High concentration pharmaceutical compositions of roflumilast for ocular delivery

Abstract

The present invention relates to a high-concentration ophthalmic pharmaceutical formulation of roflumilast, a phosphodiesterase-4 inhibitor, suitable for intravitreal administration or other ocular administration to injection sites inside or outside the eye and orbit. The composition can comprise about 2% to about 5% w / v roflumilast, a viscosity agent, a tonicity agent, a buffer, a surfactant, and water. The pharmaceutical composition contains little or no impurities, is stable, can be injected from a 27-gauge or 30-gauge syringe with minimal force, and delivers therapeutic levels of drug to the ocular surface, anterior compartment, vitreous / posterior compartment, and related tissues or cavities surrounding the eye.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 407,366, filed September 16, 2022, which is incorporated herein by reference.

[0002]

[0002] The present invention relates to pharmaceutically effective ophthalmic compositions having high concentrations of the phosphodiesterase-4 inhibitor roflumilast. Additionally, the present invention includes methods of treatment by administering said compositions. [Background technology]

[0003] Roflumilast is a potent, selective, long-acting inhibitor of phosphodiesterase (PDE) type 4 with anti-inflammatory and potential anti-tumor activity. It 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 and allergen-induced airway disorders (e.g., bronchitis, asthma, COPD), skin diseases (e.g., proliferative, inflammatory, and allergen-induced skin disorders), and systemic inflammation in the gastrointestinal region (Crohn's disease and ulcerative colitis). Oral pharmaceutical compositions of roflumilast are currently sold under the trade names Daliresp® (USA) and Daxas® (Europe), and topical roflumilast cream compositions for use in skin diseases are currently sold under the trade name Zoryve™ (USA).

[0004]

[0004] Roflumilast and its synthesis are described in U.S. Patent No. 5,712,298. Pharmaceutical compounds with phosphodiesterase (PDE) 4 inhibitory properties, such as roflumilast, have been recognized as therapeutically effective and useful for treating inflammatory disorders, such as psoriasis and atopic dermatitis. While the therapeutic efficacy of oral and dermatological pharmaceutical compositions has been investigated, there is a need for high-concentration ophthalmic pharmaceutical compositions of roflumilast suitable for treating ocular inflammatory and immune-mediated disorders, particularly those suitable for delivery to the anterior and posterior compartments of the eye, or to surrounding tissues or cavities of the eye. The current market for anti-inflammatory ophthalmic drugs is largely based on antibiotics, immunosuppressants, and steroids, many of which do not meet the clinical needs of long-term inflammatory diseases or have significant long-term comorbidities and safety issues. Thus, there is a significant unmet need for anti-inflammatory ophthalmic formulations of roflumilast in convenient, tolerable forms suitable for the ocular surface, anterior compartment, or vitreous / posterior compartment of the eye. The majority of the market for high-concentration drugs suitable for delivery to the anterior or posterior compartments of the eye (also known as the vitreous and / or retina) is focused on systemic biologic agents that target mechanisms other than inflammation (e.g., anti-angiogenic agents), anti-inflammatory steroids available in high-concentration or long-acting formulations in the form of polymeric implants or depots at the back of the eye, or single inflammatory pathways such as TNF. While some anti-inflammatory ophthalmic drugs are available in injectable or other forms for emergency use in post-surgical or post-procedural settings, long-term options that are both effective and avoid the safety concerns associated with steroid-based drugs are very limited. Further limiting the market is that many anti-inflammatory medications traditionally applied to the ocular surface or anterior chamber (the front of the eye) for medium- to long-term use either have molecular weights that are too large for ocular delivery or have unpredictable pharmacokinetics (PK) in ocular tissue compartments that make them unsuitable for consistent use in the inner, posterior, and vitreous compartments.

[0005]

[0005] Local delivery of drugs to the eye is challenging because ophthalmic pharmaceuticals must balance tolerability, sterility, safety, and efficacy. It is extremely challenging to develop stable ophthalmic formulations that can be made under sterile conditions and deliver effective doses to the eye while maintaining physicochemical properties and remaining within a narrow range of pH and inactive ingredients that are tolerable to the eye. Excipients used for ocular delivery can potentially exhibit ocular toxicity, further exacerbating the disorder and symptoms associated with the disorder being treated. Developing highly concentrated pharmaceutical compositions for ocular delivery can be particularly challenging due to physical limitations. Ocular delivery is focused on the ocular surface, anterior segment, or posterior / vitreous segment. Ocular surface formulations, often delivered by patients as eye drops one to four times daily (or more frequently in the case of steroid tapering), present the additional challenge of dosing consistency and flexibility required to deliver an effective dose, despite common operator errors encountered in home-based patient delivery: sterility issues, variability in delivered volume, patient compliance, and accuracy of administration location. Patients with long-term ocular disease also have higher sensitivity to active and inactive ingredients and preservatives, presenting additional challenges for formulations. Most highly concentrated drugs intended for use inside the eye, within the anterior or posterior / vitreous compartment, must typically be delivered via injection to various relevant tissues or cavities, presenting unique challenges for ocular surface delivery. Due to the overall small size of the ocular compartment, the volume of the delivered product must be strictly limited; typically, 50–100 μl is the preferred volume, with a maximum safe volume of approximately 200 μL unless pre-injection paracentesis is performed. When reaching the internal compartment of the eye via injection, regardless of the injection site, it is desirable to limit the number of applications (injections) to minimize the risk of introducing infectious agents into the patient and to limit physical stress on the injection site, particularly when treating chronic conditions. There is also a need for concentrated formulations for injection into the periorbital tissues and cavities of the eye to minimize the frequency of injections. Summary of the Invention [Problem to be solved by the invention]

[0006] The need for extremely small injection volumes and sufficiently high drug payloads within those small injection volumes to limit injection frequency has created a need for higher drug concentrations for use in many ophthalmic disorders. Injections are also restricted to physician administration, placing a burden on both patients and medical institutions in terms of convenience. [Means for solving the problem]

[0007]

[0007] The present invention relates to a high-concentration ophthalmic pharmaceutical composition of roflumilast, a phosphodiesterase-4 inhibitor. In certain embodiments, the ophthalmic pharmaceutical formulation comprises about 2% to about 5% w / v roflumilast, a viscosity agent, a tonicity agent, a buffer, a surfactant, and water. The ophthalmic pharmaceutical composition is suitable for intravitreal or other injection-based administration to a target tissue within the eye, or to the tissue or cavity around the eye or orbit. In certain embodiments, the ophthalmic pharmaceutical composition comprises a viscosity agent selected from the group consisting of hydroxypropylmethylcellulose, 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 an acetate buffer and a citrate buffer (e.g., sodium acetate and sodium citrate). In certain embodiments, the ophthalmic pharmaceutical composition further comprises a surfactant, preferably a polysorbate (e.g., polysorbate 20). In certain embodiments, the pH of the composition is between 5.5 and 7.5.

[0008] In certain embodiments, the ophthalmic pharmaceutical composition comprises about 2% to about 5% w / v roflumilast, about 0.2% to about 0.8% w / v carboxymethylcellulose sodium, about 0.2% to about 0.8% w / v sodium chloride, about 0.02% to about 0.25% w / v polysorbate 20, about 0.005% to about 0.20% w / v potassium chloride, about 0.005% to about 0.20% w / v calcium chloride, about 0.005% to about 0.20% w / v magnesium chloride, about 0.005% to about 0.20% w / v sodium acetate, about 0.005% to about 0.20% w / v sodium citrate, and water. The ophthalmic pharmaceutical composition is suitable for intravitreal or other injection-based administration to the eye or tissues or cavities surrounding the eye. In certain embodiments, the pH of the composition is between 5.5 and 7.5.

[0009] In certain embodiments, the pharmaceutical composition has a particle size distribution characterized by a d90 value of about 20 μm or less. In certain embodiments, the pharmaceutical composition has a particle size distribution characterized by a d90 value of about 15 μm or less. In certain embodiments, the pharmaceutical composition has a particle size distribution characterized by a d90 value of about 10 μm or less.

[0010] In certain embodiments, the pharmaceutical composition is injectable from a 27G syringe needle with a force of less than about 3.00 N. In certain embodiments, the pharmaceutical composition is injectable from a 30G syringe needle with a force of less than about 3.50 N.

[0011] In certain embodiments, the ophthalmic pharmaceutical composition contains or contains low amounts of impurities. In certain embodiments, the pharmaceutical composition has less than about 0.5%, less than about 0.2%, or essentially 0% impurities after terminal sterilization (e.g., gamma irradiation). The gamma dose rate, irradiation dose, and irradiation time affect the molecular structure of the irradiated sample in different ways. This is because irradiation can affect the chemical and physical structure of the drug, formulation excipients, and packaging materials. Gamma irradiation is a sterilization process using ionizing radiation that eliminates any microorganisms that may be present by exposing the sample to gamma rays. According to ISO 11137, the typical dose for radiation sterilization is 25-40 kGy. The accuracy and effectiveness of gamma irradiation during the sterilization procedure are important considerations, especially for intravitreal or other injections. To ensure that the sterilization procedure is reliable and reproducible, several dosimeters should be used within a tray of medicinal product samples to record the dose distribution and uncertainty. From a statistical standpoint, the uncertainty in uniform irradiation must be less than 10% to conclude that a batch or sample is uniformly irradiated.

[0012] A typical dose mapping procedure involves placing a tray with samples of the injectable product on a stand located in the center of a sample chamber that generates gamma radiation. At least two dosimeters are placed on the sample, one above the tray and one below. In addition to measurements with a separate monitoring dosimeter (Dmon), which is usually placed above the sample tray, assessments of the minimum dose (Dmin) and maximum dose (Dmax) are also made. Dosimeter placement and measurements should be repeated in accordance with ISO 11137-3. Dmin, Dmax, and Dmon are calculated as the average values ​​of the measurements taken.

[0013] In certain embodiments, a method is provided for treating an ocular disorder in a patient. 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 comprises about 2% to about 5% w / v roflumilast. In certain embodiments, the ocular disorder is anterior uveitis, posterior uveitis, panuveitis, or intermediate uveitis; or uveitis associated with HLA-B27, juvenile idiopathic arthritis, Behçet's disease, ankylosing spondylitis, Vogt-Koyanagi-Harada syndrome (VKH), or autoimmune disease; ocular graft-versus-host disease, Stevens-Johnson syndrome / toxic epidermal necrolysis (TENS), diabetic retinopathy, or diabetic macular edema. retinal vein occlusion, age-related macular degeneration (AMD) including dry, geographic atrophy, or exudative AMD, choroidal neovascularization, retinal vasculitis (drug-related / iatrogenic, non-infectious / sterile, or idiopathic), choroidal thickening associated with thyroid eye disease, Coats' disease, central serous retinopathy or chorioretinopathy, sterile or infectious endopthalmitis, retinitis, choroiditis, anterior or posterior scleritis / episcleritis, corneal endotheliitis (bacterial, uveitis ... Inflammation associated with hereditary retinal diseases, including retinitis pigmentosa, Stargardt disease, Leber congenital amaurosis, Leber hereditary optic neuropathy, Usher syndrome, X-linked retinoschisis, choroidal atrophy, zonular occult outer retinal abnormalities, pathological myopia, vitreous adhesion, retinal detachment, choroidal detachment and hemorrhage, choroidal tears, choroidal folds, Selected from the group consisting of proliferative vitreoretinopathy, idiopathic ischemia, total color blindness, retinopathy of prematurity, gyral chorioretinal atrophy, central areolar choroidal atrophy, punctate inner choroidopathy, multifocal choroiditis, choroiditis, choroidal granuloma, choroidal dystrophy, choroidal fibrosis, acute posterior multifocal spotty pigment epitheliopathy, creeping choroidopathy, birdshot chorioretinopathy, multiple vanishing white dot syndrome, retinoblastoma, choroidal melanoma, retinal lymphoma, and iatrogenic posterior or vitreous cavity inflammation.In certain embodiments, the pharmaceutical composition delivers therapeutic levels of roflumilast to one or more of the cornea, limbus, conjunctiva, eyelid, lacrimal and meibomian glands, lens, pupil, iris, anterior sclera, ciliary body, lacrimal gland, aqueous humor, inner or endothelium or inner layer of the cornea, lacrimal gland, lymph node, posterior sclera, retina, choroid, macula retina, fovea, optic nerve head, optic nerve, vitreous humor, or hyaloid duct.

[0014]

[0014] The accompanying figures, which are incorporated herein and form a part of this disclosure, help to illustrate various embodiments of the present invention and, together with the specification, further serve to describe the invention to enable one skilled in the art to make and use the embodiments disclosed herein. Error bars in the figures are standard deviations. [Brief explanation of the drawings]

[0015] [Figure 1]

[0015] Figure 1 is a graph showing particle size distribution plots (time vs. particle size, in μm) for exemplary ophthalmic pharmaceutical compositions before gamma irradiation. [Figure 2]

[0016] 1 is a graph showing particle size distribution plots (time vs. particle size, in μm) for exemplary ophthalmic pharmaceutical compositions after gamma irradiation. [Figure 3]

[0017] 1 is a graph plotting the injection force (unit: N) for an ophthalmic pharmaceutical composition using a 27G needle. [Figure 4]

[0018] 1 is a graph plotting injection force (unit: N) for an ophthalmic pharmaceutical composition using a 30G needle. [Figure 5]

[0019] FIG. 1 shows an HPLC assay for an ophthalmic pharmaceutical composition of an exemplary pharmaceutical composition. [Figure 6]

[0020] FIG. 1 shows an HPLC assay for an ophthalmic pharmaceutical composition of an exemplary pharmaceutical composition. [Figure 7-1]

[0021] Figure 7A is a graph showing plots of roflumilast tissue retention on days 15 and 30 for the primary retinal / posterior or vitreous tissue after administration of a single dose (50 μL) of a 3% pharmaceutical composition into the vitreous humor space via intravitreal injection. Figure 7B is a graph showing plots of roflumilast N-oxide tissue retention on days 15 and 30 for the primary retinal / posterior or vitreous tissue after administration of a single dose (50 μL) of a 3% pharmaceutical composition into the vitreous humor space via intravitreous injection. Figure 7C is a graph showing plots of roflumilast tissue retention on days 15 and 30 for the primary retinal / posterior or vitreous tissue after administration of a single dose (50 μL) of a 3% pharmaceutical composition into the vitreous humor and suprachoroidal space via suprachoroidal injection. FIG. 7D is a graph showing plots of tissue retention of roflumilast N-oxide at 15 and 30 days for the primary retinal / posterior or vitreous tissues after administration of a single dose (50 μL) of a 3% pharmaceutical composition into the vitreous humor and suprachoroidal space via suprachoroidal injection. [Figure 7-2] Same as above [Figure 8]

[0022] 1 is a graph showing a plot of ocular tolerability scores for a dose-ranging study in Dutch Belted rabbits involving intravitreal injections of vehicle 2% and 5% ophthalmic pharmaceutical compositions into both eyes. A self-aggregating depot of the product was visible in the vitreous for up to 60 days. DETAILED DESCRIPTION OF THE INVENTION

[0016]

[0023] It is understood that this invention is not limited to the particular methodology, protocols, and reagents described herein, as these may vary. It is also 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 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.

[0017]

[0024] All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety unless otherwise stated. Where the same term is defined in a publication, patent, or patent application incorporated herein by reference and in this disclosure, the definition in this disclosure shall prevail. For publications, patents, and patent applications referenced to describe a particular type of compound, chemical reaction, etc., the portion relating to such compound, chemical reaction, etc. is a part of the document incorporated herein by reference.

[0018]

[0025] It should be noted that, as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, "an active ingredient" includes both a single ingredient and two or more different ingredients.

[0019]

[0026] The term "about," when used in connection with a numerical value, is intended to encompass numerical values ​​in a range having a lower limit of 5% less than the stated numerical value and an upper limit of 5% greater than the stated numerical value.

[0020]

[0027] 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 eye disease" refers to tissues associated with and diseases affecting the anterior chamber or anterior cavity of the eye, including the iris, ciliary body and lens, the anterior sclera, the aqueous humor, and the endothelium or innermost layer of the cornea. Anterior eye diseases are distinct from diseases affecting the vitreous cavity, posterior tissues, or eye diseases, such as those affecting the retina, and are also distinct from diseases that directly affect the ocular surface or tissues facing the external environment, such as the conjunctival tissues of the cornea, or the ocular surface and tear film. The term "vitreous cavity" or "vitreous cavity eye disease" refers to tissues associated with or diseases affecting the vitreous cavity, which begins at the posterior lens and extends through and includes the retina and choroid, vitreous humor, and posterior sclera, down 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 eyelid and surrounding tissues, or the muscles around the eye or orbit, or the space behind the eye, or diseases associated with these tissues and cavities.

[0021]

[0028] The terms "ocular disorder," "ocular condition," or "ocular disorder" refer to a disease or condition of the eye(s) that may threaten vision, result in ocular discomfort or abnormalities, and may be a precursor to systemic health problems. The ocular surface is composed of the cornea (particularly including the corneal epithelium and stroma), limbus, conjunctiva, eyelids, lacrimal and meibomian glands, and interconnecting superficial nerves. The anterior chamber is composed of the lens, pupil, iris, anterior sclera, ciliary body, lacrimal glands, aqueous humor, and the inner or endothelium or lining of the cornea, lacrimal glands, and lymph nodes. The vitreous cavity is composed of the posterior sclera, retina, choroid, retinal macula, fovea, optic nerve head, optic nerve, vitreous humor, and hyaloid ducts. The eye as a whole is supported by various intraocular and extraorbital muscles and ligaments, which comprise the extraorbital space.

[0022]

[0029] The term "effective" refers to an amount of a compound, agent, substance, formulation, or composition that is sufficient to reduce the severity of disease symptoms, increase the frequency and duration of disease symptom-free periods, or prevent functional or disability impairment due to distress. The amount may be as a single dose or in a multiple dose regimen, and may be alone or in combination with other compounds, agents, or substances. One of ordinary skill in the art can determine such amounts based on factors such as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0023]

[0030] "Pharmaceutically acceptable" means generally safe for administration to humans or animals. Preferably, a pharmaceutically acceptable component is one that has been approved by a federal or state regulatory agency for use in animals, more particularly humans, or is listed in the U.S. Pharmacopeia, published by the United States Pharmacopeial Convention, Inc., Rockville, Md., or other generally recognized pharmacopeia.

[0024]

[0031] A "pharmaceutical composition" according to the present invention may be in the form of a composition in which different active ingredients and diluents and / or carriers are admixed with one another, or it may take the form of a combined preparation in which the active ingredients are present in partly or completely distinct forms. An example for such a combination or combined preparation is a kit of parts.

[0025]

[0032] The term "roflumilast," as used in this application, unless otherwise specified or unless it is clear from the context that a reference is to roflumilast itself, refers to roflumilast, its physical forms, its salts, metabolites of roflumilast, including roflumilast N-oxide, and salts thereof.

[0026]

[0033] As used herein, the term "subject" or "patient" most preferably refers to a human. The term "subject" or "patient" can include any mammal that can benefit from the compounds described herein.

[0027]

[0034] A "therapeutic amount" or "therapeutically effective amount" is an amount of a therapeutic agent sufficient to achieve its intended purpose. The effective amount of a given therapeutic agent varies depending on factors such as the nature of the agent, the route of administration, the size of the subject to which the therapeutic agent is given, and the purpose of administration. The effective amount in each individual case can be determined empirically by those skilled in the art using methods established in the art.

[0028]

[0035] As used herein, "treat" a disease or disorder, "treating" a disease or disorder, or "treatment" means achieving one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the onset of symptoms characteristic of the disorder(s) being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing the recurrence of the disorder(s) in a patient who previously had the disorder(s); and (e) limiting or preventing the recurrence of symptoms in a patient who was previously symptomatic for the disorder(s).

[0029]

[0036] The present invention relates to a stable ophthalmic pharmaceutical composition of roflumilast, a phosphodiesterase-4 inhibitor. Roflumilast has the formula (I):

[0030] [ka]

[0031] wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyridin-4-yl. is a compound of

[0032]

[0037] Roflumilast has the chemical name N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide. The N-oxide of roflumilast has the chemical name 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl 1-oxide)benzamide. Roflumilast and its synthesis, its use as a phosphodiesterase (PDE) 4 inhibitor, and roflumilast formulations are described in U.S. Pat. No. 5,712,298, which is incorporated herein by reference. Ophthalmic pharmaceutical compositions can contain roflumilast as a free base or a pharmaceutically acceptable salt. Exemplary salts of roflumilast are those described in paragraphs

[0012] and

[0013] of U.S. Patent Application Publication US2006 / 0084684, the disclosure of which is incorporated herein by reference. In certain embodiments, the pharmaceutical composition comprises a metabolite of roflumilast as the active ingredient, including the N-oxide of the pyridine residue of roflumilast or a salt thereof.

[0033]

[0038] In certain embodiments, the ophthalmic pharmaceutical composition can contain roflumilast in the range of about 2.0% w / v to about 6.5% w / v, or about 2.0% w / v to about 5.5% w / v, or about 2.0% to about 5.0% w / v. For example, the ophthalmic pharmaceutical composition can contain roflumilast in any of the following w / v percentages: 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%, 5.10%, 5.11%, 5.12%, 5.13%, 5.14%, 5.15%, 5.16%, 5.17%, 5.18%, 5.19%, 5.20%, 5.21%, 5.22%, 5.23%, 5.24%, 5.25%, 5.26%, 5.27%, 5.28%, 5.29%, 5.30%, 5.31%, 5.32%, 5.33%, 5.34%, 5.35%, 5.36%, 5.37%, 5.38%, 5.39%, 5.40%, 5.41%, 5.42%, 5.4 .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.

[0034]

[0039] In certain embodiments, the ophthalmic pharmaceutical composition can be a suspension, solution, emulsion, eye drops, eye ointment, cream, gel, spray, injectable formulation (intravitreal, subconjunctival, suprachoroidal, sub-Tenon, periorbital, peribulbar, retrobulbar, retroorbital, or other injection), depot formulation (alone or in combination with a depot or device), implantable absorbable polymer device, or absorbent contact lens. In certain embodiments, the pharmaceutical composition is intravitreal, subconjunctival, subretinal, intracameral, sub-Tenon, periorbital, peribulbar, retrobulbar, suprachoroidal injection, delivery via a port or drug-eluting material, delivery via a cannula, delivery via a needle, or delivery via other injection sites and delivery methods.

[0035]

[0040] It has been shown throughout the literature that high concentration ophthalmic pharmaceutical compositions, such as steroids or other drugs formulated for use as intravitreal or other intraorbital injections, can also be administered via injection outside the peripheral tissue. T. Ciuella et al., Microinjection via the Suprachoroidal Space: A Review of a Novel Mode of Administration. Am. J. Manag. Care, Vol. 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, Vol. 13 (7): 967 (2021); A. Hadayer, Delivery of Steroids into the Eye for the Treatment of Macular Edema, Expert Opn. Drug Deliv., Vol. 13 (8): 1083-1091 (2016); T. Yasukawa et al., Recent Advances in Intraocular Drug Delivery Systems, Recent Pat. Drug Deliv. Formul., Vol. 5 (1)-1-10 (2011). Administration outside the surrounding tissue can be accomplished using the same delivery device, for example, a 27 gauge or 30 gauge needle as 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, Vol. 38:692-697 (2010).

[0036]

[0041] In certain embodiments, the pharmaceutical composition may be in the form of an implant, e.g., an intravitreal implant, a transscleral implant, a sustained-release implant, a biodegradable or non-biodegradable implant material, a bioadhesive polymer, a hydrogel, a nanoparticle, a viral vector, an adhesive sphere, a micelle, a microsphere, a thermogel, a liposome, a nanoliposome, a lipid nanoparticle, an extracellular vesicle, an exosome, a thermogel, a mucoadhesive gel, a crystal, a microemulsion, a nanoemulsion, an emulsion, a dendrimer, polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), silicone, poly(ethylene glycol) (PEG), cross-linked poly(ethylene glycol) (PEG), poly(lactic-co-glycolic acid) (PLGA), polyglycolic acid (PGA), and poly(caprolactone) (PCL), polyethylene terephthalate (PET), a polyimide, an antibody, collagen, hyaluronic acid, an extracellular matrix, a silica or silicon matrix, or any combination thereof. In a preferred embodiment, the pharmaceutical composition is a suspension suitable for intravitreal, suprachoroidal, or subtenon administration, in which 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.

[0037]

[0042] 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 additional excipients, including, for example, stabilizers, preservatives, wetting agents, diluents, pH adjusters, or absorption enhancers. In certain embodiments, the ophthalmic pharmaceutical composition can also be used for anterior or vitreous / posterior ophthalmic conditions in the form of an injection (intravitreal, suprachoroidal, or other), a depot, an implantable absorbent polymeric device for placement in any ophthalmic or peripheral tissue, an in situ forming gel, or a drug / device combination, in which the active ingredient (i.e., roflumilast) is suspended with one or more of the above-mentioned excipients, such as a viscosity agent, a polymer (i.e., PLGA), a surfactant, or a buffer, with or without a device or inert depot compound.

[0038]

[0043] In certain embodiments, the viscosity agent is a cellulose derivative. In certain embodiments, the viscosity agent is at least one selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), or methylcellulose. In certain embodiments, the viscosity agent is polyvinylpyrrolidinone or povidone (PVP), hypromellose (HPMC), or polyvinyl alcohol (PVA). In certain embodiments, the viscosity agent is dextran or gelatin. Additionally, the viscosity agent can include carbomer, in certain embodiments, carbomer copolymer type A or carbomer copolymer type B, including, for example, those sold under the trade name Carbopol® by Lubrizol®. In certain embodiments, the ophthalmic pharmaceutical formulation can comprise a viscosity agent in the range of about 0.1% w / v to about 5.0% w / v, or about 0.1% w / v to about 4.0% w / v, or about 0.1% w / v to about 3.0% w / v, or about 0.1% w / v to about 2.0% w / v, or about 0.1% to about 1.0% w / v, or about 0.1% to about 0.8% w / v, or about 0.2% to about 1.0% w / v, or about 0.2% to about 0.8% w / v. For example, an ophthalmic medication may contain any of the following w / v percentages of a 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 ... 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.

[0039]

[0044] In certain embodiments, the tonicity agent is at least one selected from the group consisting of sodium chloride, potassium chloride, glycerin, and glucose. In a preferred embodiment, the tonicity agent is at least one selected from the group consisting of sodium chloride and potassium chloride. In certain embodiments, the ophthalmic pharmaceutical formulation may contain the tonicity agent in a range of about 0.05% w / v to about 3.0% w / v, or about 0.05% w / v to about 2.0% w / v, or about 0.05% w / v to about 1.0% w / v, or about 0.1% to about 0.8% w / v, or about 0.1% to about 0.5% w / v, or about 0.2% to about 0.8% w / v, or about 0.2% to about 0.5% w / v. For example, the ophthalmic medication may contain any of the following w / v percentages of tonicity agent: 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.

[0040]

[0045] 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 the surfactant in a range of about 0.02% w / v to about 3.0% w / v, or about 0.02% w / v to about 2.5% w / v, or about 0.02% w / v to about 2.0% w / v, or about 0.02% to about 1.0% w / v, or about 0.02% to about 0.5% w / v, or about 0.02% to about 0.25% w / v. For example, an ophthalmic medication may contain any of the following w / v percentages of surfactant: 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.

[0041]

[0046] In certain embodiments, the buffer is at least one selected from the group consisting of citrate buffer, phosphate buffer, Tris-HCl (Tris), acetate buffer, and borate buffer. In certain embodiments, the ophthalmic pharmaceutical formulation may contain about 0.5% w / v to about 7.5% w / v, about 0.5% w / v to about 5.0% w / v, about 0.5% to about 3.0% w / v, about 0.5% w / v to about 2.0% w / v, or about 0.5% to about 1.0% w / v of the buffer. For example, an ophthalmic medication may contain any of the following w / v percentages of buffer: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 7%, 1.8%, 1.9%, 1.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 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.

[0042]

[0047] 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.

[0043]

[0048] Roflumilast is subject to hydrolysis in certain ophthalmic pharmaceutical compositions and certain standard sterile manufacturing processes. In certain embodiments, the pH of the ophthalmic pharmaceutical composition is adjusted to reduce the rate of hydrolysis of roflumilast.

[0044]

[0049] In certain embodiments, the osmolality of the ophthalmic pharmaceutical composition is about 250 mOsm / kg to 330 mOsm / kg, more preferably about 270 mOsm / kg to about 300 mOsm / kg, and even more preferably 270 mOsm / kg to 280 mOsm / kg.

[0045]

[0050] The ophthalmic pharmaceutical composition of the present invention is stable and exhibits a particle size distribution suitable for ocular delivery. The particle size of the ophthalmic pharmaceutical composition for suspension can be evaluated using laser diffraction. Laser diffraction is recognized by standards and guidance organizations, including ISO and ASTM, and is widely used to determine particle size distribution. In the evaluation, a sample is passed through a laser beam, which causes laser light scattering at a series of angles. A detector positioned at a fixed angle measures the light scattering intensity at that position. A mathematical model is then applied to generate a particle size distribution.

[0046]

[0051] In particle size determination, the median is defined as the value where half of the population lies above this point and half lies below this point. For particle size distributions, the median is called the D50. The D50 is the size that divides the distribution, with half occupying the upper half of this diameter and half occupying the lower half. The width of the distribution can also be characterized by using some combination of one, two, or three values ​​on the x-axis, usually the D10, D50, and D90. The D50 (or median), as discussed above, refers to the diameter below which half of the population lies. Similarly, 90 percent of the distribution lies below the D90, and 10 percent of the population lies below the D10.

[0047]

[0052] In certain embodiments of the present invention, the ophthalmic pharmaceutical composition, prior to preferential processing, exhibits a particle size distribution characterized by a d90 value of about 50 μm or less. 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 certain embodiments, the pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of 20 μm or less. In certain embodiments, the pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of 15 μm or less. In a preferred embodiment, the pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of 10 μm or less.

[0048]

[0053] In certain embodiments of the present invention, the ophthalmic pharmaceutical composition is stable and has no impurities or limited impurities.In certain embodiments, the pharmaceutical composition has less than about 1.0%, or less than about 0.5%, or less than about 0.2%, or essentially 0% impurities after terminal sterilization (e.g., gamma irradiation or dry heat sterilization).The amount of impurities can be evaluated using HPLC assay.

[0049]

[0054] The ophthalmic pharmaceutical composition can be administered via a syringe needle for intravitreal administration. In certain embodiments, the ophthalmic pharmaceutical composition is easily injected from a syringe needle with minimal force. In certain embodiments, the pharmaceutical composition is injectable from a 27-gauge (G) syringe needle with an outer diameter of 0.41 mm with a force of less than about 3.00 N. In certain embodiments, the pharmaceutical composition is injectable from a 30-gauge (G) syringe needle with an outer diameter of 0.31 mm with a force of less than about 3.50 N. Given the ease of injection with minimal force from both 27-gauge and 30-gauge needles, it is reasonable to expect that both smaller gauge needles (30-33 gauge) or larger gauge needles (25-27 gauge) will be suitable for use.

[0050]

[0055] The inventors of the present application have identified that roflumilast combined with multiple viscosity agents undergoes particle size growth and aggregation in certain heat-transfer ophthalmic pharmaceutical manufacturing processes designed to sterilize the formulation. The inventors of the present application have discovered certain methods that avoid this heat-transfer-induced aggregation during roflumilast sterile processing in the same container as inactive ingredients, including excipients, surfactants, etc., and can reduce the rate of particle size growth and aggregation while maintaining product efficacy. Blending a sterilized API with sterilized inactive ingredients reduces particle aggregation by reducing the need for additional energy inputs, such as autoclaving, which can cause particle aggregation. In certain embodiments, roflumilast can be sterilized using slow dry heat sterilization, gamma irradiation, or other API sterilization methods at temperatures below the melting point of roflumilast, while sterilizing the inactive ingredients using a standard autoclave, thereby creating a final blended formulation that is optimized for potency, purity, and particle size, making it an ideal ophthalmic pharmaceutical composition for ophthalmic use.

[0051]

[0056] In certain embodiments of the present invention, the sterility and safety of a product can be ensured through terminal sterilization followed by sterility testing. Sterility can be ensured for the pharmaceutical compositions listed herein by dry heat, gamma, or X-ray irradiation, followed by sterility testing. The accuracy and range of gamma irradiation is verified via dosimeter recording of the total exposure received in all quadrants of the gamma chamber. Furthermore, sterility can be tested through a standard two-week post-sterilization screening. The inventors have evaluated both nonclinical and clinical batches in this manner, and both demonstrated sufficient terminal sterility and passed the two-week sterility test without microbial growth. Furthermore, injectable products can be controlled for endotoxins. In certain embodiments, the final injectable product can have less than 1 endotoxin unit per milliliter (i.e., <1 EU / ml).

[0052]

[0057] Terminal sterilization can be used for injectable pharmaceutical compositions because the compositions are injected directly into the eye or its surrounding tissues or cavities (subconjunctival, intravitreal, suprachoroidal, periocular, or other sites). Terminal sterilization ensures that both the product and the vial are sterile. Pre-sterilized needles and syringes are readily available for use with such pharmaceutical compositions and product configurations. In certain embodiments, the injectable product can be provided in a pre-filled syringe. In certain embodiments, a resuspendable sterile suspension can be provided in a crimp-capped vial, which is used with a separate, pre-sterilized needle to ensure sterility throughout the process. The pharmaceutical composition is resuspended in the suspension by vortexing, shaking, or mixing, and then the product is drawn up through a pre-sterilized needle prior to injection. The pre-sterilized needle for drawing up the suspension can be a lower gauge needle, which can then be replaced with a higher gauge needle for injection (injections are usually performed with a 27-30 gauge needle), or the same needle can be used for drawing up and injection as long as sterility is maintained.

[0053]

[0058] In certain embodiments of the present invention, a method for producing an ophthalmic pharmaceutical composition of roflumilast is provided. The pharmaceutical composition can include the pharmaceutical composition described above. The method can include sterilizing roflumilast using a form of slow dry heat or low-level irradiation sterilization. Sterilization can be achieved by slow dry heat sterilization at a temperature below the melting point of roflumilast (approximately 159.7°C), terminal gamma irradiation, or other sterilization methods. The method can further include sterilizing at least one inactive ingredient selected from the group consisting of viscosity agents, tonicity agents, surfactants, and buffers using a standard autoclave. The method can further include mixing the sterilized roflumilast with the sterilized inactive ingredients to prepare a stable ophthalmic pharmaceutical composition of roflumilast. In certain embodiments, the prepared pharmaceutical composition is a suspension.

[0054]

[0059] In certain embodiments, the method can further include subjecting the stable ophthalmic pharmaceutical composition of roflumilast to clarification filtration to further reduce particle size aggregation and create an optimal suspension.Clarification filtration can be used to produce a stable ophthalmic pharmaceutical composition of roflumilast, where the pharmaceutical composition has a particle size distribution characterized by a d90 value of 10 μm or less, further differentiating it for ocular use, especially in patients who may be sensitive to existing ophthalmic medications.Different formulations may also respond differently to the filtration process, due to differences in the formation of aggregates in some formulations.

[0055]

[0060] The ophthalmic pharmaceutical composition of the present invention can be administered to the eye or other sites in the surrounding tissues or cavities via intravitreal injection or injection. The pharmaceutical composition of roflumilast can be administered to the eye of a patient with an ocular disorder or ocular condition. In certain embodiments, the pharmaceutical composition disclosed herein can be administered to treat anterior uveitis, posterior uveitis, panuveitis, or intermediate uveitis; or uveitis associated with HLA-B27, juvenile idiopathic arthritis, Behcet's disease, ankylosing spondylitis, VKH, or autoimmune disease; ocular graft-versus-host disease, Stevens-Johnson syndrome / TENS, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, dry type, geographic atrophy. age-related macular degeneration (AMD), including exudative AMD, choroidal neovascularization, retinal vasculitis (drug-related / iatrogenic, non-infectious / sterile, or idiopathic), choroidal thickening associated with thyroid eye disease, Coats' disease, central serous retinopathy or chorioretinopathy, sterile or infectious endophthalmitis, retinitis, choroiditis, anterior or posterior scleritis / episcleritis, corneal endotheliitis (bacterial, viral, fungal, or non-infectious), and other diseases of the anterior and posterior tissues of the eye. ocular complications of inflammatory diseases of the eye or 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, choroidal atrophy, zonular occult outer retinal abnormalities, pathological myopia, vitreous adhesion, retinal detachment, choroidal detachment and hemorrhage, choroidal tears, choroidal folds, proliferative vitreoretinopathy, idiopathic ischemia, color blindness, retinopathy of prematurity, cerebral It is administered as an injection to treat an ocular disorder selected from the group consisting of gyral choroidal atrophy, central areolar choroidal atrophy, punctate medial choroidopathy, multifocal choroiditis, choroiditis, choroidal granuloma, choroidal dystrophy, choroidal fibrosis, acute posterior multifocal spotted pigment epitheliopathy, creeping choroidopathy, birdshot chorioretinopathy, multiple vanishing white dot syndrome, retinoblastoma, choroidal melanoma, retinal lymphoma, and iatrogenic posterior or vitreous cavity inflammation.

[0056]

[0061] In certain embodiments, the ophthalmic pharmaceutical compositions disclosed herein are administered as an injection into the periorbital space via local, orbital, peribulbar, or other injection. In certain embodiments, the ophthalmic pharmaceutical compositions disclosed herein are designed to treat eyelid or extraorbital or periorbital pain and inflammation due to trauma, autoimmune disease, microbial infection, or other systemic disease; thyroid eye disease, meibomian gland disorders, blepharitis, ocular ciccatricial 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 eyelid, ocular rosacea, neuromyelitis optica, histiocytic orbital lesions, periorbital capillary hemangioma, or extraorbital ocular complications of systemic sclerosis, scleroderma, or other autoimmune diseases, and other diseases of the periorbital space.

[0057]

[0062] Injections can also be used post-operatively to treat pain and inflammation in cataracts, LASIK, PRK, PTK, full-thickness or partial-thickness keratotomy or keratoplasty, glaucoma-related surgery, inflammation associated with gene therapy or cell therapy infusion, or other surgical conditions and procedures where inflammation is a concern and therapeutic intervention by injection is appropriate. The ocular disorders treatable by the methods described herein can be acute or chronic. In certain embodiments, the method is used to treat patients with ocular inflammatory disorders or immune disorders. In certain embodiments, the inflammatory disorder or immune disorder can be one of the disorders identified above.

[0058]

[0063] In preferred embodiments, the ocular disorder is posterior uveitis, panuveitis, or intermediate uveitis; or uveitis associated with HLA-B27, juvenile idiopathic arthritis, Behcet's disease, ankylosing spondylitis, VKH, or autoimmune disease; diabetic retinopathy, diabetic macular edema, cystoid macular edema, retinal vein occlusion, age-related macular degeneration including dry, geographic atrophy, or exudative AMD and choroidal neovascularization, thyroid eye disease, sterile or infectious endophthalmitis, and iatrogenic inflammation of the vitreous or posterior cavity.

[0059]

[0064] In certain embodiments, the pharmaceutical composition is administered as a regimen, for example, as a regimen at regular intervals. For example, the pharmaceutical composition can be administered directly to the ocular surface as drops or ointments, once a day, twice a day, three times a day, four times a day, once a week, twice a week, three times a week, or four times a week, monthly, as needed (PRN), or can be used in a treatment-extension mode. In certain embodiments, the pharmaceutical composition can be administered as part of a maintenance dose or as a dose-titrating regimen. The pharmaceutical composition can be administered for a prescribed period. For example, the pharmaceutical composition can be administered for a period of about 2 days to at least about 6 weeks, or until an improvement in the eye condition or disease is observed. Exemplary periods for the duration of a treatment regimen include 1 week, 2 weeks, 1 month, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or 1 year. For example, the pharmaceutical composition can be administered as an injection or as an implantable device, depot, or adsorbable device, and can be administered weekly, monthly, once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks, once every 3 months, once every 6 months, as needed (PRN), according to a physician's instructions, or according to some clinical criteria, such as a treatment-extension regimen or other criteria. The pharmaceutical composition can be administered as an open-ended, ongoing treatment.

[0060]

[0065] The following examples illustrate, without limitation, certain specific embodiments of the present invention. [Example]

[0061]

[0066] While various embodiments have been described herein, 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 described exemplary embodiments. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[0062]

[0067] Example 1

[0068] An ophthalmic pharmaceutical composition having the composition listed in Table 1 was prepared. A vehicle was prepared in a 100 mL glass bottle. Carboxymethylcellulose sodium was weighed and added. 90 mL of water for injection was added to the glass bottle. The resulting mixture was stirred until the carboxymethylcellulose sodium was dissolved. The remaining excipients (except roflumilast) were added, and the mixture was stirred until the excipients were dissolved. Water was added qs 100 mL. Roflumilast (previously jet-milled) was added to a 20 mL glass vial, and 10 mL of vehicle was added. A uniform suspension was formed by homogenizing the suspension using a high-shear mixer (Polyton Model PT 10 / 35). The mixing time was 2 minutes, with 30 sets of a shear rate of 8000 at controlled room temperature.

[0063] [Table 1]

[0064]

[0069] Example 2

[0070] The particle size distribution of the ophthalmic pharmaceutical composition of Example 1 was evaluated. The size of particles suspended in a liquid vehicle was evaluated using laser light scattering with a Horiba LA-950V2 Particle Size Analyzer. Particle size distribution was evaluated before and after gamma irradiation. Particle size distribution plots are shown in Figure 1 (before gamma irradiation) and Figure 2 (before gamma irradiation). The results are shown in Table 2.

[0065] [Table 2]

[0066]

[0071] Example 3

[0072] The injection force required to inject the pharmaceutical composition of Example 1 from a 27 gauge x 1 / 2 inch (1.27 cm) and a 30 gauge x 1 / 4 inch (approximately 0.63 cm) syringe needle was evaluated. 1 ml of the resuspended formulation was drawn up into a 1 ml BD syringe and a 30G x 1 / 2" BD (or 27G x 1 / 4" NIPRO) needle, respectively. The needles were connected to a Kd Scientific Hz50 / 60 Force Meter, and injection of the material was initiated using the following parameters: 1 ml syringe, inner diameter (ID) = 4.54 mm, rate = 2 ml / min. The force meter measured the injection force required to completely eject the contents of the pharmaceutical composition.

[0067]

[0073] Plots of injection input are shown in Figure 3 (27 gauge syringe needle) and Figure 4 (30 gauge syringe needle). Results are shown in Table 3. The pharmaceutical composition could be injected from the 27 gauge and 30 gauge syringe needles with minimal force, indicating that the pharmaceutical composition is suitable for intravitreal injection.

[0068] [Table 3]

[0069]

[0074] Example 4

[0075] HPLC chromatography was used to evaluate impurities in the pharmaceutical compositions. The pharmaceutical compositions were evaluated before and after gamma irradiation. The HPLC assay was performed using the conditions listed in Table 4.

[0070] [Table 4]

[0071]

[0076] The HPLC chromatograms are shown in Figure 5 (before gamma irradiation) and Figure 6 (after gamma irradiation). The HPLC chromatograms show that no significant, detectable (LLOQ) impurities were observed in the post-gamma irradiation samples.

[0072]

[0077] The ability to produce tissue retention at therapeutic levels was tested, and the results are summarized in Figures 7A-D. In the experiment, groups of 10 Dutch-belted rabbits received a single dose of the ophthalmic pharmaceutical composition described in Example 1 on day 1, administered as either bilateral intravitreal (IVT) or suprachoroidal (SCS) injections. Ocular tissues, including aqueous humor, conjunctiva, sclera, cornea, iris / ciliary body, lens, vitreous humor, retina, and retinal pigment epithelium (RPE) / choroid, as well as plasma, were collected at predetermined time points over a three-month period following dosing. Figures 7A and 7B provide the tissue retention of roflumilast and roflumilast N-oxide, respectively, after IVT injection. Figures 7C and 7D provide the tissue retention of roflumilast and roflumilast N-oxide, respectively, after SCS injection. Tissue concentration results demonstrate that after IVT injection, plasma exposure was minimal, undissolved, aggregated drug was still present in the vitreous at 30 days post-dose, and therapeutically relevant concentrations of medication were present in the vitreous, iris / ciliary body, retina, and retinal pigment epithelium (RPE) / choroid up to 30 days post-dose. After SCS injection, plasma concentrations were higher than those for IVT, with therapeutically relevant concentrations observed in the iris / ciliary body and RPE / choroid at 15 days and in the vitreous and iris / ciliary body at 30 days.

[0073]

[0078] Figure 8 shows the ocular tolerability scores for groups of three Dutch Belted rabbits receiving a single bilateral intravitreal administration of the formulation described in Example 1, i.e., either vehicle / 0%, 2%, or 5% ophthalmic pharmaceutical composition (Example 1, varying concentrations of roflumilast), followed by 28 days of observation. The ocular tolerability dose-ranging study showed that the product was generally well tolerated, with no injection site issues or general irritation, and no snow globe effect within the vitreous or aggregation on the lens. The product created a self-aggregating depot, and no particles were observed throughout the vitreous or aggregation on the lens, both of which are important for vision. The 5% composition resulted in a slightly higher incidence / severity of vitreous cells, while the 2% composition was generally found to be well tolerated.

[0074]

[0079] The foregoing description has been presented for purposes of illustration and description. It is not intended that the invention be limited to the precise form disclosed. Those skilled in the art will recognize that modifications and substitutions to the basic invention specification are possible.

Claims

1. about 2% to about 5% w / v roflumilast; a viscosity agent selected from the group consisting of hydroxypropyl methylcellulose, polyvinylpyrrolidone, or sodium carboxymethylcellulose; tonicity agents, including sodium chloride; surfactants, buffering agents, and water A highly concentrated ophthalmic pharmaceutical composition comprising: Suitable for intravitreal administration to the eye or other injectable or depot-based administration, Ophthalmic pharmaceutical compositions.

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

3. 2. The ophthalmic pharmaceutical composition of claim 1, wherein the buffering agent is sodium acetate and sodium citrate.

4. 2. The ophthalmic pharmaceutical composition of claim 1, wherein the surfactant is a polysorbate.

5. 2. The ophthalmic pharmaceutical composition of claim 1, wherein the pH is between 5.5 and 7.

5.

6. 10. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical formulation does not contain any preservatives or antibacterial agents.

7. 2. The ophthalmic pharmaceutical composition of claim 1, having a particle size distribution characterized by a d90 value of about 15 μm or less.

8. 2. The ophthalmic pharmaceutical composition of claim 1, which is injectable from a 30G syringe needle with a force of less than about 3.50 N from a 30G needle.

9. 10. The ophthalmic pharmaceutical composition of claim 1, which is injectable from a 27G syringe needle with a force of less than about 3.00 N.

10. 10. The ophthalmic pharmaceutical composition of claim 1, which has been subjected to terminal sterilization by gamma irradiation or dry heat sterilization to achieve less than about 0.2% impurities.

11. about 2% to about 5% w / v roflumilast; about 0.2% to about 0.8% w / v sodium carboxymethylcellulose; about 0.2% to about 0.8% w / v sodium chloride; about 0.02% to about 0.25% w / v polysorbate 20, about 0.005% to about 0.20% w / v potassium chloride; about 0.005% to about 0.20% w / v calcium chloride; about 0.005% to about 0.20% w / v magnesium chloride; about 0.005% to about 0.20% w / v sodium acetate; about 0.005% to about 0.20% w / v sodium citrate, and water A highly concentrated ophthalmic pharmaceutical composition comprising: the pH is between 5.5 and 7.5; Suitable for intravitreal administration to the eye or other injectable or depot-based administration, Ophthalmic pharmaceutical compositions.

12. 12. The ophthalmic pharmaceutical composition of claim 11, having a particle size distribution characterized by a d90 value of about 15 μm or less.

13. 12. The ophthalmic pharmaceutical composition of claim 11, which is injectable from a 30G syringe needle with a force of less than about 3.50 N from a 30G needle.

14. 12. The ophthalmic pharmaceutical composition of claim 11, which is injectable from a 27G syringe needle with a force of less than about 3.00 N.

15. 12. The ophthalmic pharmaceutical composition of claim 11, which has been subjected to terminal sterilization by gamma irradiation or dry heat sterilization to achieve less than about 0.2% impurities.

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

17. The ocular disorder may be anterior uveitis, posterior uveitis, panuveitis, or intermediate uveitis; uveitis associated with HLA-B27, juvenile idiopathic arthritis, Behçet's disease, ankylosing spondylitis, Vogt-Koyanagi-Harada syndrome (VKH), or autoimmune disease; ocular graft-versus-host disease, Stevens-Johnson syndrome / toxic epidermal necrolysis, diabetic retinopathy, diabetic macular edema, retinal vein occlusion; dry, geographic atrophy, or Age-related macular degeneration (AMD), including exudative AMD, choroidal neovascularization, retinal vasculitis (drug-related / iatrogenic, non-infectious / sterile, or idiopathic), choroidal thickening associated with thyroid eye disease, Coats' disease, central serous retinopathy or chorioretinopathy, sterile or infectious endophthalmitis, retinitis, choroiditis, anterior or posterior scleritis / episcleritis, corneal endotheliitis (bacterial, viral, fungal, or non-infectious), and corneal endotheliitis of the anterior and posterior tissues of the eye. Other inflammatory diseases 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, choroidal atrophy, zonular occult outer retinal abnormalities, pathological myopia, vitreous adhesion, retinal detachment, choroidal detachment and hemorrhage, choroidal tears, choroidal folds, proliferative vitreoretinopathy, idiopathic ischemia, total color blindness, prematurity 17. The method of claim 16, wherein the retinal and / or vitreous cavity inflammation is selected from the group consisting of retinopathy, gyral chorioretinal atrophy, central areolar choroidal atrophy, punctate inner choroidopathy, multifocal choroiditis, choroiditis, choroidal granuloma, choroidal dystrophy, choroidal fibrosis, acute posterior multifocal spotty pigment epitheliopathy, creeping choroidopathy, birdshot chorioretinopathy, multiple vanishing white dot syndrome, retinoblastoma, choroidal melanoma, retinal lymphoma, or iatrogenic posterior or vitreous cavity inflammation.

18. 17. The method of claim 16, wherein the pharmaceutical composition provides for delivery and use that is well tolerated.

19. 17. The method of claim 16, wherein the injection is intravitreal, subconjunctival, subretinal, intracameral, subtenon, periorbital, peribulbar, retrobulbar, retroorbital, or suprachoroidal.

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

Images