeutically effective amount of roflumilast is administered to a patient in need thereof. The ophthalmic pharmaceutical compositions may be formulated into such formulations using a number of methods well known and widely used by those of ordinary skill in the art. For example, the ophthalmic pharmaceutical composition may be a gel, ointment, cream, solution, suspension or other topical formulation. In certain embodiments, the ophthalmic pharmaceutical composition may be a periocular or subconjunctival implant, or an injection through a different site (intravitreal, subconjunctival, sub-tenon's capsule, suprachoroidal space, or other site), or an intracorneal or intravitreal implant, injection, or depot. In a preferred embodiment, the ophthalmic pharmaceutical composition is directly topically applied to the eye in the form of a suspension.
In certain embodiments, the ophthalmic pharmaceutical composition may comprise about 0.01% to about 5.0% w/v, or about 0.01% to about 3.0% w/v, or about 0.01% 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 roflumilast. For example, the ophthalmic pharmaceutical composition comprises roflumilast :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% or the like in any of the following w/v percentages.
In certain embodiments, the ophthalmic pharmaceutical composition may be a suspension, solution, eye drops, eye ointment, gel, cream, spray, nasal spray, injectable formulation (intravitreal, subconjunctival, sub-tenon's capsule (sub-tenon), suprachoroidal or other injection) or adsorptive device or implant, or depot or adsorptive contact lens. In a preferred embodiment, the pharmaceutical composition is a suspension in which the active ingredient (i.e. roflumilast) is suspended in a pharmaceutical carrier and/or excipient. In certain embodiments, the roflumilast ophthalmic pharmaceutical composition comprises a viscosity agent, a surfactant, and a buffer. In certain embodiments, the ophthalmic pharmaceutical composition may comprise one or more additional excipients including, for example, stabilizers, preservatives, wetting agents, diluents, pH adjusting agents, tonicity agents, or absorption enhancing agents. In certain embodiments, the ophthalmic pharmaceutical composition may also be used in the anterior or posterior segment cases in the form of: injections (intravitreal, suprachoroidal or otherwise), depots, implantable adsorption devices for placement of any eye or surrounding tissue, in situ gel formation, or drug/device combinations, wherein the active ingredient (i.e. roflumilast) is suspended with one or more of the above excipients, such as viscosity agents, surfactants or buffers; with or without a device or inert reservoir compound.
In certain embodiments, the viscosity agent is at least one selected from hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone or povidone, carboxymethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, or polyvinyl alcohol (PVA). In certain embodiments, the viscosity agent is dextran or gelatin. Additionally, in certain embodiments, the viscosity agent may include a carbomer, such as a type A carbomer copolymer or a type B carbomer copolymer, including a combination ofUnder the trade nameThose sold. In certain embodiments, the ophthalmic pharmaceutical formulation may comprise from 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% w/v to about 1.0% w/v, or about 0.1% w/v to about 0.5% w/v of the viscosity agent. For example, the ophthalmic drug comprises any of the following w/v percentages of viscosity 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%, and the like.
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 comprise from about 0.05% w/v to about 3.0% w/v, or from about 0.05% w/v to about 2.0% w/v, or from about 0.05% to about 1.0% w/v, or from about 0.1% to about 0.5% w/v of surfactant. For example, the ophthalmic pharmaceutical formulation comprises any of the following w/v percentages of surfactant :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%, and the like.
In certain embodiments, the buffer is at least one selected from the group consisting of citrate, phosphate, tris-HCl (Tris), acetate and borate buffers. In certain embodiments, the ophthalmic pharmaceutical formulation may comprise 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 buffer. For example, the ophthalmic drug comprises 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%,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.
In certain embodiments, the ophthalmic pharmaceutical formulation is an ointment. The ointment may comprise an inactive ingredient selected from petrolatum, mineral oil. In such embodiments, the ophthalmic pharmaceutical formulation may comprise therapeutically effective amounts of roflumilast, petrolatum, and mineral oil. In certain embodiments, the composition comprises 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 roflumilast. In certain embodiments, the composition comprises about 75% to about 85% w/w petrolatum, or more preferably about 75% to about 80% w/w petrolatum. In certain embodiments, the composition comprises about 15% to about 25% w/w mineral oil, or more preferably about 15% to about 20% w/w mineral oil. The ointments may provide benefits over suspensions, including, for example, increased contact time and increased concentration of dissolved drug in the drug delivery system, which may be important for water insoluble drugs such as roflumilast.
The inventors of the present application have determined that roflumilast hydrolyzes in certain ophthalmic pharmaceutical compositions as well as in certain standard aseptic manufacturing processes. In certain embodiments, the ophthalmic pharmaceutical composition has a pH of 5.5 to 7.5. In a preferred embodiment, the ophthalmic pharmaceutical composition has a pH of about 6.0 to about 6.7 to reduce the rate of hydrolysis of roflumilast. In certain embodiments, the ophthalmic pharmaceutical composition has a pH of about 6.2 to about 6.7, or in certain embodiments, 6.3 to 6.6. In certain embodiments, the osmolality of the ophthalmic pharmaceutical composition is about 270 to 330mOsm/kg, more preferably about 270 to about 300mOsm/kg, and even more preferably 270 to 280mOsm/kg.
The ophthalmic pharmaceutical compositions of the present invention are stable and exhibit a particle size distribution suitable for ocular delivery. For suspensions, the particle size of the ophthalmic pharmaceutical composition can be assessed using laser diffraction methods. Laser diffraction is accepted by standards and guidelines including ISO and ASTM and is widely used to determine particle size distribution. In performing the evaluation, the laser beam is passed through the sample, causing the laser to scatter at a series of angles. A detector placed at a fixed angle measures the intensity of scattered light at that location. A mathematical model is then applied to generate the particle size distribution.
In particle size determination, the median is defined as the value: half of the population is above this point and half is below this point. For particle size distribution, the median value is referred to as D50. D50 is the size: which divides the distribution into half above the diameter and half below the diameter. The width of the distribution may also be characterized by reference to one, two or three values on the x-axis, typically some combination of D10, D50 and D90. As described above, D50 (or median) refers to the diameter: the total half is below this value. Likewise, 90% of the distribution is below D90, while 10% of the population is below D10.
In certain embodiments of the invention, the ophthalmic pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of less than or equal to about 50 μm 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 less than or equal to 10 μm.
In certain embodiments, slow dry heat sterilization, gamma irradiation or other sterilization methods at temperatures below the melting point of roflumilast may be used to sterilize the pharmaceutical compositions of roflumilast. In certain embodiments, gamma radiation or other end product sterilization methods can be used to sterilize the end pharmaceutical product in its end packaging by application of low to moderate levels of gamma radiation to ensure sterility, which is the preferred embodiment for maximizing high patient safety and comfort, as the product need not contain preservatives that are known to produce stinging upon use. In certain embodiments, the ophthalmic pharmaceutical composition may be characterized by a retained potency greater than 99% of the original value of the active substance. In certain embodiments, the efficacy retained is greater than 99.1%, 99.2%, 99.3%, 99.4% or 99.5% of the original value of the active substance.
The following examples illustrate certain embodiments of the invention, but are not limiting.
Examples
While various embodiments have been described above, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.
Example 1
An ophthalmic pharmaceutical composition comprising roflumilast as listed in table 1 was prepared.
Table 1: roflumilast ophthalmic drug suspension
Example 2
An ophthalmic pharmaceutical composition comprising roflumilast as listed in table 2 was prepared.
Table 2: roflumilast ophthalmic suspension
Composition of the components | %w/v |
Roflumilast | 0.1%w/v |
Hydroxyethyl cellulose | 0.35%w/v |
Polysorbate 80 | 0.1%w/v |
Phosphate/citrate agents | 0.45%/0.05% |
Water for injection | Proper amount is added to 1.0mL |
Example 3
An ophthalmic pharmaceutical composition comprising roflumilast as listed in table 3 was prepared.
Table 3: roflumilast ophthalmic drug suspension
Example 4
An ophthalmic pharmaceutical composition comprising roflumilast as set forth in table 4 was prepared.
Table 4: roflumilast ophthalmic suspension
Composition of the components | %w/v |
Roflumilast | 0.1%w/v |
Carboxymethyl cellulose | 0.5%w/v |
Polysorbate 80 | 0.1%w/v |
Phosphate/citrate buffer | 0.45%/0.05% |
Water for injection | Proper amount is added to 1.0mL |
Examples 5 and 6
An ophthalmic pharmaceutical ointment containing roflumilast as listed in table 5 was prepared.
Table 5: roflumilast eye ointment
Composition of the components | Example 5 (% w/w) | Example 6 (% w/w) |
Roflumilast | 0.1%w/w | 1%w/w |
Mineral oil | 20.2%w/w | 20%w/w |
Vaseline | 79.7%w/w | 79%w/w |
Example 7
An ophthalmic pharmaceutical composition comprising roflumilast as set forth in table 6 was prepared.
Table 6:0.1% w/v roflumilast ophthalmic drug suspension
Excipient | Concentration (mg/mL) |
Roflumilast | 1.0 |
Carbomer 974B (Lubrizol) | 2.5 |
Tyloxapol | 0.5 |
Sodium chloride | 3.0 |
Mannitol (mannitol) | 3.0 |
Propylene glycol | 14.0 |
NaOH/HCl | Adjusting pH to 7.4 as required |
Example 8
Two animal studies were performed to evaluate roflumilast safety and tolerability (example 7). Roflumilast showed good tolerability in both animal models, which is highly relevant for human models. The first study was a 3 day rabbit tolerability test and the second study was a 5 day rabbit tolerability model, with the result that the drug was found to have no effect on ocular tissue nor on animal body weight. Animals in these studies either maintained weight or increased normal weight during the study period. It is well known that ocular tolerance in rabbits is an alternative indicator of tolerance in humans to ophthalmic formulations, while body weight is an indicator of overall health of animals.
Example 9
The safety of roflumilast (example 7, BID) was compared with the safety of corticosteroids (prednisolone acetate suspension, 1%, QID to BID) and antihistamines (olopatadine hcl ophthalmic solution, 0.1%, QID to BID) in preclinical models of mice with allergic conjunctivitis with long-term inflammation over 24 days. In preclinical models of mice with short-and long-term inflammation caused by antigenic stimulation of systemic and local ragweed allergens (SRWs), n=70 female Balb C mice in a stimulated environment (68-79 df,50% +/-20% humidity, 55-60 ventilations/hour) were systemically exposed to SRWs by subcutaneous injections in both hind legs on days 0 and 11 during day 17. Next, it was exposed to local SRW stimulation on day 18 (first local stimulation-baseline), followed by first local drug treatment of roflumilast (example 7), carrier treatment with inactive drug, frequent dose (BID-QID) high dose 1% prednisolone treatment, or frequent dose (BID-QID) 0.1% olopatadine treatment. Mice were randomized on day 18 (10 per group) based on clinical levels of hyperemic response. Mice were then treated with prophylactic drugs for two days (days 19-20) and then followed by their response to drug treatment (roflumilast topical ophthalmic suspension and vehicle were BID, two positive controls (prednisolone and olopatadine) were QID, TID or BID) at days 21-24 prior to twice daily local stimulation of SRW antigen (within 30-90 minutes of drug treatment).
Drug administration was started only on day 18. During the study period, the body weight of the mice was determined after study days 11, 18 and 24. Figure 1 shows the body weight of mice after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%) measured in animal model studies. Mice exposed to high frequency, high doses of corticosteroid lose weight during days 18-24, which is a typical response of mice exposed to corticosteroids. Despite the different responses from humans, even local corticosteroid exposure is a hallmark of overall systemic health risk. In the roflumilast group, no effect on body weight, cage side observations, food consumption or other markers of general ocular or systemic health was found, indicating good tolerability of the drug. Inflammatory clinical responses were also examined at days 18, 21 (early) and 22, 23 and 24 (late) for congestion, eyelid swelling, secretions and squints. Figure 2 shows the clinical response of hyperemia after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%) measured in animal model studies. Fig. 3 shows the clinical response of eyelid swelling after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%) measured in animal model studies. Fig. 4 shows the clinical response of secretions measured in animal model studies after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%). Fig. 5 shows the clinical response of squint after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%) measured in animal model studies.
As shown in fig. 5, both corticosteroid and antihistamine groups increased in squinting frequency during the study, which can also be considered as a sign of local irritation. The squint cases of the roflumilast group and the carrier group are light, and are particularly obvious in the early stage. No group was found to present cage edge safety or behavioural problems other than weight loss and squinting as described above. Thus, in this preclinical study, roflumilast and the vehicle group showed better tolerability relative to the active control group, which represents the current therapeutic standard for human topical drug treatment for most OSDs.
Further, as shown in fig. 2-5, preclinical mouse models of chronic inflammation caused by systemic and local models of allergic conjunctivitis show that roflumilast is able to ameliorate the inflammatory clinical response of congestion, eyelid swelling, secretions and squints compared to baseline. The significance relative to baseline was not measured in this experiment. Although the overall baseline inflammatory levels observed in this model are relatively low, therapeutic interventions generally perform better than baseline and provide clinical improvements, including the roflumilast group. The corticosteroid group performed better than the other groups in a short time and at the clinical endpoint, but was not consistent, suggesting that roflumilast can provide similar levels of efficacy without the safety concerns described above.
Example 10
As part of the murine preclinical model discussed in example 9, control of cytokine up-regulation was measured by comparing the levels of cytokines in conjunctival and corneal tissue at the end of the experimental schedule as a marker of drug control of inflammation after administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%). The results of these cytokine-based inflammation measurements are shown in fig. 6-8 and described below. Figure 6 shows Th2 cytokine responses measured in animal model studies following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%). Figure 7 shows Th17 cytokine responses measured in animal model studies following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%). Figure 8 shows Th1 cytokine responses and chemokine KC/GRO (also known as CXCL 1) responses measured in animal model studies following administration of roflumilast topical ophthalmic suspension (0.1%), vehicle, prednisolone acetate ophthalmic suspension (1.0%) and olopatadine hydrochloride ophthalmic solution (0.1%).
Cell inflammation measured by terminal cytokine levels is not only at higher absolute levels, but also the variability between groups is greater than clinical results, making it a useful indicator of disease response. Although the causes of long-term inflammation (systemic and local antigen stimulation of SRW) began on day 1 and day 18, respectively, the drug treatment for each group in each of these experiments began only on day 18 of a total of 24 days, which resulted in long-term inflammation over time prior to any treatment administration. However, of the samples in which seven eyes were pooled into four samples (pooled to ensure adequate cytokine concentrations), only roflumilast-treated animals had undetectable cytokine levels (the major tissue and response mechanisms of the underlying allergic conjunctivitis disease state of the model) in all four samples of all four cytokines of the conjunctiva associated with Th2 responses-i.e., IL2, IL4, IL5 and IL10. In this end value assay, undetectable levels mean that the cytokine is not present in the model or tissue, or that the formulation successfully reduces the cytokine below a measurable limit, completely down-regulating the particular cytokine. The higher the relative level of cytokine (measured in pg/μg of relevant tissue), the greater the inflammatory effect of the cytokine on the ocular tissue. The goal of the treatment is to reduce the cytokines to undetectable or as close as possible to undetectable and to understand in which tissues the inflammatory targets are most relevant. Neglecting treatment criteria for such diseases, which are generally known to have a rapid response (e.g. olopatadine) or a profound and long lasting response (e.g. corticosteroids), have significantly higher residual levels of cytokines in conjunctival Th2 cytokine samples with less control over their inflammatory effects on the disease. Of the Th17 and Th1 cytokines (two known primary mechanisms of PDE-4 inhibition), roflumilast has a very pronounced effect on IL-6 and IL-12p70 in the conjunctiva (p < 0.0005) compared to steroids and antihistamines (also pronounced compared to the vehicle), and no statistical differences from corticosteroids (for TNF- α in the conjunctiva and IL-6 and TNF- α in the cornea, which are tissues not directly related to the model), suggesting cytokine transport in ocular tissues. Among Th1 cytokines, the formulation also showed similar levels of cytokine and chemokine modulation as olopatadine and corticosteroids, which are generally associated with early allergic mast cell driven responses (as demonstrated by the strong response of IL-1b to olopatadine in the cornea). Corticosteroids (known for their effect on Th1 pathway) show a highly pronounced down-regulating effect on IL-12p70 in corneal tissue, which is associated with Th1 activation.
Th2 cytokines are particularly important for allergic and short-term inflammatory diseases because they activate B cells, which in turn adapt to the defense against parasites that trigger IgE by IL-4, eosinophil-dependent inflammation, usually triggered by IL-5, and mast cell proliferation and degranulation cascades (IL 3/IL 4). Th 17-driven cytokine responses are important drivers of autoimmune signaling and CD4+ effector responses, and are therefore highly correlated with autoimmune and immune-mediated diseases (including many ocular diseases) that generally exhibit Th17 and Th1 cytokine upregulation, which appears to be a particular inflammatory combination. IL-17, IL-17F, IL, IL-22, and TNF- α are important T cell drivers of tissue inflammation and neutrophil activation and recruitment. Th1 cytokines such as IL-1, INF-gamma and TNF-beta play an important role in autoimmune diseases, although they are also frequently upregulated in preventing infiltration of infectious agents and macrophages (Kaiko et al., immunology 2008). Th2 and Th17 cytokines are associated with inflammatory driven diseases, including ocular inflammatory diseases (Sakkas 2017). Tan et al (2014) and Liu et al (2017) studied the correlation of Th17 cytokines with various forms of dry eye disease, and found that the etiology of dry eye disease was increasingly consistent with a high correlation with inflammatory drivers and had good correlation, e.g., cytokine elevation of Th17 cell cascade. In addition, they found that higher levels of Th17 cytokine expression correlated with dry eye clinical severity markers such as OSDI, schirmer test, CFS, etc. Thus, it is widely supported that cytokine up-regulation of all Th17, th1 and Th2 cytokines is a good indicator of ocular disease inflammation; cytokine-related inflammation is associated with disease severity; the ability to down-regulate these cytokines may be an effective tool in controlling these diseases. Cytokine down-regulation is a rational therapeutic goal as well as a positive outcome of the studies mentioned in this application, since its involvement is related to the worsening of disease severity. In example 14, the inventors have surprisingly found that cytokine measurements are a better endpoint for observing and estimating inflammation and immune activation in murine models, as well as immune control and anti-inflammatory success of the tested agents, and that roflumilast agents perform better than corticosteroids and antihistamines in down-regulating several key cytokines known to be associated with a large number of ocular diseases.
Furthermore, while this study was performed in the allergic conjunctivitis model, the increase in systemic stimulus testing (run-in) was tailored to provide observations that mimic long-term inflammation and immune-mediated ocular stress. Thus, these cytokine results are applicable to many other diseases. Although examples 13 and 14 relate to the allergic conjunctivitis model, and thus cytokine upregulation was highest in conjunctiva with Th2 cytokines, corneal involvement was also observed in this study. The Th2 and Th17 cytokine effects observed in this study indicate their potential impact on a variety of related ocular diseases. Many ocular diseases and severity have a broad range of cytokine markers involved, including Demodex blepharitis (Th 17: IL-7, IL-12, IL-17; kim et al, 2010), JIA-related uveitis (Th 17; WALSCHIELD, 2019), graft versus host disease after ocular allogeneic stem cell transplantation (IFN-gamma (early), IL-6 (late); riemens 2012), and recurrent herpetic stromal keratitis (Th 17/Th1; rajasagi 2019).
Surprisingly, the inventors of the present application found that local rather than systemic administration of roflumilast in small and convenient doses provides an effective response to IL-6 and IL-12 cytokines important for Th17 and IL-2, IL-4 and IL-5 associated with Th 2-driven inflammation. The results in example 14 demonstrate that roflumilast has a broad range of immunomodulatory and anti-inflammatory effects associated with a variety of ocular diseases, again demonstrating that this agent is similar to or more effective than other common immunomodulatory, immunosuppressant and anti-inflammatory agents, yet has better safety and convenience.
Example 11
A study was conducted to assess ocular tolerability of 1% roflumilast in an ointment formulation (example 6) or 0.1% roflumilast in two suspension formulations (examples 1 and 3) in male netherlands rabbits (n=3 per group) with repeated topical ocular administration at increased dosing concentrations and/or frequency. The vector group is not included. The test material was ready-to-use with a dose volume of 40 μl per eye and the suspension was shaken well before administration. Queue a receives BID administration of the ointment (example 6), or QID administration of the suspension (examples 1 and 3) to test for tolerability of increased dosing frequency (i.e., beyond the expected clinical dosing frequency). Parameters evaluated include mortality/morbidity, clinical observations, body weight, ophthalmic examinations (including slit-lamp biomicroscopy of Hackett-McDonald scores and indirect ophthalmoscopy by institutional certified veterinary ophthalmologists). A 5 μm thick slice was prepared for each eye (5 slices per eye). The central portion of each eyeball including the optic nerve and visual zone was stained with hematoxylin and eosin (H & E) and examined using an optical microscope. Eye examination of OE was performed at baseline and days 1, 3 and 5. Eyes were collected for histopathological examination about 30 minutes to 1 hour after the last dose on day 5.
Double sided BID administration of 1% roflumilast ophthalmic ointment (example 6) for 5 days resulted in mild to moderate blepharitis on day 5. The tolerability of the 0.1% roflumilast ophthalmic suspension administered in HPMC (example 1) or PVP (example 3) was good with no findings observed during the ophthalmic examination, including: congestion, bulbar conjunctival edema, secretions, turbidity, corneal pannus, pupillary light reflex, aqueous humor flash or cells, vitreous cells (vitrous cells), or choroidal, retinal or optic neuropathology. In addition, all animals maintained weight or increased normal amounts of weight over a period of 5 days.
Histopathological evaluation showed that 1/6 eyes receiving 1% ointment (example 1) and 3/6 eyes receiving 0.1% roflumilast ophthalmic suspension in PVP formulation (example 3) had slightly increased monocytes at the limbus. No other abnormalities were found by any eyes. Limbal infiltration is mild, in the normal range; thus, no adverse ocular pathology associated with the test article was observed in this cohort. In addition, no histopathological signs of cataract, retinal detachment or retinal degeneration were found.
These data demonstrate that even though the administration was 5 days at an increasing frequency of 2 or 4 times per day (respectively), 1% roflumilast ointment (example 6) and 0.1% roflumilast suspension (examples 1 and 3) were well tolerated in the netherlands rabbits. Roflumilast ointment (example 6) caused mild inflammation of the eyelid, but this was not considered disadvantageous.
Example 12
A study was performed to evaluate ocular tolerability of 0.1% roflumilast ointment (example 5) in new zealand white rabbits or roflumilast suspensions (0.3%, 1% or 3%) in the higher concentration range studied in the netherlands rabbits than in the previous study (examples 1 and 3). Rabbits (n=3 per group) received QD administration of roflumilast or placebo ointment, or QID administration of roflumilast suspension. The dose volume for each eye was 40 μl and the suspension was shaken well before administration. Parameters evaluated include mortality/morbidity, clinical observations, body weight, ophthalmic examinations (including slit-lamp biomicroscopy of Hackett-McDonald scores and indirect ophthalmoscopy by institutional certified veterinary ophthalmologists). A 5 μm thick slice was prepared for each eye (5 slices per eye). The central portion of each eyeball, including the optic nerve and the visual zone, was stained with H & E and examined using an optical microscope. OE was performed at baseline and on days 1,3 and 5. Eyes were collected for histopathological examination about 45 minutes to 6.5 hours after the last dose on day 5.
Once daily single-sided administration of 0.1% roflumilast ophthalmic ointment (example 5) caused 1/3 of mild blepharitis on day 5; this finding was not observed in the contralateral placebo eye. Double sided QID administration of 0.3%, 1% or 3% roflumilast ophthalmic suspensions (examples 1 and 3) was well tolerated, with no findings observed during ophthalmic examination, including: congestion, bulbar conjunctival edema, secretions, turbidity, corneal pannus, pupillary light reflex, aqueous humor flash or cells, vitreous cells, or choroidal, retinal or optic neuropathology. In addition, all animals maintained weight or increased normal amounts of weight over a period of 5 days.
Histopathological evaluation showed that in one eye treated with 0.1% ointment (example 5) and one eye treated with placebo ointment, there was mild mononuclear inflammatory cell infiltration in the limbus and ciliary body. Treatment with 0.3% roflumilast ophthalmic suspension resulted in one eye treated with the suspension (example 3) having mild/focal subconjunctival mononuclear cell infiltration and one eye treated with the suspension (example 1) having a small number of mononuclear cells in the vitreous. Multiple eyes receiving 1% and 3% roflumilast ophthalmic suspensions showed mild mononuclear inflammatory cell infiltration in limbal and subconjunctival areas. Infiltration severity was lower, but the incidence appeared to increase at high doses. No such slight inflammatory differences were observed between the two suspension vehicles. In addition, no histopathological signs of cataract, retinal detachment or retinal degeneration were found. Thus, no adverse ocular pathology associated with the test article was observed in this cohort.
Example 13
To further test the tolerability and safety of roflumilast topical ophthalmic suspensions over an extended dosing range and frequency and prolonged dosing time (similar to the dosing length used in human clinical trials), the pharmaceutical composition was used in GLP toxicology studies with 13 weeks of treatment in rabbits. The vehicle of the local ophthalmic suspension of roflumilast at a concentration of 0.1%, 0.3% or 1.0% (example 3, table 3), or the vehicle of the control (physiological saline or the same local ophthalmic suspension of roflumilast (example 1, table 1, minus any active pharmaceutical ingredient) was administered to New Zealand white rabbits at TID (3 times per day) over 13 weeks, followed by a recovery period of 4 weeks, both male and female animals were tested, n=7 animals in each sex/dose group, total n=56, clinical observations made on animals, morbidity/mortality, weight, food consumption, ocular pressure, corneal thickness, mcDondald-Shadduck score ophthalmic exams, electroretinogram (ERG), clinical pathology (hematology, coagulation, clinical chemistry), systemic exposure, organ weight, and three areas of particular interest in the evaluation study of anti-inflammatory drug standard therapy were known human side effects, there were some inter-species differences, changes in intraocular pressure (total thickness) of animals, cornea thickness and thickness as well as in the cornea of animals were not providing a graph of the cornea thickness measurement (IOP) as shown in FIG. 11, providing a graph of the results of the central study, no weight measurement of the cornea thickness as shown in FIG. 11, no graph of the results were provided during the central study (IOP) were provided for the results were carried out in the graph (FIG. 11), there were some transient changes in IOP or corneal thickness in some eyes or sexes, but none of these were considered adverse.
The foregoing description has been provided for the purposes of illustration and description. The description is not intended to limit the invention to the precise form disclosed. Those skilled in the art will appreciate that modifications and substitutions may be made to the basic inventive description.
Claims (19)
1. A method for treating a patient suffering from an ocular inflammatory disorder or an immune-mediated disorder, comprising:
Administering an ophthalmic pharmaceutical suspension comprising a therapeutically effective amount of roflumilast or a pharmaceutically acceptable salt thereof to the ocular surface of the patient,
Wherein the administration results in a reduction of at least one side effect compared to administration of an immunosuppressant, immunomodulator or non-steroidal anti-inflammatory agent.
2. The method according to claim 1, wherein the immunosuppressant, immunomodulator or non-steroidal anti-inflammatory agent is an ophthalmic prednisolone topical composition or an antihistamine olopatadine topical composition.
3. The method according to claim 1, wherein the side effect is an ocular side effect selected from the group consisting of: increased intraocular pressure, thinned cornea, sclera and epithelial tissue, perforation of cornea, sclera and epithelial tissue, delayed or reduced wound or epithelial healing, vision deficiency, burning sensation, stinging, foreign body sensation, congestion, eyelid edema, pain, ocular itching, urticaria, rash, allergic reaction, keratitis, conjunctivitis, subcapsular cataract formation, glaucoma, optic nerve injury, corneal ulceration, mydriasis, vision deficiency, burning sensation, stinging, foreign body sensation, increased sensitivity to fungal, bacterial or viral infections, reactivation of fungal or viral infections, masking of acute suppurative infections, increased post-operative blister formation, dry eye, punctate keratopathy, central serous chorioretinopathy, pharmaceutical eye disease, loss of accommodation, ptosis, acute anterior uveitis or eye perforation.
4. The method according to claim 1, wherein the side effect is a systemic side effect selected from the group consisting of: blood glucose changes, weight gain or loss, reduced systemic wound healing, susceptibility to systemic microbial infection, irritation of surrounding tissues of the eye, cold syndrome, pharyngitis, weakness, back pain, headache, cough, nausea, rhinitis, sinusitis, osteoporosis, dysgeusia or dysgeusia, or sulfite-related allergic reactions.
5. The method according to claim 2, wherein the topical composition of prednisone Long Huoao lotadine is a suspension.
6. The method according to claim 1, wherein said administering results in an additional measure of reduced frequency of administration or convenience of administration compared to administration of an immunosuppressant, immunomodulator or a non-steroidal anti-inflammatory agent.
7. The method according to claim 1, wherein said administration down-regulates cytokine or chemokine activity driven by inflammatory stress in at least one ocular tissue selected from the group consisting of corneal and conjunctival tissue.
8. The method according to claim 1, wherein said administering results in disease modifying activity in at least one supporting tissue or gland of the patient, said at least one supporting tissue or gland selected from the group consisting of cornea, conjunctiva, meibomian gland, iris, uvea, retina, or choroid.
9. The method according to claim 1, wherein the ocular inflammatory disorder or immune-mediated disorder is an ocular surface disease selected from the group consisting of: post-operative pain and inflammation of cataracts or other ocular surgery or laser treatment, corneal refractive surgery followed by opacification, post-operative full or partial thickness corneal transplants, dry eye syndrome including sjogren's syndrome or other autoimmune or inflammatory dry eye disease, evaporative or dry eye disease, ocular graft versus host disease, ocular rosacea, allergic conjunctivitis or allergic keratoconjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, keratitis, herpetic or viral keratitis, inflammation including herpetic or viral stromal keratitis/herpetic or viral blepharitis or conjunctivitis, herpes zoster related inflammation, inflammation secondary to other infectious agents including bacterial, viral or fungal infections, inflammation secondary to ocular chemical burns, ocular history-about syndrome/toxic epidermonecrosis, uveitis including juvenile idiopathic arthritis, seborrheic or other forms of blepharitis, corneal stem cell deficiency, meibomian gland dysfunction, episcleritis, pterygium, herpes zoster, phlyctenulosis), ocular infections (contact dermatitis), ocular infections or other ocular infections, but commonly used in the treatment of the eye, such as those with the eye, or other eye infections, but commonly used in the treatment of the eye, such conditions as corneal or other eye infections.
10. The method according to claim 1, wherein the ocular inflammatory disorder or immune-mediated disorder is an anterior or posterior segment disease of the eye selected from the group consisting of: anterior uveitis, total uveitis, 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, retinitis, ocular manifestations of behcet's disease, or other retinopathy or anterior segment diseases.
11. The method according to claim 1, wherein the ocular inflammatory disorder or immune-mediated disorder is dry eye, uveitis, or herpetic or viral keratitis.
12. A method for treating a patient suffering from an ocular inflammatory disorder or an immune-mediated disorder, comprising:
administering to the patient an ophthalmic pharmaceutical suspension comprising a therapeutically effective amount of roflumilast or a pharmaceutically acceptable salt or metabolite thereof,
Wherein the administration down-regulates cytokine activity driven by inflammatory stress in at least one ocular tissue selected from the group consisting of corneal and conjunctival tissue.
13. The method according to claim 12, wherein said administering results in disease modifying activity in at least one supporting tissue or gland of the patient selected from the group consisting of cornea, conjunctiva, meibomian gland, sclera, ciliary body, iris, lens, uvea, choroid, retinal Pigment Epithelium (RPE) or retina.
14. The method according to claim 12, wherein the ocular inflammatory disorder or immune-mediated disorder is an ocular surface disease selected from the group consisting of: post-operative pain and inflammation of cataracts or other ocular surgery or laser treatment, corneal refractive surgery followed by opacification, post-operative full or partial thickness corneal transplants, dry eye syndrome including sjogren's syndrome or other autoimmune or inflammatory dry eye disease, evaporative or dry eye disease, ocular graft versus host disease, ocular rosacea, allergic conjunctivitis or allergic keratoconjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, keratitis, herpetic or viral keratitis, inflammation including herpetic or viral stromal keratitis/herpetic or viral blepharitis or conjunctivitis, herpes zoster-related inflammation, inflammation secondary to other infectious agents including bacterial, viral or fungal infections, inflammation secondary to ocular chemical burns, ocular history-about syndrome/toxic epidermonecrosis, uveitis including juvenile idiopathic arthritis, seborrheic or other forms of blepharitis, corneal stem cell deficiency, meibomian gland dysfunction, episcleritis, pterygium, folliculitis, contact dermatitis, corneal inflammation, ocular inflammation, other infections or other infectious agents such as bacterial, viral or fungal infections, ocular history, but commonly used in patients due to the healing of the eye, or other biological infections.
15. The method according to claim 12, wherein the ocular inflammatory disorder or immune-mediated disorder is an anterior or posterior segment disease of the eye selected from the group consisting of: anterior uveitis, total uveitis, 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, retinitis, ocular manifestations of behcet's disease, or other anterior or posterior segment diseases.
16. The method according to claim 12, wherein the ocular inflammatory disorder is dry eye, uveitis, or herpetic or viral stromal keratitis.
17. The method according to claim 12, wherein said administering results in an additional measure of reduced frequency of administration or convenience of administration compared to administration of an immunosuppressant, immunomodulator or a non-steroidal anti-inflammatory agent.
18. A method for treating a patient suffering from an ocular inflammatory disorder or an immune-mediated disorder, comprising:
administering to the patient an ophthalmic pharmaceutical suspension comprising a therapeutically effective amount of roflumilast or a pharmaceutically acceptable salt or metabolite thereof,
Wherein the administration down-regulates cytokine activity in a manner that is superior to down-regulating cytokine by administration of an immunosuppressant, immunomodulator or a non-steroidal anti-inflammatory agent.
19. The method according to claim 18, wherein said immunosuppressant, immunomodulator or non-steroidal anti-inflammatory agent is an ophthalmic prednisolone topical composition or an antihistamine olopatadine topical composition.
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Application Number | Priority Date | Filing Date | Title |
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US63/247,174 | 2021-09-22 | ||
US63/251,874 | 2021-10-04 |
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