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`1
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`AMN1017
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`Mylan (IPR2019-01095) MYLAN1017, p. 001
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`19107DIV(AP)
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`TOPICAL DAPSONE AND DAPSONE/ADAPALENE COMPOSITIONS AND
`
`METHODS FOR USE THEREOF
`
`By
`
`Kevin S. Warner, Ajay P. Parashar, Vijaya Swaminathan, and Varsha Bhatt
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`[001] This application is a divisional of copending U.S. Patent Application No.
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`14/082,955, filed on November 18, 2013, which claims the benefit of U.S. Provisional
`
`Application Ser. No. 611728,403 filed on November 20, 2012 and U.S. Provisional
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`Application Ser. No. 611770,768 filed on February 28, 2013, all of which are incorporated by
`
`reference herein in their entirety.
`
`FIELD
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`[002] The present embodiments relate generally to compositions useful for treating a
`
`variety of dermatological conditions. In particular, some embodiments relate to dapsone and
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`dapsone/adapalene compositions and methods for use thereof.
`
`BACKGROUND
`
`[003] Acne is a group of common skin conditions characterized by the so-called
`
`"acneiform" or acne-like skin eruptions, which can be contaminated with bacteria, such as
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`Propionibacterium acnes, and can also be marked by inflammation. Acne tends to occur in
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`the areas of skin where the sebaceous glands are most active, such as the face. Acne is
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`associated with psychological trauma, and, if left untreated, can lead to scar formation and
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`disfigurement.
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`[004] Classification and the diagnosis of various acne conditions can be complex,
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`and even contradictory. Given this complexity and unpredictability, medication and other
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`therapies, are often developed on a trial-and-error basis in order to determine the most
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`effective course of treatment for a particular patient. The outcome of any particular acne
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`treatment regimen greatly varies from patient to patient, as well as throughout treatment of a
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`particular patient. In addition to the complexity and variability of acne conditions, treatment
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`efficacy can be greatly affected by a patient's compliance with the treatment regimen.
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`Patient compliance during acne treatment may be influenced by side effects, which, for
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`19107DIV(AP)
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`topical medications, commonly include redness, itching, and skin peeling. The complexity of
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`the drug regimen can also negatively affect patient compliance, particularly where two or
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`more different topical medications are prescribed simultaneously. Another factor that
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`negatively affects patient compliance is the cost of a drug regiment, which is considerably
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`higher when multiple medications are prescribed. In some countries, acne is considered a
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`cosmetic problem, and acne treatments are not covered by insurance plans, thus further
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`increasing patient's treatment costs. Certain compositions for treatment of acne are available.
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`Many of the available compositions include one active agent known to have anti-acne
`
`activity. Stability of compositions with multiple anti-acne agents can be problematic. Also,
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`these compositions can be difficult to manufacture.
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`[005] The problems described above are not confined to the treatment or acne, but
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`are also applicable to a variety of other skin conditions, including, but not limited, to
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`conditions or classes of conditions with complex or unknown etiology and that are difficult to
`
`classify or diagnose, in which, nevertheless, topical application of agents are known to be
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`effective at least in some cases. Examples of such conditions or classes of conditions include
`
`psoriasis, rosacea and ichthyosis.
`
`[006] Accordingly, there is a continuing need for compositions and methods used in
`
`a treatment of a variety of skin conditions, such as acne, in which topical application is
`
`potentially effective. The compositions and methods provided herein address these and other
`
`needs in the art.
`
`SUMMARY
`
`[007] Dapsone, (4,4'-diaminodiphenyl sulfone) is a medicament possessing several
`
`beneficial medicinal activities. Dapsone is typically administered as one of the medicinal
`
`agents used in the treatment of leprosy. Dapsone and its derivatives are also effective for
`
`treatment of bacterial infections, protozoal infections such as malaria, pneumocystis carinii,
`
`and plasmonic infections such as toxoplasmosis.
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`[008] Dapsone is also useful as an anti-inflammatory agent. It has been used to treat
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`skin diseases characterized by the abnormal infiltration of neutrophils, such as Dermatitis
`
`herpetiformis, linear IgA dermatosis, pustular psoriasis, pyoderma gangrenosum, acne
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`vulgaris, and Sweet's Syndrome.
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`[009] Use of topical compositions of dapsone can be problematic. Topical
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`compositions may act as drying agents for the skin. They remove essential oils and natural
`
`skin softeners from the skin thus causing it to be dry, itch and crack. Inclusion of exogeneous
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`Mylan (IPR2019-01095) MYLAN1017, p. 007
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`19107DIV(AP)
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`skin emollients, oils and the like, however, causes phase separation and precipitation of
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`dapsone. Use of typical emulsifiers does not solve the dapsone precipitation owing to the
`
`lowered dapsone solubility and conflicting physical characteristics of the phases of the
`
`resulting composition. In particular, topical compositions including dapsone and methods are
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`needed that would, for example, exhibit improved effectiveness, reduced side effects, or both,
`
`when used in a particular patient with a skin condition. Such improved topical compositions
`
`including dapsone and methods of their uses are also needed to improve treatment of patients
`
`with acne or suspected acne. The present dapsone and dapsone/adapalene compositions can
`
`be useful for treating a variety of dermatological conditions. Some useful compositions
`
`include dapsone and/or adapalene in a polymeric viscosity builder. Some compositions can
`
`be adjusted to optimize the dermal delivery profile of dapsone to effectively treat
`
`dermatological conditions and improve the efficiency of pharmaceutical products applied to
`
`the skin. Diethylene glycol monoethyl ether is a solubilizer for dapsone, thereby allowing
`
`compositions to be prepared with increased solubilized concentrations of dapsone. As a
`
`result, the compositions described herein are effective in treating dermatological conditions in
`
`a subject in need thereof.
`
`[010] Moreover, it has been found that use of a polymeric viscosity builder
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`minimizes the intensity of yellowing of the composition caused by the increased solubility of
`
`dapsone in diethylene glycol monoethyl ether. In addition, the polymeric viscosity builder
`
`influences dapsone crystallization. This, in turn, results in compositions with improved
`
`aesthetics (i.e., reduction in particle size which minimizes "gritty" feeling upon application).
`
`[011]
`
`In one embodiment, there are provided compositions including dapsone, a first
`
`solubilizing agent which is diethylene glycol monoethyl ether, optionally at least one second
`
`solubilizing agent, a polymeric viscosity builder, and water, wherein the dapsone is present at
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`a concentration of about 5% w/w to about 10% w/w.
`
`[012]
`
`In one embodiment, there are provided compositions including dapsone, a first
`
`solubilizing agent which is diethylene glycol monoethyl ether, optionally at least one second
`
`solubilizing agent, a polymeric viscosity builder, and water, wherein the dapsone is present at
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`a concentration of about 3% w/w to 8% w/w.
`
`[013]
`
`In another embodiment,
`
`there are provided methods
`
`for
`
`treating a
`
`dermatological condition. Such methods can be performed, for example, by administering to
`
`a subject in need thereof a therapeutically effective amount of a pharmaceutical composition
`
`described herein.
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`19107DIV(AP)
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`BRIEF DESCRIPTION OF THE FIGURES
`
`[014] Figure 1 presents the impact of an acrylamide/sodium acryloyldimethyltaurate
`
`copolymer emulsion viscosity builder on color change.
`
`[015] Figure 2 presents the impact of an acrylamide/sodium acryloyldimethyltaurate
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`copolymer emulsion viscosity builder on dapsone crystal growth.
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`[016] Figure 3 presents the impact of anti-oxidants and chelating agents on color
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`change.
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`DETAILED DESCRIPTION
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`[017]
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`It is to be understood that both the foregoing general description and the
`
`following detailed description are exemplary and explanatory only and do not restrict the
`
`claims. As used herein, the use of the singular includes the plural unless specifically stated
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`otherwise. As used herein, "or" means "and/or" unless stated otherwise. Furthermore, use of
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`the term "including" as well as other forms, such as "includes," and "included," is not
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`limiting. The section headings used herein are for organizational purposes only and are not to
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`be construed as limiting the subject matter described.
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`[018] Some embodiments include compositions and products for treatment of skin
`
`conditions and methods of treating skin conditions. The term "skin condition" as used herein
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`encompasses human and animal conditions, disorders, or diseases affecting skin. Such skin
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`conditions include, but are not limited to, conditions involving skin inflammation, conditions
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`involving sebaceous glands and hair follicles, conditions characterized by acneiform
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`symptoms, and conditions involving skin dryness, skin thickening, skin scaling or skin
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`flaking. Skin conditions that can be treated using some compositions, products and methods
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`described herein include, but are not limited to, acne, rosacea, folliculitis, perioral dermatitis,
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`photodamage, skin aging, psoriasis, ichtiosis, atopic dermatitis, treatment of chronic wounds,
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`bed sores, keratosis piralis, scars, including surgical and acne scars, sebaceous cysts,
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`inflammatory dermatoses, post inflammatory hyperpigmentation, eczema, xerosis, pruritis,
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`lichen planus, nodular prurigo, eczema, and miliaria.
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`[019] The term "acne," as used herein, encompasses skin conditions involving
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`acneiform or acne-like symptoms. For example, a skin condition characterized by follicular
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`eruptions, such as papules and pustules resembling acne, can be categorized as acne. It is to
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`be understood that the term "acne" is not to be limited to diseases and conditions
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`characterized by papules and pustules, but can be characterized by a variety of symptoms. It
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`19107DIV(AP)
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`is also to be understood that a particular patient having acne can be in remission, or the
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`patient's acne can be controlled by continuing treatments, and therefore the patient can
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`exhibit reduced symptoms or be asymptomatic. Nevertheless, continuing treatment of acne
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`can be recommended in such a patient in order to reduce the probability of the return of the
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`acne symptoms.
`
`[020] Symptoms of acne or acne-like conditions include, but are not limited to, the
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`appearance of various skin lesions. The term "lesion" is generally used to denote an infected
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`or diseased patch of skin. A lesion can involve an infected sebaceous gland. Some lesions
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`are more severe than others. Examples of skin lesions are comedones, macules, papules,
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`pustules, nodules and cysts. The term "comedo" (plural "comedones") is used to describe a
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`sebaceous follicle plugged with dirt, other cells, tiny hairs, or bacteria. Comedones include
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`the so-called "blackheads," which can also refer to as "open comedones," which have a spot
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`or a surface that appears black. Comedones also include slightly inflamed, skin colored
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`bumps, as well as "whiteheads," which have a spot or a surface that appears white. The term
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`"macule" generally refers to a flat spot or area of the skin with a changed color, such as a red
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`spot. The term "pustule" is generally used to refer to an inflamed, pus-filled lesion, or a
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`small inflamed elevation of the skin that is filled with pus. The term "papule" is generally
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`used to refer to a small, solid, usually inflammatory elevation of the skin that does not contain
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`pus. The term "nodule" is generally used to refer to an elevation of a skin that is similar to a
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`papule but is white and dome-shaped. Colloquially, a papule, a pustule or a nodule can be
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`referred to as "a pimple" or "a zit." The term "cyst" generally refers to an abnormal
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`membranous sac containing a liquid or semi-liquid substance containing white blood cells,
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`dead cells, and bacteria. Cysts can be painful and extend to deeper layers of skin.
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`[021]
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`In dermatological science and dermatological and cosmetology practice, acne
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`can be classified or categorized into one or more types or categories, according to one or
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`more lines of categorization, such as a predominantly observed type of symptoms, severity of
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`condition or predominant localization. It is to be understood that classification of acne into
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`one of the subtypes does not mean that the characteristics of the classified condition are
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`limited to the symptoms associated with the specific type.
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`[022] Comedonal acne is characterized by the appearance of non-inflammatory
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`lesions, such as blackheads and whiteheads. Localized cystic acne is characterized by
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`appearance of a few cysts on face, chest and back. Diffuse cystic acne is characterized by
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`the appearance of cysts on wide areas of face, chest and back. Nodular acne is characterized
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`by the appearance of nodules. Nodulocystic acne is characterized by appearance of nodules
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`19107DIV(AP)
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`and cysts. Acne vulgaris is a common form of acne characterized by the appearance of
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`several types of lesions, which may appear together or separately. Individual acne lesions
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`usually last less than two weeks but the deeper papules and nodules may persist for months.
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`Acne vulgaris commonly affects adolescents, but it may also appear, persist or become more
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`severe in adulthood. Acne vulgaris may occur on the face, chest, back and sometimes even
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`more extensively.
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`[023] Depending on severity, acne can be mild, moderate or severe. Mild acne is
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`generally categorized by the appearance of with blackheads and whiteheads, but can also
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`include papules and pustules. Moderate acne is generally characterized by appearance of
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`more painful, deep-rooted, inflamed lesions, which can result in scarring. Severe acne is
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`characterized by the appearance of deep-rooted inflammatory lesions, including cysts and
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`nodules which can be painful and can produce scarring. Acne conglobata is a category of
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`acne characterized by highly inflammatory cysts that communicate under the skin with
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`abscesses and burrowing sinus tracts.
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`[024] Some other skin conditions exhibiting acne-like symptoms which can be
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`treated by the compositions and methods described herein are discussed below. Pyoderma
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`faciale, also known as rosacea fulminans, is a condition that appears in females and is
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`characterized by abrupt appearance of inflamed cysts and nodules localized on the face.
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`Rosacea, which can be referred to as acne rosacea, is a condition that can affects both the skin
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`and the eyes and is characterized by redness, bumps, pimples, and, in advanced stages,
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`thickened skin on the nose. In some classification systems, rosacea and acne are considered
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`as separate conditions. Rosacea usually occurs on the face, although the neck and upper
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`chest are also sometimes involved. A mild degree of eye (ocular) involvement occurs in more
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`than fifty percent of people with rosacea. Perioral dermatitis is characterized by the
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`appearance of small tiny papules, pustules, red bumps and scaling with intense itching. It is
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`usually localized to the surrounding area of the mouth and on the chin, or extends to involve
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`the eyelids and the forehead. Gram-negative folliculitis is a bacterial infection characterized
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`by the appearance of pustules and cysts, possibly occurring as a complication resulting from a
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`long term antibiotic treatment of acne vulgaris.
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`[025] As used herein, the terms "treatment" or "treating" in reference to a skin
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`condition generally mean "having positive effect on a skin condition" and encompass
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`alleviation of at least one symptom of a skin condition, a reduction in the severity of the skin
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`conditions, or delay, prevention, or inhibition of the progression of the skin condition.
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`Treatment need not mean that the condition is totally cured. A composition or a product
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`19107DIV(AP)
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`useful for treatment of a skin condition, or a method of treating a skin condition, needs only
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`to reduce the severity of a skin condition, reduce the severity of symptoms associated
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`therewith, provide improvement to a patient's quality of life, or delay, prevent, or inhibit the
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`onset of symptoms of a skin condition.
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`[026]
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`In one embodiment, there are provided compositions including dapsone, a first
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`solubilizing agent which is diethylene glycol monoethyl ether, optionally at least one second
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`solubilizing agent, a polymeric viscosity builder, and water, wherein the dapsone is present at
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`a concentration of about 5% w/w to about 10% w/w, about 1% w/w to about 10% w/w, about
`
`3% w/w to about 10% w/w, about 3% w/w to about 8% w/w, about 4% w/w to about 6%
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`w/w, or about 5%. In certain embodiments, dapsone is present in the composition at 5.0%,
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`5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, or 10.0% w/w.
`
`[027]
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`In
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`some
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`embodiments,
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`the
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`polymeric
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`viscosity builder
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`IS
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`an
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`acrylamide/sodium acryloyldimethyltaurate copolymer, and further includes isohexadecane,
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`sorbitan oleate, water, and Polysorbate 80.
`
`In some embodiments, the polymeric viscosity
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`builder is present at a concentration of about 2% w/w to about 6% w/w.
`
`In some
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`embodiments, the polymeric viscosity builder is present at a concentration of about 3% w/w
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`to about 5% w/w. In some embodiments, the polymeric viscosity builder is present in the
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`composition at about 4% w/w.
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`[028]
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`In some embodiments, diethylene glycol monoethyl ether is present at a
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`concentration of about 25% w/w to about 40% w/w. In some embodiments, diethylene glycol
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`monoethyl ether is present at a concentration of about 30% w/w to about 40% w/w. In some
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`embodiments, diethylene glycol monoethyl ether is present at a concentration of about 35%
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`w/w to about 40% w/w.
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`[029]
`
`In some embodiments, diethylene glycol monoethyl ether is present at a
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`concentration of about 10% w/w to about 40% w/w, about 20% w/w to about 30% w/w, or
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`about 25%.
`
`[030]
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`In another embodiment, there are provided compositions further including
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`adapalene. In some embodiments, adapalene is present at a concentration of about 0.1% w/w
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`to about 0.3% w/w.
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`[031]
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`In some embodiments, the second solubilizing agent is selected from alcohols,
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`glycols, esters, ethers, or silicones. Such second solubilizing agents include, but are not
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`limited to, PEG 400, lactic acid, dimethyl isosorbide, propylene glycol, propylene carbonate,
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`hexylene glycol, isostearyl alcohol, benzyl alcohol, diethyl sebacate, and ethanol.
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`19107DIV(AP)
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`[032]
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`In certain embodiments, the second solubilizing agent is propylene glycol. In
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`some embodiments, propylene glycol is present at a concentration of about 2% w/w to 8%
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`w/w.
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`In some embodiments, propylene glycol is present at a concentration of about 3% w/w
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`to 7% w/w. In some embodiments, propylene glycol is present in the composition at about
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`5%w/w.
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`[033]
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`In certain embodiments, the second solubilizing agent is propylene carbonate.
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`In some embodiments, propylene carbonate is present at a concentration of about 2% w/w to
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`8% w/w.
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`In some embodiments, propylene carbonate is present at a concentration of about
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`3% w/w to 7% w/w.
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`In some embodiments, propylene carbonate is present in the
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`composition at about 5% w/w.
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`[034]
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`In certain embodiments, the second solubilizing agent is ethanol.
`
`In some
`
`embodiments, ethanol is present at a concentration of about 1% w/w to about 5% w/w.
`
`In
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`some embodiments, ethanol is present at a concentration of about 2% w/w to about 4% w/w.
`
`In some embodiments, ethanol is present in the composition at about 3% w/w.
`
`[035]
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`[036]
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`In some embodiments, the compositions further include methyl paraben.
`
`In other embodiments,
`
`the compositions
`
`further
`
`include carbomer
`
`homopolymer type C. In some embodiments, carbomer homopolymer type C is present at a
`
`concentration of about 0.7% w/w to about 1.5% w/w.
`
`In other embodiments, carbomer
`
`homopolymer type C is present at a concentration of about 0.85% w/w to about 1.0% w/w.
`
`[037]
`
`In some embodiments, the compositions further include a neutralizing agent.
`
`In certain embodiments, the neutralizing agent is an ionic or amine buffer.
`
`In certain
`
`embodiments, the neutralizing agent is sodium hydroxide or triethanolamine.
`
`Use of a
`
`neutralizing agent results in compositions typically having a pH from 5.5 to 6.5.
`
`[038]
`
`In some embodiments, the compositions further include a chelating agent. In
`
`some embodiments, the chelating agent is ethylenediamine tetraacetic acid (EDTA). EDTA
`
`is typically present in the compositions from about 0.02% w/w to about 0.04% w/w.
`
`In
`
`certain embodiments, EDTA is present in the compositions at about 0.03% w/w.
`
`[039] Compositions described herein are typically in the form of a gel, an emulsion,
`
`a cream, a liquid, a paste, a lotion, a nanoemulsion, a microemulsion, a reverse emulsion, or a
`
`liposomal cream.
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`EMBODIMENTS
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`[040] The following embodiments are specifically contemplated herein.
`
`Embodiment 1.
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`A composition comprising dapsone, a first solubilizing agent
`
`which is diethylene glycol monoethyl ether, optionally at least one second solubilizing
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`agent, a polymeric viscosity builder, and water, wherein the dapsone is present in the
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`composition at a concentration of about 3% w/w to about 10% w/w.
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`Embodiment 2.
`
`The composition of embodiment 1, wherein the diethylene
`
`glycol monoethyl ether is present at a concentration of about 10% w/w to about 40%
`
`w/w.
`
`Embodiment 3.
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`The composition of embodiment 1, wherein the diethylene
`
`glycol monoethyl ether is present at a concentration of about 20% w/w to about 30%
`
`w/w.
`
`Embodiment 4.
`
`The composition of embodiment 1, wherein the diethylene
`
`glycol monoethyl ether is present in the composition at a concentration of about 25%
`
`w/w.
`
`Embodiment 5.
`
`The composition of embodiment 1,
`
`further compnsmg
`
`adapalene.
`
`Embodiment 6.
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`The composition of embodiment 5, wherein the adapalene is
`
`present at a concentration of about 0.1% w/w to about 0.3% w/w.
`
`Embodiment 7.
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`The composition of embodiment 1 wherein
`
`the second
`
`solubilizing agent is selected an alcohol, a glycol, an ester, or an ether.
`
`Embodiment 8.
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`The composition of embodiment 1, wherein the second
`
`solubilizing agent is PEG 400, lactic acid, dimethyl isosorbide, propylene glycol,
`
`propylene carbonate, hexylene glycol, isostearyl alcohol, diethyl sebacate, or ethanol.
`
`Embodiment 9.
`
`The composition of embodiment 8, wherein the second
`
`solubilizing agent is propylene glycol.
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`Embodiment 10.
`
`The composition of embodiment 9, wherein the propylene
`
`glycol is present in the composition at a concentration of about 5% w/w.
`
`Embodiment 11.
`
`The composition of embodiment 8, wherein the second
`
`solubilizing agent is propylene carbonate.
`
`Embodiment 12.
`
`The composition of embodiment 11, wherein the propylene
`
`carbonate is present in the composition at a concentration of about 5% w/w.
`
`Embodiment 13.
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`The composition of embodiment 8, wherein the second
`
`solubilizing agent is ethanol.
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`Embodiment 14.
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`The composition of embodiment 13, wherein the ethanol IS
`
`present in the composition at a concentration of about 3% w/w.
`
`Embodiment 15.
`
`The composition of embodiment 1, wherein the polymeric
`
`viscosity builder
`
`compnses
`
`an
`
`acrylamide/sodium
`
`acryloyldimethyltaurate
`
`copolymer.
`
`Embodiment 16.
`
`The composition of embodiment 1, wherein the polymeric
`
`viscosity builder is present at a concentration of about 2% w/w to about 6% w/w.
`
`Embodiment 1 7.
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`The composition of embodiment 1, wherein the polymeric
`
`viscosity builder is present at a concentration of about 4% w/w.
`
`Embodiment 18.
`
`The composition of embodiment 1, further comprising methyl
`
`paraben.
`
`Embodiment 19.
`
`The composition of embodiment 1,
`
`further compnsmg
`
`Carbomer interpolymer type A, Carbomer interpolymer type B, or Carbomer
`
`Homopolymer Type C.
`
`Embodiment 20.
`
`The composition of embodiment 19, wherein the Carbomer
`
`Homopolymer Type C is present at a concentration of about 0. 7% w/w to about 1.5%
`
`w/w.
`
`Embodiment 21.
`
`The composition of embodiment 19, wherein the Carbomer
`
`Homopolymer Type C is present at a concentration of about 0.85% w/w to about
`
`1.5%w/w.
`
`Embodiment 22.
`
`The composition of embodiment 19, wherein the Carbomer
`
`interpolymer Type A is present at a concentration of about 1% w/w to 2% w/w.
`
`Embodiment 23.
`
`The composition of embodiment 19, wherein the Carbomer
`
`interpolymer Type B is present at a concentration of about 0.1% w/w to about 0.5%
`
`w/w.
`
`Embodiment 24.
`
`The composition of embodiment 1, further compnsmg a
`
`neutralizing agent.
`
`Embodiment 25.
`
`The composition of embodiment 24 wherein the neutralizing
`
`agent is NaOH or triethanolamine.
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`Embodiment 26.
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`The composition of embodiment 1 further compnsmg a
`
`chelating agent.
`
`Embodiment 27.
`
`The composition of embodiment 26, wherein the chelating
`
`agent is ethylene diamine tetraacetic acid.
`
`Embodiment 28.
`
`The composition of embodiment 27, wherein the ethylene
`
`diamine tetraacetic acid is present at a concentration of about 0.02% w/w to about
`
`0.04%w/w.
`
`Embodiment 29.
`
`The composition of embodiment 27, wherein the ethylene
`
`diamine tetraacetic acid is present in the composition at about 0.03% w/w.
`
`Embodiment 30.
`
`The composition of embodiment 1 wherein the composition is
`
`in the form of a gel, a suspension, an emulsion, a cream, a liquid, a paste, a lotion, a
`
`nanoemulsion, a microemulsion, a reverse emulsion, or a liposomal cream.
`
`Embodiment 31.
`
`A method for treating a dermatological condition comprising
`
`administering to a subject in need thereof a therapeutically effective amount of a
`
`composition of embodiment 1.
`
`Embodiment 32.
`
`The method of embodiment 31 wherein the condition is acne
`
`vulgaris, rosacea, atopic dermatitis, treatment of chronic wounds, bed sores, keratosis
`
`piralis,
`
`sebaceous
`
`cysts,
`
`inflammatory
`
`dermatoses,
`
`post
`
`inflammatory
`
`hyperpigmentation, eczema, xerosis, pruritis,
`
`lichen planus, nodular prurigo,
`
`dermatitis, eczema, or miliaria.
`
`Embodiment 3 3.
`
`The method of embodiment 32 wherein the condition is acne
`
`vulgaris.
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`Embodiment 34.
`
`The composition of embodiment 1, 2, 3, or 4, further
`
`comprising adapalene.
`
`Embodiment 35.
`
`The composition of embodiment 34, wherein the adapalene is
`
`present at a concentration of about 0.1% w/w to about 0.3% w/w.
`
`Embodiment 36.
`
`The composition of embodiment 1, 2, 3, 4, 34, or 35, wherein
`
`the second solubilizing agent is selected an alcohol, a glycol, an ester, or an ether.
`
`Embodiment 3 7.
`
`The composition of embodiment 1, 2, 3, 4, 34, 35, or 36,
`
`wherein the second solubilizing agent is PEG 400, lactic acid, dimethyl isosorbide,
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`propylene glycol, propylene carbonate, hexylene glycol, isostearyl alcohol, diethyl
`
`sebacate, or ethanol.
`
`Embodiment 38.
`
`The composition of embodiment 37, wherein the second
`
`solubilizing agent is propylene glycol.
`
`Embodiment 3 9.
`
`The composition of embodiment 38, wherein the propylene
`
`glycol is present in the composition at a concentration of about 5% w/w.
`
`Embodiment 40.
`
`The composition of embodiment 37, wherein the second
`
`solubilizing agent is propylene carbonate.
`
`Embodiment 41.
`
`The composition of embodiment 40, wherein the propylene
`
`carbonate is present in the composition at a concentration of about 5% w/w.
`
`Embodiment 42.
`
`The composition of embodiment 37, wherein the second
`
`solubilizing agent is ethanol.
`
`Embodiment 43.
`
`The composition of embodiment 42, wherein the ethanol IS
`
`present in