Methods for Ophthalmic Delivery of Roflumilast

Abstract

Ophthalmic delivery method of roflumilast. The inventors have made the surprising discovery that administration of a pharmaceutical composition comprising roflumilast to the cornea results in preferential delivery of the drug in an outward direction through the ocular surface and anterior ocular tissues. In contrast to delivery of roflumilast to the skin, which moves primarily across various tissues of the skin, or many other topical ophthalmic pharmaceutical compositions, which move through the cornea to the aqueous humor, delivery of the drug to the eye and the cornea moves in an outward direction to the ocular surface and anterior ocular tissues. Such a method can provide higher levels of drug to the cornea and other ocular surface and anterior ocular tissues (e.g., iris-ciliary body, sclera, conjunctiva and aqueous humor) compared to the interior or posterior tissues of the eye.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 148008, filed February 10, 2021, and U.S. Provisional Patent Application No. 63 / 261404, filed September 20, 2021, the disclosures of which are incorporated by reference in their entireties into this specification.

[0002]

[0002] The present invention relates to methods for the ophthalmic delivery of roflumilast, a phosphodiesterase-4 inhibitor, and more particularly, to methods for delivering roflumilast to target the ocular surface and anterior segment tissues, such as the cornea, including the corneal epithelium and corneal endothelium, the iris-ciliary body, the lens, the sclera, the conjunctiva, and the aqueous humor. [Background technology]

[0003]

[0003] Roflumilast is a long-acting inhibitor of phosphodiesterase (PDE) type 4, with anti-inflammatory and potential antitumor activity. It is known that roflumilast is suitable as a bronchial therapeutic 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 such as, 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 marketed under the trademarks Daliresp® (USA) and Daxas® (Europe).

[0004]

[0004] Roflumilast and its synthesis are described in US Patent Publication No. 5712298. It has been recognized that pharmaceutical compounds with phosphodiesterase (PDE) inhibitory properties, such as roflumilast, are therapeutically effective and useful in the treatment of inflammatory disorders, such as asthma, COPD, inflammatory bowel disease, psoriasis and atopic dermatitis. Although the therapeutic effectiveness of oral and transdermal pharmaceutical compositions has been investigated, there is a need for ophthalmic pharmaceutical compositions of roflumilast suitable for the treatment of ocular inflammatory disorders.

[0005]

[0005] Drug delivery to the eye is very challenging, as pharmaceutical ophthalmic agents must balance sterility, tolerability, convenience, safety and efficacy. Developing a stable ophthalmic formulation that can be made under sterile conditions while retaining physicochemical properties, can remain within a narrow pH range, in which the inactive ingredients are tolerated by the eye, and can be delivered to the eye in an effective dose in a manner that is convenient for frequent use by the patient is very difficult to achieve. Ophthalmic delivery typically focuses on the ocular surface, anterior segment, or posterior segment. Formulations for the ocular surface and anterior segment are often delivered or instilled by the patient as eye drops on a 1-4 times per day schedule, with the added challenge of having to address sterility in actual use. The potential for fluctuating temperature and humidity conditions, as well as the increased potential for somewhat improper delivery to the appropriate ocular tissue, can cause variability in delivery volume, placement, and potential sterility issues, both in the pharmaceutical product and in the delivery device, when the agent is delivered in a multiple use / multiple dose delivery system. Also, patients with long-term inflammatory eye disease may have increased or heightened sensitivity to many active and inactive ingredients and preservatives, creating additional formulation challenges. Today's market for anti-inflammatory topical ocular surface treatments is largely comprised of three classes: antibiotics, immunosuppressants, and steroids; however, many of the medications within these classes either do not meet the clinical requirements of long-term inflammatory disease or present significant long-term comorbidities and safety issues. Thus, there is currently a high unmet need for ophthalmic formulations of anti-inflammatory agents, such as roflumilast, that can deliver effective drugs to target tissues of the eye in a convenient, tolerable, and safe form. Convenient and effective delivery of drugs to the eye is even more challenging when optimizing delivery of the drug to the ocular surface and anterior segment tissues while minimizing exposure of posterior tissues. Delivering an effective dose to the ocular surface and anterior compartment while avoiding unnecessary exposure to the drug in posterior segment tissues has not previously been considered feasible.

[0006] Currently, there is a need for ophthalmic delivery of roflumilast that selectively results in high levels of the drug at the ocular surface and anterior segment tissues that are often affected by inflammatory eye diseases. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent Publication No. 5,712,298 Summary of the Invention

[0008]

[0007] The present invention relates to an ophthalmic delivery method of roflumilast. As disclosed herein, the inventors of the present invention have made the surprising discovery that topical administration of a pharmaceutical composition comprising roflumilast to the cornea delivers the drug laterally to the ocular surface and anterior tissues. In contrast to the delivery of roflumilast to the skin, which moves directly through various tissues of the skin in succession, or the transcorneal delivery of many current ophthalmic drugs, the delivery of a pharmaceutical composition comprising roflumilast to the cornea moves laterally through the ocular surface tissues and enters the anterior compartment via peripheral tissues. Such a method can provide higher levels of drug to the cornea, ocular surface and anterior tissues (e.g., cornea, conjunctiva, iris-ciliary body, sclera, aqueous humor, and lens) compared to posterior tissues (e.g., vitreous humor and retina).

[0009] In one embodiment, a method of treating a patient having an ocular inflammatory disorder is provided. The method comprises administering to the cornea of ​​the patient a composition comprising a therapeutically effective amount of roflumilast or a pharma- ceutical acceptable salt thereof. Surprisingly, it has been found that roflumilast preferentially migrates outwardly through the ocular surface and anterior tissues, rather than across the cornea. In certain embodiments, the composition is a suspension.

[0010] In certain embodiments, administration provides elevated levels of roflumilast in the cornea of ​​the eye, as well as the peripheral orbital tissues of the conjunctiva, iris-ciliary body, lens, and sclera of the patient, relative to the posterior ocular compartment (retina, vitreous humor) of the patient. Administration can provide elevated levels of roflumilast in the sclera, iris-ciliary body, lens, conjunctiva, and aqueous humor of the patient's eye, as well as the cornea, relative to the posterior ocular tissues of the patient.

[0011]

[0010] Furthermore, administration can result in a depot effect, characterized by an increased concentration of roflumilast in an ocular tissue or component in the patient's cornea, conjunctiva, iris-ciliary body, sclera, aqueous humor or lens, compared to the concentration of roflumilast at an earlier period after administration.

[0012] In another aspect, a method for delivering roflumilast to the ocular surface or anterior ocular tissue of a patient is provided, the method comprising administering to the cornea of ​​the patient a composition comprising a therapeutically effective amount of roflumilast or a pharma- ceutical acceptable salt thereof, the composition delivering roflumilast in an outward direction through the ocular surface and anterior tissue.

[0013] In another aspect, there is provided a method of treating a patient suffering from an ocular surface or anterior segment disorder, the method comprising administering to the cornea of ​​the patient a therapeutically effective amount of a composition comprising roflumilast or a pharma- ceutical acceptable salt thereof, the composition preferentially delivering elevated levels of roflumilast to the patient's ocular surface or anterior segment tissues relative to the posterior compartment, including the retina and vitreous humor, of the patient's eye. [Brief description of the drawings]

[0014]

[0013] The accompanying drawings, which are incorporated herein and form a part of this disclosure, are useful for illustrating various aspects of the invention and, together with the description, serve to further explain the invention so as to enable one skilled in the art to make and use the aspects disclosed herein. Error bars in the drawings are standard deviation values. [Figure 1]FIG. 1 is a schematic diagram of a subject's eye for purposes of illustrating the transport of roflumilast in accordance with certain embodiments of the present invention. [Diagram 2]

[0015] FIG. 2 is a flow diagram illustrating the various compartments of the eye and possible routes for ophthalmic delivery of pharmaceutical ingredients. [Diagram 3]

[0016] 3 is a graph showing roflumilast or roflumilast n-oxide concentrations in various components of the eye following administration of a single 25 μL dose of 0.1% w / v roflumilast in healthy Dutch Belted Rabbits. The x-axis is time in hours and the y-axis is the concentration of roflumilast or roflumilast n-oxide (ng / mL). [Figure 4]

[0017] 4 is a graph showing roflumilast concentrations in various components of the eye following administration of a single 25 μL dose of 0.1% w / v roflumilast in healthy Dutch-belted rabbits. The x-axis is time in hours and the y-axis is roflumilast concentration (ng / mL). [Diagram 5]

[0018] 5 is a graph showing roflumilast concentrations in various compartments of the eye following a single 25 μL dose of 0.1% w / v roflumilast suspension in healthy Dutch-belted rabbits. The x-axis is time in hours and the y-axis is roflumilast concentration (ng / mL). [Figure 6]

[0019] 6 is a graph showing the concentration of roflumilast or roflumilast n-oxide in various components of the eye following 5 days of administration of 25 μL doses of 0.1% w / v roflumilast in healthy Dutch-belted rabbits (twice daily (BID) for 4 days and single dose (QD) on day 5). The x-axis is time in hours and the y-axis is the concentration of roflumilast or roflumilast n-oxide (ng / mL). [Figure 7]

[0020] Figure 7 is a graph showing roflumilast concentrations in various components of the eye following 5 days of administration of 25 μL doses of 0.1% w / v roflumilast in healthy Dutch-belted rabbits (twice daily (BID) for 4 days and single dose (QD) on day 5). The x-axis is time in hours and the y-axis is roflumilast concentration (ng / mL). [Figure 8]

[0021] Figure 8 is a graph showing roflumilast concentrations in various components of the eye following 5 days of administration of a 25 μL dose of 0.1% w / v roflumilast suspension (twice daily (BID) for 4 days and a single dose (QD) on day 5) in healthy Dutch-belted rabbits. The x-axis is time in hours and the y-axis is roflumilast concentration (ng / mL). [Figure 9]

[0022] 9 is a graph showing roflumilast concentrations in various components of the eye from tissues harvested within 2.5 hours of the final dose after 3 μL doses of 0.1% w / v roflumilast suspension administered twice daily (BID) for 7 days in a mouse model of inflammatory disease (female Balb / C mice with immune-induced allergic conjunctivitis due to systemic and topical application of ragweed). The x-axis reflects various components of the eye and the y-axis is roflumilast concentration (ng / g or ng / mL). [Figure 10]

[0023] 10 is a graph showing plasma roflumilast concentrations after 5 days of administration (twice daily (BID) for 4 days and a single dose (QD) on day 5) of three different ophthalmic compositions at 40 μL doses of 0.1% w / v roflumilast in healthy Dutch Belted rabbits. The x-axis is time in hours and the y-axis is roflumilast concentration (ng / mL). [Figure 11]

[0024] 11 is a graph showing plasma roflumilast n-oxide concentrations after 5 days of administration of 40 μL doses of three different ophthalmic compositions at 0.1% w / v roflumilast dose (twice daily (BID) for 4 days and a single dose (QD) on day 5) in healthy Dutch Belted rabbits. The x-axis is time in hours and the y-axis is roflumilast n-oxide concentration (ng / mL). [Figure 12]

[0025] 12 is a graph showing conjunctival roflumilast concentrations following 5 days of administration of 40 μL doses of three different ophthalmic compositions at 0.1% w / v roflumilast dose (twice daily (BID) for 4 days and a single dose (QD) on day 5) in healthy Dutch Belted rabbits. The x-axis is time in hours and the y-axis is roflumilast concentration (ng / mL). [Figure 13]

[0026] 13 is a graph showing corneal roflumilast concentrations after 5 days of administration of 40 μL doses of three different ophthalmic compositions at 0.1% w / v roflumilast dose (twice daily (BID) for 4 days and a single dose (QD) on day 5) in healthy Dutch Belted rabbits. The x-axis is time in hours and the y-axis is roflumilast concentration (ng / mL). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015]

[0027] It is to be understood that the present invention is not limited to the specific methodology, protocols, and reagents described herein, which may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which 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.

[0016]

[0028] All publications, patents and patent applications cited in this specification are incorporated herein by reference in their entirety 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 and patent applications that are referenced to describe a particular type of compound, chemical property, etc., the part related to such compound, chemical property, etc. is the document part that is incorporated herein by reference.

[0017]

[0029] 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.

[0018]

[0030] The term "about," when used in connection with a numerical value, is meant 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.

[0019]

[0031] The term "anterior tissue" or "anterior compartment" of the eye refers to ocular tissues or compartments located at the front of the eye, behind the ocular surface, such as the iris-ciliary body, aqueous humor, corneal endothelium, and lens.

[0020]

[0032] The term "effective" refers to an amount of a compound, agent, substance, formulation or composition sufficient to reduce the severity of disease symptoms, increase the frequency and duration of disease symptom-free periods, or prevent impairment or disability due to disease affliction. This amount can be as a single dose or according to a multiple dose regimen, alone or in combination with other compounds, agents or substances. One of ordinary skill in the art will be able to determine such amounts based on factors such as the size of the subject, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0021]

[0033] The term "ocular disorder", "ocular condition", or "ocular disorder" refers to a disease / disease of the eye(s) that may threaten vision, cause ocular discomfort, or indicate a systemic health problem. The term "ocular surface disease" or "ocular surface disorder" refers to any disease / disease that affects the ocular surface sites, such as the pre-cornea and exterior cornea (including the corneal epithelium and corneal stroma), conjunctiva, sclera (non-posterior portion), eyelids, lacrimal and meibomian glands, and interconnecting nerves. The term "anterior segment disease" or "anterior segment disorder" refers to any disease / disease that affects the anterior segments, such as the internal cornea (including the corneal endothelium), aqueous humor, and the anterior surface of the lens.

[0022]

[0034] The term "ocular surface" refers to the surface located at the front of the eye, including the anterior cornea, cornea, conjunctiva, sclera (non-posterior portion), and eyelid tissue.

[0035] "Pharmaceutically acceptable" generally means safe for administration to humans or animals. Preferably, a pharma- ceutically acceptable ingredient is one that has been approved by a federal or state regulatory agency for use in animals, and more particularly in humans, or is listed in the United States Pharmacopeia, published by the United States Pharmacopeial Convention, Inc., Rockville, Md., or other generally recognized pharmacopoeias.

[0023]

[0036] A "pharmaceutical composition" according to the invention can be in the form of a composition in which the various active ingredients and diluents and / or carriers are mixed with one another, or it can take the form of a combined preparation in which the active ingredients are present in a partially or completely separate form. An example of such a combination or combined preparation is a kit-of-parts.

[0024]

[0037] The term "posterior tissues" or "posterior compartment" of the eye refers to ocular tissues or compartments located posterior to the anterior compartment toward the back of the eye, such as the posterior lens, vitreous humor, choroid, RPE, and retina.

[0025]

[0038] The term "roflumilast" as used in this application refers to roflumilast, prodrugs, and salts thereof, unless otherwise specified or unless it is clear from the context that the reference is to roflumilast itself.

[0026]

[0039] 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]

[0040] 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 according to methods established in the art.

[0028]

[0041] As used herein, "treat," "treating," or "treatment" of a disease or disorder means achieving one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the 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 patients who previously had the disorder(s); and (e) limiting or preventing the recurrence of symptoms in patients previously symptomatic for the disorder(s).

[0029]

[0042] The present invention relates to an ophthalmic delivery method of roflumilast.As disclosed herein, the inventors of the present invention have made the surprising discovery that administration of a pharmaceutical composition comprising roflumilast to the cornea results in drug delivery that preferentially moves outwardly through the eye.In contrast to the delivery of roflumilast to the skin, which moves primarily across various tissues of the skin, and many ophthalmic drugs that move across the cornea, the delivery of the present invention to the eye and the cornea moves outwardly toward the ocular surface and anterior tissues.Such a method can provide higher levels of drug to the cornea and ocular surface and anterior tissues compared to the posterior segment.

[0030]

[0043] Roflumilast has the formula (I):

[0031] [ka]

[0032] [In the formula, R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyrid-4-yl] It is a compound of the formula:

[0033]

[0044] 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 Publication No. 5,712,298, which is incorporated herein by reference.

[0034]

[0045] In the present invention, roflumilast is administered to the eye of a patient.The pharmaceutical composition comprising roflumilast can be administered in the form of conventional ophthalmic pharmaceutical preparations, as known to those skilled in the art.For example, the ophthalmic pharmaceutical preparation can be in the form of ophthalmic pharmaceutical suspension or solution.In certain embodiments, the ophthalmic pharmaceutical preparation can be an ointment or other topical delivery to the eye surface.

[0035]

[0046] Roflumilast can be administered to the eye of a patient with an ocular disorder or disease. The methods disclosed herein deliver high levels of roflumilast to the cornea of ​​a patient. Administration using the disclosed methods results in high levels of roflumilast in the cornea, e.g., the cornea, sclera, conjunctiva, iris-ciliary body, and ultimately the aqueous humor of the eye and the patient's lens, compared to the patient's posterior ocular tissues. Furthermore, administration can result in a depot effect in one or more ocular tissues or ocular tissue components, such as the cornea, conjunctiva, iris-ciliary body, sclera, or aqueous humor. The depot effect is characterized by an increase in the concentration of roflumilast in an ocular tissue or component compared to the concentration of roflumilast in an ocular tissue or component at an earlier time period after administration. The methods disclosed herein can achieve therapeutic amounts of roflumilast for a sustained period of time in the ocular surface and anterior compartment, e.g., the cornea, aqueous humor, iris-ciliary body, conjunctiva, and sclera. For example, in certain embodiments, the methods disclosed herein can provide a therapeutic amount for at least 4 hours, at least 8 hours, at least 12 hours, at least 16 hours, at least 20 hours, at least 24 hours, or more.

[0036]

[0047] FIG. 1 is a schematic diagram of the anterior half of a subject's eye for the purpose of illustrating the movement of roflumilast in the eye according to certain embodiments of the present invention. Illustrated in FIG. 1 are the corneal epithelium 101, corneal stroma 102, corneal endothelium 103, conjunctiva 104, aqueous humor 105, pupil 106, iris-ciliary body 107, lens 108, and posterior compartment 109. In certain embodiments, roflumilast is administered onto the corneal surface 110 via an ophthalmic pharmaceutical composition (e.g., a suspension). Administration of an ophthalmic suspension drops the drug onto the ocular surface 110, which allows the drug to move from the ocular surface 110 to the transitional tissue 111 between the ocular surface and the anterior compartment, and then to the anterior compartment 112. That is, after administration of an ophthalmic pharmaceutical composition of roflumilast, the drug moves from 110 to 111 to 112. Without wishing to be bound by theory, the unique lipophilic nature of the compound and the epithelial cornea promotes ocular drug pathways and longer ocular surface residence, preventing more direct passage 110 to 112 through the corneal stroma and corneal endothelium, a pathway used by many other ocular therapeutics. In certain embodiments, the amount of roflumilast that migrates to the posterior segment 113 is limited.

[0037]

[0048] Figure 2 is a flow diagram showing the various compartments of the eye and possible routes of ophthalmic delivery of pharmaceutical ingredients. The various compartments of the eye, including the anterior cornea 201, the conjunctiva 202, the corneal epithelium 203, the anterior sclera 204, the iris-ciliary body 205, the lens 206, the aqueous humor 207, the posterior sclera 208, the choroid 209, the retina 210, the vitreous humor 211, the corneal stroma 212, and the corneal endothelium 213, where topical drugs are instilled, are represented by boxes in the flow diagram. The arrows connecting the boxes indicate possible routes of drug migration. In certain embodiments, the ophthalmic pharmaceutical composition of roflumilast is administered onto the surface of the cornea 201 via an ophthalmic pharmaceutical composition (e.g., a suspension or ointment), as indicated by the thick black arrow. Roflumilast can migrate from the cornea 201 to the conjunctiva 202 and corneal epithelium 203, then migrate laterally to the anterior scleral transition / anterior tissue 204 and iris-ciliary body 205 before migrating further to the anterior compartment and lens 206 and aqueous humor 207, and finally in a reduced volume to the posterior compartment of the patient. In contrast, as shown by the thinner dotted lines, many other ocular therapeutics deliver drugs from the anterior cornea 201 to the corneal epithelium 203, through the corneal stroma 212 and corneal endothelium 213 to the aqueous humor 207, and then to the iris-ciliary body 205 and lens 206. Systemic exposure typically occurs via the aqueous humor 207 and vascular apparatus in either manner. The administration methods disclosed herein can result in favorable pharmacokinetic profiles that allow for the treatment of ocular surface and anterior tissue disorders.

[0038]

[0049] The method of the present invention can be used to treat ocular surface or anterior diseases that do not require invasive techniques but require long-term pharmacological treatment. These are usually treated with existing anti-inflammatory drugs that have various short-term and long-term side effects, especially when used over a long period of time. These ocular surface and anterior diseases include: postoperative inflammation, blurred vision after corneal refractive surgery, dry eye syndrome, evaporative dry eye disease, ocular graft versus host disease, ocular complications of Sjogren's disease, inflammatory dry eye disease, ocular rosacea, allergic conjunctivitis or keratoconjunctivitis, atopic keratoconjunctivitis, phlyctenosis, staphylococcal hypersensitivity, Mooren's ulcer, endotheleitis, vernal keratoconjunctivitis, superior limbus. Keratoconjunctivitis, postoperative penetrating or partial keratoplasty, keratitis, herpetic stromal keratitis / herpetic blepharitis or herpetic keratitis, including conjunctivitis, inflammation associated with varicella zoster, inflammation secondary to other infectious agents, inflammation secondary to chemical burns of the eye, uveitis, including uveitis of juvenile idiopathic arthritis, seborrheic or other forms of blepharitis, corneal epithelial cell deficiency, meibomian gland dysfunction, episcleritis, pingueculitis, and pterygium. Ocular surface or anterior segment disorders treatable by the methods described herein can be acute or chronic.

[0039]

[0050] In certain embodiments, the method is used to treat a patient having an ocular inflammatory disorder, hi certain embodiments, the inflammatory disorder is selected from the group consisting of dry eye, herpetic eye disease, blepharitis, or uveitis.

[0040]

[0051] In the present invention, the patient is administered an ophthalmic pharmaceutical composition. The ophthalmic pharmaceutical composition can include roflumilast as a free base or a pharma- ceutical acceptable salt. Representative 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 ophthalmic pharmaceutical composition can include an active metabolite or prodrug of roflumilast or its salt.

[0041]

[0052] Ophthalmic pharmaceutical compositions can be formulated into such preparations using several methods well known and widely used by those skilled in the art. In certain embodiments, the ophthalmic pharmaceutical composition is administered topically directly to the eye in the form of a suspension, solution, eye drops, eye ointment, gel, spray, or absorbent contact lens. In a preferred embodiment, the pharmaceutical composition is a suspension in which the active ingredient (i.e., roflumilast) is suspended in a pharmaceutical carrier and / or excipient. In certain embodiments, the ophthalmic pharmaceutical composition can include one or more of a buffer, a viscosity agent, a surfactant, a stabilizer, a preservative, a wetting agent, a diluent, a pH adjuster, a tonicity agent, a stabilizer, or an absorption enhancer.

[0042]

[0053] In certain embodiments, the ophthalmic pharmaceutical composition includes roflumilast in an amount that can range from about 0.01% w / v to about 7.5% w / v, or from about 0.01% w / v to about 5% w / v, or from about 0.1% w / v to about 3% w / v. Exemplary ranges are from about 0.01% w / v to about 5% w / v, or from about 0.01% w / v to about 3% w / v, or from about 0.1% w / v to about 3% w / v, or from about 0.3% w / v to about 3.0% w / v. For example, an ophthalmic medication may contain roflumilast in any of the following w / v percentages: 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%, 2.1%, 2.2%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 2.9%, 2.1%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 2.9%, 2.1%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 2.9%, 2.1 ...1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 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.

[0043]

[0054] In certain embodiments, the ophthalmic pharmaceutical composition includes a carbomer, such as carbomer copolymer type A or carbomer copolymer type B, including those marketed under the trade name Carbopol® by Lubrizol®. In certain embodiments, the ophthalmic pharmaceutical composition includes a carboxymethylcellulose or a salt thereof, such as sodium carboxymethylcellulose. In certain embodiments, the ophthalmic pharmaceutical composition includes a methacrylate or ethacrylate derivative, such as those marketed under the trade name Eudragit.

[0044]

[0055] In certain embodiments, the viscosity agent is at least one selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), polyvinylpyrrolidone or povidone, carboxymethylcellulose, hypromellose, methylcellulose, or polyvinyl alcohol (PVA). In certain embodiments, the viscosity agent is dextran or gelatin. In addition, the viscosity agent can include carbomer, for example, carbomer copolymer type A or carbomer copolymer type B, including those marketed under the trade name Carbopol by Lubrizol®. In certain embodiments, the ophthalmic pharmaceutical formulation can include 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 0.5% w / v. For example, the 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%, 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.

[0045]

[0056] 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 can include 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, the ophthalmic medication may contain any of the following w / v percentages of surfactant: 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 7%, 1.8%, 1.9%, 1.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, etc.

[0046]

[0057] In certain embodiments, the buffer is at least one selected from the group consisting of citrate, phosphate, Tris-HCl (Tris), acetate, and borate buffers. In certain embodiments, the ophthalmic pharmaceutical formulation may contain a buffer 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, 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%, 2.10%, 2.12%, 2.14%, 2.16%, 2.18%, 2.19%, 2.26%, 2.28%, 2.29%, 2.30%, 2.31%, 2.32%, 2.33%, 2.34%, 2.35%, 2.36%, 2.37%, 2.38%, 2.39%, 2.40%, 2.41%, 2.42%, 2.43%, 2.44%, 2.45%, 2.46%, 2.47%, 2.48%, 2.49 ... 3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0% etc.

[0047]

[0058] In certain embodiments, the ophthalmic pharmaceutical composition comprises a therapeutically effective amount of roflumilast, a viscosity 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 and 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 15 μm or less.

[0048]

[0059] In certain embodiments, the ophthalmic pharmaceutical composition comprises a therapeutically effective amount of roflumilast, a viscosity agent comprising hydroxyethylcellulose, a surfactant, and a buffer. In certain embodiments, the surfactant is a polysorbate. In certain embodiments, the buffer is a phosphate and 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 15 μm or less.

[0049]

[0060] In certain embodiments, the ophthalmic pharmaceutical composition comprises a therapeutically effective amount of roflumilast, a viscosity agent comprising polyvinylpyrrolidone, a surfactant, and a buffer. In certain embodiments, the surfactant is tyloxapol. In certain embodiments, the buffer is a phosphate and 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 15 μm or less.

[0050]

[0061] In certain embodiments, the ophthalmic pharmaceutical composition comprises a therapeutically effective amount of roflumilast, a viscosity agent comprising carboxymethylcellulose, a surfactant, and a buffer. In certain embodiments, the surfactant is a polysorbate. In certain embodiments, the buffer is a phosphate and 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 15 μm or less.

[0051]

[0062] In certain embodiments, the ophthalmic pharmaceutical formulation is an ointment. The ointment can include an inactive ingredient selected from the group consisting of petrolatum, mineral oil. In such embodiments, the ophthalmic pharmaceutical formulation can include therapeutically effective amounts 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, such as increased contact time and increased concentration of soluble drug in the administration system, which can be important for water-insoluble drugs such as roflumilast.

[0052]

[0063] In a preferred embodiment, the pH of the ophthalmic pharmaceutical composition is about 5.6 to about 8.3, about 6.0 to about 8.0, about 7.0 to about 8.0, about 6.0 to about 6.7, about 6.2 to about 6.7, or about 6.3 to about 6.6. It has been confirmed that roflumilast undergoes hydrolysis in certain ophthalmic pharmaceutical compositions and under certain standard aseptic manufacturing processes. In a specific embodiment, the pH of the ophthalmic pharmaceutical composition is about 6.0 to about 6.7 to reduce the hydrolysis rate of roflumilast. In a preferred embodiment, the pH of the ophthalmic pharmaceutical composition is about 6.2 to about 6.7, more preferably about 6.3 to about 6.6. In a preferred embodiment, the osmolality of the ophthalmic pharmaceutical composition is from about 270 mOsm / kg to about 330 mOsm / kg, more preferably from about 270 mOsm / kg to about 300 mOsm / kg, and even more preferably from 270 mOsm / kg to 280 mOsm / kg.

[0053]

[0064] The ophthalmic pharmaceutical composition can be stable and exhibit a particle size distribution suitable for ophthalmic delivery. The particle size of the 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. The evaluation is performed by passing a laser beam through the sample, which results in the laser light being scattered at a range of angles. A detector positioned at a fixed angle measures the intensity of the light scattered at that location. A mathematical model is then applied to generate the particle size distribution.

[0054]

[0065] In particle size determination, the median is defined as the value above which half of the population lies and below which half lies. In the case of particle size distributions, the median is called the D50. The D50 is the size that divides the distribution in half above and half below this diameter. The width of the distribution can also be characterized by quoting one, two or three values ​​on the x-axis, typically some combination of D10, D50 and D90. As mentioned above, the D50 (i.e. the median) refers to the diameter below which half of the population is smaller. Similarly, 90 percent of the distribution is smaller than the D90 and 10 percent of the population is smaller than the D10.

[0055]

[0066] 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 before 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 15 μm or less.

[0056]

[0067] In certain embodiments, the pharmaceutical composition is administered as a regimen, for example at regular intervals. For example, the pharmaceutical composition can be administered 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. In certain embodiments, the pharmaceutical composition can be administered as part of a maintenance dose or titration dose regimen. The pharmaceutical composition can be administered for a predetermined period of time or indefinitely. 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 disease or disorder is observed. Representative periods for 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. In preferred embodiments, the topical pharmaceutical composition is administered twice or three times a day for a period of at least 3 months, 4 months, 5 months, 6 months, 1 year, etc. In certain embodiments, the representative period for treatment can be indefinite.

[0057]

[0068] The following examples illustrate certain aspects of the invention without, however, limiting them. EXAMPLES

[0058]

[0069] While various embodiments have been described above, it should be understood that they are presented by way of example only, and not limitation. Thus, the breadth and scope of the present disclosure should not be limited by any of the above-described representative embodiments. Moreover, unless otherwise indicated herein or clearly contradicted by context, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure.

[0059]

[0070] Example 1

[0071] Ophthalmic pharmaceutical compositions containing roflumilast were prepared. Two suspension formulations shown in Tables 1 and 2 were prepared.

[0060] [Table 1]

[0061] [Table 2]

[0062]

[0072] Example 2

[0073] A 5-day ophthalmic pharmacokinetic preclinical study was conducted in Dutch-belted rabbits (n=36) in three arms (Cohort 1: n=3, no active treatment; Cohort 2: n=15, 1-day dosing; Cohort 3: n=18, 5-day dosing). The 1-day dosing regimen included a single dose, whereas the 5-day dosing regimen included BID dosing on days 1-4 and a single dose on day 5. Each dose consisted of 25 μL of ophthalmic suspension containing 0.1% roflumilast, applied to both eyes of the subjects. The suspensions shown in Table 2 were used in Example 2. Plasma samples were collected on days 1 and 5. Plasma concentrations and concentrations in other tissues and components of the eye, including the cornea (Cr), aqueous humor (AqH), iris-ciliary body (ICB), lens, retina-choroid plexus (Retina), vitreous humor (Vit) and sclera (Sclr), were analyzed at various time points.

[0063]

[0074] The results of the study in Dutch Belted rabbits are shown in Figures 3-8. Figures 3 and 4 show the concentrations of roflumilast and roflumilast n-oxide in plasma and in various components of the eye on study day 1 after a single dose was administered to the subjects. Figure 3 shows the concentrations of roflumilast or roflumilast n-oxide in plasma, aqueous humor, retina-choroid plexus and vitreous. Figure 4 shows the concentrations of roflumilast in the cornea, iris-ciliary body, sclera and lens (after 1 hour). In both Figures 3 and 4, the x-axis is time in hours and the y-axis is the concentration of roflumilast or roflumilast n-oxide (ng / mL).

[0064]

[0075] Figures 3 and 4 show that the variability of the drug in the cornea over time is large. In the cornea, sclera, iris-ciliary body and aqueous humor, there is an increase in the level of roflumilast after administration, followed by a decrease in the level. Surprisingly, the results show that the drug reaches the ocular surface and anterior eye regions, such as the iris-ciliary body, sclera and aqueous humor. The results further show that the drug moves outwardly in the eye. The Cmax observed for the iris-ciliary body was observed after the Cmax for the sclera. The n-oxide of roflumilast was only observed within the analytical detection limits in the plasma and not in any of the ocular components.

[0065]

[0076] FIG. 5 is a graph showing roflumilast concentrations in the aqueous humor, cornea, iris-ciliary body, and sclera of the eye after a single 25 μL dose of a 0.1% w / v suspension of roflumilast. The x-axis is time in hours, and the y-axis is the concentration of roflumilast (ng / mL). FIG. 5 also illustrates drug levels versus EC50 and IC50 levels for the corresponding drugs and tissues, indicating that the drug is present in therapeutic amounts in various tissues of the eye. One hour after administration, elevated drug levels were observed in the eye components. Surprisingly, a depot effect is observed, with increased drug levels several hours after administration (e.g., 7-8 hours after drug administration) compared to earlier periods. The relative levels of drug in the various eye components illustrated in FIGS. 3-5, including the low levels present in the lens, indicate that the drug is moving outward in the eye rather than directly across the cornea through the aqueous humor to the lens, even on day 1 of the study.

[0066]

[0077] Figures 6 and 7 show the concentrations of roflumilast and roflumilast n-oxide in plasma and various components of the eye (Figure 6 only) on study day 5 after administration of a 25 μL dose of 0.1% w / v roflumilast for 5 days. Figure 6 shows the roflumilast concentrations in the aqueous humor, retina-choroid plexus and vitreous humor. Figure 6 also shows the concentration of roflumilast n-oxide in plasma. Figure 7 shows the roflumilast concentrations in the cornea, iris-ciliary body, sclera and lens (0.5 hours). In both Figures 6 and 7, the x-axis is time in hours and the y-axis is the concentration (ng / mL) of roflumilast or roflumilast n-oxide (Figure 6 only).

[0067]

[0078] Figures 6 and 7 show that the variability of drug over time in the cornea and retina is large. The results show that at time zero on day 5, some components of the eye (e.g., cornea and sclera) have non-zero drug levels. This observation shows that in these components of the eye, drug from the previous day's drug administration is still present. Furthermore, this observation shows that a depot effect is observed in the cornea with the administration of roflumilast to the eye after only a few days of use. Again, surprisingly, the results show that the drug reaches the ocular surface and anterior eye tissues, such as the cornea, iris-ciliary body, sclera and aqueous humor. Furthermore, the results show that the exposure of drug from the previous day's drug administration is still seen in the ocular surface and anterior eye. For example, the concentration level in the cornea also shows that a steady state of drug exists after 5 days of administration.

[0068]

[0079] FIG. 8 is a graph showing roflumilast concentrations in the aqueous humor, cornea, iris-ciliary body, and sclera of the eye after 5 days of administration of a 25 μL dose of a 0.1% w / v suspension of roflumilast. The x-axis is time in hours and the y-axis is the concentration of roflumilast (ng / mL). FIG. 8 also illustrates drug levels relative to the EC50 and IC50 levels of the drug for the target tissue, which shows that the drug is present in therapeutic amounts in various tissues of the eye. Concentration levels in various components of the eye show that the drug concentration reached a steady state after 5 days of administration. The relative levels of drug in various components of the eye shown in FIGS. 6-8, including low levels present in the lens, show that the drug is moving outward in the eye at therapeutically relevant levels, as presented in FIG. 2.

[0069]

[0080] Example 3

[0081] A 7-day ocular preclinical and pharmacokinetic study was conducted in mice. Ophthalmic suspensions containing 0.1% roflumilast were applied twice daily for 7 days to both eyes of 10 subjects as test substances for the treatment of immune-mediated allergic conjunctivitis models initiated by both systemic and local sensitization with ragweed. The suspensions shown in Table 2 were used in Example 3. Immediately after the last clinical intervention and final observation (30 minutes after the last dose), the animals were euthanized and both eyes were enucleated with the optic nerve attached (OU). The cornea, lens, conjunctiva and eye cup from the right eye (OD) were harvested, weighed and flash frozen for bioanalysis. Immediately after euthanasia, K was administered via cardiac puncture. 2 Up to 1 mL of whole blood was collected in EDTA tubes, kept on ice, and then processed within 30 minutes to obtain plasma by removing the supernatant after centrifugation at 3000×g. All samples were collected and prepared approximately 2.5 hours after the last dose administration in the study. Roflumilast was detectable (lower limit of quantification (LLOQ)=0.025 ng / mL) in plasma and tissue samples from animals treated with 0.1% roflumilast in ophthalmic suspension (mean=1.5 ng / mL).

[0070]

[0082] The results of the study are shown in Figure 9. Figure 9 shows the average concentration of roflumilast in plasma and various ocular components on the seventh day of the study, after the second of the seven days of twice-daily administration. Figure 9 shows that the levels of roflumilast are elevated in the cornea and conjunctiva after administration. Surprisingly, the results show that the drug reaches the ocular surface and anterior eye regions, such as the cornea, and this result was confirmed in a second species. Without being bound by theory, in this model of active disease rather than healthy rabbit studies, the additional permeability of ocular tissues may allow higher ocular concentrations in anterior tissues such as the lens (adapted for the anatomy and pharmacokinetic properties of the species). Scholz et al., “Pilocarpine permeability across ocular tissues and cell cultures: influence of formulation parameters,” J Ocul Pharmacol Ther. 2002 Oct.;18(5):455-68; Kannan et al., “Impairment of conjunctival glutathione secretion and ion transport by oxidative stress in an adenovirus type 5 ocular infection model of pigmented rabbits,” Free Radic Biol Med. 2004 Jul. 15; 37(2):229-38.

[0071]

[0083] Example 4

[0084] Further pharmaceutical compositions containing roflumilast suitable for use in the disclosed methods have been prepared. The ophthalmic pharmaceutical compositions containing roflumilast described in Tables 3, 4, 5, 6 and 7 have been prepared.

[0072] [Table 3]

[0073] [Table 4]

[0074] [Table 5]

[0075] [Table 6]

[0076] [Table 7]

[0077]

[0085] Example 5

[0086] A 5-day ophthalmic preclinical pharmacokinetic study was conducted in healthy Dutch-belted rabbits in three different groups (group 1: n=21, formulation in Table 7; group 2: n=21, formulation in Table 5; and group 3: n=21, formulation in Table 3). Each group received 40 μL of the ophthalmic suspension or ointment described in Table 7 (group 1), Table 5 (group 2), or Table 3 (group 3) BID for 4 days and QD on day 5. Plasma concentrations of roflumilast and roflumilast n-oxide were measured at regular intervals after the final dose. Additionally, concentrations of roflumilast in the cornea and conjunctiva were measured at various time points after the final dose.

[0078]

[0087] The results of the study in Dutch Belted rabbits are shown in Figures 10-13. Figures 10 and 11 show the concentrations of roflumilast and roflumilast n-oxide in plasma after 4 days of BID administration and 5 days of QD administration. Figure 10 shows the plasma roflumilast concentrations 0, 0.5, 1, 2, 4, 8 and 24 hours after the final administration of each group. Figure 11 shows the plasma roflumilast n-oxide concentrations 0, 0.5, 1, 2, 4, 8 and 24 hours after the final administration of each group. Figure 12 shows the conjunctival roflumilast concentrations 0, 0.5, 1, 2, 4, 8 and 24 hours after the final administration of each group. Figure 13 shows the corneal roflumilast concentrations 0, 0.5, 1, 2, 4, 8 and 24 hours after the final administration of each group. In Figures 10-13, the x-axis is time in hours and the y-axis is the concentration of roflumilast or roflumilast n-oxide (ng / mL). Figures 10-13 show that these additional formulations resulted in elevated levels of roflumilast in the cornea and conjunctiva after administration. Again, surprisingly, the results show that the drug is reaching the ocular surface and anterior eye regions, such as the cornea and conjunctiva, at therapeutic levels.

[0079]

[0088] Figure 10 is a graph showing plasma roflumilast concentrations after administration of 40 μL doses of three separate formulations of 0.1% w / v roflumilast for 5 days, administered twice daily (BID) for 4 days, followed by a single dose on day 5. The x-axis is time in hours and the y-axis is the concentration of roflumilast (ng / mL). Plasma concentration levels indicate a decline in plasma drug concentration after the final dose, and times for which no data are shown were BLQ.

[0080]

[0089] Figure 11 is a graph showing plasma roflumilast n-oxide concentrations after administration of 40 μL doses of three separate formulations of 0.1% w / v roflumilast for 5 days, administered twice daily (BID) for 4 days, followed by a single dose on day 5. The x-axis is time in hours and the y-axis is the concentration of roflumilast (ng / mL). Plasma concentration levels indicate a decline in plasma drug concentration after the final dose, and times for which no data are shown were BLQ.

[0081]

[0090] FIG. 12 is a graph showing conjunctival roflumilast concentrations after 5 days of administration of 40 μL doses of three separate formulations of 0.1% w / v roflumilast, administered twice daily (BID) for 4 days followed by a single dose on day 5. The x-axis is time in hours and the y-axis is roflumilast concentration (ng / mL). Each time point reflects n=6 eyes. Conjunctival concentration levels show that steady-state drug concentrations were reached at >5 ng / g at 0 hours prior to administration for the formulations in Tables 3 and 5 and >90 ng / g for the formulations in Table 7, and remained steady over 24 hours. The larger surface area of ​​the conjunctiva and its heterogeneity may contribute to the accumulation of suspended particles on the ocular surface.

[0082]

[0091] FIG. 13 is a graph showing corneal roflumilast concentrations after 5 days of administration of 40 μL doses of three separate formulations of 0.1% w / v roflumilast, administered twice daily (BID) for 4 days followed by a single dose on day 5. The x-axis is time in hours and the y-axis is concentration of roflumilast (ng / mL). Each time point reflects n=6 eyes. Corneal concentration levels show that formulations in Tables 3, 5 and 7 reached steady-state drug concentrations at well above 35 ng / g at 0 hours prior to administration and remained steady and high over 24 hours.

[0083]

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

[0084] 101 Corneal epithelium 102 Corneal stroma 103 Corneal endothelium 104 Conjunctiva 105 Aqueous humor 106 Pupil 107 Iris-Ciliary Body 108 Crystalline Lens 109 Rear compartment 110 Ocular surface 111 Transition organization 112 Front Section 113 Posterior segment 201 Anterior cornea 202 Conjunctiva 203 Corneal epithelium 204 Anterior Sclera 205 Iris-Ciliary Body 206 Crystalline Lens 207 Aqueous humor 208 Posterior Sclera 209 Choroid 210 Retina 211 Vitreous humor 212 Corneal stroma 213 Corneal endothelium

Claims

1. 1. An ophthalmic pharmaceutical composition comprising a therapeutically effective amount of roflumilast or a pharma- ceutical acceptable salt thereof for use in a method for treating a patient having an inflammatory disorder of the ocular surface or anterior ocular tissue, the method comprising administering the ophthalmic pharmaceutical composition to the cornea of ​​the patient; The ophthalmic pharmaceutical composition, wherein the composition delivers roflumilast to the cornea of ​​the patient such that roflumilast migrates laterally through the ocular surface and anterior ocular tissues following delivery.

2. The ophthalmic pharmaceutical composition of claim 1 which is a suspension.

3. 2. The ophthalmic pharmaceutical composition of claim 1, wherein said administration results in a higher level of roflumilast in the cornea of ​​the patient's eye compared to the lens of the patient's eye.

4. 2. The ophthalmic pharmaceutical composition of claim 1, wherein said administration results in higher levels of roflumilast in the cornea, sclera, iris-ciliary body, conjunctiva and aqueous humor of the patient's eye compared to posterior segment tissues of the patient.

5. The ophthalmic pharmaceutical composition of claim 1, wherein the administration produces a depot effect characterized by an increased corneal roflumilast concentration in the patient's cornea compared to the corneal roflumilast concentration at an earlier time point after administration.

6. The ophthalmic pharmaceutical composition of claim 1, wherein the administration produces a depot effect characterized by an increased concentration of roflumilast in the iris-ciliary body of the patient compared to the concentration of roflumilast in the iris-ciliary body at an earlier time point after administration.

7. The ophthalmic pharmaceutical composition of claim 1, wherein the administration produces a depot effect characterized by an increased scleral roflumilast concentration in the patient's sclera compared to the scleral roflumilast concentration at an earlier time point after administration.

8. 1. An ophthalmic pharmaceutical composition comprising a therapeutically effective amount of roflumilast or a pharma- ceutical acceptable salt thereof for use in a method for treating a patient having an inflammatory disorder of the ocular surface or anterior ocular tissue, the method comprising administering the ophthalmic pharmaceutical composition to the cornea of ​​the patient; The ophthalmic pharmaceutical composition, wherein the composition delivers a higher level of roflumilast to the ocular surface or anterior segment of the patient compared to the posterior segment of the patient's eye.

9. The ophthalmic pharmaceutical composition of claim 8 which is a suspension.

10. The ophthalmic pharmaceutical composition of claim 8 , wherein the ocular surface or anterior segment is the cornea.

11. The ophthalmic pharmaceutical composition according to claim 8 , wherein the ocular surface or anterior segment is the sclera.

12. The ophthalmic pharmaceutical composition according to claim 8, wherein the ocular surface or anterior segment is the iris-ciliary body.

13. The ophthalmic pharmaceutical composition of claim 8 , wherein the ocular surface or anterior segment is aqueous humor.

14. The ophthalmic pharmaceutical composition according to claim 8 , wherein the ocular surface or anterior segment is the conjunctiva.

15. The ophthalmic pharmaceutical composition of claim 10, wherein the administration produces a depot effect characterized by an increased corneal roflumilast concentration in the patient's cornea compared to the corneal roflumilast concentration at an earlier time point after administration.

16. The ophthalmic pharmaceutical composition of claim 12, wherein the administration produces a depot effect characterized by an increased concentration of roflumilast in the iris-ciliary body of the patient compared to the concentration of roflumilast in the iris-ciliary body at an earlier time point after administration.

17. The ophthalmic pharmaceutical composition of claim 11, wherein the administration produces a depot effect in the patient's sclera characterized by an increased scleral roflumilast concentration compared to the scleral roflumilast concentration at an earlier time point after administration.

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