Topical roflumilast for the treatment of atopic dermatitis / seborrheic dermatitis

Abstract

A method of treating a patient's skin condition or disease, including psoriasis, atopic dermatitis, and seborrheic dermatitis, by topically applying a pharmaceutical composition containing roflumilast to the patient. This method rapidly (e.g., within 24 or 48 hours) relieves itching experienced by the patient, such as itching as measured by the Most Severe Itching Digital Rating Scale (WI-NRS). The method may also reduce itching by 4 or more points as measured by the WI-NRS.

Description

Cross-reference to related applications

[0001] This application claims the benefits of U.S. Provisional Application No. 63 / 538,667, filed September 15, 2023, and U.S. Provisional Application No. 63 / 543,858, filed October 12, 2023, the disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0002] The subject matter disclosed herein generally relates to methods for treating a patient’s skin condition or disease by topically applying a pharmaceutical composition containing roflumilast to the patient. These methods can rapidly (e.g., within 24 or 48 hours) relieve itching experienced by the patient, such as itching as measured by the Most Severe Itching Number Rating Scale (WI-NRS). Background Technology

[0003] Roflumilast is a phosphodiesterase (PDE) type 4 inhibitor. Oral compositions of roflumilast are currently marketed under the brand names Daliresp® (in the US) and Daxas® (in Europe). Oral compositions of roflumilast are indicated for the treatment of patients with severe chronic obstructive pulmonary disease (COPD) with a history of chronic bronchitis and exacerbations, to reduce the risk of COPD exacerbations. Topical compositions of roflumilast are currently marketed under the brand name Zoryve®. Topical compositions of roflumilast are indicated for the treatment of plaque psoriasis, including erosion sites. Summary of the Invention

[0004] This invention relates to a method of treating a patient's skin condition or disease by topically applying a pharmaceutical composition containing roflumilast to the patient. The method includes applying the pharmaceutical composition containing roflumilast to the patient. In some embodiments, the patient is suffering from a skin condition or disease selected from the group consisting of psoriasis, atopic dermatitis, and seborrheic dermatitis. The method can rapidly (e.g., within 24 or 48 hours) relieve itching experienced by the patient, such as itching as measured by the Most Severe Pruritus Digital Rating Scale (WI-NRS).

[0005] In some embodiments, a method for treating a patient's skin condition or disease is provided. In some embodiments, the method is used to treat psoriasis, atopic dermatitis, or seborrheic dermatitis. In some embodiments, the method includes topically applying a pharmaceutical composition containing roflumilast to a patient. In some embodiments, the method rapidly (e.g., within 24 or 48 hours) relieves itching experienced by the patient, such as itching as measured by the Most Severe Pruritus Digital Rating Scale (WI-NRS). In some embodiments, the pharmaceutical composition containing roflumilast relieves itching 24 hours after topical application in a patient with atopic dermatitis. In some embodiments, topical application of the roflumilast composition reduces the severity of itching. In some embodiments, topical application of the roflumilast composition reduces the distress caused by itching.

[0006] In some embodiments, a method is provided to relieve itching in a patient suffering from a skin condition or disease. The method comprises topically applying a pharmaceutical composition containing roflumilast to the patient. The method rapidly and significantly relieves itching in the patient. In some embodiments, the method relieves itching in the patient within 24 hours or less following topical application of the roflumilast-containing pharmaceutical composition. The method reduces itching by 1 or more points, 2 or more points, 3 or more points, 4 or more points, 5 or more points, or 6 or more points as measured by WI-NRS. In some embodiments, the method reduces itching by 4 or more points as measured by WI-NRS within four weeks following application of the roflumilast-containing pharmaceutical composition. In some embodiments, the method reduces itching by 4 or more points as measured by WI-NRS within four weeks following once-daily application of the roflumilast-containing pharmaceutical composition.

[0007] In some embodiments, a method is provided to relieve itching in patients aged 2 to 5 years who suffer from skin conditions or disorders. The method comprises topically applying a pharmaceutical composition containing roflumilast to the patient. The method rapidly and significantly relieves itching in the patient. In some embodiments, the method relieves itching in the patient within 24 hours or less following topical application of the roflumilast-containing pharmaceutical composition. The method reduces itching by 1 or more points, 2 or more points, 3 or more points, 4 or more points, 5 or more points, or 6 or more points as measured by WI-NRS. In some embodiments, the method reduces itching by 4 or more points as measured by WI-NRS within four weeks following application of the roflumilast-containing pharmaceutical composition. In some embodiments, the method reduces itching by 4 or more points as measured by WI-NRS within four weeks following once-daily application of the roflumilast-containing pharmaceutical composition. Attached Figure Description

[0008] The accompanying drawings, which are incorporated herein and constitute a part of this disclosure, help to illustrate various embodiments of the invention and, together with this specification, further serve to describe the invention so that those skilled in the art can make and use the embodiments disclosed herein. Error bars in the figures represent standard deviation values.

[0009] Figure 1 Line graphs showing the mean daily WI-NRS score over time for the two treatment groups (0.15% roflumilast cream versus mediator) in Study 1 as described in Example 6 are provided.

[0010] Figure 2 Line graphs showing the mean daily WI-NRS score over time for the two treatment groups (0.15% roflumilast cream versus mediator) in Study 2 as described in Example 6 are provided.

[0011] Figure 3 Line graphs showing the percentage change in daily WI-NRS over time relative to baseline for the two treatment groups (0.15% roflumilast cream versus mediator) in Study 1 as described in Example 6 are provided.

[0012] Figure 4 Line graphs showing the percentage change in daily WI-NRS over time relative to baseline for the two treatment groups (0.15% roflumilast cream versus mediator) in Study 2 as described in Example 6 are provided.

[0013] Figure 5 A line graph showing the average change of WI-NRS scores relative to baseline in Study 1, as described in Example 6, is provided.

[0014] Figure 6 A line graph showing the average change of WI-NRS scores relative to baseline in Study 2, as described in Example 6, is provided.

[0015] Figure 7 A line graph showing the mean daily WI-NRS score over time for the treatment group (0.05% roflumilast cream as a contrast medium) as described in Example 7 is provided.

[0016] Figure 8 Line graphs showing the percentage change in daily WI-NRS over time relative to baseline for the two treatment groups (0.05% roflumilast cream as a contrast medium) as described in Example 7 are provided.

[0017] Figure 9 A line graph showing the mean change in WI-NRS scores over time relative to baseline for the treatment group (0.05% roflumilast cream contrast agent) as described in Example 7 is provided.

[0018] Figure 10This study shows the proportion of patients aged ≥12 years with a baseline Most Severe Pruritus Numerical Rating Scale (WI-NRS) score ≥4 who improved their WI-NRS score by ≥4 points over time relative to their trial baseline, including patients treated once daily and those treated twice weekly. Detailed Implementation

[0019] Before describing the invention in detail below, it should be understood that the invention is not limited to the specific methods, schemes, and reagents described herein, as these methods, schemes, and reagents may vary. It should also 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 invention, which is defined 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 pertains.

[0020] Note that, unless explicitly indicated otherwise by the context, the singular forms “a / an” and “the” as used herein include plural indicators. Thus, for example, “active ingredient” includes a single ingredient and two or more different ingredients.

[0021] When used with numerical values, the term "about" is intended to cover values ​​that are 5% smaller than the indicated value at the lower limit and 5% larger than the indicated value at the upper limit.

[0022] The term "effective" means that the amount of a compound, agent, substance, formulation, or composition is sufficient to reduce the severity of disease symptoms, increase the frequency and duration of asymptomatic periods of disease, or prevent damage or disability caused by disease. The amount may be a single dose, or, according to a multiple-dose regimen, used alone or in combination with other compounds, agents, or substances.

[0023] The term "pharmaceuticalally acceptable" means that it is generally safe for use in humans or animals. Preferably, a pharmaceutically acceptable component is a component approved by a federal or state regulatory agency or listed in the United States Pharmacopeia (published by the United States Pharmacopeia Commission, Inc. (Rockville Md.)) or other recognized pharmacopoeia for use in animals and more specifically in humans.

[0024] The "pharmaceutical composition" according to the invention can exist in the form of a composition in which different active ingredients and diluents and / or carriers are mixed together, or it can exist in the form of a combination formulation in which the active ingredients are present in some or completely different forms. An example of such a combination or combination formulation is a kit-of-parts.

[0025] As used in this application, the term "roflumilast" refers to roflumilast and its salts, unless otherwise specified, or unless the context clearly indicates that it refers to roflumilast itself.

[0026] As used herein, the term "subject" or "patient" preferably refers to a human being. The term "subject" or "patient" can include any mammal that may benefit from the compounds described herein.

[0027] A "therapeutic dose" or "therapeutic effective dose" is the amount of a therapeutic agent sufficient to achieve the intended purpose. The effective dose of a given therapeutic agent can vary depending on factors such as the nature of the agent, the route of administration, the body size of the subject receiving the agent, and the purpose of administration.

[0028] For the purpose of administering a drug or composition, the term "topical" means the application of such a drug or composition to an epithelial surface outside the body, including the skin or cornea. For the purpose of such administration, local delivery to the mucous membrane surface of a body opening (such as the mouth, vagina, or rectum) is considered a local administration.

[0029] As used herein, “treat,” “treating,” or “treatment” for a disease or symptom means achieving one or more of the following: (a) reducing the severity and / or duration of the symptom; (b) limiting or preventing the development of characteristic symptoms of the treated symptom; (c) suppressing the worsening of characteristic symptoms of the treated symptom; (d) limiting or preventing the recurrence of the symptom in a patient who previously had the symptom; and (e) limiting or preventing the recurrence of symptoms in a patient who previously had symptoms of the symptom.

[0030] The abbreviation "w / v" indicates the relative concentration of each component in the composition, expressed as "weight-to-volume ratio".

[0031] The abbreviation "w / w" indicates the relative concentration of each component in a composition, expressed as "weight to weight" (i.e., percentage refers to the percentage of the total weight), rather than based on volume or other quantities.

[0032] This invention relates to a method of treating a patient by administering a pharmaceutical composition of roflumilast to the patient. In some embodiments, the method includes topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a phosphodiesterase-4 inhibitor, roflumilast, or a pharmaceutically acceptable salt thereof.

[0033] Roflumilast is a compound of formula (I): Wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyridin-4-yl.

[0034] The chemical name of roflumilast is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide. Roflumilast and its synthesis are described in U.S. Patent No. 5,712,298, which is incorporated herein by reference. Pharmaceutical compositions described herein may include roflumilast in the form of a free base or a pharmaceutically acceptable salt. Exemplary salts of roflumilast are those described in paragraphs

[0012] and

[0013] of U.S. Patent Application Publication No. US 2006 / 0084684, the disclosure of which is incorporated herein by reference.

[0035] Methods to relieve itching In some embodiments, a method for treating a patient's skin condition or disease is provided. The method includes topical application of a pharmaceutical composition containing roflumilast to the patient. The method can rapidly (e.g., within 24 or 48 hours) relieve itching experienced by the patient, such as itching measured by the Most Severe Pruritus Digital Rating Scale (WI-NRS).

[0036] The WI-NRS is a simple, single-item index used to assess the severity of the most intense itch a patient has reported over the past 24 hours. See, for example, Newton 2019. The WI-NRS is determined by a daily assessment of the most severe itch recorded by the subject over the past 24 hours. The scale ranges from 0 to 10 ("no itch" to "most severe itch imaginable" or "most severe itch imaginable"). Patients are asked to "circle the number that best describes the severity of your itch over the past 24 hours." If the patient is a pediatrician, the WI-NRS score can be determined by the patient's parent / caregiver.

[0037] In some implementations, the patient has scalp psoriasis and the method can rapidly (e.g., within 24 or 48 hours) relieve the patient's experienced scalp itching, such as that measured by the Scalp Itching Digital Rating Scale (SI-NRS). The SI-NRS is assessed in a similar manner to the WI-NRS (as discussed above), but it is used to assess scalp itching.

[0038] In some embodiments, a method is provided to relieve itching in a patient suffering from a skin condition or disease. In some embodiments, the method is used to treat itching in a patient suffering from psoriasis, atopic dermatitis, or seborrheic dermatitis. The method includes topically applying a pharmaceutical composition containing roflumilast to the patient. The method can rapidly and significantly relieve itching in the patient. In some embodiments, the method relieves the patient's itching for less than or equal to 24 hours after topically applying the pharmaceutical composition containing roflumilast. In some embodiments, the method relieves the patient's itching for less than or equal to 48 hours after topically applying the pharmaceutical composition containing roflumilast. The method can reduce pruritus by 1 or more points, 2 or more points, 3 or more points, 4 or more points, 5 or more points, or 6 or more points as measured by WI-NRS. In some embodiments, the method reduces pruritus by 4 or more points as measured by WI-NRS within 24 hours after applying the pharmaceutical composition containing roflumilast. In some embodiments, the method reduces pruritus by 4 or more points as measured by WI-NRS within 48 hours after application of the roflumilast-containing pharmaceutical composition. In some embodiments, the method reduces pruritus by 4 or more points as measured by WI-NRS within one week after once-daily application of the roflumilast-containing pharmaceutical composition. In some embodiments, the method reduces pruritus by 4 or more points as measured by WI-NRS within two weeks after once-daily application of the roflumilast-containing pharmaceutical composition. In some embodiments, the method reduces pruritus by 4 or more points as measured by WI-NRS within four weeks after once-daily application of the roflumilast-containing pharmaceutical composition.

[0039] In some implementations, the patient is a patient with atopic dermatitis. Patients may be selected based on a diagnosis of mild to moderate atopic dermatitis according to the criteria of Hanifin and Rajka (1980). In some implementations, subjects are selected based on having at least three of the following four basic characteristics: (1) pruritus; (2) typical morphology and distribution (flexural lichenification in adults and facial and extensor lesions in infants and children); (3) chronic or chronically relapsing dermatitis; or (4) a personal or family history of atopic dermatitis. In some implementations, the patient has a history of atopic dermatitis for at least 3 months in patients aged 6–17 years, or for at least 6 months in patients aged 18 years and older. In some implementations, the patient is a patient aged 2 to 5 years. In some implementations, the patient has an Eczema Area and Severity Index (EASI) score of 5 or greater at baseline. The EASI assesses the whole body except for the scalp, palms, and soles. In some implementations, patients are rated as mild (2) or moderate (3) on the Validated Investigator Global Assessment Scale for Atopic Dermatitis (vIGA-AD) at baseline. vIGA-AD assesses the whole body except for the scalp, palms, and soles.

[0040] Dosing regimen In some embodiments, the pharmaceutical composition is administered in the form of a course of treatment, such as at fixed intervals. For example, the pharmaceutical composition may be administered once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, three times weekly, or four times weekly, once weekly, or as needed (if necessary or with a PRN). The pharmaceutical composition may be administered for a prescribed period of time. For example, the pharmaceutical composition may be administered for approximately two days or longer, or until improvement in the symptom or disease is observed. Exemplary treatment periods include: one week, two weeks, three weeks, one month, six weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, or two years. The pharmaceutical composition may be administered topically as continuous treatment without a termination time.

[0041] In some embodiments, the method includes sequentially administering multiple doses of a roflumilast-containing pharmaceutical composition to a patient. In some embodiments, the method includes: sequentially administering an initial dose of a roflumilast-containing pharmaceutical composition to a patient at a first time interval, followed by administering one or more maintenance doses of a roflumilast-containing pharmaceutical composition at a second time interval. In some embodiments, the first time interval is once daily. In some embodiments, the second time interval is twice weekly. In some embodiments, roflumilast is applied topically once daily until symptoms of a skin condition or disease improve, then the patient switches to a maintenance dosing regimen of twice weekly. In some embodiments, roflumilast is applied topically once daily until the patient is free of signs or symptoms of a skin condition or disease, then the patient switches to a maintenance dosing regimen of twice weekly.

[0042] In some embodiments, the patient is treated by topical application of the roflumilast drug composition once daily for a period of time. In some embodiments, this period may be one, two, three, four, five, six, seven, eight weeks, or longer. In some embodiments, the patient is treated with the roflumilast drug composition once daily for four weeks. Then, the patient is treated with the roflumilast drug composition twice weekly (BIW) as a maintenance dosing regimen. In some embodiments, the patient is treated by topical application of the roflumilast drug composition once daily for four weeks. Thereafter, roflumilast is administered twice weekly as long as the patient does not experience a recurrence or worsening of symptoms.

[0043] In some implementations, maintenance dosing regimens are given to patients for one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, three months, four months, five months, six months, seven months, eight months, nine months, ten months, up to one year or longer. In some implementations, the drug composition can be administered topically as continuous treatment without a termination time. During treatment, the physician may also adjust the dosing frequency based on the individual patient's needs after clinical examination. For example, a patient may switch from twice-weekly to once-daily dosing after a period of time, and then revert to twice-weekly dosing.

[0044] In some embodiments, the patient is treated with a topical application of the roflumilast composition once daily until the patient's disease is controlled. In some embodiments, the patient's disease is controlled when the patient no longer exhibits disease symptoms. The roflumilast composition is then administered to the patient twice weekly as a maintenance regimen. In some embodiments, the maintenance dose of the roflumilast drug composition maintains the patient's disease state (or disease-free state).

[0045] In some embodiments, the topical roflumilast drug composition is administered to the patient once daily until the patient's Validated Investigator Global Assessment Scale for Atopic Dermatitis (vIGA-AD) score reaches zero. After the patient's vIGA-AD score reaches zero, the roflumilast drug composition is then administered to the patient twice weekly as a maintenance dosing regimen. In some embodiments, maintenance dosing maintains the patient's vIGA-AD score, where the vIGA-AD score is zero or one. In some embodiments, maintenance dosing improves the patient's vIGA-AD score.

[0046] vIGA-AD is a static qualitative assessment of the overall severity of AD. This overall assessment scale is an ordinal scale with five severity levels (reported only as integers from 0 to 4). Each level is defined by a unique and clinically significant morphological description to minimize inter-observer variability (see Table 1). vIGA-AD assesses the entire body, excluding the scalp, palms, and soles.

[0047] Table 1. vIGA-AD score.

[0048] In some implementations, a two-stage dosing regimen can improve and maintain efficacy during administration. In some implementations, a two-stage dosing regimen can improve the vIGA-AD score by 2 grades from baseline. The two-stage dosing regimen described herein offers greater convenience to patients because it requires less frequent administration compared to previous daily dosing regimens, while still controlling the disease. The ability to maintain a twice-weekly dosing regimen for an extended period while controlling the disease, despite low systemic exposure (sometimes below the limit of quantitation), is surprising and unexpected.

[0049] Skin diseases and disorders The composition can be used in veterinary and human medicine for the treatment and prevention of skin conditions and disorders, including but not limited to proliferative, inflammatory, and allergic skin diseases such as psoriasis, scalp psoriasis or inverse psoriasis, irritant and allergic contact eczema, hand eczema, atopic dermatitis, seborrheic dermatitis, lichen simplex, sunburn, aphthous ulcers, lichen planus, vitiligo, lichen sclerosus (especially of the female genitalia), pruritus of the genital or anal area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, folliculitis and extensive pyoderma, endogenous and exogenous acne, rosacea, pruritus of unknown origin, and paresthesia. In some embodiments, the method is used to treat proliferative, inflammatory, and allergic skin diseases such as psoriasis vulgaris, eczema, acne, lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, and pyoderma. In a preferred embodiment, the method is used to treat psoriasis, atopic dermatitis, or seborrheic dermatitis. In some embodiments, the method is used to treat nodular prurigo, pigmented prurigo, or neurogenic exfoliative dermatitis.

[0050] In some embodiments, a method of treating a patient suffering from a persistent inflammatory epidermal disease is provided. The method includes topical application to the patient of a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In some embodiments, the persistent inflammatory epidermal disease is a cell dynamics and differentiation disorder. In some embodiments, the persistent inflammatory epidermal disease is selected from the group consisting of: pityriasis rubra pilaris, pityriasis rosea, pityriasis lichenoides, paresthesia, lichen planus, lichen luster, chronic simple lichen, persistent lentigines hyperkeratosis (Flegel's disease), palmoplantar hereditary hyperkeratosis, granuloma annulare, Sweet's syndrome, pyoderma gangrenosa, and urticaria, including chronic idiopathic urticaria, physical urticaria, and other forms of acquired urticaria.

[0051] In some embodiments, a method is provided for treating a patient suffering from a persistent inflammatory epidermal condition, wherein the condition is a reactive alteration condition. In some embodiments, the persistent inflammatory epidermal condition is selected from the group consisting of: perioral dermatitis, allergic contact dermatitis, irritant contact dermatitis, chafing, nummular eczematous dermatitis, pompholyx, hand eczema, and vesicular palmoplantar eczema.

[0052] In some embodiments, a method is provided for treating a patient suffering from a lip, oral, or vaginal mucosal condition. The method includes topical application to the patient of a pharmaceutical composition containing a therapeutically effective amount of roflumilast. In some embodiments, the lip, oral, or vaginal mucosal condition is selected from the group consisting of: actinic cheilitis, aphthous ulcers, vulvar aphthous ulcers, oral lichen planus, geographic tongue, lichen sclerosus (particularly lichen sclerosus of the female genitalia), pruritus gynecomastia, Behcet's disease, and linear IgA.

[0053] In some embodiments, a method for treating a patient suffering from epidermal adhesion disease is provided. The method includes topically applying a pharmaceutical composition containing a therapeutically effective amount of roflumilast to the patient. In some embodiments, epidermal adhesion disease is a bullous disease selected from the group consisting of: erythema multiforme, pemphigus, bullous pemphigoid, linear IgA dermatitis, herpes gestationis, dermatitis herpetiformis, Hailey-Hailey disease, palmoplantar pustular psoriasis, herpes simplex virus I and II, herpetic eczema, acquired epidermolysis bullosa, Behcet's disease, and Darier's disease.

[0054] In some embodiments, a method for treating a patient suffering from a condition of epidermal appendages is provided. The method includes topically applying to the patient a pharmaceutical composition containing a therapeutically effective amount of roflumilast. In some embodiments, the condition of epidermal appendages is selected from the group consisting of: acne vulgaris, fibrous alopecia on the forehead, alopecia areata, rosacea, and hidradenitis suppurativa.

[0055] In some embodiments, a method is provided for treating a patient suffering from hypopigmentation or hypermelanosis. The method includes topically applying a pharmaceutical composition containing a therapeutically effective amount of roflumilast to the patient. In some embodiments, hypopigmentation or hypermelanosis is vitiligo, pigmentary abnormalities, pityriasis alba, post-inflammatory hypopigmentation, or post-inflammatory hyperpigmentation.

[0056] In some embodiments, a method of treating a patient with cutaneous T-cell or B-cell lymphoma is provided. The method includes topical application to the patient of a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In some embodiments, the cutaneous lymphoma is selected from the group consisting of: lymphomatous papulosis, cutaneous T-cell lymphoma (CTCL), and non-mycosis fungoides cutaneous T-cell or B-cell lymphoma.

[0057] In some embodiments, a method is provided for treating a patient suffering from cutaneous manifestations of rheumatic diseases. The method includes topically applying a pharmaceutical composition containing a therapeutically effective amount of roflumilast to the patient. In some embodiments, the cutaneous manifestations of rheumatic diseases are selected from the group consisting of: cutaneous lupus erythematosus, discoid lupus erythematosus, dermatomyositis, sarcoidosis, chronic idiopathic pruritus, cutaneous vasculitis, and scleroderma / morphea.

[0058] In some embodiments, a method is provided for treating a patient with skin manifestations associated with a tumor condition. The method includes topical application to the patient of a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In some embodiments, the skin manifestations of the tumor condition are selected from the group consisting of: adverse skin reactions caused by epidermal growth factor receptor (EGFR) inhibitors, adverse skin reactions caused by cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, adverse skin reactions caused by programmed cell death-1 (PD-1) inhibitors or other checkpoint inhibitors, and adverse skin reactions caused by BRAF inhibitors.

[0059] Roflumilast dosage During the treatment regimen, each dose of roflumilast administered to the patient may contain the same or substantially the same amount of roflumilast. Alternatively, the amount of roflumilast contained in individual doses may vary during the treatment regimen. For example, the concentration of roflumilast contained in an individual pharmaceutical composition administered may increase over time (e.g., each subsequent dose may contain more roflumilast than the previous one), decrease over time (e.g., each subsequent dose may contain less roflumilast than the previous one), increase first and then decrease, decrease first and then increase, or remain the same throughout the treatment regimen.

[0060] The amount of roflumilast administered to the patient in each dose may be a therapeutically effective amount. In some embodiments, the pharmaceutical composition may contain roflumilast in the range of about 0.01% to about 3.0%, or about 0.01% to about 2.0%, or about 0.01% to about 1.0%, or about 0.01% to about 0.3%, or about 0.05% to about 0.3%, or about 0.15% to about 0.3%. For example, the pharmaceutical composition may contain any of the following concentrations of roflumilast: 0.05%, 0.15%, and 0.3%. In some embodiments, if the patient is a child aged 2 to 5 years, the pharmaceutical composition may contain 0.05% roflumilast.

[0061] Pharmaceutical Composition This invention includes a treatment method in which roflumilast, administered to a patient, is contained in a pharmaceutical composition. The pharmaceutical composition may contain roflumilast and at least one inactive ingredient, such as a pharmaceutically acceptable carrier. In a preferred embodiment, the pharmaceutical composition is a topical pharmaceutical composition containing roflumilast.

[0062] Topical pharmaceutical compositions of roflumilast are described in U.S. Patent Nos. 9,895,359, 11,534,493, 17 / 821,051, and 17 / 887,798, which are incorporated herein by reference. In some embodiments, the pharmaceutical composition is one of the compositions disclosed in U.S. Patent Nos. 9,895,359, 11,534,493, 17 / 821,051, or 17 / 887,798.

[0063] In some embodiments, the pharmaceutical compositions disclosed herein comprise diethylene glycol monoethyl ether and water. Diethylene glycol monoethyl ether, also known as 2-(2-ethoxyethoxy)ethanol or DEGEE, is marketed under several trade names, including Transcutol. ® (Gattefosse Corporation, Paramus, NJ), Carbitol™ (The Dow Chemical Company, Midland, MI), Dioxitol ® (Shell Oil Company, Houston, TX) and Poly-Solv DM (Monument Chemical, Houston, TX).

[0064] The concentration of diethylene glycol monoethyl ether in the formulation is sufficient to dissolve the active pharmaceutical ingredient and provide antimicrobial properties. In some embodiments, the pharmaceutical composition contains more than 25% w / w diethylene glycol monoethyl ether, which is sufficient to provide antimicrobial properties. In some embodiments, the amount of diethylene glycol monoethyl ether can be in the range of about 20% w / w to about 40% w / w, about 20% w / w to about 35% w / w, about 25% w / w to about 35% w / w, about 20% w / w to about 30% w / w, or about 25% w / w to about 30% w / w. For example, the pharmaceutical composition contains any of the following w / w percentages of diethylene glycol monoethyl ether: 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, etc.

[0065] In some embodiments, the pharmaceutical composition further comprises an emulsifier blend comprising cetearyl alcohol (CAS 67762 30 0), dicetyl phosphate (CAS 2197 63 9), and cetyl alcohol polyether-10 phosphate (CAS 50643-20-4). Croda manufactures an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate under the trade name Crodafos™ CES. Crodafos™ CES PHARMA is manufactured using the same starting materials and processes, but with enhanced quality control and release testing, and uses the nomenclature of cetearyl alcohol, cetearyl alcohol phosphate, and cetearyl alcohol polyether-10 phosphate to comply with standard practices for pharmaceutical excipient nomenclature. This commercially available emulsifier blend is a self-emulsifying wax, primarily composed of the waxy substance cetearyl alcohol (which is cetyl alcohol (C 16 H 34 O) and stearyl alcohol (C 18 H 38 The mixture contains 10-20% cetearyl phosphate (cetearearyl phosphate) and 10-20% cetearyl ether-10 phosphate (cetearearyl ether-10 phosphate). The self-emulsifying wax forms an emulsion when mixed with water. When Crodafos™ CES is added to water, it spontaneously forms an emulsion with a pH of approximately 3. A pH-adjusting agent, such as sodium hydroxide solution, can be added to raise the pH to the desired value.

[0066] In some embodiments, the amount of the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate can be in the range of about 5% w / w to about 20% w / w, about 6% w / w to about 20% w / w, about 8% w / w to about 20% w / w, about 6% w / w to about 15% w / w, or about 8% w / w to about 15% w / w. For example, the pharmaceutical composition comprises any of the following w / w percentages of the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate: 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.

[0067] The topical formulations disclosed herein can be emulsions, suspensions, sprays, oils, ointments, fat ointments, creams, lotions, pastes, gels, or foams. In a preferred embodiment, the pharmaceutical composition can be formulated as an emulsion, cream, or foam.

[0068] For example, the pharmaceutical composition may be formulated as an emulsion comprising a solvent, water, an emulsifier, and a humectant, or as one of the following forms: Oil-in-water emulsions: Pharmaceutical compositions can be emulsions comprising a discrete phase of hydrophobic components and a continuous aqueous phase including water, and optionally include one or more polar hydrophilic excipients, as well as solvents, cosolvents, salts, surfactants, emulsifiers, and other components. These emulsions may include water-soluble or water-swellable polymers that contribute to emulsion stabilization.

[0069] Water-in-oil emulsions: Pharmaceutical compositions can be emulsions comprising a continuous phase of hydrophobic components and an aqueous phase including water, and optionally including one or more polar hydrophilic excipients and salts or other components. These emulsions may include water-soluble or water-swellable polymers and one or more emulsifiers to help stabilize the emulsion.

[0070] Microemulsions: Pharmaceutical compositions can be clear, thermodynamically stable, isotropic liquid systems containing oil, water, and surfactants, typically used in combination with co-surfactants. Microemulsions can be water-continuous, oil-continuous, or bicontinuous mixtures. Pharmaceutical compositions may also optionally contain up to 60% by weight of water. In some compositions, higher levels may be more suitable.

[0071] Nanoemulsions: Pharmaceutical compositions can be isotropic dispersions containing water, oil, and emulsifiers. This system can be an oil-based system dispersed in an aqueous system, or an aqueous system dispersed in an oil-based system, thereby forming nanoscale droplets or an oil phase. Nanoemulsions typically have a higher loading capacity for lipophilic active ingredients than microemulsions. Hydrophobic and hydrophilic active ingredients can also be formulated into nanoemulsions. Nanoemulsions can be formed by any suitable method known in the art, including high-pressure homogenization, microfluidization, and phase transition temperature methods.

[0072] Thickening hydrogel: The pharmaceutical composition may include an aqueous phase that has been thickened by a suitable natural thickener, modified natural thickener, or synthetic thickener as described below. Alternatively, the thickening hydrogel may be thickened using a suitable polyethoxylated alkyl chain surfactant or other nonionic, cationic, or anionic system.

[0073] Thickening hydroalcoholic gel: The pharmaceutical composition may include a mixture of water and alcohol as a polar phase, which has been thickened by a suitable natural polymer, modified natural polymer, or synthetic polymer as described below. Alternatively, the thickening hydroalcoholic gel may be thickened using a suitable polyethoxylated alkyl chain surfactant or other nonionic, cationic, or anionic system. The alcohol may be ethanol, isopropanol, or other pharmaceutically acceptable alcohol. In some embodiments of the invention, the amount of alcohol (e.g., ethanol) may be less than 20%, and a formulation with self-preservative properties is still provided.

[0074] Hydrophilic gel: A pharmaceutical composition may be a system in which the continuous phase comprises at least one water-soluble or water-dispersible hydrophilic component other than water. The formulation may also optionally contain up to 60% by weight of water. In some compositions, higher levels may be more suitable. Suitable hydrophilic components include one or more diols, such as polyols like glycerol, propylene glycol, butanediol, polyethylene glycol (PEG), random copolymers or block copolymers of ethylene oxide, propylene oxide and / or butane oxide, polyalkoxylated surfactants having one or more hydrophobic moieties per molecule, silicone copolyols, mixtures of cetearyl alcohol polyether-6 and stearyl alcohol, and combinations thereof.

[0075] In addition to the active ingredient, the formulation may contain other excipients typically found in such dosage forms. These excipients vary depending on the dosage form and desired properties. The pharmaceutical compositions used in the methods disclosed herein may include one or more solvents, humectants, surfactants and emulsifiers, polymers and thickeners, or other excipients. In some embodiments, the pharmaceutical composition comprises roflumilast and one or more of the following: diethylene glycol monoethyl ether, cetearyl alcohol, dicetyl phosphate, and a cetyl alcohol polyether-10 phosphate emulsifier blend, as well as hexanediol.

[0076] solvent In some embodiments, the pharmaceutical composition may include one or more solvents or co-solvents to achieve the desired level of solubility of the active ingredient in the topical product. Solvents may also alter skin penetration or the activity of other excipients contained in the formulation. Solvents include, but are not limited to, acetone, ethanol, benzyl alcohol, butanol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, ethyl acetate, isopropanol, isopropyl isostearate, isopropyl myristate, N-methylpyrrolidone, polyethylene glycol, glycerin, propylene glycol, and SD alcohol. In some embodiments, the solvent is selected from the group consisting of: 1,3-butanediol, 1,2-hexanediol, 1,3-propanediol, 1,2-pentanediol (also known as pentanediol), dipropylene glycol, 2-(2-butoxy-ethoxy)ethanol (also known as butoxydiethylene glycol), 1,6-hexanediol, propylene glycol methyl ethyl acetate (also known as PGMEA or 1-methoxy-2-propanol acetate), 5-methyloxacyclopentan-2-one (also known as... γ-The solvents include pentylene, pantothenic acid, 1,3-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1-heptanol, 1-hexanol, 2-(2-ethoxyethoxy)ethyl acetate, 2-(2-methoxyethoxy)ethanol, 2-butoxyethanol, 2-butoxyethyl acetate, 2-ethoxyethanol, 2-ethoxyethyl acetate, 2-methoxyethanol, diethylene glycol dimethyl ether (also known as bis(2-methoxyethyl) ether), diethylene glycol, propylene glycol methyl ether, and combinations thereof. In some embodiments, the solvent is selected from the group consisting of 1,3-butanediol, 1,2-hexanediol, 1,3-propanediol, 1,2-pentanediol, dipropylene glycol, 2-(2-butoxyethoxy)ethanol, 1,6-hexanediol, propylene glycol methyl ethyl acetate, 5-methyloxacyclopentan-2-one, and pantothenic acid. When treating patients with inflammatory conditions, solvents that are not ethanol, isopropanol, or denatured alcohol are preferred.

[0077] Moisturizer In some embodiments, the pharmaceutical composition may include a humectant to improve hydration levels. The humectant may be a hydrophilic substance comprising a humectant, or it may be a hydrophobic substance comprising a moisturizing agent. Suitable moisturizers include, but are not limited to: 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetearyl alcohol, cetyl alcohol, cetyl alcohol ester wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, polydimethicone, docosyl alcohol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, ethylene glycol distearate, ethylene glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyl dodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin wax, peanut oil, petrolatum, Plastibase-50W, white petrolatum, isopropyl palmitate, and stearyl alcohol.

[0078] Surfactants and emulsifiers In some embodiments, the pharmaceutical composition may include one or more surfactants to emulsify the composition and help wet the surface of the active ingredient or excipient. As used herein, the term "surfactant" refers to an amphiphilic molecule (a molecule that simultaneously has polar and nonpolar regions and these regions are covalently bonded) capable of reducing the surface tension of water and / or the interfacial tension between water and immiscible liquids. Surfactants include, but are not limited to, sodium alkyl aryl sulfonate, Amerchol-CAB, ammonium lauryl sulfate, almond oil PEG-6 ester, Arlacel, benzalkonium chloride, cetearyl alcohol polyether-6, cetearyl alcohol polyether-12, cetearyl alcohol polyether-15, cetearyl alcohol polyether-30, cetearyl alcohol / cetearyl alcohol polyether-20, cetearyl alcohol ethylhexanoate, cetearyl alcohol polyether-10, cetearyl alcohol polyether-2, cetearyl alcohol polyether-20, cetearyl alcohol polyether-23, cholesterol polyether-24, cocamidoyl ether sulfate, and cocoamine. Oxides, cocobetaine, cocodiethanolamide, cocomonal ethanolamide, cocoyl octanoate / caprylate, disodium cocoamphodiacetate, disodium lauryl ether sulfosuccinate, disodium lauryl sulfosuccinate, disodium lauryl sulfosuccinate, disodium oleamide monoethanolamine sulfosuccinate, sodium docusate, lauryl ether-2, lauryl ether-23, lauryl ether-4, lauryl diethanolamide, lecithin, methoxy PEG-16, methyl glucosyl ether-10, methyl glucosyl ether-20, methyl glucose sesquistearate, oleyl ether-2, oleyl ether-20, PEG PEG-32 stearate, PEG-100 stearate, PEG-12 glyceryl laurate, PEG-120 methyl glucose dioleate, PEG-15 cocoamine, PEG-150 distearate, PEG-2 stearate, PEG-20 methyl glucose sesquistearate, PEG-22 methyl ether, PEG-25 propylene glycol stearate, PEG-4 dilaurate, PEG-4 laurate, PEG-45 / dodecyl glycol copolymer, PEG-5 oleate, PEG-50 stearate, PEG-54 hydrogenated castor oil, PEG-6 isostearate, PEG-60 hydrogenated castor oil, PEG-7 methyl ether, PEG-75 lanolin, PEG-8 laurate, PEG-8 stearate, Pegoxol 7 stearate, pentaerythritol cocoate, poloxamer124, Poloxamer 181, Poloxamer 182, Poloxamer 188, Poloxamer 237, Poloxamer 407, Polyglycerol-3 oleate, Polyoxyethylene alcohol, Polyoxyethylene fatty acid ester, Polyoxyethylene 20 cetearyl ether, Polyoxyethylene 40 hydrogenated castor oil, Polyoxyethylene 40 stearate, Polyoxyethylene 6 and Polyoxyethylene 32, Polyoxyethylene glycerol stearate, Polyoxyethylene stearate, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, Polysorbate 80, PPG-26 oleate, PROMULGEN™ 12. Propylene glycol diacetate, propylene glycol dioctanoate, propylene glycol monostearate, sodium xylenesulfonate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearyl alcohol polyether-2, stearyl alcohol polyether-20, stearyl alcohol polyether-21, stearyl alcohol polyether-40, tallow glyceride, and emulsifying wax. Preferably, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and cetyl alcohol polyether-10 phosphate.

[0079] Polymers and thickeners In some embodiments, the pharmaceutical composition may include soluble, swellable, or insoluble organic polymer thickeners, such as natural and synthetic polymers; or inorganic thickeners, such as acrylate copolymers, carbomer 1382, type B carbomer copolymers, type A carbomer homopolymers, type B carbomer homopolymers, type C carbomer homopolymers, carboxyvinyl copolymers, carboxymethyl cellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, and methylcellulose.

[0080] Other excipients In some embodiments, the pharmaceutical composition may include other excipients, such as fillers, carriers, and excipients commonly found in cosmetics and topical pharmaceuticals. In a preferred embodiment, the fillers, carriers, and excipients are suitable for topical application. To improve stability or aesthetics, other excipients may be added to the composition, including but not limited to defoamers, preservatives (such as parabens, benzyl alcohol, phenylmercuric acid, chlorocresol, methylparaben, propylparaben), antioxidants, chelating agents, stabilizers, buffers, pH-adjusting solutions, skin penetration enhancers, film-forming agents, dyes, pigments, diluents, fillers, fragrances, and other excipients.

[0081] The compositions according to the invention can be formulated with other active agents, depending on the other conditions being treated. Other active agents include, but are not limited to, NSAIDs (e.g., aspirin, ibuprofen, ketoprofen, naproxen), apremilast, JAK inhibitors (e.g., tofacitinib, ruxolitinib, occlacit), leukotriene inhibitors (e.g., zileuton, zafirlukast, montelukast), mast cell stabilizers (e.g., netoromil, sodium cromoglycate, ketotifen, pemirolast), and anthralin. (dithranol), azathioprine, tacrolimus, pimecrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfasalazine, mycophenolate mofetilMofetil), fumarates, and corticosteroids (such as aclometasone, amcinonide, betamethasone, clobetasol, clocotolone, mometasone, triamcinolone, fluocinolone, fluocinonide, flurandrenolide, diflorasone, desonide, desoximetasone, dexamethasone, halcinonide, and halobetasol). Hydrocortisone, methylprednisolone, prednicarbate, prednisone, corticotropin, vitamin D analogs (such as calcipotriene, calcitriol), acitretin, tazarotene, cyclosporine, resorcinol, tapinarof, colchicine, bronchodilators (such as β-agonists, anticholinergics, theophylline), and antibiotics (such as erythromycin, ciprofloxacin, metronidazole). Alternatively, other active agents can be administered as a single composition.

[0082] The compositions according to the invention can be formulated together with other antifungal agents according to the specific fungal infection to be treated. Other antifungal agents include, but are not limited to: those containing miconazole (Daktarin, Micatin, and Monistat), ciclopirox olamine (Batrafen, Loprox, Penlac, and Stieprox), clotrimazole (Canesten and Hydrozole), butenafine (Lotrimin Ultra and Mentax), terbinafine (Lamisil, Terbisil, and Zabel), amorolfine (Curanail, Loceryl, Locetar, and Odenil), and naftifine. Naftin, tolnaftate, tinactin, ketoconazole (nizoral), griseofulvin, imidazoles (bifonazole, clomidazole, econazole, fenticonazole, isoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, tioconazole), triazoles (fluconazole, itraconazole, posaconazole, noxafil, voriconazole) Drugs containing (Vfend), benzimidazole (thiabendazole), ethylparaben, flucytosine, salicylic acid, selenium sulfide, and undecenoic acid. Alternatively, other antifungal agents can be applied as a single composition.

[0083] The compositions according to the present invention can be formulated with common topical anti-inflammatory agents, including but not limited to: diflucortolone valerate, fluocinolone acetonide, fludrosol, halobetasol propionate, ancinonide, desosonide, difluralasone, halcinonide, betamethasone valerate, diflorasone diacetate, fluticasone propionate, mometasone furoate, triamcinolone acetonide, and clocotropone tertivalate. (pivalate), acetone fluocinolone acetonide, fluticasone propionate, hydrocortisone valerate, mometasone furoate, desonide, hydrocortisone butyrate, hydrocortisone propionate, hydrocortisone valerate, prednisolone, betamethasone dipropionate enhanced clobetasol propionate, aclometasone dipropionate, hydrocortisone (base, ≥2%), hydrocortisone (base, <2%), calcineurin inhibitors, and hydrocortisone acetate. Alternatively, anti-inflammatory agents can be administered as a single composition.

[0084] Manufacturing method Topical pharmaceutical compositions can be prepared using processes commonly used in the manufacture of topical pharmaceutical formulations. To prepare a single-phase formulation (such as a liquid), the components of the formulation can be combined and mixed until a homogeneous solution or suspension of the active ingredient is obtained. For example, to prepare a multiphase formulation such as an emulsion, the aqueous and oil phase components can be combined and mixed separately until a homogeneous solution is obtained. The aqueous and oil solutions can then be combined and mixed, for example, by shear mixing, to form the formulation. One or more pharmaceutical active agents can be dissolved (molecularly dispersed), complexed, or associated with excipients or other active agents, or they can be particulate (amorphous or crystalline). The oil phase can be added to the aqueous phase, or vice versa. The phases can be combined and mixed, for example, at a high temperature of 50-90°C, or at room temperature (i.e., 20-30°C), or at a temperature between room temperature and a high temperature.

[0085] The following examples illustrate certain embodiments of the present invention and are not intended to be limiting.

[0086] Example While various embodiments have been described above, it should be understood that these embodiments are presented by way of example only and are not limiting. Therefore, the breadth and scope of this disclosure should not be limited to any of the exemplary embodiments described above. Furthermore, unless otherwise indicated herein or clearly contradicted by the context, this disclosure covers any combination of the foregoing elements in all its possible variations.

[0087] Example 1 Prepare a roflumilast cream having formulation 1 as disclosed in Table 2.

[0088] Table 2. Composition of Formulation 1

[0089] Example 2 Prepare a roflumilast cream having formulation 2 as disclosed in Table 3.

[0090] Table 3. Composition of Formulation 2

[0091] Example 3 Prepare roflumilast cream having formulation 3 as disclosed in Table 4.

[0092] Table 4. Composition of Formulation 3

[0093] Example 4 Roflumilast foam having formulation 4 as disclosed in Table 5 was prepared.

[0094] Table 5. Composition of Formulation 4

[0095] Example 5 Roflumilast cream having formulation 5 as disclosed in Table 6 will be prepared.

[0096] Table 6. Composition of Formulation 5

[0097] Example 6 Two phase 3 parallel-group, double-blind, cartel-controlled studies were conducted, in which subjects aged 6 years and older with mild to moderate atopic dermatitis received a 4-week periodic application of 0.15% topical roflumilast cream or a cartel. At enrollment, subjects had ≥3% BSA involvement (excluding scalp, palms, and soles) and were classified as having mild to moderate atopic dermatitis (AD) according to the vIGA-AD assessment. After eligibility was confirmed, subjects were randomized 2:1 to either 0.15% ARQ-151 cream or a matching cartel cream. Randomization was stratified by baseline / day 1 vIGA-AD score ('mild' vs. 'severe') and by study location. Subjects / caregivers received a 4-week periodic application of 0.15% ARQ-151 cream or a cartel cream to all AD-affected areas and any new AD lesions that appeared during the study period, excluding the scalp. Regardless of whether the treatable areas of AD had cleared by week 4 / day 29, subjects / caregivers continued to treat these areas with the study drug throughout the study. At the week 4 visit, subjects were eligible to participate in a 12-month open-label extension study evaluating 0.15% topical roflumilast cream in QD.

[0098] The aim of this study was to evaluate the safety and efficacy of a contrast agent versus a 4-week course of 0.15% topical roflumilast cream applied to individuals with atopic dermatitis. Participants included male and female children and adolescents (6–17 years of age) and adults (≥18 years of age). Participants had mild to moderate atopic dermatitis with a vIGA-AD score of '2' (mild) or '3' (moderate) at study entry. Up to 50% of participants were ≥18 years of age. Approximately 650 participants were randomized in this study.

[0099] The primary efficacy endpoint was IGA success, defined as a vIGA-AD score of “clear” or “nearly clear” with a 2-level improvement from baseline at week 4.

[0100] Secondary efficacy endpoints were: (1) achieving vIGA-AD success at week 4 in subjects with a vIGA-AD score of 'moderate' at randomization; (2) achieving a WI-NRS reduction of at least 4 points at week 4 in subjects with a baseline WI-NRS ≥ 4; (3) achieving a WI-NRS reduction of at least 4 points at week 2 in subjects with a baseline WI-NRS ≥ 4; and (4) achieving a WI-NRS reduction of at least 4 points at week 4 in subjects with a baseline WI-NRS ≥ 4. (4) A reduction of at least 4 points in WI-NRS was achieved in week 1; (5) A reduction of at least 75% in eczema area and severity index (EASI-75) was achieved in week 4; (6) vIGA-AD was 'clear' or 'almost clear' in week 4; (7) vIGA-AD was achieved in week 2; (8) vIGA-AD was achieved in week 1; (9) vIGA-AD was 'clear' or 'almost clear' in week 2; and (10) vIGA-AD was 'clear' or 'almost clear' in week 1.

[0101] The study results are presented in Tables 7 and 8. The results in these tables report the outcomes on Day 2, where Day 1 is the baseline visit of the study. Therefore, Day 2 is the second day after baseline and represents the patient outcomes one day after the start of the study.

[0102] Table 7. Changes in daily WI-NRS observations relative to baseline and percentage changes relative to baseline on day 2 of the study (Study 1)

[0103] Table 8. Changes in daily WI-NRS observations relative to baseline and percentage changes relative to baseline on day 2 of the study (Study 2)

[0104] The research findings are also presented in Figure 1-6 middle. Figure 1 A line graph showing the change in mean daily WI-NRS score over time in the treatment group (0.15% roflumilast cream versus mediator) in Study 1 is provided. Figure 2 A line graph showing the change in mean daily WI-NRS score over time in the treatment group (0.15% roflumilast cream versus mediator) in Study 2 is provided. Figure 3 Line graphs showing the percentage change in daily WI-NRS over time relative to baseline for the two treatment groups (0.15% roflumilast cream versus mediator) in Study 1 are provided. Figure 4 Line graphs showing the percentage change in daily WI-NRS over time relative to baseline for the two treatment groups (0.15% roflumilast cream versus mediator) in Study 2 are provided. Figure 5 A line graph showing the average change in WI-NRS scores relative to baseline in Study 1 is provided. Figure 6A line graph showing the mean change in WI-NRS scores relative to baseline in Study 2 is provided. Figure 5 and Figure 6 As shown, pruritus was improved one day after the first application of 0.15% roflumilast cream (p<0.05).

[0105] In each study, over 30% of individuals treated with roflumilast cream achieved WI-NRS success, defined as a decrease of at least 4 points in WI-NRS relative to baseline by week 4. Furthermore, daily improvement in pruritus was observed in individuals treated with roflumilast cream, as measured by WI-NRS, with significant improvement observed 1 day after the first application (p<0.05).

[0106] Both studies met the primary endpoint of IGA success, defined as a 'cleared' or 'nearly cleared' Atopic Dermatitis Investigator Global Assessment (vIGA-AD) score at week 4, with a grade 2 improvement from baseline (Study 1: Roflumilast cream 32.0% vs. mediator 15.2%, P<0.0001; Study 2: Roflumilast cream 28.9% vs. mediator 12.0%, P<0.0001). Furthermore, rapid and significant improvements in v-IGA success were observed as early as week 2 (Study 1: Roflumilast cream 21.2% vs. mediator 6.4%, P<0.0001; Study 2: Roflumilast cream 17.7% vs. mediator 5.3%, P<0.0001).

[0107] Compared with the carcinogen, roflumilast cream also showed rapid and statistically significant improvement in key secondary endpoints. In children aged 6 years and older and adults treated with roflumilast cream, over 40% showed a 75% reduction in the Eczema Area and Severity Index (EASI-75) at week 4 compared to the carcinogen (Study 1: 43.2% vs. 22.0%, P<0.0001; Study 2: 42.0% vs. 19.7%, P<0.0001). Furthermore, in both studies, significant improvements in EASI-75 were observed as early as week 1 with roflumilast cream compared to the carcinogen (Study 1: 14.0% vs. 5.5%, p=0.0006; Study 2: 13.3% vs. 7.8%, p=0.0329). In both studies, approximately 40% of children and adults treated with roflumilast cream achieved a vIGA-AD score of clearance (0) or near clearance (1) by week 4 (Study 1: 41.5% vs. 25.2%, P<0.0001; Study 2: 39% vs. 16.9%, P<0.0001).

[0108] Example 7 A phase 3 carrier-controlled study was conducted in which subjects aged 2 to 5 years with mild to moderate atopic dermatitis received a 4-week QD application of either 0.05% topical roflumilast cream or a carrier. The aim of the study was to evaluate the safety and efficacy of a 4-week QD application of 0.05% topical roflumilast cream versus a carrier in children aged 2 to 5 years with atopic dermatitis. Participants were boys and girls aged 2 to 5 years. Participants had mild to moderate atopic dermatitis, with a vIGA-AD score of '2' (mild) or '3' (moderate) at study entry. The mean body surface area (BSA) of participants was 22% of the total, ranging from 3% to 82%. Approximately 650 participants were randomized in this study.

[0109] The study results are presented in Table 9. The results in this table report the outcomes on Day 2, where Day 1 is the baseline visit of the study. Therefore, Day 2 is the second day after baseline and represents the patient outcomes one day after the start of the study.

[0110] Table 9. Changes in daily WI-NRS observation data relative to baseline on day 2 of the study.

[0111] The research findings are also presented in Figure 7 , 8 and 9. Figure 7 A line graph showing the change in mean daily WI-NRS score over time for the treatment group (0.05% roflumilast cream versus mediator) is provided. Figure 8 Line graphs showing the percentage change in daily WI-NRS over time relative to baseline for the two treatment groups (0.05% roflumilast cream versus mediator) are provided. Figure 9 A line graph showing the mean change in WI-NRS score over time relative to baseline is provided for the treatment group (0.05% roflumilast cream as a contrast medium). Figure 9 As shown, pruritus was improved one day after the first application of 0.05% roflumilast cream (p=0.0014).

[0112] In the study, approximately 35.3% of children treated with roflumilast cream achieved WI-NRS success, defined as a decrease of at least 4 points in WI-NRS relative to baseline by week 4. Furthermore, daily improvement in pruritus was observed in children treated with roflumilast cream, as measured by WI-NRS, with significant improvement observed 1 day after the first application.

[0113] This study met the primary endpoint of IGA success, defined as a 'cleared' or 'nearly cleared' Validated Investigator Global Assessment (vIGA-AD) score with a grade 2 improvement from baseline at week 4. Regarding the primary endpoint, at week 4, 25.4% of children treated with once-daily 0.05% roflumilast cream achieved IGA success, compared to only 10.7% of children treated with the carboxyl therapy (P<0.0001), with significant improvement observed as early as week 1. In this study, at week 4, 39.4% of children treated with 0.05% roflumilast cream achieved a 75% improvement in EASI-75, compared to only 20.6% of children treated with the carboxyl therapy (P<0.0001). Furthermore, at week 4, 35.3% of children treated with roflumilast cream experienced a 4-point reduction in the most severe pruritus numerical score (WI-NRS) (compared to 18.0% of those treated with the carton [nominal P=0.0002]).

[0114] Roflumilast cream was very well tolerated. Overall, the incidence of adverse events was low in this study, and the only adverse event with an incidence ≥3% in either arm was upper respiratory tract infection. The most common adverse events (≥2%) in the roflumilast arm included upper respiratory tract infection, fever, diarrhea, and vomiting. Among the children randomly assigned to roflumilast cream in the study, 93.8% completed the entire four-week course of treatment, and discontinuation due to adverse events was rare (1.1% in the roflumilast cream group and 1.9% in the carboxylate group). These results reflect the good efficacy, safety, and tolerability of roflumilast cream in pediatric patients with atopic dermatitis.

[0115] Example 8 A phase 3 carrier-controlled study was conducted in which children aged 9 years and older and adults with moderate to severe seborrheic dermatitis received a single application (QD) of 0.3% topical roflumilast foam or a carrier for 8 weeks. The aim of the study was to evaluate the safety and efficacy of a single application of 0.3% topical roflumilast foam versus a carrier in subjects with moderate to severe seborrheic dermatitis for 8 weeks.

[0116] In this study, WI-NRS were measured in patients at baseline and one and two days after administration of roflumilast foam or mediator. The results are presented in Tables 10 and 11. Results in Table 10 report day 2 outcomes, and results in Table 11 report day 3 outcomes, where day 1 is the baseline visit of the study. Therefore, day 2 is the second day after baseline and represents patient outcomes one day after the start of the study, and day 3 is two days after baseline and represents patient outcomes two days after the start of the study.

[0117] Table 10. Changes in daily WI-NRS observation data relative to baseline on day 2 of the study.

[0118] Table 11. Changes in daily WI-NRS observation data relative to baseline on day 3 of the study.

[0119] Improvement in pruritus was observed in patients treated with roflumilast foam, with patients experiencing pruritus reduction relative to the medium at 1 and 2 days after the first application, as measured by WI-NRS. The improvement in pruritus observed in patients treated with roflumilast foam was significantly improved at 2 days after the first application, as measured by WI-NRS (p<0.05).

[0120] Example 9 A phase 3 carrier-controlled study was conducted in which subjects aged 12 years and older with scalp and body psoriasis received either a 0.3% topical roflumilast foam or a carrier-controlled treatment (QD) for 8 weeks. A total of 432 subjects were enrolled in the study. The aim of the study was to evaluate the safety and efficacy of a 0.3% topical roflumilast foam versus a carrier-controlled treatment (QD) for 8 weeks in subjects with scalp and body psoriasis.

[0121] In this study, SI-NRS were measured in patients at baseline and one day after administration of roflumilast foam or mediator. The results are presented in Table 12. The results in this table report day 2 outcomes, where day 1 is the baseline visit of the study. Therefore, day 2 is the second day after baseline and represents patient outcomes one day after the start of the study.

[0122] Table 12. Changes in daily SI-NRS observation data relative to baseline on day 2 of the study.

[0123] Improvement in scalp itching was observed in patients treated with roflumilast foam, with patients experiencing a reduction in itching relative to the medium, as measured by SI-NRS 1 day after the first application.

[0124] Example 10 A 52-week, phase 3, multicenter, open-label extension (“OLE”) of the trial described in Example 6 was performed in adults with atopic dermatitis (AD) and children ≥2 years of age. Patients who received the mediator control in Example 6 were switched to roflumilast cream in this extension. The aim of this study was to evaluate the long-term safety of QD 0.15% roflumilast cream (subjects 6 years of age and older) or QD 0.05% roflumilast cream (subjects 2 to 5 years of age) in subjects with atopic dermatitis in a multicenter, open-label, single-arm study following the completion of the previous phase 3 study. Efficacy endpoints included a validated Investigator Global Assessment (vIGA-AD) value of 0 or 1 at each assessment, and vIGA success, defined as a vIGA-AD score of 'cleared' or 'nearly cleared' with a grade 2 improvement relative to baseline. The vIGA-AD is a five-point scale ranging from 0 (cleared) to 4 (severe) used to assess inflammatory signs in atopic dermatitis. The demographic and disease characteristics of patients aged ≥6 years in the OLE trial are detailed in Table 13 below.

[0125] Table 13. Demographic and disease characteristics at the start of the trial

[0126] Secondary efficacy endpoints were: (1) a vIGA-AD value of 0 or 1 at each assessment; (2) vIGA-AD success (defined as a vIGA-AD value of 0 or 1 and an improvement of 2 grades relative to baseline); (3) changes in WI-NRS scores over time; and (4) changes in EASI scores over time.

[0127] No new safety signals were observed during the 56-week treatment period. 96.3% of patients experiencing treatment-specific adverse events (TEAEs) had mild to moderate severity. At each visit, ≥98.1% of patients reported no signs of irritation based on investigator assessment of local tolerability. Regarding patient-reported local tolerability, ≥90.5% of patients reported no or mild sensation at each visit. AEs leading to discontinuation included: atopic dermatitis (n=5), nausea (n=2), application site dermatitis (n=2), and other preferred terms (n=11; 1 patient for each preferred term). The safety population was defined as all enrolled patients who received ≥1 confirmatory dose of the investigational drug.

[0128] The research results are presented in Figure 10The figure shows a line graph depicting the proportion of patients in the study who showed an improvement of ≥4 points in WI-NRS relative to their trial baseline over the 56-week period. WI-NRS is an 11-point scale ranging from 0 [no pruritus] to 10 [most conceivable pruritus]. At week 56 of the study, among patients ≥12 years of age and with a baseline WI-NRS ≥4, 56.9% of participants who had previously been treated with 0.15% roflumilast cream continued treatment and 50.0% of participants who switched to once-daily 0.15% roflumilast cream showed significant reduction in pruritus (≥4 points) according to the daily WI-NRS. The following is a summary of the changes in vIGA-AD (Table 14) and EASI (Table 15) over time in this study.

[0129] Table 14. Changes in vIGA-AD scores over time

[0130] Table 15. Changes in EASI scores over time

[0131] Overall, the trial showed that in the 19.8% (n=130) of patients who achieved vIGA-AD 0 and switched to active BIW (body-body-waste management), the median duration of disease control was 281 days (95% confidence interval) (defined as the duration of adequate control of AD signs and symptoms with BIW after achieving vIGA-AD 0, where vIGA-AD was 0 / 1). Of these 130 patients, 75 (57.7%) remained in disease control at their last visit.

[0132] It should be understood that all embodiments described herein are applicable to all aspects of the invention, and vice versa. Other features and advantages of the invention will be apparent from the description provided herein. However, it should be understood that while the description and specific examples illustrate preferred embodiments of the invention, they are given by way of illustration only, as various changes and modifications will become apparent to those skilled in the art. The following studies and schemes illustrate embodiments of the methods described herein.

[0133] Any of the above-described protocols or similar variations thereof may be described in various documents related to the drug. These documents may include, but are not limited to, protocols, statistical analysis plans, researcher manuals, clinical guidelines, drug guidelines, risk assessment and mediation procedures, prescribing information, and other documents that may be related to the drug. In particular, it is considered that such documents may be physically packaged together with the drug according to this disclosure into a kit, which may be beneficial or required by regulatory authorities.

[0134] While the subject matter of this disclosure has been described and illustrated in considerable detail with reference to certain illustrative embodiments, including various combinations and sub-combinations of features, those skilled in the art will readily understand other embodiments, as well as variations and modifications thereof, that are covered within the scope of this disclosure. Furthermore, the description of such embodiments, combinations, and sub-combinations is not intended to convey that the claimed subject matter requires features or combinations of features other than those expressly recited in the claims. Therefore, the scope of this disclosure is intended to include all modifications and variations covered within the spirit and scope of the appended claims.

Claims

1. A method for treating a patient suffering from atopic dermatitis, the method comprising: The patient was given a topical application of a pharmaceutical composition containing 0.05% to 0.30% roflumilast once daily. The pharmaceutical composition reduces pruritus in the patient as measured by the Most Severe Pruritus Digital Rating Scale (WI-NRS) within one week after topical application.

2. The method of claim 1, wherein the pharmaceutical composition comprises 0.05% roflumilast.

3. The method of claim 1, wherein the pharmaceutical composition comprises 0.15% roflumilast.

4. The method of claim 1, wherein the pharmaceutical composition is an emulsion comprising a solvent, water, an emulsifier, and a humectant.

5. The method of claim 1, wherein the pharmaceutical composition is a cream.

6. The method of claim 5, wherein the pharmaceutical composition comprises diethylene glycol monoethyl ether.

7. The method of claim 5, wherein the pharmaceutical composition comprises an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate.

8. The method of claim 4, wherein the pharmaceutical composition comprises an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate.

9. The method of claim 7, wherein the pharmaceutical composition reduces pruritus by four points relative to baseline as measured by WI-NRS within one week after the topical application.

10. A method for treating a patient suffering from atopic dermatitis, the method comprising: The patient was given a topical application of a pharmaceutical composition containing 0.05% to 0.30% roflumilast once daily. The pharmaceutical composition relieves itching in the patient as measured by WI-NRS within 24 hours after topical application.

11. The method of claim 10, wherein the pharmaceutical composition comprises 0.05% roflumilast.

12. The method of claim 10, wherein the pharmaceutical composition comprises 0.15% roflumilast.

13. The method of claim 10, wherein the pharmaceutical composition is an emulsion comprising a solvent, water, an emulsifier, and a humectant.

14. The method of claim 10, wherein the pharmaceutical composition is a cream.

15. The method of claim 14, wherein the pharmaceutical composition comprises diethylene glycol monoethyl ether.

16. The method of claim 14, wherein the pharmaceutical composition comprises an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate.

17. The method of claim 15, wherein the pharmaceutical composition comprises an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate.

18. The method of claim 16, wherein the pharmaceutical composition reduces pruritus by four points relative to baseline as measured by the Most Severe Pruritus Digital Rating Scale (WI-NRS) within 24 hours after the topical application.

19. A method for treating a patient suffering from atopic dermatitis, the method comprising: The patient was given a topical application of a pharmaceutical composition containing 0.05% to 0.30% roflumilast once daily. The pharmaceutical composition relieves itching as measured by WI-NRS in the patient within 48 hours after topical application.

20. The method of claim 19, wherein the pharmaceutical composition comprises 0.05% roflumilast.

21. The method of claim 19, wherein the pharmaceutical composition comprises 0.15% roflumilast.

22. The method of claim 19, wherein the pharmaceutical composition is an emulsion comprising a solvent, water, an emulsifier, and a humectant.

23. The method of claim 19, wherein the pharmaceutical composition is a cream.

24. The method of claim 23, wherein the pharmaceutical composition comprises diethylene glycol monoethyl ether.

25. The method of claim 23, wherein the pharmaceutical composition comprises an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate.

26. The method of claim 24, wherein the pharmaceutical composition comprises an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate.

27. The method of claim 25, wherein the pharmaceutical composition reduces pruritus by four points relative to baseline as measured by the Most Severe Pruritus Digital Rating Scale (WI-NRS) within 24 hours after the topical application.

28. A method for treating a patient suffering from seborrheic dermatitis, the method comprising: The pharmaceutical composition containing 0.30% roflumilast was applied topically to the patient once daily. The pharmaceutical composition reduces pruritus in the patient as measured by the Most Severe Pruritus Digital Rating Scale (WI-NRS) within one week after topical application.

29. The method of claim 28, wherein the pharmaceutical composition is an emulsion comprising a solvent, water, an emulsifier, and a humectant.

30. The method of claim 28, wherein the pharmaceutical composition is a foam.

31. The method of claim 30, wherein the pharmaceutical composition comprises diethylene glycol monoethyl ether.

32. The method of claim 31, wherein the pharmaceutical composition comprises an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate.

33. The method of claim 30, wherein the pharmaceutical composition comprises an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and cetyl alcohol polyether-10 phosphate.

34. The method of claim 32, wherein the pharmaceutical composition reduces pruritus by four points relative to baseline as measured by WI-NRS within one week after the topical application.

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