High concentration pharmaceutical compositions of roflumilast for ocular delivery

Abstract

The present invention relates to high concentration ophthalmic pharmaceutical formulations of the phosphodiesterase-4 inhibitor roflumilast suitable for intravitreal administration or other ophthalmic administration to injection sites inside or outside of the eye and orbit. The composition may include from about 2% to about 5% w / v of roflumilast, a viscosity agent, a tension agent, a buffering agent, a surfactant, and water. The pharmaceutical composition is stable, almost free of impurities or free of impurities, and can be injected with minimal force from a No. 27 or No. 30 syringe to achieve therapeutic levels of drugs in the ocular surface, the anterior chamber, the vitreous / posterior chamber, and the tissue associated with the tissue or cavity around the eye.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 407,366, filed on September 16, 2022, which is incorporated herein by reference. Technical field

[0003] The present invention relates to a pharmaceutically - effective ophthalmic composition having a high concentration of the phosphodiesterase - 4 inhibitor roflumilast. Additionally, the present invention includes methods of treatment by administering the composition. Background art

[0004] Roflumilast is an effective and selective long - acting inhibitor of phosphodiesterase type 4 (PDE), which has anti - inflammatory and potential anti - tumor activities. Roflumilast is known to be suitable as a bronchial therapeutic 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 and allergen - induced airway disorders (such as bronchitis, asthma, COPD); skin diseases (such as proliferative, inflammatory and allergen - induced skin disorders), and widespread inflammation in the gastrointestinal region (Crohn's disease and ulcerative colitis). Oral pharmaceutical compositions of roflumilast are currently available under the trade name (in the United States) and (in Europe), while a topical composition of roflumilast cream for dermatological use is currently available under the trade name Zoryve TM (in the United States).

[0005] Roflumilast and its synthesis are described in U.S. Patent No. 5,712,298. It has been recognized that pharmaceutical compounds having phosphodiesterase (PDE)-4 inhibitory properties, such as roflumilast, are therapeutically effective and can be used to treat inflammatory disorders, such as psoriasis and atopic dermatitis. Although the therapeutic efficacy of oral and topical pharmaceutical compositions has been investigated, there remains a need for high-concentration ophthalmic pharmaceutical compositions of roflumilast that are suitable for treating inflammatory and immune-mediated disorders of the eye, particularly for delivery to the anterior and posterior chambers of the eye, or to tissues or cavities surrounding the eye. Most of the current market for anti-inflammatory ophthalmic drugs is based on antibiotics, immunosuppressants, and steroids, many of which do not meet the clinical needs of long-term inflammatory diseases or exhibit significant long-term comorbidities and safety issues. Accordingly, there is a highly unmet need for a convenient and tolerable form of an anti-inflammatory roflumilast ophthalmic preparation suitable for the ocular surface, the anterior chamber of the eye, or the vitreous / posterior chamber. The major markets for high-concentration drugs suitable for delivery to the anterior or posterior (also known as vitreous and / or retinal) chambers of the eye focus on mechanisms other than inflammation (such as anti-angiogenic agents), anti-inflammatory steroids obtained by delivery to the posterior eye via polymeric implants or depot forms to achieve high concentrations or long-acting formulations, or systemic biologics that target a single inflammatory pathway (such as TNF). While some anti-inflammatory ophthalmic drugs can be used in injectable or other forms for acute applications in the postoperative or post-operative setting, the long-term options are very limited, as they need to be both effective and avoid the safety issues of steroid drugs. Further limiting the market is that many anti-inflammatory drug therapies commonly used for medium- to long-term use on the ocular surface or in the anterior chamber (anterior eye) have too large a molecular weight for ocular delivery or unpredictable pharmacokinetics (PK) in ocular tissue compartments, such that consistent use in the intraocular, posterior eye, and vitreous compartments cannot be achieved.

[0006] Local delivery of drugs to the eye is very difficult because ophthalmic agents must balance tolerance, sterility, safety, and efficacy. Developing stable ophthalmic formulations is very difficult as they need to be prepared under aseptic conditions while maintaining physicochemical properties, staying within a strictly defined range of pH tolerable to the eye, and of inactive ingredients, and be delivered to the eye in an effective dose. Excipients for ocular delivery can potentially exhibit ocular toxicity and further exacerbate the disorder and associated symptoms of the condition being treated. Due to physical limitations, the development of high-concentration drug compositions for ocular delivery can be particularly difficult. Ocular delivery focuses on the ocular surface of the eye, the anterior segment of the eye, or the posterior segment / vitreous compartment. Ocular surface formulations are typically delivered by the patient as eye drops once to four times a day (or more often in the case of steroid tapering), which presents the additional challenge of requiring dosing consistency and flexibility to deliver an effective dose, as common operator errors are found in home-based patient delivery: issues of sterility, variations in delivery volume, patient compliance, and placement accuracy. Patients with long-term ocular diseases also have increased sensitivity to active and inactive ingredients and preservatives, creating additional formulation challenges. Most high-concentration agents for intraocular use within the anterior or posterior / vitreous compartments typically have to be delivered by injection into various associated tissues or cavities, which presents different challenges from formulations for ocular surface delivery. Due to the small total size of the ocular compartment, the volume of the product to be delivered must be highly restricted, typically to a preferred volume of 50 - 100 μl, with a maximum safe volume of approximately 200 μL without pre-injection puncture. When injecting into the internal compartments of the eye, regardless of the injection site, it is desirable to limit the number of administrations (injections) to minimize the risk of introducing infection to the patient and to limit the physical pressure on the injection site, especially when treating chronic diseases. Concentrated formulations for injection into the tissues and cavities around the orbit are also needed to minimize the injection frequency.

[0007] This need for very small injection volumes and a high enough drug payload within the small injection volume to limit the injection frequency has created a need for higher-concentration drugs for many ocular conditions. Injections are also limited to physician administration, resulting in a convenience burden for patients and physician offices. Summary of the Invention

[0008] The present invention relates to a high-concentration ophthalmic pharmaceutical composition of the phosphodiesterase-4 inhibitor roflumilast. In certain embodiments, the ophthalmic pharmaceutical preparation comprises from about 2% to about 5% w / v of roflumilast, a viscosity agent, a tonicity agent, a buffer, a surfactant, and water. The ophthalmic pharmaceutical composition is suitable for intravitreal administration or other injection-based administration into the target tissues of the eye, or administration into the tissues or cavities around or surrounding the eye. In certain embodiments, the ophthalmic pharmaceutical composition comprises a viscosity agent selected from hydroxypropyl methylcellulose, polyvinylpyrrolidone, or sodium carboxymethylcellulose. In certain embodiments, the tonicity agent comprises one or more of sodium chloride and potassium chloride. In certain embodiments, the ophthalmic pharmaceutical composition further comprises a buffer, preferably acetate and citrate buffers (such as sodium acetate and sodium citrate). In certain embodiments, the ophthalmic pharmaceutical composition further comprises a surfactant, preferably polysorbate (such as polysorbate 20). In certain embodiments, the pH of the composition is from 5.5 to 7.5.

[0009] In certain embodiments, the ophthalmic pharmaceutical composition comprises from about 2% to about 5% w / v of roflumilast, from about 0.2% to about 0.8% w / v of sodium carboxymethylcellulose, from about 0.2% to about 0.8% w / v of sodium chloride, from about 0.02% to about 0.25% w / v of polysorbate 20, from about 0.005% to about 0.20% w / v of potassium chloride, from about 0.005% to about 0.20% w / v of calcium chloride, from about 0.005% to about 0.20% w / v of magnesium chloride, from about 0.005% to about 0.20% w / v of sodium acetate, from about 0.005% to about 0.20% w / v of sodium citrate, and water. The ophthalmic pharmaceutical composition is suitable for intravitreal administration or other injection-based administration into the eye, or administration into the tissues or cavities around the eye. In certain embodiments, the pH of the composition is from 5.5 to 7.5.

[0010] In certain embodiments, the pharmaceutical composition has a particle size distribution characterized by a d90 value less than or equal to about 20 μm. In certain embodiments, the pharmaceutical composition has a particle size distribution characterized by a d90 value less than or equal to about 15 μm. In certain embodiments, the pharmaceutical composition has a particle size distribution characterized by a d90 value less than or equal to about 10 μm.

[0011] In certain embodiments, the pharmaceutical composition can be injected from a 27G syringe needle with a force less than about 3.00 N. In certain embodiments, the pharmaceutical composition can be injected from a 30G syringe needle with a force less than about 3.50 N.

[0012] In certain embodiments, the ophthalmic pharmaceutical composition comprises or contains a small amount of impurities. In certain embodiments, after terminal sterilization (e.g., gamma irradiation), the pharmaceutical composition has less than about 0.5%, less than about 0.2% or substantially 0% impurities. The dose rate, applied dose and time of gamma irradiation affect the molecular structure of the irradiated sample in various ways, since irradiation affects the chemical and physical structure of the drug, formulation excipients and packaging materials. Gamma radiation is an ionizing sterilization process where the sample is exposed to gamma rays to eliminate any microorganisms that may be present. According to ISO 11137, the conventional dose for irradiation sterilization is 25 - 40 kGy. It is important to consider the accuracy and effectiveness of gamma irradiation during the sterilization process, especially for intravitreal or other injections. The dose distribution and uncertainty should be recorded with several dosimeters in the pharmaceutical sample tray to confirm that the sterilization process is reliable and reproducible. Statistically, the uncertainty of uniform irradiation must be below 10% to infer that the batch or sample has been irradiated uniformly.

[0013] A typical dose distribution procedure involves placing a tray with samples of the injectable product on a rack located at the center of the sample chamber that generates gamma rays. At least two dosimeters are placed on the samples, one dosimeter above the tray and another dosimeter below the tray. In addition to the separate monitoring dosimeter (Dmon) that is typically placed above the sample tray, minimum dose (Dmin) and maximum dose (Dmax) estimations are also made. The dosimeter placement and measurements should be repeated according to ISO 11137-3. Dmin, Dmax and Dmon are calculated as the average of the measurements performed.

[0014] In certain embodiments, a method of treating an ocular disorder in a patient is provided. The method can include injecting a high-concentration ophthalmic pharmaceutical composition of roflumilast into the patient's eye. In certain embodiments, the pharmaceutical composition is one of the compositions described herein and contains from about 2% to about 5% w / v of roflumilast. In certain embodiments, the ocular disorder is selected from: anterior uveitis, posterior uveitis, pan uveitis, or intermediate uveitis; or uveitis associated with HLA-B27, juvenile idiopathic arthritis, Behçet's disease, ankylosing spondylitis, Vogt-Koyanagi-Harada syndrome (VKH), or an autoimmune disease; ocular graft-versus-host disease, Stevens-Johnson syndrome / toxic epidermal necrolysis (TENS), diabetic retinopathy, diabetic macular edema, retinal vein occlusion, age-related macular degeneration (AMD), including dry AMD, geographic atrophy, or exudative AMD, choroidal neovascularization, retinal vasculitis (drug-related / iatrogenic, non-infectious / aseptic, or idiopathic), choroidal thickening associated with thyroid eye disease, Coats disease, central serous retinopathy, or chorioretinopathy, aseptic or infectious endophthalmitis, retinitis, choroiditis, anterior or posterior scleritis / episcleritis, endothelial keratitis (bacterial, viral, fungal, or non-infectious in nature), and other inflammatory diseases of the anterior segment and posterior segment of the eye or ocular complications of other inflammatory or autoimmune diseases, inflammation associated with hereditary retinal diseases, retinitis pigmentosa, Stargardt disease, Leber congenital amaurosis, Leber hereditary optic neuropathy, Usher syndrome, X-linked retinoschisis, choroidemia, regional idiopathic outer retinal disease, myopia, vitreomacular adhesion, retinal detachment, choroidal detachment and hemorrhage, choroidal rupture, choroidal folds, proliferative vitreoretinopathy, idiopathic ischemia, achromatopsia, retinopathy of prematurity, gyrate atrophy, central areolar choroidal dystrophy, punctate inner choroidopathy, multifocal choroiditis, choroiditis, choroidal granuloma, choroidal dystrophy, choroidal fibrosis, acute posterior multifocal placoid pigment epitheliopathy, serpiginous choroiditis, birdshot retinochoroidopathy, multiple evanescent white dot syndrome, retinoblastoma, choroidal melanoma, retinal lymphoma, and iatrogenic inflammation of the posterior chamber or vitreous cavity.In certain embodiments, the pharmaceutical composition delivers a therapeutic level of roflumilast to one or more of the following: cornea, limbus, conjunctiva, eyelid, lacrimal gland and meibomian gland, lens, pupil, iris, anterior sclera, ciliary body, lacrimal gland, aqueous humor, inner or endothelial or inner layer of the cornea, lacrimal gland, lymph node, posterior sclera, retina, choroid, macula, fovea, optic disc, optic nerve, vitreous humor or vitreous canal. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The accompanying drawings are incorporated herein and constitute a part of this disclosure, which help to exemplify various embodiments of the present invention and, together with the description, further serve to describe the present invention so that those skilled in the relevant art can prepare and use the embodiments disclosed herein. The error bars in the figures are standard deviation values.

[0016] Figure 1 is a particle size distribution plot (time versus particle size in μm) of an ophthalmic pharmaceutical composition of an exemplary pharmaceutical composition before γ-irradiation.

[0017] Figure 2 is a particle size distribution plot (time versus particle size in μm) of an ophthalmic pharmaceutical composition of an exemplary pharmaceutical composition after γ-irradiation.

[0018] Figure 3 is a plot of syringe thrust (force in N) of an ophthalmic pharmaceutical composition with a 27G needle.

[0019] Figure 4 is a plot of syringe thrust (force in N) of an ophthalmic pharmaceutical composition with a 30G needle.

[0020] Figure 5 is an HPLC assay of an ophthalmic pharmaceutical composition of an exemplary pharmaceutical composition.

[0021] Figure 6 is an HPLC assay of an ophthalmic pharmaceutical composition of an exemplary pharmaceutical composition.

[0022] Figures 7A to 7D is a plot of tissue retention of roflumilast and roflumilast N-oxide in key retinal / posterior or vitreous tissues at 15 days and 30 days after a single dose (50 μL) of a 3% pharmaceutical composition was injected intravitreally or suprachoroidally into the vitreous humor and suprachoroidal space, respectively.

[0023] Figure 8 is a plot of ocular tolerance scores for a dose range experiment, including bilateral intravitreal injection of vehicle, 2% and 5% ophthalmic pharmaceutical compositions in Dutch Belted rabbits, where self-aggregating depots of the product were visible in the vitreous over 60 days. Detailed implementation manners

[0024] It should be understood that the present invention is not limited to the specific methods, experimental protocols and reagents described herein, as these can be changed. It should also be understood that the terms used herein are for the purpose of describing specific embodiments only and are 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 one of ordinary skill in the art to which this invention belongs.

[0025] Unless otherwise indicated, all publications, patents and patent applications cited herein are incorporated herein by reference in their entirety. When the same term is defined in a publication, patent or patent application incorporated herein by reference and in the present disclosure, the definition in the present disclosure shall control. For publications, patents and patent applications cited for describing a particular type of compound, chemistry, etc., the portions related to such compound, chemistry, etc. are the portions of the documents incorporated herein by reference.

[0026] Note that as used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, "active ingredient" includes a single ingredient and two or more different ingredients.

[0027] When used in conjunction with a numerical value, the term "about" means a value that encompasses a range that is 5% less than the stated value at the lower limit and 5% greater than the stated value at the upper limit.

[0028] The term "ocular surface" refers to tissues at or near the surface of the eye, including the cornea, conjunctiva or tear film. The term "anterior chamber" or "anterior chamber ocular disease" refers to tissues associated with the anterior chamber of the eye and diseases that affect the anterior chamber of the eye through the iris-ciliary body and lens, anterior sclera, aqueous humor, and corneal endothelium or innermost layer. Anterior ocular disease is different from vitreous cavity, posterior tissue or ocular diseases that affect, for example, the retina, and is different from diseases of the ocular surface or those that directly affect tissues facing the external environment such as corneal conjunctival tissue or the ocular surface and tear film. The term "vitreous cavity" or "vitreous cavity ocular disease" refers to tissues associated with the vitreous cavity or diseases that affect the vitreous cavity, which is located at a position passing from the posterior part of the lens through and including the retina and choroid, vitreous humor, posterior sclera up to the optic nerve. The term "extraorbital" or "tissues or cavities around the eye" refers to tissues associated with the outer surface of the eye or eyelids and surrounding tissues or muscles around or periorbital to the eye, or the space behind the eye, or diseases associated with these tissues and cavities.

[0029] The term "ocular disorder" or "ocular disease" refers to a disease / condition of the eye that can threaten vision, cause ocular discomfort or disturbances, and may signal systemic health problems. The ocular surface consists of the cornea (specifically including the corneal epithelium and stroma), the limbus, the conjunctiva, the eyelids, the lacrimal gland and meibomian glands, and the interconnected surface nerves. The anterior chamber consists of the lens, the pupil, the iris, the anterior sclera, the ciliary body, the lacrimal gland, the aqueous humor, and the inner or endothelial or inner layer of the cornea, lacrimal gland, and lymph nodes. The vitreous cavity consists of the posterior sclera, the retina, the choroid, the macula, the fovea, the optic disc, the optic nerve, the vitreous humor, and the vitreous canal. The eye as a whole is supported by various intraocular and extraocular muscles and ligaments that make up the extraorbital space.

[0030] The term "effective" refers to an amount of a compound, agent, substance, preparation, or composition that has a sufficient amount to result in a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or the prevention of damage or disability due to the affliction of the disease. The amount can be as a 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 can determine such an amount based on factors such as the body size of the individual, the severity of the individual's symptoms, and the specific composition or route of administration chosen.

[0031] "Pharmaceutically acceptable" means that it is generally safe when administered to humans or animals. Preferably, pharmaceutically acceptable components are those approved by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia (published by the United States Pharmacopeial Convention, Inc., Rockville, Md.) or other recognized pharmacopeias for use in animals, and more particularly in humans.

[0032] A "pharmaceutical composition" according to the present invention can exist in the form of a composition in which different active ingredients and diluents and / or carriers are mixed with each other, or can take the form of a combination preparation in which the active ingredients are present in a partially or completely different form. Examples of such combinations or combination preparations are kits.

[0033] Unless otherwise stated or unless it is clear from the context that roflumilast itself is meant, the term "roflumilast" as used in this application refers to roflumilast, its physical forms, its salts, metabolites of roflumilast, including roflumilast N-oxide and its salts.

[0034] As used herein, the term "individual" or "patient" most preferably refers to a human. The term "individual" or "patient" can include any mammal that can benefit from the compounds described herein.

[0035] "Therapeutically effective amount" or "therapeutically effective dose" means an amount of a therapeutic agent sufficient to achieve the desired purpose. The effective amount of a given therapeutic agent will vary depending on factors such as, for example, the nature of the agent, the route of administration, the body size of the individual receiving the agent, and the purpose of administration. The effective amount in each individual case can be determined empirically by a person skilled in the art according to established methods in the art.

[0036] 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 disorder; (b) limiting or preventing the development of characteristic symptoms of the disorder being treated; (c) inhibiting the worsening of characteristic symptoms of the disorder being treated; (d) limiting or preventing recurrence of the disorder in a patient who has previously had the disorder; and (e) limiting or preventing recurrence of symptoms in a patient who has previously had the disorder.

[0037] The present invention relates to a stable ophthalmic pharmaceutical composition of the phosphodiesterase-4 inhibitor roflumilast. Roflumilast is a compound of formula (I):

[0038]

[0039] wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyridin-4-yl.

[0040] 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, the use of roflumilast as a phosphodiesterase (PDE) 4 inhibitor, and the formulations of roflumilast are described in U.S. Patent No. 5,712,298, which is incorporated herein by reference. The ophthalmic pharmaceutical composition can 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.

[0041] In certain embodiments, the ophthalmic pharmaceutical composition may comprise from about 2.0% w / v to about 6.5% w / v, or from about 2.0% w / v to about 5.5% w / v, or from about 2.0% to about 5.0% w / v of roflumilast. For example, the ophthalmic pharmaceutical comprises roflumilast at any of the following percentages (w / v): 2.0%, 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%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, etc.

[0042] In certain embodiments, the ophthalmic pharmaceutical composition may be a suspension, solution, emulsion, eye drop, eye ointment, cream, gel, spray, injectable preparation (intravitreal, subconjunctival, suprachoroidal, sub-tenon, peribulbar, periorbital, retrobulbar, postorbital or other injections), depot preparation (either alone or in combination with a depoting agent or device), implantable absorbent polymer device or adsorbent contact lens. In certain embodiments, the pharmaceutical composition is administered by intravitreal, subconjunctival, subretinal, intracameral, sub-tenon, peribulbar, periorbital, retrobulbar, postorbital, suprachoroidal injection, delivery via a port or drug eluting material, cannula delivery, needle delivery or other injection sites and delivery methods.

[0043] The literature indicates that highly concentrated ophthalmic drug compositions formulated for intravitreal or other intraorbital injections, such as steroids or other drugs, can also be administered by external injection into the surrounding tissue. T. Ciuella et al., Microinjection via the Suprachoroidal Space: A Review of a Novel Mode of Administration. Am. J. Manag. Care, 28(13 Suppl.): S242-252 (2022); L. Naftali Ben Haim et al., Drug Delivery to the Suprachoroidal Space for the Treatment of Retinal Diseases, Pharmaceutics 13(7):967 (2021); A. Hadayer, Delivery of Steroids into the Eye for the Treatment of Macular Edema, Expert Opn. Drug Deliv., 13(8):1083-1091 (2016); T. Yasukawa et al., Recent Advances in Intraocular Drug Delivery Systems, Recent Pat. Drug Deliv. Formul., 5(1)-1-10 (2011). It can be administered from the outside to the surrounding tissue by using the same delivery device, such as the 27-gauge or 30-gauge needles disclosed herein. See Tomas Ortiz-Basso et al., Triamcinolone for the Treatment of Ophthalmopathy Tested with Short Tau Inversion Recovery Magnetic Resonance, Ophtal. Plast. Reconstr. Surg., Vol. 35, No. 1 (2019); Ayman Alkawas et al., Orbital Steroid Injection Versus Oral Steroid Therapy in Management of Thyroid-Related Ophthalmopathy, Clinical and Experimental Ophthalmology, 38:692-697 (2010).

[0044] In certain embodiments, the pharmaceutical composition can be in the form of an implant, such as an intravitreal implant, a transscleral implant, a sustained-release implant, a biodegradable or non-biodegradable implant material, a bioadhesive polymer, a hydrogel, nanoparticles, a viral vector, an adhesive microsphere, a micelle, a microsphere, a thermogel, a liposome, a nano-liposome, a lipid nanoparticle, an extracellular vesicle, an exosome, a temperature-sensitive gel, a mucoadhesive gel, a crystal, a microemulsion, a nanoemulsion, an emulsion, a dendrimer, polyvinyl alcohol (PVA), ethylene-vinyl acetate (EVA), polysiloxane, poly(ethylene glycol) (PEG), cross-linked poly(ethylene glycol) (PEG), poly(lactic-co-glycolic acid) (PLGA), poly(glycolic acid) (PGA), and poly(caprolactone) (PCL), polyethylene terephthalate (PET), polyimide, an antibody, collagen, hyaluronic acid, an extracellular matrix, silica or a silica matrix, or any combination thereof. In a preferred embodiment, the pharmaceutical composition is a suspension suitable for intravitreal, suprachoroidal, or sub-Tenon's capsule administration, wherein the active ingredient (i.e., roflumilast) is suspended in a pharmaceutical carrier and / or excipient. In certain embodiments, roflumilast is a free-flowing resuspendable suspension suitable for intravitreal administration or other injection.

[0045] In certain embodiments, the ophthalmic pharmaceutical composition comprises a viscosity agent, a tonicity agent, a buffer, and water. In certain embodiments, the pharmaceutical composition further comprises a surfactant. In certain embodiments, the ophthalmic pharmaceutical composition can comprise one or more other excipients, including, for example, a stabilizer, a preservative, a wetting agent, a diluent, a pH adjuster, or an absorption enhancer. In certain embodiments, the ophthalmic pharmaceutical composition can also be used in the form of an injection (intravitreal, suprachoroidal, or otherwise) for anterior segment or vitreous / posterior segment conditions, as a depot, an implantable absorbent polymer device for placement in any ocular or periocular tissue, an in situ-forming gel, or a drug / device combination, wherein the active ingredient (i.e., roflumilast) is suspended with one or more of the above excipients, such as a viscosity agent, a polymer (i.e., PLGA), a surfactant, or a buffer; with or without a device or an inert depot compound.

[0046] In certain embodiments, the viscosity agent is a cellulose derivative. In certain embodiments, the viscosity agent is at least one selected from sodium carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), carboxymethyl cellulose (CMC), or methylcellulose. In certain embodiments, the viscosity agent is polyvinylpyrrolidone or povidone (PVP), hydroxypropyl methylcellulose (HPMC), or polyvinyl alcohol (PVA). In certain embodiments, the viscosity agent is dextran or gelatin. Additionally, in certain embodiments, the viscosity agent may comprise carbomer, such as carbomer copolymer type A or carbomer copolymer type B, including those sold under the trade name . In certain embodiments, the ophthalmic pharmaceutical preparation may comprise from about 0.1% w / v to about 5.0% w / v, or from about 0.1% w / v to about 4.0% w / v, or from about 0.1% w / v to about 3.0% w / v, or from about 0.1% w / v to about 2.0% w / v, or from about 0.1% to about 1.0% w / v, or from about 0.1% to about 0.8% w / v, or from about 0.2% to about 1.0% w / v, or from about 0.2% to about 0.8% w / v of the viscosity agent. For example, the ophthalmic pharmaceutical comprises the viscosity agent in any of the following percentages (w / v): 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.

[0047] In certain embodiments, the tonicity agent is at least one selected from sodium chloride, potassium chloride, glycerol, and dextrose. In a preferred embodiment, the tonicity agent is at least one selected from sodium chloride and potassium chloride. In certain embodiments, the ophthalmic pharmaceutical preparation may contain 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 0.8% w / v, or from about 0.1% to about 0.5% w / v, or from about 0.2% to about 0.8% w / v, or from about 0.2% to about 0.5% w / v of the tonicity agent. For example, the ophthalmic pharmaceutical contains the tonicity agent in any of the following percentages (w / v): 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.

[0048] In certain embodiments, the surfactant is at least one selected from polysorbates (including polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80) and tyloxapol. In certain embodiments, the ophthalmic pharmaceutical preparation may contain from about 0.02% w / v to about 3.0% w / v, or from about 0.02% w / v to about 2.5% w / v, or from about 0.02% w / v to about 2.0% w / v, or from about 0.02% to about 1.0% w / v, or from about 0.02% to about 0.5% w / v, or from about 0.02% to about 0.25% w / v of the surfactant. For example, the ophthalmic pharmaceutical contains the surfactant in any of the following percentages (w / v): 0.02%, 0.05%, 0.075%, 0.1%, 0.15%, 0.2%, 0.25%, 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.

[0049] In certain embodiments, the buffering agent is at least one selected from citrate, phosphate, Tris-HCl (Tris), acetate, and borate buffers. In certain embodiments, the ophthalmic pharmaceutical formulation may comprise from about 0.5% w / v to about 7.5% w / v, or from about 0.5% w / v to about 5.0% w / v, or from about 0.5% to about 3.0% w / v, or from about 0.5% w / v to about 2.0% w / v, or from about 0.5% to about 1.0% w / v of the buffering agent. For example, the ophthalmic pharmaceutical comprises the buffering agent in any of the following percentages (w / v): 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.

[0050] In certain embodiments, the ophthalmic pharmaceutical formulation does not contain any preservatives or antimicrobial agents, as most ophthalmic preservatives and antimicrobial agents are known to cause discomfort, burning, stinging, or irritation to patients.

[0051] Roflumilast may undergo hydrolysis in certain ophthalmic pharmaceutical compositions and under certain standard aseptic preparation processes. In certain embodiments, the pH of the ophthalmic pharmaceutical composition is adjusted to reduce the hydrolysis rate of roflumilast.

[0052] In certain embodiments, the weight osmotic concentration of the ophthalmic pharmaceutical composition is from about 250 mOsm / kg to 330 mOsm / kg, more preferably from about 270 mOsm / kg to about 300 mOsm / kg, and even more preferably 270 mOsm / kg to 280 mOsm / kg.

[0053] The ophthalmic pharmaceutical composition of the present invention is stable and exhibits a particle size distribution suitable for ocular delivery. For suspensions, the particle size of the ophthalmic pharmaceutical composition can be evaluated using laser diffraction methods. Laser diffraction has been recognized by standard and guiding institutions such as ISO and ASTM and is widely used for determining particle size distributions. When conducting the evaluation, a 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 the scattered light at that position. A mathematical model is then applied to generate the particle size distribution.

[0054] In particle size determination, the median is defined as the value such that half of the population lies above this point and half lies below it. For a particle size distribution, the median is referred to as D50. D50 is the size that divides the distribution such that half is greater than this diameter and half is less than it. The distribution width can 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 the median) refers to the diameter below which half of the population lies. Similarly, 90% of the distribution is below D90, while 10% of the population is below D10.

[0055] In certain embodiments of the present invention, the ophthalmic pharmaceutical composition has a particle size distribution characterized by a d90 value less than or equal to about 50 μm prior to preferred processing. In certain embodiments, the ophthalmic pharmaceutical composition has a particle size distribution characterized by a d90 value of from about 5 μm to about 25 μm. In certain embodiments, the pharmaceutical composition has a particle size distribution characterized by a d90 value of from about 5 μm to about 15 μm. In certain embodiments, the pharmaceutical composition has a particle size distribution characterized by a d90 value less than or equal to 20 μm. In certain embodiments, the pharmaceutical composition has a particle size distribution characterized by a d90 value less than or equal to 15 μm. In a preferred embodiment, the pharmaceutical composition has a particle size distribution characterized by a d90 value less than or equal to 10 μm.

[0056] In certain embodiments of the present invention, the ophthalmic pharmaceutical composition is stable and free of impurities or has limited impurities. In certain embodiments, after terminal sterilization (e.g., γ-irradiation or dry heat sterilization), the pharmaceutical composition has less than about 1.0%, or less than about 0.5%, or less than about 0.2%, or substantially 0% impurities. HPLC assays can be used to evaluate the amount of impurities.

[0057] The ophthalmic pharmaceutical composition can be administered through a syringe needle for intravitreal administration. In certain embodiments, the ophthalmic pharmaceutical composition can be easily injected from the syringe needle with minimal force. In certain embodiments, the pharmaceutical composition can be injected from a 27-gauge (G) syringe needle with an outer diameter of 0.41 mm with a force less than about 3.00 N. In certain embodiments, the pharmaceutical composition can be injected from a 30-gauge (G) syringe needle with an outer diameter of 0.31 mm with a force less than about 3.50 N. Since both 27-gauge and 30-gauge needles are easy to inject with minimal force, it is reasonable to expect that smaller gauge needles (30 to 33 gauge) or larger gauge needles (25 to 27 gauge) are suitable for use.

[0058] The inventors of the present application have determined that roflumilast in combination with various viscosity agents undergoes an increase in particle size and aggregation in certain heat transfer ophthalmic drug preparation methods designed for formulation sterilization. The inventors of the present application have discovered certain methods of avoiding such aggregation, which results in heat transfer during the aseptic processing of roflumilast in the same container as inactive ingredients (including excipients, surfactants, etc.), and the methods are capable of reducing the rate of particle size increase and aggregation while maintaining product potency. Mixing the sterile API with sterile inactive ingredients reduces particle aggregation, which is achieved by reducing the need for additional energy input, such as autoclaving, that can cause particle aggregation. In certain embodiments, slow dry heat sterilization, gamma radiation, or other sterilization methods of the API at a temperature below the melting point of roflumilast can be used to sterilize roflumilast, while standard autoclaving methods can be used to sterilize the inactive ingredients prior to the final mixed formulation that produces the ophthalmic drug composition, which is optimized in terms of potency, purity, and particle size and is ideal for ocular use.

[0059] In certain embodiments of the present invention, product sterility and safety can be ensured by terminal sterilization followed by sterility testing. Using the pharmaceutical compositions listed herein, dry heat or gamma or x-ray radiation can provide sterility assurance followed by sterility testing. The accuracy and extent of gamma radiation are verified by dosimeter recordings of the total radiation experienced in all quadrants of the gamma-ray chamber. In addition, sterility can be screened by standard two-week screening tests after sterilization. The inventors have evaluated non-clinical and clinical batches in this manner, both of which have verified sufficient terminal sterilization and no microbial growth by two-week sterility testing. Additionally, injectable products can control endotoxins. In certain embodiments, the final injectable product can have less than 1 endotoxin unit (i.e., <1 EU / ml) per milliliter.

[0060] Terminal sterilization can be used for pharmaceutical compositions administered by injection because the compositions are injected directly into the eye or surrounding tissues or cavities (whether subconjunctival, intravitreal, suprachoroidal, peribulbar or other sites). Terminal sterilization ensures that both the product and the vial are sterile. Prefilled syringes and needles can be readily obtained for use with such pharmaceutical compositions and product types. In some embodiments, the product for injection can also be provided in a prefilled syringe. In some embodiments, a resuspendable sterile suspension is provided in a crimp-capped vial and is used with a separate presterilized needle to ensure sterility throughout the process. The pharmaceutical composition is resuspended by vortexing, shaking or mixing, and then the product is withdrawn through a presterilized needle prior to injection. The presterilized needle used to withdraw the suspension can be a lower gauge needle, which is then replaced with a higher gauge needle for injection (injection is typically accomplished with a 27 to 30 gauge needle), or the same needle can be used for withdrawal and injection, provided that aseptic conditions are maintained.

[0061] In certain embodiments of the present invention, there is provided a method of preparing a roflumilast ophthalmic pharmaceutical composition. The pharmaceutical composition can comprise the above-described pharmaceutical composition. The method can comprise sterilizing roflumilast in the form of slow dry heat or low level radiation sterilization. The sterilization can be achieved by slow dry heat sterilization at a temperature below the melting point of roflumilast (about 159.7 °C), terminal γ-radiation or other sterilization methods. The method can further comprise sterilizing at least one inactive ingredient selected from viscosity agents, tonicity agents, surfactants and buffering agents using standard autoclaving methods. The method can further comprise mixing the sterilized roflumilast with the sterilized inactive ingredients to prepare a stable roflumilast ophthalmic pharmaceutical composition. In some embodiments, the pharmaceutical composition prepared is a suspension.

[0062] In some embodiments, the method can further comprise subjecting the stable roflumilast ophthalmic pharmaceutical composition to clarity filtration to further reduce particle aggregation and produce an optimal suspension. Clarity filtration can be used to prepare a stable roflumilast ophthalmic pharmaceutical composition, wherein the pharmaceutical composition has a particle size distribution characterized by a d90 value of less than or equal to 10 μm, which is further differentiated for use in the eye, particularly for patients who may be sensitive to existing ophthalmic agents. Due to differences in aggregate formation in some formulations, different formulations can respond differently to the filtration process.

[0063] The ophthalmic pharmaceutical composition of the present invention can be administered via intravitreal injection or to other sites within or around the eye tissues or cavities. The pharmaceutical composition of roflumilast can be administered to the eye of a patient suffering from an ophthalmic disorder or condition. In certain embodiments, the pharmaceutical compositions disclosed herein are administered as an injection to treat ophthalmic disorders selected from the following: anterior uveitis, posterior uveitis, panuveitis or intermediate uveitis; or uveitis associated with HLA-B27, juvenile idiopathic arthritis, Behçet's disease, ankylosing spondylitis, VKH or autoimmune diseases; ocular graft-versus-host disease, Stevens-Johnson syndrome / TENS, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, age-related macular degeneration (AMD), including dry AMD, geographic atrophy or exudative AMD, choroidal neovascularization, retinal vasculitis (drug-related / iatrogenic, non-infectious / aseptic or idiopathic), choroidal thickening associated with thyroid eye disease, Coats' disease, central serous retinopathy or chorioretinopathy, aseptic or infectious endophthalmitis, retinitis, choroiditis, anterior or posterior scleritis / superficial scleritis, endothelial keratitis (bacterial, viral, fungal or non-infectious in nature), and other inflammatory diseases of the anterior segment and posterior segment tissues of the eye or other inflammatory or autoimmune disease-related ocular complications, inflammation associated with hereditary retinal diseases, retinitis pigmentosa, Stargardt's disease, Leber congenital amaurosis, Leber hereditary optic neuropathy, Usher syndrome, X-linked retinoschisis, choroideremia, regional idiopathic outer retinal disease, myopia, vitreomacular adhesion, retinal detachment, choroidal detachment and hemorrhage, choroidal rupture, choroidal folds, proliferative vitreoretinopathy, idiopathic ischemia, achromatopsia, retinopathy of prematurity, gyrate atrophy, central areolar choroidal dystrophy, punctate inner choroidopathy, multifocal choroiditis, choroiditis, choroidal granuloma, choroidal dystrophy, choroidal fibrosis, acute posterior multifocal placoid pigment epitheliopathy, serpiginous choroidopathy, birdshot retinochoroidopathy, multiple evanescent white dot syndrome, retinoblastoma, choroidal melanoma, retinal lymphoma and iatrogenic inflammation of the posterior chamber or vitreous cavity.

[0064] In certain embodiments, the ophthalmic pharmaceutical compositions disclosed herein are administered as an injection in the periorbital space by topical injection, orbital injection, peribulbar injection, or other injection. In certain embodiments, the ophthalmic pharmaceutical compositions disclosed herein are designed to treat the following diseases: pain and inflammation of the eyelids or extraocular or periorbital regions due to trauma, autoimmune diseases, microbial infections, or other systemic diseases; thyroid eye disease, meibomian gland disorders, blepharitis, ocular cicatricial pemphigus, mucous membrane pemphigus, orbital inflammatory pseudotumor, idiopathic or nonspecific orbital inflammation; granulomatosis with polyangiitis (GPA), Wegener's granulomatosis, orbital (including lacrimal gland) sarcoidosis, chalazion, hordeolum, atopic dermatitis of the eyelids, ocular rosacea, neuromyelitis optica, histiocytic orbital lesion, periorbital capillary hemangioma, or extraocular ocular complications of systemic sclerosis, scleroderma, or other autoimmune diseases, as well as other diseases of the periorbital space.

[0065] The injection can also be used for postoperative treatment of pain and inflammation associated with cataract, LASIK, PRK, PTK, full-thickness or partial-thickness keratotomy, or corneal transplantation, glaucoma-related surgical procedures, inflammation associated with gene or cell therapy infusion, or other surgical conditions and procedures that may cause inflammation and are suitable for injection treatment intervention. The ocular conditions that can be treated by the methods described herein can be acute or chronic. In certain embodiments, the methods are used to treat patients suffering from inflammatory or immune disorders of the eye. In certain embodiments, the inflammatory or immune disorder can be one of the above-mentioned disorders.

[0066] In a preferred embodiment, the ocular condition is posterior uveitis, panuveitis, or intermediate uveitis; or uveitis associated with HLA-B27, juvenile idiopathic arthritis, Behçet's disease, ankylosing spondylitis, VKH, or autoimmune diseases; diabetic retinopathy, diabetic macular edema, cystoid macular edema, retinal vein occlusion, age-related macular degeneration, including dry AMD, geographic atrophy, or exudative AMD and choroidal neovascularization, thyroid eye disease, sterile or infectious endophthalmitis, and iatrogenic inflammation of the vitreous cavity or posterior chamber.

[0067] In certain embodiments, the pharmaceutical composition is administered according to a regimen such as a regular administration schedule. For example, the pharmaceutical composition can be administered directly to the ocular surface as drops or ointment on an as-needed (PRN) basis, once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, three times weekly, or four times weekly, once monthly, or in a therapeutic and extended manner. In certain embodiments, the pharmaceutical composition can be administered as part of a maintenance dose or titration dose regimen. The pharmaceutical composition can be administered for a specified period of time. For example, the pharmaceutical composition can be administered for a period of about two days to at least about six weeks, or until improvement of the ocular condition or disease is observed. Exemplary periods of 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 can be administered as an injection or as an implantable device, depot, or absorbable device, and can be administered once weekly, once monthly, 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 quarterly, once every six months, on an as-needed (PRN) basis, according to physician guidance, or according to some clinical criteria such as treatment criteria and extension criteria or other criteria. The pharmaceutical composition can be administered as an open-ended continuous treatment.

[0068] The following examples illustrate certain embodiments of the invention, without limitation.

[0069] Example

[0070] Although multiple embodiments have been described herein, it should be understood that they are presented by way of example and not limitation. Accordingly, the breadth and scope of the present disclosure should not be limited by any of the exemplary embodiments described. Additionally, unless otherwise indicated herein or clearly contradicted by the context, the present disclosure encompasses any combination of the above elements in all possible variations thereof.

[0071] Example 1

[0072] Prepare an ophthalmic pharmaceutical composition having the composition shown in Table 1. Prepare the medium in a 100 mL glass bottle. Weigh sodium carboxymethylcellulose and add it. Add 90 mL of water for injection to the glass bottle. Stir the resulting mixture until the sodium carboxymethylcellulose dissolves. Add the remaining excipients (except roflumilast), and stir the mixture until the excipients dissolve. Add an appropriate amount of water to 100 mL. Add roflumilast (previously treated with an air jet mill) to a 20 mL glass vial, and add 10 mL of the medium. The suspension is homogenized using a high-shear mixer (Polyton Model PT 10 / 35) to form a uniform suspension. At a controlled room temperature, the mixing time is 2 minutes at a shear rate of 8000, a total of 30 in a group.

[0073] Table 1. Ophthalmic pharmaceutical composition of roflumilast

[0074] Ingredient % w / v Roflumilast 5.0％ Sodium carboxymethyl cellulose 0.50％ Sodium chloride 0.60％ Polysorbate 20 0.15％ Potassium chloride 0.05％ Calcium chloride (dihydrate) 0.05％ Magnesium chloride (hexahydrate) 0.05％ Sodium acetate (trihydrate) 0.10％ Sodium citrate (dihydrate) 0.10％ 1N HCl Adjusted to pH ~6.5 Water for injection Add appropriate amount to 10.0 mL

[0075] Example 2

[0076] Evaluate the particle size distribution of the ophthalmic pharmaceutical composition of Example 1. Use a Horiba LA-950V2 particle size analyzer to evaluate the size of the particles suspended in the liquid medium using laser scattering. Evaluate the particle size distribution before and after γ-irradiation. The particle size distribution diagrams are as shown in Figure 1 (before γ-irradiation) and Figure 2 (after γ-irradiation). The results are shown in Table 2.

[0077] Table 2. Particle size evaluation

[0078] Sample Dv10 (μm) Dv50 (μm) Dv90 (μm) Before γ-irradiation 2.683 5.143 9.909 After γ-irradiation 2.308 4.315 7.898

[0079] Example 3

[0080] Evaluate the syringe thrust required to inject the pharmaceutical composition of Example 1 from a 27G x 1 / 2" and 30G x 1 / 4" syringe needle. Withdraw 1 ml of the resuspended preparation into a 1 ml BD syringe and a 30G x 1 / 2" BD (or 27G x 1 / 4" NIPRO) needle respectively. Connect the needle to a Kd Scientific Hz 50 / 60 dynamometer, use the following parameters (1 ml syringe inner diameter (ID) = 4.54 mm, speed = 2 ml / min), and start the discharge of the material. Determine the syringe thrust required to completely discharge the content of the pharmaceutical composition through the dynamometer.

[0081] The syringe thrust curve is as shown in Figure 3 (27G syringe needle) and Figure 4(30-gauge syringe needle) as shown. The results are shown in Table 3. The pharmaceutical composition can be injected out of a 27-gauge syringe needle and a 30-gauge syringe needle with minimal force, indicating that the pharmaceutical composition is suitable for intravitreal injection.

[0082] Table 3. Syringe Thrust Evaluation

[0083] Sample Needle diameter Force (N) Force (pounds (lbs)) 27G needle 4.54 3.00 0.674 30G needle 4.54 2.90 0.652

[0084] Example 4

[0085] The impurities in the pharmaceutical composition were evaluated using HPLC chromatography. The pharmaceutical composition was evaluated before and after γ-irradiation. HPLC determination was performed using the conditions shown in Table 4.

[0086] Table 4. HPLC Conditions

[0087]

[0088] The HPLC chromatograms are as shown in Figure 5 (before γ-irradiation) and Figure 6 (after γ-irradiation). The HPLC chromatograms indicate that no significant detectable (LLOQ) impurities were observed in the samples after γ-irradiation.

[0089] The ability to provide tissue retention at the therapeutic level was tested, and the results are outlined in Figure 7A to D. In the experiment, on day 1, a single dose of the ophthalmic pharmaceutical composition described in Example 1 was administered to 10 Dutch Belted rabbits per group by bilateral intravitreal (IVT) or by suprachoroidal (SCS) injection. Within 3 months after administration, eye tissues, including aqueous humor, conjunctiva, sclera, cornea, iris / ciliary body, lens, vitreous humor, retina, and retinal pigment epithelium (RPE) / choroid, and plasma were collected at predetermined time points. Figure 7A and 7B respectively provide the tissue retention of roflumilast and roflumilast N-oxide after IVT injection. Figure 7C and 7D respectively provide the tissue retention of roflumilast and roflumilast N-oxide after SCS injection. The tissue concentration results indicate that after IVT injection, plasma exposure was minimal, undissolved and aggregated drug remained in the vitreous for up to 30 days after administration, and therapeutically relevant concentrations of the drug were present in the vitreous, iris / ciliary body, retina, and retinal pigment epithelium (RPE) / choroid for up to 30 days after administration. After SCS injection, plasma concentrations were higher than those after IVT, and therapeutically relevant concentrations were found in the iris / ciliary body and RPE / choroid on day 15 and in the vitreous and iris / ciliary body on day 30.

[0090] Figure 8 The ocular tolerance scores are shown for groups of 3 Dutch Belted rabbits each, given a single bilateral intravitreal administration of the formulation described in Example 1, using the vehicle / 0%, 2% or 5% ophthalmic pharmaceutical compositions (Example 1, with varying roflumilast concentrations), and observed for 28 days. The ocular tolerance dose range study showed that the product was generally well tolerated, with no injection site issues or general inflammation, no snowglobe effect in the vitreous humor or aggregation on the lens. The product formed a depot of self-aggregates, with no particles found throughout the vitreous and no aggregation on the lens, both of which are important for vision. The 5% composition resulted in a slight increase in the incidence / severity of vitreous cells, but the 2% composition was found to be generally well tolerated.

[0091] The foregoing specification has been provided for purposes of illustration and description. This specification is not intended to limit the invention to the precise form disclosed. Modifications and substitutions to the description of the basic invention will be apparent to those of ordinary skill in the art.

Claims

1. A high-concentration ophthalmic pharmaceutical composition, comprising: About 2% to about 5% w / v of roflumilast; A viscosity agent selected from hydroxypropyl methylcellulose, polyvinylpyrrolidone, or sodium carboxymethylcellulose; An isotonic agent comprising sodium chloride; A surfactant; A buffer; and Water, wherein the ophthalmic pharmaceutical composition is suitable for intravitreal administration or other injection-based or depot-based administration into the eye.

2. The ophthalmic pharmaceutical composition according to claim 1, wherein the viscosity agent is sodium carboxymethylcellulose.

3. The ophthalmic pharmaceutical composition according to claim 1, wherein the buffer is sodium acetate and sodium citrate.

4. The ophthalmic pharmaceutical composition according to claim 1, wherein the surfactant is polysorbate.

5. The ophthalmic pharmaceutical composition according to claim 1, wherein the pH of the composition is 5.5 to 7.

5.

6. The ophthalmic pharmaceutical composition according to claim 1, wherein the ophthalmic pharmaceutical preparation does not contain any preservatives or antimicrobial agents.

7. The ophthalmic pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a particle size distribution characterized by a d90 value less than or equal to about 15 μm.

8. The ophthalmic pharmaceutical composition according to claim 1, wherein the pharmaceutical composition can be injected from a 30G syringe needle with a force of less than about 3.50 N from a 30G needle.

9. The ophthalmic pharmaceutical composition according to claim 1, wherein the pharmaceutical composition can be injected from a 27G syringe needle with a force of less than about 3.00 N.

10. The ophthalmic pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has been terminally sterilized by gamma irradiation or dry heat sterilization to achieve less than about 0.2% impurities.

11. A high-concentration ophthalmic pharmaceutical composition, comprising: About 2% to about 5% w / v of roflumilast; About 0.2% to about 0.8% w / v of sodium carboxymethylcellulose; About 0.2% to about 0.8% w / v of sodium chloride; About 0.02% to about 0.25% w / v of polysorbate 20; About 0.005% to about 0.20% w / v of potassium chloride; About 0.005% to about 0.20% w / v of calcium chloride; About 0.005% to about 0.20% w / v of magnesium chloride; About 0.005% to about 0.20% w / v of sodium acetate; About 0.005% to about 0.20% w / v of sodium citrate; and Water, wherein the pH of the composition is 5.5 to 7.5, and wherein the ophthalmic pharmaceutical composition is suitable for intravitreal administration or other injection-based or depot-based administration into the eye.

12. The ophthalmic pharmaceutical composition according to claim 11, wherein the pharmaceutical composition has a particle size distribution characterized by a d90 value less than or equal to about 15 μm.

13. The ophthalmic pharmaceutical composition according to claim 11, wherein the pharmaceutical composition can be injected from a 30G syringe needle with a force of less than about 3.50 N from a 30G needle.

14. The ophthalmic pharmaceutical composition according to claim 11, wherein the pharmaceutical composition can be injected from a 27G syringe needle with a force of less than about 3.00 N.

15. The ophthalmic pharmaceutical composition according to claim 11, wherein the pharmaceutical composition has been terminally sterilized by gamma irradiation or dry heat sterilization to achieve less than about 0.2% impurities.

16. A method of treating an ocular disorder in a patient, which comprises: injecting a high-concentration ophthalmic pharmaceutical composition of roflumilast into the eye of a patient, wherein the pharmaceutical composition comprises: about 2% to about 5% w / v of roflumilast; a viscosity agent; an isotonic agent; a buffer; a surfactant; and water.

17. The method of claim 16, wherein the ocular disorder is selected from: anterior uveitis, posterior uveitis, panuveitis or intermediate uveitis; uveitis associated with HLA-B27, juvenile idiopathic arthritis, Behçet's disease, ankylosing spondylitis, Vogt-Koyanagi-Harada disease (VKH) or an autoimmune disease; ocular graft-versus-host disease, Stevens-Johnson syndrome / toxic epidermal necrolysis, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, age-related macular degeneration (AMD), including dry AMD, geographic atrophy or exudative AMD, choroidal neovascularization, retinal vasculitis (drug-related / iatrogenic, non-infectious / aseptic or idiopathic), choroidal thickening associated with thyroid eye disease, Coats' disease, central serous retinopathy or chorioretinopathy, aseptic or infectious endophthalmitis, retinitis, choroiditis, anterior or posterior scleritis / superficial scleritis, endothelial keratitis (bacterial, viral, fungal or non-infectious in nature), and other inflammatory diseases of the anterior segment and posterior segment tissues of the eye or other inflammatory or autoimmune disease ocular complications, inflammation associated with hereditary retinal diseases, retinitis pigmentosa, Stargardt's disease, Leber congenital amaurosis, Leber hereditary optic neuropathy, Usher syndrome, X-linked retinoschisis, choroideremia, regional idiopathic outer retinal disease, myopia, vitreomacular adhesion, retinal detachment, choroidal detachment and hemorrhage, choroidal rupture, choroidal folds, proliferative vitreoretinopathy, idiopathic ischemia, achromatopsia, retinopathy of prematurity, gyrate atrophy, central areolar choroidal dystrophy, punctate inner choroidopathy, multifocal choroiditis, choroiditis, choroidal granuloma, choroidal dystrophy, choroidal fibrosis, acute posterior multifocal placoid pigment epitheliopathy, serpiginous choroiditis, birdshot retinochoroidopathy, multiple evanescent white dot syndrome, retinoblastoma, choroidal melanoma, retinal lymphoma or iatrogenic posterior chamber or vitreous cavity inflammation.

18. The method of claim 16, wherein the pharmaceutical composition results in well-tolerated delivery and use.

19. The method of claim 16, wherein the injection is intravitreal, subconjunctival, subretinal, intracameral, sub-Tenon's, periocular, peribulbar, retrobulbar, postorbital or suprachoroidal injection.

20. The method according to claim 17, wherein the pharmaceutical composition delivers a therapeutic level of roflumilast to one or more of the following: cornea, limbus, conjunctiva, eyelid, lacrimal gland and meibomian gland, lens, pupil, iris, anterior sclera, ciliary body, lacrimal gland, aqueous humor, inner or endothelial or inner layer of the cornea, lacrimal gland, lymph node, posterior sclera, retina, choroid, macula, fovea, optic disc, optic nerve, vitreous humor, vitreous canal, or extraorbital or periorbital tissues and muscle / connective tissue.

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