USOO9517219B2
`
`(12) United States Patent
`US 9,517,219 B2
`(10) Patent No.:
`Warner et al.
`(45) Date of Patent:
`Dec. 13, 2016
`
`(54)
`
`TOPICAL DAPSONE AND
`DAPSONE/ADAPALENE COMPOSITIONS
`AND METHODS FOR USE THEREOF
`
`(56)
`
`References Cited
`U. S. PATENT DOCUMENTS
`
`(71)
`
`Applicant: Allergan, Inc., Irvine, CA (US)
`
`(72)
`
`Inventors: Kevin S. Warner, Anaheim, CA (US);
`Ajay P. Parashar, Fairfax, VA (US);
`Vijaya Swaminathan, San Francisco,
`CA (US); Varsha Bhatt, San Francisco,
`CA (US)
`
`(73)
`
`Assignee: Allergan, Inc., Irvine, CA (US)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`5,532,219 A *
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`5,863,560 A
`5,989,571 A *
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`7/1996 McGeer ............... A61K31/145
`514/42
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`1/1999 Osborne
`11/1999 Santa ....................... A61K9/12
`424/401
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`6,060,085 A
`6,620,435 B1
`7,531,694 132
`8,586,010 132*
`
`5/2000 Osborne
`9/2003 Osborne
`5/2009 Villa et al.
`11/2013 Garrett ..................... A61K8/46
`424/59
`................ A61K9/0014
`9,161,926 132* 10/2015 Warner
`2006/0204526 A1
`9/2006 Lathrop et a1.
`2010/0029781 A1
`2/2010 Morris
`2010/0130613 A1
`5/2010 Dreno
`2012/0064144 A1*
`3/2012 Benhamou ........... A61K 9/7023
`424/443
`
`FOREIGN PATENT DOCUMENTS
`
`(21)
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`Appl. No.: 14/885,805
`
`(22)
`
`Filed:
`
`Oct. 16, 2015
`
`(65)
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`Prior Publication Data
`
`US 2016/0030580 A1
`
`Feb. 4, 2016
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`W0
`WO
`W0
`W0
`WO
`WO
`W0
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`WO 2009/061298 Al *
`2009-108147
`WO 2009/108147 Al *
`WO 2010/105052 Al *
`WO2010105052 Al
`WO2011-014627
`WO 2011/014627 Al *
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`5/2009
`9/2009
`9/2009
`9/2010
`9/2010
`2/2011
`2/2011
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`Related U.S. Application Data
`
`(62)
`
`Division of application No. 14/082,955, filed on Nov.
`18, 2013, now Pat. No. 9,161,926.
`
`(60)
`
`Provisional application No. 61/728,403, filed on Nov.
`20, 2012, provisional application No. 61/770,768,
`filed on Feb. 28, 2013.
`
`Int. Cl.
`
`(51)
`
`A61K 31/136
`A61K 31/192
`A61K 9/00
`A61K 31/145
`A61K 47/32
`A61K 47/10
`A61K 47/14
`A61K 47/18
`A61K 47/34
`U.S. Cl.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`CPC ........... A61K 31/192 (2013.01); A61K 9/0014
`(2013.01); A61K 31/136 (2013.01); A61K
`31/145 (2013.01); A61K 47/10 (2013.01);
`A61K 47/14 (2013.01); A61K 47/183
`(2013.01); A61K 47/32 (2013.01); A61K 47/34
`(2013.01)
`
`Field of Classification Search
`None
`
`See application file for complete search history.
`
`(52)
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`(58)
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`OTHER PUBLICATIONS
`
`Draelos, Zoe D. et a1., TWO Randomized Studies Demonstrate the
`Efficacy and Safety of Dapsone Gel, 5% for the Treatment of Acne
`Vulgaris, Journal of American Academy of Dermatology, Mar.
`2007, 26 Pages, 56, US.
`Lubrizol (Online). “Viscosity of CARBOPOL Polymers in Aqueous
`Systems”.
`(Retrieved Mar.
`18, 2014). Retrieved from the
`Internet<URL:http://WWW.lubrizol.com/Life-Science/Documents/
`Pharmaceutical/Technical-Data-Sheets/TDS-730-Viscosity-
`Carbopol-in-Aqueous-Systems.pdf>.
`Notification of Transmittal of the International Search Report and
`the Written Opinion of the International Searching Authority, or the
`Declaration, International Application No. PCT/US2013/0706l3,
`International Filing Date, Nov. 18, 2013, Date of Mailing Feb. 12,
`2014.
`
`* cited by examiner
`
`Primary Examiner 7 Leslie A. Royds Draper
`(74) Attorney, Agent, or Firm 7 Laura L. Wine
`
`ABSTRACT
`(57)
`Dapsone and dapsone/adapalene compositions can be useful
`for treating a variety of dermatological conditions. The
`compositions of this disclosure include dapsone and/or
`adapalene in a polymeric viscosity builder. Subject compo-
`sitions can be adjusted to optimize the dermal delivery
`profile of dapsone to effectively treat dermatological condi-
`tions and improve the efficiency of pharmaceutical products
`applied to the skin. Use of the polymeric viscosity builder
`provides compositions with increased concentrations of
`diethylene glycol monoethyl ether relative to compositions
`without the polymeric viscosity builder.
`8 Claims, 3 Drawing Sheets
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`Almirall EXHIBIT 2054
`Almirall EXHIBIT 2054
`Amneal v. Almirall
`Amneal v. Almirall
`IPR2018-00608
`IPR2018—00608
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`U.S. Patent
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`Dec. 13, 2016
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`Sheet 1 013
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`US 9,517,219 B2
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`Figure 1. Appearance of formulations following 4 weeks of storage
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`Al
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`tinitiai time oint
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`A2 at initial time oint
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` A1 after 4 weeks storage at 25°C
`A2 after 4 weeks storage at 25°C
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`A] after 4 weeks storage at 409C
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`A2 after 4 weeks storage at 40"C
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`U.S. Patent
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`Dec. 13, 2016
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`Sheet 2 013
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`US 9,517,219 B2
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`Figure 2. Polarized light images of dapsone in suspension formulations
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`U.S. Patent
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`Dec. 13, 2016
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`Sheet 3 013
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`US 9,517,219 B2
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`Figure 3. Appearance of formulations with antioxidants or chelating agents over 4 weeks
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`A5 at Initial timepoint
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`A6 at Initial timepoint
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`A7 at initial timepoint
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`A5 after 4 weeks storage at A6 after 4 weeks storage at
`40%:
`40"C
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`A7 after 4 weeks
`storage at 40%:
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`US 9,517,219 B2
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`1
`TOPICAL DAPSONE AND
`DAPSONE/ADAPALENE COMPOSITIONS
`AND METHODS FOR USE THEREOF
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a divisional of copending US. patent
`application Ser. No. 14/082,955, filed on Nov. 18, 2013,
`which claims the benefit of US. Provisional Application Ser.
`No. 61/728,403 filed on Nov. 20, 2012 and US. Provisional
`Application Ser. No. 61/770,768 filed on Feb. 28, 2013, all
`of which are incorporated by reference herein in their
`entirety.
`
`FIELD
`
`The present embodiments relate generally to composi-
`tions useful for treating a variety of dermatological condi-
`tions. In particular, some embodiments relate to dapsone and
`dapsone/adapalene compositions and methods
`for use
`thereof.
`
`BACKGROUND
`
`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 Propioni—
`bacterium acnes, and can also be marked by inflammation.
`Acne tends to occur in the areas of skin where the sebaceous
`
`glands are most active, such as the face. Acne is associated
`with psychological trauma, and, if left untreated, can lead to
`scar formation and disfigurement.
`Classification and the diagnosis of various acne condi-
`tions can be complex, and even contradictory. Given this
`complexity and unpredictability, medication and other thera-
`pies, are often developed on a trial-and-error basis in order
`to determine the most effective course of treatment for a
`
`particular patient. The outcome of any particular acne treat-
`ment regimen greatly varies from patient to patient, as well
`as throughout treatment of a particular patient. In addition to
`the complexity and variability of acne conditions, treatment
`eflicacy can be greatly affected by a patient’s compliance
`with the treatment regimen. Patient compliance during acne
`treatment may be influenced by side effects, which, for
`topical medications, commonly include redness, itching, and
`skin peeling. The complexity of the drug regimen can also
`negatively affect patient compliance, particularly where two
`or more different topical medications are prescribed simul-
`taneously. Another factor that negatively affects patient
`compliance is the cost of a drug regiment, which is consid-
`erably higher when multiple medications are prescribed. In
`some countries, acne is considered a cosmetic problem, and
`acne treatments are not covered by insurance plans, thus
`further increasing patient’s treatment costs. Certain compo-
`sitions for treatment of acne are available. Many of the
`available compositions include one active agent known to
`have anti-acne activity. Stability of compositions with mul-
`tiple anti-acne agents can be problematic. Also, these com-
`positions can be diflicult to manufacture.
`The problems described above are not confined to the
`treatment or acne, but are also applicable to a variety of other
`skin conditions, including, but not limited, to conditions or
`classes of conditions with complex or unknown etiology and
`that are diflicult to classify or diagnose, in which, neverthe-
`less, topical application of agents are known to be effective
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`in some cases. Examples of such conditions or
`at least
`classes of conditions include psoriasis, rosacea and ichthyo-
`sis.
`
`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 pro-
`vided herein address these and other needs in the art.
`
`SUMMARY
`
`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, pneumocyslis carinii, and plas-
`monic infections such as toxoplasmosis.
`Dapsone is also useful as an anti-inflammatory agent. It
`has been used to treat skin diseases characterized by the
`abnormal
`infiltration of neutrophils, such as Dermatitis
`herpetiformis, linear IgA dermatosis, pustular psoriasis, pyo-
`derma gangrenosum, acne vulgaris, and Sweet’s Syndrome.
`Use of topical compositions of dapsone can be problem-
`atic. Topical 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 exogenous skin emollients, oils and the like,
`however, causes phase separation and precipitation of dap-
`sone. 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 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 con-
`ditions. Some useful compositions include dapsone and/or
`adapalene in a polymeric viscosity builder. Some composi-
`tions can be adjusted to optimize the dermal delivery profile
`of dapsone to effectively treat dermatological conditions and
`improve the efliciency 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.
`
`it has been found that use of a polymeric
`Moreover,
`viscosity builder minimizes the intensity of yellowing of the
`composition caused by the increased solubility of dapsone in
`diethylene glycol monoethyl ether. In addition, the poly-
`meric viscosity builder influences dapsone crystallization.
`This, in turn, results in compositions with improved aes-
`thetics (i.e., reduction in particle size which minimizes
`“gritty” feeling upon application).
`In one embodiment,
`there are provided compositions
`including dapsone, a first solubilizing agent which is dieth-
`ylene glycol monoethyl ether, optionally at least one second
`solubilizing agent, a polymeric viscosity builder, and water,
`wherein the dapsone is present at a concentration of about
`5% w/w to about 10% w/w.
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`US 9,517,219 B2
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`3
`there are provided compositions
`In one embodiment,
`including dapsone, a first solubilizing agent which is dieth-
`ylene glycol monoethyl ether, optionally at least one second
`solubilizing agent, a polymeric Viscosity builder, and water,
`wherein the dapsone is present at a concentration of about
`3% w/w to 8% w/w.
`
`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 phar-
`maceutical composition described herein.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`FIG. 1 presents the impact of an acrylamide/sodium
`acryloyldimethyltaurate
`copolymer
`emulsion Viscosity
`builder on color change.
`FIG. 2 presents the impact of an acrylamide/sodium
`acryloyldimethyltaurate
`copolymer
`emulsion Viscosity
`builder on dapsone crystal growth.
`FIG. 3 presents the impact of anti-oxidants and chelating
`agents on color change.
`
`DETAILED DESCRIPTION
`
`It is to be understood that both the foregoing general
`description and the following detailed description are exem-
`plary and explanatory only and do not restrict the claims. As
`used herein, the use of the singular includes the plural unless
`specifically stated otherwise. As used herein, “or” means
`“and/or” unless stated otherwise. Furthermore, use of the
`term “including” as well as other forms, such as “includes,”
`and “included,” is not limiting. The section headings used
`herein are for organizational purposes only and are not to be
`construed as limiting the subject matter described.
`Some embodiments include compositions and products
`for treatment of skin conditions and methods of treating skin
`conditions. The term “skin condition” as used herein encom-
`
`passes human and animal conditions, disorders, or diseases
`affecting skin. Such skin conditions include, but are not
`limited to, conditions involving skin inflammation, condi-
`tions involving sebaceous glands and hair follicles, condi-
`tions characterized by acneiform symptoms, and conditions
`involving skin dryness, skin thickening, skin scaling or skin
`flaking. Skin conditions that can be treated using some
`compositions, products and methods described herein
`include, but are not limited to, acne, rosacea, folliculitis,
`perioral dermatitis, photodamage, skin aging, psoriasis, ich-
`thyosis, atopic dermatitis, treatment of chronic wounds, bed
`sores, keratosis pilaris scars, including surgical and acne
`scars,
`sebaceous cysts,
`inflammatory dermatoses, post
`inflammatory hyperpigmentation, eczema, xerosis, pruritus,
`lichen planus, nodular prurigo, eczema, and miliaria.
`The term “acne,” as used herein, encompasses skin con-
`ditions involving acneiform or acne-like symptoms. For
`example, a skin condition characterized by follicular erup-
`tions, such as papules and pustules resembling acne, can be
`categorized as acne. It is to be understood that the term
`“acne” is not
`to be limited to diseases and conditions
`
`characterized by papules and pustules, but can be charac-
`terized by a Variety of symptoms. It is also to be understood
`that a particular patient having acne can be in remission, or
`the patient’s acne can be controlled by continuing treat-
`ments, and therefore the patient can exhibit reduced symp-
`toms or be asymptomatic. Nevertheless, continuing treat-
`ment of acne can be recommended in such a patient in order
`to reduce the probability of the return of the acne symptoms.
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`Symptoms of acne or acne-like conditions include, but are
`not limited to, the appearance of Various skin lesions. The
`term “lesion” is generally used to denote an infected or
`diseased patch of skin. A lesion can involve an infected
`sebaceous gland. Some lesions are more severe than others.
`Examples of skin lesions are comedones, macules, papules,
`pustules, nodules and cysts. The term “comedo” (plural
`“comedones”)
`is used to describe a sebaceous follicle
`plugged with dirt, other cells, tiny hairs, or bacteria. Come-
`dones include the so-called “blackheads,” which can also
`refer to as “open comedones,” which have a spot or a surface
`that appears black. Comedones
`also include slightly
`inflamed, skin colored bumps, as well as “whiteheads,”
`which have a spot or a surface that appears white. The term
`“macule” generally refers to a flat spot or area of the skin
`with a changed color, such as a red spot. The term “pustule”
`is generally used to refer to an inflamed, pus-filled lesion, or
`a small inflamed elevation of the skin that is filled with pus.
`The term “papule” is generally used to refer to a small, solid,
`usually inflammatory elevation of the skin that does not
`contain pus. The term “nodule” is generally used to refer to
`an elevation of a skin that is similar to a papule but is white
`and dome-shaped. Colloquially, a papule, a pustule or a
`nodule can be referred to as “a pimple” or “a zit.” The term
`“cyst” generally refers to an abnormal membranous sac
`containing a liquid or semi-liquid substance containing
`white blood cells, dead cells, and bacteria. Cysts can be
`painful and extend to deeper layers of skin.
`In dermatological science and dermatological and cosme-
`tology practice, acne can be classified or categorized into
`one or more types or categories, according to one or more
`lines of categorization, such as a predominantly observed
`type of symptoms, severity of condition or predominant
`localization. It is to be understood that classification of acne
`
`into one of the subtypes does not mean that the character-
`istics of the classified condition are limited to the symptoms
`associated with the specific type.
`Comedonal acne is characterized by the appearance of
`non-inflammatory lesions, such as blackheads and white-
`heads. Localized cystic acne is characterized by appearance
`of a few cysts on face, chest and back. Diffuse cystic acne
`is characterized by the appearance of cysts on wide areas of
`face, chest and back. Nodular acne is characterized by the
`appearance of nodules. Nodulocystic acne is characterized
`by appearance of nodules and cysts. Acne vulgaris is a
`common form of acne characterized by the appearance of
`several
`types of lesions, which may appear together or
`separately. Individual acne lesions usually last less than two
`weeks but the deeper papules and nodules may persist for
`months. Acne vulgaris commonly affects adolescents, but it
`may also appear, persist or become more severe in adult-
`hood. Acne vulgaris may occur on the face, chest, back and
`sometimes even more extensively.
`Depending on severity, acne can be mild, moderate or
`severe. Mild acne is generally categorized by the appearance
`of with blackheads and whiteheads, but can also include
`papules and pustules. Moderate acne is generally character-
`ized by appearance of more painful, deep-rooted, inflamed
`lesions, which can result in scarring. Severe acne is char-
`acterized by the appearance of deep-rooted inflammatory
`lesions, including cysts and nodules which can be painful
`and can produce scarring. Acne conglobata is a category of
`acne characterized by highly inflammatory cysts that com-
`municate under the skin with abscesses and burrowing sinus
`tracts.
`
`Some other skin conditions exhibiting acne-like symp-
`toms which can be treated by the compositions and methods
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`US 9,517,219 B2
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`5
`described herein are discussed below. Pyoderma faciale, also
`known as rosacea fulminans, is a condition that appears in
`females and is characterized by abrupt appearance of
`inflamed cysts and nodules localized on the face. Rosacea,
`which can be referred to as acne rosacea, is a condition that
`can affects both the skin and the eyes and is characterized by
`redness, bumps, pimples, and, in advanced stages, thickened
`skin on the nose. In some classification systems, rosacea and
`acne are considered as separate conditions. Rosacea usually
`occurs on the face, although the neck and upper chest are
`also sometimes involved. A mild degree of eye (ocular)
`involvement occurs in more than fifty percent of people with
`rosacea. Perioral dermatitis is characterized by the appear-
`ance of small tiny papules, pustules, red bumps and scaling
`with intense itching. It is usually localized to the surround-
`ing area of the mouth and on the chin, or extends to involve
`the eyelids and the forehead. Gram-negative folliculitis is a
`bacterial infection characterized by the appearance of pus-
`tules and cysts, possibly occurring as a complication result-
`ing from a long term antibiotic treatment of acne vulgaris.
`As used herein, the terms “treatment” or “treating” in
`reference to a skin condition generally mean “having posi-
`tive effect on a skin condition” and encompass alleviation of
`at least one symptom of a skin condition, a reduction in the
`severity of the skin conditions, or delay, prevention, or
`inhibition of the progression of the skin condition. Treat-
`ment need not mean that the condition is totally cured. A
`composition or a product useful for treatment of a skin
`condition, or a method of treating a skin condition, needs
`only to reduce the severity of a skin condition, reduce the
`severity of
`symptoms
`associated therewith,
`provide
`improvement to a patient’s quality of life, or delay, prevent,
`or inhibit the onset of symptoms of a skin condition.
`In one embodiment,
`there are provided compositions
`including dapsone, a first solubilizing agent which is dieth-
`ylene glycol monoethyl ether, optionally at least one second
`solubilizing agent, a polymeric viscosity builder, and water,
`wherein the dapsone is present at 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% w/w, or about
`5%.
`In certain embodiments, dapsone is present
`in the
`composition at 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%,
`8.5%, 9.0%, 9.5%, or 10.0% w/w.
`In some embodiments, the polymeric viscosity builder is
`an acrylamide/sodium acryloyldimethyltaurate copolymer,
`and further includes isohexadecane, sorbitan oleate, water,
`and Polysorbate 80. In some embodiments, the polymeric
`viscosity builder is present at a concentration of about 2%
`w/w to about 6% w/w. In some embodiments, the polymeric
`viscosity builder is present at a concentration of about 3%
`w/w to about 5% w/w. In some embodiments, the polymeric
`viscosity builder is present in the composition at about 4%
`w/w.
`
`In some embodiments, diethylene glycol monoethyl ether
`is present at a concentration of about 25% w/w to about 40%
`w/w. In some embodiments, diethylene glycol monoethyl
`ether is present at a concentration of about 30% w/w to about
`40% w/w. In some embodiments, diethylene glycol mono-
`ethyl ether is present at a concentration of about 35% w/w
`to about 40% w/w.
`
`In some embodiments, diethylene glycol monoethyl ether
`is present at a concentration of about 10% w/w to about 40%
`w/w, about 20% w/w to about 30% w/w, or about 25%.
`
`6
`In another embodiment, there are provided compositions
`further including adapalene. In some embodiments, ada-
`palene is present at a concentration of about 0.1% w/w to
`about 0.3% w/w.
`
`In some embodiments, the second solubilizing agent is
`selected from alcohols, glycols, esters, ethers, or silicones.
`Such second solubilizing agents include, but are not limited
`to, PEG 400,
`lactic acid, dimethyl isosorbide, propylene
`glycol, propylene carbonate, hexylene glycol,
`isostearyl
`alcohol, benzyl alcohol, diethyl sebacate, and ethanol.
`In certain embodiments, the second solubilizing agent is
`propylene glycol. In some embodiments, propylene glycol is
`present at a concentration of about 2% w/w to 8% w/w. In
`some embodiments, propylene glycol is present at a con-
`centration of about 3% w/w to 7% w/w. In some embodi-
`
`ments, propylene glycol is present in the composition at
`about 5% w/w.
`
`In certain embodiments, the second solubilizing agent is
`propylene carbonate. In some embodiments, propylene car-
`bonate is present at a concentration of about 2% w/w to 8%
`w/w. In some embodiments, propylene carbonate is present
`at a concentration of about 3% w/w to 7% w/w. In some
`
`10
`
`15
`
`20
`
`25
`
`embodiments, propylene carbonate is present in the compo-
`sition at about 5% w/w.
`
`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 some
`
`30
`
`35
`
`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.
`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 embodi-
`
`ments, carbomer homopolymer type C is present at a con-
`centration of about 0.85% w/w to about 1.0% w/w.
`
`40
`
`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 trietha-
`nolamine. Use of a neutralizing agent results in composi-
`tions typically having a pH from 5.5 to 6.5.
`In some embodiments, the compositions further include a
`chelating agent. In some embodiments, the chelating agent
`is ethylene diamine tetraacetic acid (EDTA). EDTA is typi-
`cally 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.
`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.
`
`EMBODIMENTS
`
`The following embodiments are specifically contemplated
`herein.
`
`Embodiment 1
`
`A composition comprising dapsone, a first solubilizing
`agent which is diethylene glycol monoethyl ether, optionally
`at least one second solubilizing agent, a polymeric viscosity
`
`45
`
`50
`
`55
`
`60
`
`65
`
`70f12
`
`7 of 12
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`7 of 12
`
`

`

`US 9,517,219 B2
`
`7
`builder, and water, wherein the dapsone is present in the
`composition at a concentration of about 3% w/w to about
`10% w/w.
`
`Embodiment 2
`
`The composition of embodiment 1, wherein the diethyl-
`ene glycol monoethyl ether is present at a concentration of
`about 10% w/w to about 40% w/w.
`
`8
`Embodiment 13
`
`The composition of embodiment 8, wherein the second
`solubilizing agent is ethanol.
`
`Embodiment 14
`
`The composition of embodiment 13, wherein the ethanol
`is present in the composition at a concentration of about 3%
`w/w.
`
`10
`
`Embodiment 3
`
`Embodiment 15
`
`The composition of embodiment 1, wherein the diethyl-
`ene glycol monoethyl ether is present at a concentration of
`about 20% w/w to about 30% w/w.
`
`15
`
`Embodiment 4
`
`The composition of embodiment 1, wherein the polymeric
`Viscosity builder comprises an acrylamide/sodium acry-
`loyldimethyltaurate copolymer.
`
`Embodiment 16
`
`The composition of embodiment 1, wherein the diethyl-
`ene glycol monoethyl ether is present in the composition at
`a concentration of about 25% w/w.
`
`20
`
`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 5
`
`Embodiment 17
`
`The composition of embodiment 1, further comprising
`adapalene.
`
`Embodiment 6
`
`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
`
`The composition of embodiment 1 wherein the second
`solubilizing agent is selected an alcohol, a glycol, an ester,
`or an ether.
`
`Embodiment 8
`
`The composition of embodiment 1, wherein the second
`solubilizing agent is PEG 400, lactic acid, dimethyl isosor-
`bide, propylene glycol, propylene carbonate, hexylene gly-
`col, isostearyl alcohol, diethyl sebacate, or ethanol.
`
`Embodiment 9
`
`25
`
`30
`
`35
`
`40
`
`45
`
`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 comprising
`Carbomer interpolymer type A, Carbomer interpolymer type
`B, or Carbomer Homopolymer Type C.
`
`Embodiment 20
`
`The composition of embodiment 19, wherein the Car-
`bomer 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 8, wherein the second
`solubilizing agent is propylene glycol.
`
`50
`
`The composition of embodiment 19, wherein the Car-
`bomer Homopolymer Type C is present at a concentration of
`about 0.85% w/w to about 1.5% w/w.
`
`Embodiment 10
`
`Embodiment 22
`
`The composition of embodiment 9, wherein the propylene
`glycol is present in the composition at a concentration of
`about 5% w/w.
`
`55
`
`The composition of embodiment 19, wherein the Car-
`bomer interpolymer Type A is present at a concentration of
`about 1% w/w to 2% w/w.
`
`Embodiment 11
`
`Embodiment 23
`
`The composition of embodiment 8, wherein the second
`solubilizing agent is propylene carbonate.
`
`Embodiment 12
`
`The composition of embodiment 11, wherein the propyl-
`ene carbonate is present in the composition at a concentra-
`tion of about 5% w/w.
`
`60
`
`65
`
`The composition of embodiment 19, wherein the Car-
`bomer 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 comprising a
`neutralizing agent.
`
`80f12
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`8 of 12
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`8 of 12
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`

`

`9
`Embodiment 25
`
`10
`Embodiment 36
`
`US 9,517,219 B2
`
`The composition of embodiment 24 wherein the neutral-
`izing agent is NaOH or triethanolamine.
`
`Embodiment 26
`
`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 37
`
`The composition of embodiment 1 further comprising a
`chelating agent.
`
`Embodiment 27
`
`The composition of embodiment 26, wherein the chelat-
`ing agent is ethylene diamine tetraacetic acid.
`
`Embodiment 28
`
`10
`
`15
`
`The composition of embodiment 1, 2, 3, 4, 34, 35, or 36,
`wherein the second solubilizing agent is PEG 400, lactic
`acid, dimethyl isosorbide, propylene glycol, propylene car-
`bonate, hexylene glycol, isostearyl alcohol, diethyl sebacate,
`or ethanol.
`
`Embodiment 38
`
`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.
`
`20
`
`The composition of embodiment 37, wherein the second
`solubilizing agent is propylene glycol.
`
`Embodiment 39
`
`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 composi-
`tion is in the form of a gel, a suspension, an emulsion, a
`cream, a liquid, a paste, a lotion, a nanoemulsion, a micro-
`emulsion, a reverse emulsion, or a liposomal cream.
`
`Embodiment 31
`
`A method for treating a dermatological condition com-
`prising administering to a subject in need thereof a thera-
`peutically effectiVe amount of a composition of embodiment
`1.
`
`Embodiment 32
`
`The method of embodiment 31 wherein the condition is
`
`treatment of
`rosacea, atopic dermatitis,
`acne Vulgaris,
`chronic wounds, bed sores, keratosis pilaris, sebaceous
`cysts, inflammatory dermatoses, post inflammatory hyper-
`pigmentation, eczema, xerosis, pruritus,
`lichen planus,
`nodular prurigo, dermatitis, eczema, or miliaria.
`
`Embodiment 33
`
`The method of embodiment 32 wherein the condition is
`
`acne Vulgaris.
`
`Embodiment 34
`
`The composition of embodiment 1, 2, 3, or 4, further
`comprising adapalene.
`
`Embodiment 35
`
`The composition of embodiment 34, wherein the ada-
`palene is present at a concentration of about 0.1% w/w to
`about 0.3% w/w.
`
`The composition of embodiment 38, wherein the propyl-
`ene glycol is present in the composition at a concentration of
`about 5% w/w.
`
`25
`
`Embodiment 40
`
`30
`
`The composition of embodiment 37, wherein the second
`solubilizing agent is propylene carbonate.
`
`Embodiment 41
`
`35
`
`The composition of embodiment 40, wherein the propyl-
`ene carbonate is present in the composition at a concentra-
`tion of about 5% w/w.
`
`Embodiment 42
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 the composition at a concentration of about 3%
`w/w.
`
`Embodiment 44
`
`The composition of embodiment 1, 2, 3, 4, 34, 35, 36, 37,
`38, 39, 40, 41, 42, or 43, wherein the polymeric Viscosity
`builder comprises an acrylamide/sodium acryloyldimethyl-
`taurate copolymer.
`
`Embodiment 45
`
`The composition of embodiment 1, 2, 3, 4, 34, 35, 36, 37,
`38, 39, 40, 41, 42, 43, or 44, wherein the polymeric Viscosity
`builder is present at a concentration of about 2% w/w to
`about 6% w/w.
`
`Embodiment 46
`
`The composition of embodiment 45, wherein the poly-
`meric Viscosity builder