Ophthalmic pharmaceutical composition of roflumilast

Abstract

The present invention relates to a stable ophthalmic pharmaceutical formulation of roflumilast, a phosphodiesterase-4 inhibitor, and a method for making the same. The novel ophthalmic pharmaceutical formulation of roflumilast may include a thickener, a surfactant, and a buffering agent. In a preferred embodiment, the pH of the ophthalmic pharmaceutical composition is between 6.0 and 6.7. The method for making the stable ophthalmic pharmaceutical formulation of roflumilast may include processing of separate active and inactive ingredients. Additionally, the method may include clarification filtration to mitigate particle size aggregation and generate an optimized suspension. Additionally, the method may include terminal sterilization of the final drug product.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 261,404, filed September 20, 2021, which is incorporated by reference herein.

[0002]

[0002] The present invention relates to a stable, pharma- ceutical effective ophthalmic composition of roflumilast, a phosphodiesterase-4 inhibitor. More particularly, the present invention relates to a novel ophthalmic pharmaceutical composition of roflumilast that includes a viscosity enhancer, a surfactant, and a buffer. In addition, the present invention includes a method for producing a pharma-ceutical effective ophthalmic composition of roflumilast that optimizes the potency and purity of the composition. [Background technology]

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

[0004]

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

[0005]

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

[0006]

[0006] The present invention relates to a stable ophthalmic pharmaceutical composition of roflumilast, a phosphodiesterase-4 inhibitor. In certain embodiments, the ophthalmic pharmaceutical formulation of roflumilast includes a thickener, a surfactant, and a buffer. The inventors of the present application have found that due to the extremely low solubility of roflumilast at the target pH for acceptable ocular delivery, it is indeed very difficult to create conditions in which roflumilast remains in suspension with optimal potency, particle size distribution, low levels of degradants, optimal resuspension, and the ability to maintain stability through sterile conditions. The inventors have found that there are significant limitations on the conditions and processes under which a clinically suitable formulation can be produced. The formulation of the present invention can address these issues and challenges within the range of roflumilast concentrations.

[0007]

[0007] The inventors of the present application have confirmed that roflumilast is subject to hydrolysis in a specific ophthalmic pharmaceutical composition with a low possibility. The inventors of the present application have discovered that the ophthalmic pharmaceutical composition of the present invention can reduce the rate of hydrolysis. In a specific embodiment, the pH of the ophthalmic pharmaceutical composition is between about 6.0 and 6.7, which can reduce the rate of hydrolysis of roflumilast, thereby minimizing the ratio of other substances in the drug and increasing the purity and efficacy of the product.

[0008]

[0008] One embodiment of the present invention provides an ophthalmic pharmaceutical composition comprising a therapeutically effective amount of roflumilast, a viscosity enhancing agent comprising hydroxypropyl methylcellulose, a surfactant, and a buffer. In certain embodiments, the surfactant is a polysorbate. In certain embodiments, the buffer is a phosphate buffer and a citrate buffer. In certain embodiments, the pharmaceutical composition is a suspension. In a preferred embodiment, the pharmaceutical composition has a particle size distribution characterized by a d90 value of about 5 μm to about 25 μm, or more preferably, about 10 μm or less.

[0009]

[0009] Another embodiment of the present invention provides an ophthalmic pharmaceutical composition comprising a therapeutically effective amount of roflumilast, a viscosity enhancing agent comprising hydroxyethylcellulose, a surfactant, and a buffer. In certain embodiments, the surfactant is a polysorbate. In certain embodiments, the buffer is a phosphate buffer and a citrate buffer. In certain embodiments, the pharmaceutical composition is a suspension. In a preferred embodiment, the pharmaceutical composition has a particle size distribution characterized by a d90 value of about 5 μm to about 25 μm, or more preferably, about 10 μm or less.

[0010]

[0010] Another embodiment of the present invention provides an ophthalmic pharmaceutical composition comprising a therapeutically effective amount of roflumilast, a viscosity enhancing agent comprising polyvinylpyrrolidone, a surfactant, and a buffer. In certain embodiments, the surfactant is tyloxapol. In certain embodiments, the buffer is a phosphate buffer and a citrate buffer. In certain embodiments, the pharmaceutical composition is a suspension. In a preferred embodiment, the pharmaceutical composition has a particle size distribution characterized by a d90 value of about 5 μm to about 25 μm, or more preferably, about 10 μm or less.

[0011]

[0011] Another embodiment of the present invention provides an ophthalmic pharmaceutical composition comprising a therapeutically effective amount of roflumilast, a viscosity enhancing agent comprising carboxymethylcellulose, a surfactant, and a buffer. In certain embodiments, the surfactant is a polysorbate. In certain embodiments, the buffer is a phosphate buffer and a citrate buffer. In certain embodiments, the pharmaceutical composition is a suspension. In a preferred embodiment, the pharmaceutical composition has a particle size distribution characterized by a d90 value of about 5 μm to about 25 μm, or more preferably, about 10 μm or less.

[0012] Another embodiment of the present invention provides a stable sterile ophthalmic ointment composition comprising a therapeutically effective amount of roflumilast, petrolatum, and mineral oil. In a particular embodiment, the composition comprises about 0.1% to about 1.0% w / w roflumilast, about 75% to about 85% w / w petrolatum, and about 20% to about 25% w / w mineral oil.

[0013] Another embodiment of the present invention provides a method for producing a stable ophthalmic pharmaceutical composition of roflumilast under aseptic conditions. The method includes: (a) sterilizing roflumilast using a form of heat sterilization or radiation sterilization; (b) autoclaving at least one inactive ingredient selected from the group consisting of a viscosity enhancer, a surfactant, and a buffer; and (c) mixing the sterilized roflumilast with the at least one sterilized inactive ingredient to produce a stable ophthalmic pharmaceutical composition of roflumilast. In certain embodiments, the roflumilast is sterilized using dry heat sterilization at a temperature below the melting point of roflumilast. In certain embodiments, low levels of gamma radiation are used to sterilize the roflumilast. In certain embodiments, the ophthalmic pharmaceutical composition of roflumilast is a suspension.

[0014]

[0014] Another embodiment of the present invention provides a method for producing a stable ophthalmic pharmaceutical composition of roflumilast, comprising: (a) mixing roflumilast with at least one sterilized inactive ingredient to obtain a pharmaceutical composition; (b) packaging the pharmaceutical composition; and (c) terminally sterilizing the pharmaceutical composition in the package by using gamma irradiation.

[0015]

[0015] Another embodiment of the present invention provides a method for producing a stable ophthalmic pharmaceutical suspension of roflumilast, thereby further reducing the particle size of the ophthalmic pharmaceutical composition of roflumilast. In certain embodiments, the method further comprises filtering the stable ophthalmic pharmaceutical composition of roflumilast using clarifying filtration to produce a suspension having a particle size distribution characterized by a d90 value of about 10 μm or less.

[0016]

[0016] The accompanying drawings, which are incorporated herein and form a part of this disclosure, serve to illustrate various embodiments of the invention and, together with the description, further serve to explain the invention so as to enable one skilled in the art to make and use the embodiments disclosed herein. Error bars in the figures are standard deviation values. [Brief description of the drawings]

[0017] [Figure 1] 1 is a particle size distribution plot for an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.30% hydroxypropylmethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate after autoclaving and sonicating the formulation. [Diagram 2]

[0018] 1 is a particle size distribution plot for an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.35% hydroxyethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate after autoclaving and sonicating the formulation. [Diagram 3]

[0019] 1 is a particle size distribution plot for an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.60% polyvinylpyrrolidone, 0.3% tyloxapol, 0.45% phosphate, and 0.05% citrate after autoclaving and sonicating the formulation. [Figure 4]

[0020] 1 is a particle size distribution plot for an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.50% carboxymethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate after autoclaving and sonicating the formulation. [Figure 5A]

[0021] FIG. 2 is an HPLC chromatogram of an exemplary ophthalmic pharmaceutical composition comprising 0.10% roflumilast, 0.30% hydroxypropylmethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate at a pH of 7.4 under pre-autoclaved conditions. [Figure 5B]

[0022] HPLC chromatogram of an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.30% hydroxypropylmethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate at a pH of 7.4 under post-autoclave conditions. [Figure 5C]

[0023] FIG. 2 is an HPLC chromatogram of an exemplary ophthalmic pharmaceutical composition comprising 0.10% roflumilast, 0.30% hydroxypropyl methylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate at a pH of 6.4-6.5 under pre-autoclaved conditions. [Figure 5D]

[0024] FIG. 2 is an HPLC chromatogram of an exemplary ophthalmic pharmaceutical composition comprising 0.10% roflumilast, 0.30% hydroxypropylmethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate under post-autoclaving conditions at a pH of 6.4-6.5. [Figure 6A]

[0025] FIG. 2 is an HPLC chromatogram of an exemplary ophthalmic pharmaceutical composition comprising 0.10% roflumilast, 0.50% carboxymethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate at a pH of 7.4 under pre-autoclaved conditions. [Figure 6B]

[0026] 4 is an HPLC chromatogram of an exemplary ophthalmic pharmaceutical composition comprising 0.10% roflumilast, 0.50% carboxymethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate at a pH of 7.4 under post-autoclave conditions. [Figure 6C]

[0027] FIG. 2 is an HPLC chromatogram of an exemplary ophthalmic pharmaceutical composition comprising 0.10% roflumilast, 0.50% carboxymethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate at a pH of 6.4-6.5 under pre-autoclaving conditions. [Figure 6D]

[0028] FIG. 2 is an HPLC chromatogram of an exemplary ophthalmic pharmaceutical composition comprising 0.10% roflumilast, 0.50% carboxymethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate under post-autoclaving conditions at a pH of 6.4-6.5. [Figure 7]

[0029] 1 is a particle size distribution plot comparing non-autoclaved conditions with mixing and storage for 7 days at a pH of 7.4 for an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.30% hydroxypropyl methylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate. [Figure 8]

[0030] 1 is a particle size distribution plot comparing autoclaving conditions with mixing and storage for 7 days at a pH of 7.4 for an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.30% hydroxypropyl methylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate. [Figure 9]

[0031] 1 is a particle size distribution plot comparing non-autoclaved conditions with mixing and storage for 7 days at a pH of 7.4 for an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.50% carboxymethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate. [Figure 10]

[0032] 1 is a particle size distribution plot comparing autoclaving conditions with mixing and storage for 7 days at a pH of 7.4 for an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.50% carboxymethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate. [Figure 11]

[0033] 1 is a particle size distribution plot comparing non-autoclaved and autoclaved conditions with stirring for an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.30% hydroxypropyl methylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate at a pH of 6.4 to 6.5. [Figure 12]

[0034] 1 is a particle size distribution plot comparing non-autoclaved and autoclaved conditions with stirring for an ophthalmic pharmaceutical composition containing 0.10% roflumilast, 0.50% carboxymethylcellulose, 0.1% polysorbate, 0.45% phosphate, and 0.05% citrate at a pH of 6.4 to 6.5. [Figure 13]

[0035] 1 is a plot comparing the median particle size and HPLC potency of exemplary ophthalmic pharmaceutical compositions of roflumilast and roflumilast API. [Figure 14]

[0036] 1 is a particle size distribution plot for bulcloflumilast API after dry heat sterilization. [Figure 15-1]

[0037] FIG. 15A is a particle size distribution plot for a roflumilast suspension before terminal gamma sterilization.

[0038] FIG. 15B is a particle size distribution plot immediately after terminal gamma sterilization. [Figure 15-2]

[0039] FIG. 15C is a particle size distribution plot 3 days after terminal gamma sterilization.

[0040] FIG. 15D is a particle size distribution plot 7 days after terminal gamma sterilization. [Figure 16A]

[0041] 13 is a particle size distribution plot for 0.1% roflumilast suspension after terminal gamma sterilization under different stability conditions (5° C., 25° C., and 40° C.). [Figure 16B]

[0042] 13 is a particle size distribution plot for 0.3% roflumilast suspension after terminal gamma sterilization under different stability conditions (5° C., 25° C., and 40° C.). [Figure 16C]

[0043] 1 is a particle size distribution plot for 1.0% roflumilast suspension after terminal gamma sterilization under different stability conditions (5° C., 25° C., and 40° C.). [Figure 17A]

[0044] Percentage of impurities after terminal gamma sterilization under different stability conditions (5° C., 25° C., and 40° C.) for 0.1% roflumilast suspension. [Figure 17B]

[0045] Percentage of impurities after terminal gamma sterilization under different stability conditions (5° C., 25° C., and 40° C.) for 0.3% roflumilast suspension. [Figure 17C]

[0046] Percentage of impurities after terminal gamma sterilization under different stability conditions (5° C., 25° C., and 40° C.) for 1.0% roflumilast suspension. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018]

[0047] It is to be understood that the present invention is not limited to the specific methodology, protocols, and reagents described herein, as they may vary. It is also to be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.

[0019]

[0048] All publications, patents and patent applications cited herein are incorporated herein in their entirety by reference unless otherwise stated.When the same term is defined in a publication, patent, or patent application and in this disclosure incorporated herein by reference, the definition in this disclosure represents the controlling definition.For publications, patents, patent applications that are referenced to describe a particular type of compound, chemistry, etc., the portion that relates to such compound, chemistry, etc. is the portion of the document that is incorporated herein by reference.

[0020]

[0049] It should be noted that as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, "an active ingredient" includes both a single ingredient and two or more distinct ingredients.

[0021]

[0050] 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.

[0022]

[0051] The term "effective" refers to an amount of a compound, drug, substance, preparation or composition that is sufficient to reduce the severity of disease symptoms, increase the frequency and duration of disease symptom-free periods, or prevent functional impairment or disability due to disease affliction. The amount may be administered alone or in combination with other compounds, drugs or substances, either as a single dose or in a multiple dose regimen. Those skilled in the art can determine such amounts based on factors such as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0023]

[0052] "Pharmaceutically acceptable" means generally safe for administration to humans or animals. Preferably, a pharmaceutically acceptable ingredient is one that has been approved by a federal or state government regulatory agency for use in animals, more particularly humans, or is listed in the United States Pharmacopeia, published by the United States Pharmacopeia, Inc., Rockville Md., or other generally recognized pharmacopoeias.

[0024]

[0053] A "pharmaceutical composition" according to the invention may be in the form of a composition in which the different active ingredients and the diluents and / or carriers are mixed with one another, or it may take the form of a combined preparation in which the active ingredients are partially or wholly present in different forms. An example of such a combination or combined preparation is a kit-of-parts.

[0025]

[0054] The term "roflumilast," as used in this application, refers to roflumilast, its salts, the N-oxide of roflumilast and its salts, and other metabolites, unless otherwise specified or clear from the context that reference is to roflumilast itself.

[0026]

[0055] As used herein, the term "subject" or "patient" most preferably refers to a human. The term "subject" or "patient" may include any mammal that may benefit from the compounds described herein.

[0027]

[0056] A "therapeutic amount" or a "therapeutically effective amount" is an amount of a therapeutic agent sufficient to achieve its intended purpose. The effective amount of a given therapeutic agent varies depending on factors such as the nature of the agent, the route of administration, the size of the subject receiving the therapeutic agent, and the purpose of administration. The effective amount in each individual case can be empirically determined by those skilled in the art using methods established in the art.

[0028]

[0057] As used herein, "treat," "treating," or "treatment" of a disease or disorder means accomplishing one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing the recurrence of the disorder(s) in patients who previously had the disorder(s); and (e) limiting or preventing the recurrence of symptoms in patients who previously had symptoms of the disorder(s).

[0029]

[0058] 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-dichloropyrid-4-yl.

[0059] Roflumilast has the chemical name N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide. The N-oxide of roflumilast has the chemical name 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl 1-oxide)benzamide. Roflumilast and its synthesis, use of roflumilast as a phosphodiesterase (PDE) 4 inhibitor, and roflumilast formulations are described in U.S. Patent No. 5,712,298, which is incorporated herein by reference. The ophthalmic pharmaceutical composition may include roflumilast as a free base or a pharma-ceutical acceptable salt thereof. Exemplary salts of roflumilast are those described in U.S. Patent Application Publication No. 2006 / 0084684, paragraphs "0012" and "0013", the disclosure of which is incorporated herein by reference. In certain embodiments, the pharmaceutical composition comprises as an active ingredient a metabolite of roflumilast, including an N-oxide of the pyridine residue of roflumilast, or a salt thereof.

[0032]

[0060] In certain embodiments, the ophthalmic pharmaceutical composition may contain roflumilast in the range of about 0.01% w / v to about 5.0% w / v, or about 0.01% w / v to about 3.0% w / v, or about 0.01% w / v to about 2.0% w / v, or about 0.01% to about 1.0% w / v, or about 0.01% to about 0.3% w / v. For example, an ophthalmic medication may contain roflumilast in any of the following w / v percentages: 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 7%, 1.8%, 1.9%, 1.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, etc.

[0033]

[0061] In certain embodiments, the ophthalmic pharmaceutical composition may be a suspension, a solution, an eye drop, an eye ointment, a gel, a cream, a spray, an intranasal spray, an injectable formulation (intravitreal, subconjunctival, subtenon, suprachoroidal or other injection), or an adsorbent implant injection, a depot or an adsorbent contact lens. In a preferred embodiment, the pharmaceutical composition is a suspension, and the active ingredient (i.e., roflumilast) is suspended in a pharmaceutical carrier and / or excipient. In certain embodiments, the ophthalmic pharmaceutical composition of roflumilast includes a thickening agent, a surfactant, and a buffering agent. In certain embodiments, the ophthalmic pharmaceutical composition may include one or more additional excipients, including, for example, a stabilizer, a preservative, a wetting agent, a diluent, a pH adjuster, a tonicity agent, or an absorption enhancer. In certain embodiments, the ophthalmic pharmaceutical compositions may also be utilized in the form of injections (intravitreal, suprachoroidal, or other), as depots, implantable adhesive devices for any ophthalmic or peripheral tissue placement, in situ forming gels, or drug / device combinations in anterior or posterior ocular locations, where the active ingredient (i.e., roflumilast) is suspended with one or more excipients as described above, such as, for example, viscosity enhancing agents, surfactants, or buffers; with or without a device or inert depot compound.

[0034]

[0062] In certain embodiments, the thickening agent is at least one selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), polyvinylpyrrolidone or povidone (PVP), carboxymethylcellulose, hypromellose, methylcellulose, or polyvinyl alcohol (PVA).In certain embodiments, the thickening agent is dextran or gelatin.In addition, the thickening agent may include carbomer, such as carbomer copolymer type A or carbomer copolymer type B, including those sold under the trade name Carbopol by Lubrizol® in certain embodiments. In certain embodiments, the ophthalmic pharmaceutical formulation may contain a viscosity enhancing agent in the range of about 0.1% w / v to about 5.0% w / v, or about 0.1% w / v to about 4.0% w / v, or about 0.1% w / v to about 3.0% w / v, or about 0.1% w / v to about 2.0% w / v, or about 0.1% to about 1.0% w / v, or about 0.1% to about 0.5% w / v. For example, for ophthalmic drugs, the rates are: 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%, Containing any of the following w / v percentages of thickening agent: 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.

[0035]

[0063] In certain embodiments, the surfactant is at least one selected from the group consisting of polysorbates (including polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80) and tyloxapol. In certain embodiments, the ophthalmic pharmaceutical formulation may contain a surfactant in the range of about 0.05% w / v to about 3.0% w / v, or about 0.05% w / v to about 2.0% w / v, or about 0.05% to about 1.0% w / v, or about 0.1% to about 0.5% w / v. For example, ophthalmic medications may contain any of the following w / v percentages of surfactants: 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.

[0036]

[0064] In certain embodiments, the buffering agent is at least one selected from the group consisting of citrate, phosphate, Tris-HCl (Tris), acetate, and borate buffering agents. In certain embodiments, the ophthalmic pharmaceutical formulation may contain a buffering agent in the range of about 0.5% w / v to about 7.5% w / v, or about 0.5% w / v to about 5.0% w / v, or about 0.5% to about 3.0% w / v, or about 0.5% w / v to about 2.0% w / v, or about 0.5% to about 1.0% w / v. For example, for ophthalmic drugs, the rates were: 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%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.7%, 3.8%, 3.9%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.7%, 3.8%, 3.9%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.7%, 3.8%, 3.9%, 3.1%, 3.2%, 3.3%, 3.4%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.1%, 3.2%, 3.3%, 3.4%, 3.4%, 3.5%, 3.7%, 3.8%, 3.9%, 3.1%, 3.2%, 3.3%, 3.4%, 3.4%, 3.5%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9 %, 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. w / v percent of buffer.

[0037]

[0065] In certain embodiments, the ophthalmic pharmaceutical formulation is an ointment. The ointment may include an inactive ingredient selected from the group consisting of petrolatum, mineral oil. In such embodiments, the ophthalmic pharmaceutical formulation may include a therapeutically effective amount of roflumilast, petrolatum, and mineral oil. In certain embodiments, the composition includes about 0.1% w / v to about 3.0% w / v, or about 0.1% w / v to about 2.0% w / v, or about 0.1% to about 1.0% w / v of roflumilast. In certain embodiments, the composition includes about 75% to about 85% w / w of petrolatum, or more preferably about 75% to about 80% w / w of petrolatum. In certain embodiments, the composition includes about 15% to about 25% w / w of mineral oil, or more preferably about 15% to about 20% w / w of mineral oil. Ointments can offer advantages compared to suspensions, including, for example, increased contact time and increased soluble drug concentration in the dosage system, which can be important for water-insoluble drugs such as roflumilast.

[0038]

[0066] The inventors of the present application have confirmed that roflumilast undergoes hydrolysis in a specific ophthalmic pharmaceutical composition under a specific standard sterile manufacturing process with a low probability. The inventors of the present application have discovered that the ophthalmic pharmaceutical composition of the present invention can reduce the rate of hydrolysis. In a specific embodiment, the pH of the ophthalmic pharmaceutical composition is between about 6.0 and about 6.7 to reduce the rate of hydrolysis of roflumilast. In a preferred embodiment, the pH of the ophthalmic pharmaceutical composition is between about 6.2 and about 6.7, more preferably between about 6.3 and about 6.6. In a preferred embodiment, the osmolality of the ophthalmic pharmaceutical composition is about 270 mOsm / kg to 330 mOsm / kg, more preferably about 270 mOsm / kg to about 300 mOsm / kg, and even more preferably 270 mOsm / kg to 280 mOsm / kg.

[0039]

[0067] The ophthalmic pharmaceutical composition of the present invention is stable and exhibits a particle size distribution suitable for delivery to the eye. The particle size of the ophthalmic pharmaceutical composition for suspension can be determined using a laser diffraction method. Laser diffraction is recognized by standards and guidance organizations, including ISO and ASTM, and is widely used to determine particle size distribution. In performing the determination, the sample passes through a laser beam, which causes the laser light to scatter at a range of angles. A detector placed at a fixed angle measures the intensity of the light scattered at that position. A mathematical model is then applied to generate the particle size distribution.

[0040]

[0068] In particle size determination, the median is defined as the value above which half of the population lies and below which half lies. In terms of particle size distribution, the median is called the D50. The D50 is the size that divides the distribution so that half is above this diameter and half is below this diameter. The distribution width can also be typically characterized by listing one, two, or three values ​​on the x-axis, such as some combination of D10, D50, and D90. The D50 (or median), as discussed above, refers to the diameter below which half of the population lies. Similarly, 90 percent of the distribution is below the D90 and 10 percent of the population is below the D10.

[0041]

[0069] In certain embodiments of the present invention, the ophthalmic pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of about 50 μm or less, prior to preferential processing. In certain embodiments, the ophthalmic pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of about 5 μm to about 25 μm. In certain embodiments, the pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of about 5 μm to about 15 μm. In a preferred embodiment, the pharmaceutical composition exhibits a particle size distribution characterized by a d90 value of about 10 μm or less.

[0042]

[0070] The inventors of the present application have confirmed that roflumilast combined with multiple viscosity enhancers undergoes particle size growth and aggregation in a specific heat-transferring ophthalmic pharmaceutical manufacturing process designed to sterilize the formulation. The inventors of the present application have discovered a specific method to avoid this aggregation-causing heat transfer during sterilization of roflumilast in the same container as inactive ingredients, including excipients, surfactants, etc., which can reduce the rate of particle size growth and aggregation while maintaining the potency of the product. Blending both sterilized API and sterilized inactive materials reduces particle aggregation by reducing the need for additional energy inputs such as autoclaving, which can cause particle aggregation. In certain embodiments, dry heat sterilization at temperatures below the melting point of roflumilast, gamma irradiation, or other sterilization methods of API can be used to sterilize roflumilast, while standard autoclaving can be used to sterilize the inactive materials before the final blended formulation for an ophthalmic pharmaceutical composition optimized for ideal potency, purity, and particle size for use in the eye is produced. In certain embodiments, gamma irradiation or other final product sterilization methods may be used to sterilize the drug product and ensure the final product is sterile in the package as a way to further ensure sterility assurance and patient safety. The inventors of the present application have discovered certain methods of terminal sterilization that avoid product degradation or further generation of impurities. In certain embodiments, the packaged ophthalmic pharmaceutical composition may be characterized by a retention potency of greater than 99% of the original value of the active agent. In certain embodiments, the retention potency is greater than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, or 99.8% of the original value of the active agent.

[0043]

[0071] In a particular embodiment of the present invention, a method for preparing an ophthalmic pharmaceutical composition of roflumilast is provided. The pharmaceutical composition may include the pharmaceutical composition described above. The method may include sterilizing roflumilast using a form of dry heat sterilization or low-level radiation sterilization. Sterilization may be achieved by dry heat sterilization at a temperature below the melting point of roflumilast (approximately 159.7°C), gamma irradiation, or other sterilization methods. The method may further include sterilizing at least one inactive ingredient selected from the group consisting of thickeners, surfactants, and buffers using standard autoclaving. The method may further include mixing sterilized roflumilast and sterilized inactive ingredients to prepare a stable ophthalmic pharmaceutical composition of roflumilast. In a particular embodiment, the prepared pharmaceutical composition is a suspension.

[0044]

[0072] In certain embodiments, the method can further comprise subjecting the stable ophthalmic pharmaceutical composition of roflumilast to clarification filtration to further reduce particle size aggregation and produce optimal suspension.Clarification filtration can be used to produce the stable ophthalmic pharmaceutical composition of roflumilast, which has a particle size distribution characterized by a d90 value of 10 μm or less, which is further differentiated for use in eyes, particularly for use in patients who may be hypersensitive to existing ophthalmic agents.Different formulations may respond differently to filtration treatment due to differences in the formation of aggregates in some formulations.

[0045]

[0073] In a particular embodiment of the present invention, a method for producing an ophthalmic pharmaceutical composition of roflumilast is provided. The pharmaceutical composition may include the pharmaceutical composition described above. The method may include preparation of the pharmaceutical composition under GLP or GMP conditions, followed by low-level radiation sterilization of the final drug product in the final packaging, called terminal sterilization. Sterilization may be achieved by gamma irradiation at low or medium doses (e.g., low doses of 18-25 kilograys or medium doses of 25-28 kilograys). A typical radiation dose mapping procedure involves placing a tray with samples on a platform located in the center of a gamma generation chamber. At least two dosimeters are placed on the samples, one above the tray and the other below the tray. Minimum dose (Dmin) and maximum dose (Dmax) estimates are performed, plus a separate monitoring dosimeter (Dmon) is typically placed above the sample tray. Dosimeter placement and measurements are typically repeated in accordance with ISO 11137-3. Dmin, Dmax, and Dmon are calculated as the average of the measurements performed. This sterilization method is preferred for patient use because both the product and the packaging are sterile, providing additional assurance that the product has the sterility required for single-use clinical applications. In certain embodiments, the prepared pharmaceutical composition is a suspension.

[0046]

[0074] The ophthalmic pharmaceutical composition of the present invention can be administered directly to the ocular surface of a patient, and the teachings herein can also be used to produce injectable or implantable formulations for ophthalmic use on the surface, anterior, or posterior of the eye.The pharmaceutical composition of roflumilast can be administered to the eye of a patient with an ocular disorder or condition.The ophthalmic pharmaceutical composition of the present invention that is applied to ocular surface disease can be used to treat ocular disorders without the need for invasive techniques that are sometimes required to deliver drugs to the anterior or posterior of the eye. Examples of ocular surface eye disorders that may be treated by the methods disclosed herein include: post-operative pain and inflammation from cataract or other ophthalmic surgery or laser treatment, blurred vision after corneal refractive surgery, post-operative full or partial thickness corneal transplant, dry eye syndromes including Sjogren's syndrome or other autoimmune or inflammatory dry eye disease, evaporative or desiccant dry eye disease, ocular graft versus host disease, ocular rosacea, allergic conjunctivitis or keratoconjunctivitis, atopic conjunctivitis, vernal keratoconjunctivitis, keratitis, keratitis including keratitis herpes, herpes blepharitis or herpetic conjunctivitis, herpes zoster. associated inflammation, inflammation secondary to other infectious agents such as bacterial, viral, or fungal infections, inflammation secondary to ocular chemical burns, ocular Stevens-Johnson syndrome / toxic epidermolysis, uveitis including juvenile idiopathic arthritis uveitis, seborrheic or other forms of blepharitis, limbal stem cell deficiency, meibomian gland dysfunction, episcleritis, pingueculitis, pterygium, phlyctenular conjunctivitis, staphylococcal hypersensitivity, Mooren's ulcer, endotheliitis, superior limbal keratoconjunctivitis, or other ocular conditions traditionally treated with steroids where the patient is contraindicated due to a medical history such as intraocular pressure, wound healing, fungal infection, etc.Certain embodiments in which these formulations may be used as multiple injectable or depot formulations may be used to treat ocular complications of anterior or posterior inflammatory ocular diseases such as anterior uveitis, panuveitis and posterior uveitis (infectious or non-infectious), juvenile idiopathic arthritis-associated uveitis, late complications of Behcet's disease, ocular graft-versus-host disease, Stevens-Johnson syndrome, diabetic retinopathy, diabetic macular edema, geographic atrophy, dry or wet age-related macular degeneration, retinal vein occlusion, retinal vasculitis (drug-induced / iatrogenic, non-infectious / sterile, or idiopathic), 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 and posterior tissues of the eye or other inflammatory or autoimmune diseases. Injectables can also be used postoperatively to treat the pain and inflammation associated with cataract, LASIK, full or partial thickness keratoplasty, glaucoma-related surgical procedures, instillation of gene or cell therapy, or other surgical conditions and procedures where inflammation is a concern.The eye disorder 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.In certain embodiments, the inflammatory disorder can be one of the disorders identified above.

[0047]

[0075] In certain embodiments, the pharmaceutical composition is administered according to a regimen, such as at regular intervals. For example, the pharmaceutical composition may 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, or as needed (PRN). In certain embodiments, the pharmaceutical composition may be administered as part of a maintenance or titration regimen. The pharmaceutical composition may be administered for a prescribed period of time. For example, the pharmaceutical composition may be administered for a period of about 2 days to at least about 6 weeks, or until an improvement in the ocular condition or disease is observed. Exemplary periods of treatment regimens include 1 week, 2 weeks, 1 month, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or 1 year. For example, the pharmaceutical composition may be administered as an injection or as an implantable, depot, or adsorbent device, once a week, once a month, once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks, once a quarter, once every 6 months, as needed (PRN), as directed by a physician, or according to some clinical criteria, such as treatment and extension or other criteria. The pharmaceutical composition may be administered as an open-ended continuous treatment.

[0048]

[0076] The following examples illustrate certain embodiments of the invention without limiting them. EXAMPLES

[0049]

[0077] While various embodiments have been described herein, it should be understood that these are presented by way of example only and not by way of limitation. Thus, the breadth and scope of the present disclosure should not be limited by any of the exemplary embodiments described. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure unless otherwise indicated herein or clearly contradicted by context.

[0050]

[0078] Nine ophthalmic pharmaceutical compositions containing roflumilast were prepared, as set forth in Example 1, which includes different pharmaceutical compositions of a 0.1% roflumilast suspension, Examples 5-6, which include different pharmaceutical compositions of an ointment, and Examples 7-9, which include different pharmaceutical compositions containing a range of concentrations of roflumilast in the same pharmaceutical composition.

[0051]

[0079] Example 1

[0080] Ophthalmic pharmaceutical compositions containing roflumilast were prepared as set forth in Table 1. Figure 1 provides particle size distribution plots after autoclaving and sonication of the formulations.

[0052] [Table 1]

[0053]

[0081] Example 2

[0082] Ophthalmic pharmaceutical compositions containing roflumilast were prepared as set forth in Table 2. Figure 2 provides particle size distribution plots after autoclaving and sonication of the formulations.

[0054] [Table 2]

[0055]

[0083] Example 3 Ophthalmic pharmaceutical compositions containing roflumilast were prepared as set forth in Table 3. Figure 3 provides particle size distribution plots after autoclaving and sonication of the formulations.

[0056] [Table 3]

[0057]

[0084] Example 4

[0085] Ophthalmic pharmaceutical compositions containing roflumilast were prepared as set forth in Table 4. Figure 4 provides particle size distribution plots after autoclaving and sonication of the formulations.

[0058] [Table 4]

[0059]

[0086] Examples 5 and 6

[0087] Pharmaceutical ophthalmic ointments containing roflumilast as set forth in Table 5 were prepared.

[0060] [Table 5]

[0061]

[0088] Examples 7 to 9

[0089] Ophthalmic pharmaceutical suspensions were prepared containing roflumilast in different suspension concentrations as set forth in Table 6. The formulations were prepared using the same excipients as set forth in Examples 1 and 3, but with different concentrations of roflumilast.

[0062] [Table 6]

[0063]

[0090] Example 10

[0091] Examples 1-4 were prepared with a pH of 7.4. Impurities of the formulations were measured using HPLC. An HPLC assay was used to quantify roflumilast and its impurities by verifying peak elution times compared to a reference standard and measuring peak areas. Figures 5A-D provide HPLC chromatograms for the pre-autoclaving (Figures 5A and 5C) and post-autoclaving (Figures 5B and 5D) sterilization cycles of Example 1. Figures 5A and 5B provide HPLC chromatograms for Example 1 formulated at a final pH of 7.4, illustrating detectable impurities due to hydrolysis of roflumilast under heat transfer. Figures 5C and 5D provide HPLC chromatograms for Example 1 formulated at a final pH of 6.4-6.5, illustrating nearly undetectable impurities due to lack of hydrolysis. Figures 6A-6D provide HPLC chromatograms for the pre-autoclaving (Figures 6A and 6C) and post-autoclaving (Figures 6B and 6D) sterilization cycles of Example 4. Figures 6A and 6B provide HPLC chromatograms for Example 4 formulated at a final pH of 7.4, illustrating detectable impurities due to hydrolysis of roflumilast under thermal transfer. Figures 6C and 6D provide HPLC chromatograms for Example 4 formulated at a final pH of 6.4-6.5, illustrating nearly undetectable impurities due to lack of hydrolysis. The impurities of each of Examples 1-4 were determined to be approximately 0.25% or greater than 0.25%. It was determined that the impurities were mostly attributable to hydrolysis of roflumilast.

[0064]

[0092] Examples 1 and 4 were reformulated at a pH of 6.4-6.5. Phosphate / citrate buffer was used in an amount of 0.25% / 0.5% for the reformulated compositions having a pH of 6.4-6.5 compared to 0.45% / 0.5% for the compositions having a pH of 7.4. Impurities in Examples 1 and 4 were measured using the same method (HPLC) as described above. Analytical results are set forth in Table 7 below.

[0065] [Table 7]

[0066]

[0093] The impurities in Examples 1 and 4 (pH=6.4-6.5) were determined to be below the limit of quantitation. Adjusting the pH of the ophthalmic pharmaceutical composition to 6.4-6.5 was determined to reduce the hydrolysis impurity to below the limit of quantitation.

[0067]

[0094] Example 11

[0095] The particle size distribution of the ophthalmic pharmaceutical compositions of Examples 1-4 having a pH of 7.4 was determined. The size of the particles suspended in the liquid vehicle was evaluated using laser light scattering using a Horiba LA-950V2 particle size analyzer. For each of Examples 1-4, the particle size distribution was determined: (i) before autoclaving; (ii) before autoclaving, after 3 minutes of sonication; (iii) before autoclaving, after 3 minutes of sonication and 7 days of storage; (iv) after autoclaving; (v) after autoclaving, after 3 minutes of sonication; and (vi) after autoclaving, after 3 minutes of sonication and 7 days of storage.

[0068]

[0096] Comparative data for the suspension formulations of Examples 1-4 are provided in Table 8 below. Figures 7 and 8 provide particle size distribution plots for Example 1 at a pH of 7.4, comparing non-autoclaved (Figure 7) and autoclaved (Figure 8) conditions with mixing and storage for 7 days. Figures 9 and 10 provide particle size distribution plots for Example 4 at a pH of 7.4, comparing non-autoclaved (Figure 9) and autoclaved (Figure 10) conditions with mixing and storage for 7 days.

[0069] [Table 8]

[0070]

[0097] Example 12

[0098] The particle size of the ophthalmic pharmaceutical compositions of Examples 1 and 4 having a pH of 6.4-6.5 was determined. For Examples 1 and 4, the particle size was determined: (i) before autoclaving, after stirring for 60 minutes; (ii) before autoclaving, after stirring overnight; and (iii) after autoclaving, after stirring overnight. Comparative data for the suspension formulations of Examples 1 and 4 are provided in Table 9 below. Figure 11 provides particle size distribution plots for Example 1 at a pH of 6.4-6.5, comparing non-autoclaved and autoclaved conditions with stirring. Figure 12 provides particle size distribution plots for Example 4 at a pH of 6.4-6.5, comparing non-autoclaved and autoclaved conditions with stirring. Figure 13 includes plots comparing median particle sizes for Examples 1 and 4 at a pH of 6.4-6.5, comparing non-autoclaved and autoclaved conditions with stirring. Figure 13 also includes HPLC potency results as well as API median particle size.

[0071]

[0099] The data indicates that formulating at a pH of 6.4-6.5 mitigates particle size increase and polydispersity. The data suggests that a pH of 6.4-6.5 reduces aggregation due to amide hydrolysis compared to a pH of 7.4.

[0072] [Table 9]

[0073] [000100] Example 13 The effect of dry heat sterilization on roflumilast was determined. Roflumilast bulk API was dried at 137° C. for 20 hours. The particle size of roflumilast was measured. FIG. 14 provides a particle size distribution plot for the bulk API after dry heat sterilization. As illustrated in FIG. 14, dry heat sterilization does not significantly affect the particle size distribution of the API, which was previously reported by the API manufacturer to have a D90 of approximately 10 μm.

[0074] [000101] Example 14 [000102] The effect of terminal sterilization on the 0.1% pharmaceutical composition suspension of roflumilast set forth in Table 10 was determined before and after terminal sterilization.

[0075] [Table 10]

[0076] [000103] The pharmaceutical composition suspension of roflumilast in 1 ml samples was terminally sterilized and particle size was determined after 1 week of accelerated stability study (60°C). As illustrated in Figures 15A-D, terminal gamma sterilization does not significantly affect the particle size distribution of the final drug product. Figure 15A illustrates the particle size distribution before terminal gamma sterilization. Figure 15B illustrates the particle size distribution immediately after terminal gamma sterilization (i.e., after T0 terminal gamma sterilization). Figure 15C illustrates the particle size distribution 3 days after terminal gamma sterilization. Figure 15D illustrates the particle size distribution 1 week (7 days) after terminal gamma sterilization.

[0077] [000104] The pH, osmolality, and impurities (RT, PA, and %PA) were also determined for the three concentrations of pharmaceutical compositions set forth in Table 10. These properties were determined under accelerated stability conditions (60°C) prior to terminal gamma sterilization (pre-gamma T0) and 0, 3, and 7 days after terminal gamma sterilization (post-gamma days 0, 3, and 7). The results of the pH analysis are set forth in Table 11. As illustrated in Table 11, the pH decreased only a minimal amount after terminal gamma sterilization.

[0078] [Table 11]

[0079] [000105] The results of the osmolality analysis are set forth in Table 12. As illustrated in Table 12, there was no significant change in osmolality following terminal gamma sterilization.

[0080] [Table 12]

[0081] [000106] Terminal gamma sterilization did not significantly affect the levels of impurities, as illustrated in Table 13. Only the 0.1% concentration formulation had less than 0.3% impurities, while the other two concentrations had no impurities.

[0082] [Table 13]

[0083] [000107] Example 15 [000108] The effect of terminal sterilization on three different concentrations of suspension of roflumilast was further determined under three conditions at three stability time points to confirm that no appreciable degradation or particle size increase occurred over time, and no additional impurities occurred through storage at different temperatures (5, 25, and 40°C). The pharmaceutical composition (Example 14) set forth in Table 10 was prepared with three different concentrations of roflumilast, 0.1%, 0.3%, and 1.0% roflumilast. As illustrated in Figures 15A, 15B, and 15C, terminal gamma sterilization did not significantly affect the particle size of samples at 1 month, 2 months, or 3 months for all three concentrations. Note that the data analysis for the first month (0.1% concentration) was excluded due to sampling error, which was corrected in the second run (for the 0.3% concentration). Furthermore, as illustrated in Figures 16A, 16B, and 16C, gamma sterilization did not significantly affect the levels of impurities (all remained below 0.5% of active drug, well below the percentages of all suspension materials).

[0084] [000109] The foregoing description has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed. Those skilled in the art will recognize that modifications and substitutions to the basic description of the invention may be made.

Claims

1. Therapeutic dose of roflumilast; Thickening agent containing polyvinylpyrrolidone; Surfactants; and cushioning agent Includes, An ophthalmic pharmaceutical composition having a pH of 6.0 to 6.7 and being in the form of a suspension.

2. Therapeutic dose of roflumilast; Thickening agent containing hydroxypropylmethylcellulose; Surfactants; and cushioning agent Includes, An ophthalmic pharmaceutical composition having a pH of 6.0 to 6.7 and being in the form of a suspension.

3. Therapeutic dose of roflumilast; Thickening agent containing carboxymethylcellulose; Surfactants; and cushioning agent Includes, An ophthalmic pharmaceutical composition having a pH of 6.0 to 6.7 and being in the form of a suspension.

4. The ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein the surfactant is tyroxapol.

5. An ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein the surfactant is a polysorbate.

6. The ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein the buffering agent is a phosphate buffering agent and a citrate buffering agent.

7. An ophthalmic pharmaceutical composition according to any one of claims 1 to 3, having a particle size distribution characterized by a d90 value of approximately 5 μm to approximately 25 μm.

8. An ophthalmic pharmaceutical composition according to any one of claims 1 to 3, having a particle size distribution characterized by a d90 value of approximately 10 μm or less.

9. An ophthalmic pharmaceutical composition according to any one of claims 1 to 3, which maintains a percentage of roflumilast greater than 99% of the percentage of roflumilast before final sterilization.

10. The ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein roflumilast is present in an amount of 0.01% w / v to 5.0% w / v.

11. An ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein the amount of the thickening agent is 0.1% w / v to 5.0% w / v.

12. An ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein the amount of surfactant is 0.05% w / v to 3.0% w / v.

13. An ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein the buffering agent is present in an amount of 0.5% w / v to 7.5% w / v.

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