Dosage regimen for using a topical roflumilast composition

Abstract

This method involves treating a patient's skin condition or disease by topically applying a pharmaceutical composition containing roflumilast. Treatment methods include once-daily application of the roflumilast composition for a period of time, followed by twice-weekly application of the roflumilast composition as a maintenance dosing regimen.

Description

Cross-reference to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 537,186, filed September 7, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The topics disclosed herein generally relate to methods of treating a patient's skin conditions or disorders by topically applying a pharmaceutical composition containing roflumilast to the patient. Treatment methods include once-daily application of a topical roflumilast preparation until symptoms improve, followed by a maintenance dosing regimen of twice-weekly application. 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 comprises sequentially applying multiple doses of 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.

[0005] 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 the 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 (i.e., less than a daily time interval, wherein the patient is administered the medication twice within a given week, such as Monday and Thursday or Tuesday and Friday).

[0006] This invention provides a method for treating a patient. In some embodiments, the patient is treated by topical application of a roflumilast pharmaceutical composition once daily for a period of time. In some embodiments, this period is one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, or longer. In some embodiments, the roflumilast pharmaceutical composition is applied topically to the patient once daily for four weeks. Then, the roflumilast pharmaceutical composition is administered to the patient twice weekly (BIW) as a maintenance dosing regimen. In some embodiments, the patient is treated by topical application of one or more doses of the roflumilast pharmaceutical composition once daily for four weeks. Thereafter, a maintenance dose is administered to the patient twice weekly as long as the patient does not experience a recurrence or worsening of symptoms.

[0007] In some implementations, the maintenance dosing regimen may last 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, or up to one year or longer. In some implementations, the pharmaceutical composition may be applied 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 following clinical examination. For example, a patient may switch from twice-weekly dosing to once-daily dosing after a period of time.

[0008] In some embodiments, the patient is treated by topical application of the drug 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 drug composition is then administered to the patient twice weekly as a maintenance dosing regimen. In some embodiments, the twice-weekly maintenance dosing of the roflumilast drug composition maintains the patient's disease state (or disease-free state).

[0009] In some embodiments, the 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, twice-weekly maintenance dosing of the roflumilast drug composition maintains the patient's vIGA-AD score, where the vIGA-AD score is zero or one. Attached Figure Description

[0010] 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.

[0011] Figure 1 This 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

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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 disease onset or 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] The abbreviation "w / v" indicates the relative concentration of each component in the composition, expressed as "weight-to-volume ratio".

[0024] 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.

[0025] 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.

[0026] Roflumilast is a compound of formula (I): Wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyridin-4-yl.

[0027] 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.

[0028] Dosing regimen 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 sequentially administering multiple doses of the pharmaceutical composition containing roflumilast to the patient. In some embodiments, the method includes sequentially administering an initial dose of the pharmaceutical composition containing roflumilast to the patient at a first time interval, followed by administering one or more maintenance doses of the pharmaceutical composition containing roflumilast 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 the skin condition or disease improve, after which 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 the skin condition or disease, after which the patient switches to a maintenance dosing regimen of twice weekly. In some embodiments, the patient voluntarily receives the medication and / or receives the medication according to a predetermined schedule.

[0029] In some embodiments, a patient is treated by topical application of a roflumilast drug composition once daily for a period of time. In some embodiments, this period may be one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, or longer. In some embodiments, a roflumilast drug composition is applied to the patient once daily for four weeks. Then, the roflumilast drug composition is applied to the patient twice weekly (BIW) as a maintenance dosing regimen. In some embodiments, a patient is treated by topical application of a roflumilast drug composition once daily for four weeks. Thereafter, roflumilast is applied twice weekly as long as the patient does not experience a recurrence or worsening of symptoms. For example, in one embodiment, a patient with atopic dermatitis is treated by topical application of a drug composition containing 0.05% or 0.15% roflumilast once daily for four weeks, followed by topical application of the drug composition twice weekly, with the twice-weekly application starting after four weeks of once-daily application. Alternatively, in one embodiment, a patient with atopic dermatitis is treated by topical application of a roflumilast pharmaceutical composition to the patient once daily until the patient’s validated Atopic Dermatitis Investigator Global Assessment Scale score reaches zero, wherein the pharmaceutical composition contains 0.05% or 0.15% roflumilast, and then the pharmaceutical composition is applied topically to the patient twice a week, wherein the twice-weekly application begins after the once-daily application.

[0030] 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 pharmaceutical composition can be applied 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 following clinical examination. For example, a patient may switch from twice-weekly dosing to once-daily dosing after a period of time, and then back to twice-weekly dosing.

[0031] In some embodiments, the patient is treated with a once-daily topical application of the roflumilast composition 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 a week as a maintenance regimen. In some embodiments, maintenance administration of the roflumilast pharmaceutical composition maintains the patient's disease state (or disease-free state).

[0032] 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 (or, in some embodiments, one). 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. The twice-weekly maintenance dose can be continued for any period deemed helpful, such as at least 52 weeks. In some embodiments, maintenance dosing is able to maintain the patient's vIGA-AD score at zero or one for at least 124 days, or even for at least 52 weeks. In some embodiments, maintenance dosing is able to maintain the patient's vIGA-AD score at zero or one during roflumilast administration. In some embodiments, maintenance dosing is able to improve the patient's vIGA-AD score.

[0033] 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.

[0034] Table 1. vIGA-AD scores

[0035] Two-stage dosing regimens can improve and maintain efficacy during administration. In some implementations, a two-stage dosing regimen can improve vIGA-AD scores by 2 grades from baseline. The two-stage dosing regimens described herein offer greater convenience to patients because they require 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 simultaneously controlling the disease, despite low systemic exposure (sometimes below the limit of quantitation), is surprising and unexpected.

[0036] 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, genital or anal pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, folliculitis and extensive pyoderma, endogenous and exogenous acne, and rosacea. 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.

[0037] 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 keratosis, granuloma annulare, Sweet's syndrome, pyoderma gangrenosa, and urticaria, including chronic idiopathic urticaria, physical urticaria, and other forms of acquired urticaria.

[0038] 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.

[0039] 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, pruritus gynecologica, Behcet's disease, and linear IgA.

[0040] 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, the epidermal adhesion disease is a vesicular or bullous condition 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 disease.

[0041] 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 and other scarring alopecia, alopecia areata, rosacea, and hidradenitis suppurativa.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] In some embodiments, a method is provided for treating a patient suffering from 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: skin adverse reactions caused by epidermal growth factor receptor (EGFR) inhibitors, skin adverse reactions caused by cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, skin adverse reactions caused by programmed cell death-1 (PD-1) inhibitors, and skin adverse reactions caused by BRAF inhibitors.

[0046] 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.

[0047] 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, the concentration of roflumilast is 0.05% in patients aged 2-5 years. In some embodiments, the concentration of roflumilast is 0.15% in patients aged 6 years or older.

[0048] 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.

[0049] 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 any one of U.S. Patent Nos. 9,895,359, 11,534,493, 17 / 821,051, or 17 / 887,798.

[0050] 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).

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] For example, the pharmaceutical composition can be formulated into 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.

[0056] 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 carriers 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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 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.

[0061] 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, blends of cetearyl alcohol-6 with stearyl alcohol, and combinations thereof.

[0062] 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 type 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 roflurazide and one or more of the following: diethylene glycol monoethyl ether, cetearyl alcohol, dicetearyl phosphate, and a cetyl alcohol polyether-10 phosphate emulsifier blend, as well as hexanediol. In some embodiments, the cream comprises a solvent, an emulsifier (e.g., cetearyl alcohol, dicetearyl phosphate, cetyl alcohol polyether-10 phosphate, or combinations thereof), water, and a humectant.

[0063] 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 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-valerolactone). The solvents include: panthenol, 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-butoxy-ethoxy)ethanol, 1,6-hexanediol, propylene glycol methyl ethyl acetate, 5-methyloxacyclopentan-2-one, and panthenol. When treating patients with inflammatory conditions, solvents that are not ethanol, isopropanol, or denatured alcohol are preferred.

[0064] Moisturizer In some embodiments, the pharmaceutical composition may include a humectant to improve hydration levels. The humectant may be a hydrophilic substance comprising a wetting agent, or it may be a hydrophobic substance comprising a skin-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.

[0065] 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, diethanolamide lauryl acid, 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.

[0066] 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.

[0067] 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, compatibilizers, fragrances, and other excipients.

[0068] 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 and / or TYK2 inhibitors (e.g., tofacitinib, ruxolitinib, occlacit), leukotriene inhibitors (e.g., zileuton, zafirlukast, Montelukast), BET inhibitors (e.g., thiazo-triazo-1,4-diazazepine, molibresib, dBET1, QCA570, GSK778, ABBV744), STAT... Inhibitors of STAT6, STAT3, and STAT5 (e.g., Static, Fludarabine, Bosutinib, Resveratrol, Cryptotranshinone, Nicolasamide, Napabucasin), mast cell stabilizers (e.g., Nedocromil, 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.

[0069] 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.

[0070] 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), 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.

[0071] 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.

[0072] The following examples illustrate certain embodiments of the present invention and are not intended to be limiting.

[0073] 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.

[0074] Example 1 Prepare a roflumilast cream having formulation 1 as disclosed in Table 2.

[0075] Table 2. Composition of Formulation 1

[0076] Example 2 Prepare a roflumilast cream having formulation 2 as disclosed in Table 3.

[0077] Table 3. Composition of Formulation 2

[0078] Example 3 Prepare roflumilast cream having formulation 3 as disclosed in Table 4.

[0079] Table 4. Composition of Formulation 3

[0080] Example 4 Roflumilast foam of formulation 4 disclosed in Table 5 was prepared.

[0081] Table 5. Composition of Formulation 4

[0082] Example 5 Roflumilast cream having formulation 5 as disclosed in Table 6 will be prepared.

[0083] Table 6. Composition of Formulation 5

[0084] Example 6 A phase III, multicenter, open-label clinical trial was conducted to investigate the efficacy of topical roflumilast cream in the treatment of patients with atopic dermatitis. The primary objective of this study was to evaluate the long-term safety in subjects with atopic dermatitis treated with either 0.15% topical roflumilast cream (≥6 years of age) or 0.05% topical roflumilast cream (2 to 5 years of age) in a multicenter, open-label, single-arm study.

[0085] The primary endpoint of this study was adverse events or serious adverse events. Secondary endpoints included: a validated investigator global assessment (“vIGA-AD”) value of 0 or 1 at each assessment; vIGA-AD success (defined as a vIGA-AD value of 0 or 1 with a grade 2 improvement relative to baseline); changes in the most severe pruritus numerical score (“WI-NRS”) over time; and changes in the eczema area and severity index (“EASI”) score over time.

[0086] All patients participating in this Phase III study applied 0.15% or 0.05% roflumilast topical cream once daily until week 4 of the study. Patients aged 2–5 years received 0.05% roflumilast topical cream, and patients aged 6 years and older received 0.15% roflumilast. Subjects reaching 6 years of age during the study period switched from 0.05% roflumilast topical cream to 0.15% roflumilast topical cream at their first planned clinical visit after their 6th birthday. The study drug was applied to all affected areas except the scalp for up to 24 or 52 weeks. Starting from the week 4 visit, any subject whose vIGA-AD was confirmed to be 0 by the investigator at a planned or unplanned clinical visit switched from once daily to twice weekly application of roflumilast topical cream. The instructions for twice weekly application are to apply roflumilast topical cream on two non-consecutive days each week (e.g., Monday and Thursday) to areas frequently and / or recently affected by atopic dermatitis, as well as any areas where atopic dermatitis is developing.

[0087] Clinical visits and telephone contacts were scheduled at weeks 4, 12, 18, 24, 30, 36, 44, and 52 of the study. At clinical visits, subjects receiving twice-weekly treatment (“maintenance therapy”) were permitted to continue maintenance therapy if their vIGA-AD was 0 or 1. Subjects assessed at clinical visits with a vIGA-AD of 2 or higher were instructed to resume daily application of roflumilast topical cream. If signs or symptoms of atopic dermatitis were not adequately controlled with maintenance therapy, patients could resume daily dosing even if their vIGA-AD was 1.

[0088] By weeks 24 and 52 of the study, 20.1% (N=132) of roflumilast patients achieved vIGA-AD = 0 and switched to maintenance therapy. The median duration of the first maintenance therapy period was ≥124 days in the 24-week cohort and ≥270 days in the 52-week cohort. 65% of these patients were still receiving maintenance therapy at their last visit. Disease control was defined as a vIGA-AD score of 0, switching to maintenance therapy, and maintaining a vIGA-AD score of 0 or 1. Results are summarized in Tables 7-13.

[0089] Table 7. Summary of Study Treatment Exposure and Compliance

[0090] Table 8. Summary of Study Treatment Exposure and Compliance

[0091] Table 9. Summary of the duration (days) of the initial maintenance dosing interval

[0092] Table 10. Summary of the duration (days) of the initial maintenance dosing interval

[0093] Table 11. Summary of the duration (days) of the first disease control interval

[0094] Table 12. Summary of the duration (days) of the first disease control interval

[0095] Results from this Phase III study showed that 46.1% and 51.0% of patients, respectively, achieved a vIGA-AD score of 0 or 1 at weeks 28 and 56, in addition to a grade 2 improvement relative to baseline. Furthermore, 61.5% and 66.2% of patients, respectively, showed a 75% improvement in EASI relative to baseline at weeks 28 and 56, respectively. Overall, the incidence of adverse events was low, and most were mild to moderate. The most frequently reported adverse events (≥2%) included COVID-19, upper respiratory tract infection, nasopharyngitis, and headache. Overall, only 3.0% of trial participants discontinued the study due to adverse events.

[0096] The results further indicated that 20.1% of the subjects (n=132) achieved zero vIGA-AD and switched to twice-weekly (BIW) dosing. The median duration of the initial BIW period was at least 270 days, with at least 124 days in the week 24 cohort and at least 270 days in the week 52 cohort. 65% of these subjects received a single BIW dosing until the last dosing. The mean percentage of total study days receiving maintenance dosing among the 132 patients was 64.1%, and the median was 62.4%. 67.4% of patients received maintenance dosing for more than 50% of the study period, and 42.4% received maintenance dosing for more than 75% of the study period.

[0097] Using the following definition of "disease control," 130 patients (19.8%) met the definition: a vIGA-AD score of 0, switching to BIW (biologically modified) medication, and maintaining a vIGA-AD score of 0 or 1. The median duration of the first "disease control" period was 281 days. 57.7% of patients maintained "disease control" until their last visit. Among these 130 patients, the average percentage of total study days achieving "disease control" was 62.4%, and the median was 60.9%.

[0098] Example 7 A 52-week, phase 3, multicenter, open-label extension 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 0.15% 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.

[0099] Table 13. Demographic and disease characteristics at the start of the trial

[0100] 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.

[0101] 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.

[0102] The research results are presented in Figure 1The figure shows a line graph depicting the proportion of patients in the study who showed an improvement of ≥4 points in the WI-NRS relative to their trial baseline over a 56-week period. The WI-NRS is an 11-point scale ranging from 0 [no pruritus] to 10 [the most conceivable pruritus]. Below is a summary of the changes in vIGA-AD (Table 14) and EASI (Table 15) over time in this study.

[0103] Table 14. Changes in vIGA-AD scores over time

[0104] Table 15. Changes in EASI scores over time

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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 drug composition containing 0.05% or 0.15% roflumilast was applied topically to the patient once a day for four weeks. as well as The drug composition is applied topically to the patient twice a week. The application of twice-weekly administration begins after four weeks of daily administration.

2. The method of claim 1, wherein, with twice-weekly application, the patient maintains a validated Atopic Dermatitis Investigator Global Assessment Scale score of zero or one for 124 days.

3. The method of claim 1, wherein, with twice-weekly application, the patient maintains a validated Atopic Dermatitis Investigator Global Assessment Scale score of zero or one for 52 weeks.

4. The method of claim 1, wherein, with once-daily administration, the patient's validated Atopic Dermatitis Investigator Global Assessment Scale score is zero or one.

5. The method of claim 4, wherein the pharmaceutical composition is administered to the patient twice a week for two to fifty-two weeks.

6. The method of claim 4, wherein, with twice-weekly application, the patient maintains a validated Atopic Dermatitis Investigator Global Assessment Scale score of zero or one for 52 weeks.

7. The method of claim 1, wherein the pharmaceutical composition is a cream comprising a solvent, an emulsifier, water, and a moisturizer.

8. The method of claim 7, wherein the emulsifier comprises cetearyl alcohol, dicetyl phosphate, cetyl alcohol polyether-10 phosphate, or a combination thereof.

9. The method of claim 7, wherein, with twice-weekly application, the patient maintains a validated Atopic Dermatitis Investigator Global Assessment Scale score of zero or one for 124 days.

10. The method of claim 7, wherein, with twice-weekly application, the patient maintains a validated Atopic Dermatitis Investigator Global Assessment Scale score of zero or one for fifty-two weeks.

11. A method for treating a patient suffering from atopic dermatitis, the method comprising: The drug composition containing 0.05% or 0.15% roflumilast was applied topically to the patient once a day until the patient’s validated Investigator’s Global Assessment Scale score for atopic dermatitis reached zero. The drug composition is applied topically to the patient twice a week. The twice-weekly application begins after the once-daily application.

12. The method of claim 11, wherein, with twice-weekly application, the patient maintains a validated Atopic Dermatitis Investigator Global Assessment Scale score of zero or one for 124 days.

13. The method of claim 11, wherein, with twice-weekly application, the patient maintains a validated Atopic Dermatitis Investigator Global Assessment Scale score of zero or one for fifty-two weeks.

14. The method of claim 11, wherein the pharmaceutical composition is administered once daily for four weeks prior to the commencement of twice-weekly administration.

15. The method of claim 14, wherein the pharmaceutical composition is administered twice daily for two to fifty-two weeks.

16. The method of claim 11, wherein the pharmaceutical composition is a cream comprising a solvent, an emulsifier, water, and a moisturizer.

17. The method of claim 16, wherein, with twice-weekly application, the patient maintains a validated Atopic Dermatitis Investigator Global Assessment Scale score of zero or one for 124 days.

18. The method of claim 16, wherein, with twice-weekly application, the patient maintains a validated Atopic Dermatitis Investigator Global Assessment Scale score of zero or one for fifty-two weeks.

19. The method of claim 16, wherein the emulsifier comprises cetearyl alcohol, dicetyl phosphate, cetyl alcohol polyether-10 phosphate, or a combination thereof.

20. The method of claim 19, wherein, with twice-weekly application, the patient maintains a validated Atopic Dermatitis Investigator Global Assessment Scale score of zero or one for fifty-two weeks.

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