111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US009161926B2
`
`c12) United States Patent
`Warner et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,161,926 B2
`Oct. 20, 2015
`
`(54) TOPICAL DAPSONE AND
`DAPSONE/ADAPLENE COMPOSITIONS AND
`METHODS FOR USE THEREOF
`
`7,531,694 B2 *
`2006/0204526 A1
`2010/0029781 A1
`2010/0130613 A1 *
`
`5/2009 Villa eta!. ...................... 568/28
`9/2006 Lathrop et a!.
`2/2010 Morris
`5/2010 Dreno ........................... 514/569
`
`(71) Applicant: Allergan, Inc., Irvine, CA (US)
`
`FOREIGN PATENT DOCUMENTS
`
`(72)
`
`Inventors: Kevin S. Warner, Anaheim, CA (US);
`Ajay P. Parashar, San Diego, CA (US);
`Vijaya Swaminathan, San Francisco,
`CA (US); Varsha Bhatt, San Francisco,
`CA (US)
`
`wo
`wo
`wo
`wo
`wo
`
`2009-108147
`WO 2009/108147 A1 *
`WO 2010/105052 A1 *
`2011-014627
`W02011/014627 A1 *
`
`9/2009
`9/2009
`9/2010
`2/2011
`2/2011
`
`(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.
`
`(21) Appl. No.: 14/082,955
`
`(22) Filed:
`
`Nov. 18, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2014/0142184Al
`
`May 22,2014
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/728,403, filed on Nov.
`20, 2012, provisional application No. 61/770,768,
`filed on Feb. 28, 2013.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 311136
`A61K 311192
`A61K9/00
`(52) U.S. Cl.
`CPC ............. A61K 311192 (2013.01); A61K 910014
`(2013.01); A61K 311136 (2013.01)
`(58) Field of Classification Search
`CPC ........................... A61K 31/136; A61K 9/0014
`USPC .......................................................... 514/646
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,863,560 A
`6,060,085 A
`6,620,435 B1
`
`111999 Osborne
`5/2000 Osborne
`9/2003 Osborne
`
`OTHER PUBLICATIONS
`
`Lubrizol [Online]. "Viscosity of CARBO POL Polymers in Aqueous
`Systems". [Retrieved Mar. 18, 20 14]. Retrieved from the Internet:
`<URL: http:/ /www.lubrizol.com/Life-Science/Documents/Pharma(cid:173)
`ceutical/Technical-Data-Sheets/TDS-730-Viscosity-Carbopol-in(cid:173)
`Aqueous-Systems.pdf>. *
`Draelos, Zoe D. et al, 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.
`Notification of Transmittal of the International Search Report and the
`Written Opinion of the International Searching Authority, or the
`Declaration, International Application No. PCT/US2013/070613,
`International Filing Date, Nov. 18, 2013, Date of Mailing Feb. 12,
`2014.
`
`* cited by examiner
`
`Primary Examiner- Leslie A. Royds Draper
`(74) Attorney, Agent, or Firm- Laura L. Wine; Joel B.
`German; Debra D. Condino
`
`(57)
`
`ABSTRACT
`
`Dapsone and dapsone/adapalene compositions can be useful
`for treating a variety of dermatological conditions. The com(cid:173)
`positions of this disclosure include dapsone and/or adapalene
`in a polymeric viscosity builder. Subject 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. Use
`of the polymeric viscosity builder provides compositions
`with increased concentrations of diethylene glycol monoet(cid:173)
`hyl ether relative to compositions without the polymeric vis(cid:173)
`cosity builder.
`
`6 Claims, 3 Drawing Sheets
`
`AMN1076
`Amneal v. Almirall, LLC
`IPR2019-00207
`
`1
`
`

`

`U.S. Patent
`
`Oct. 20, 2015
`
`Sheet 1 of 3
`
`US 9,161,926 B2
`
`Figure 1. Appearance of formulations following 4 weeks of storage
`
`At at initial timepoint
`
`A2 at initial timepoint
`
`Al after 4 weeks storage at 25°C
`
`A2 after 4 weeks storage at 25°C
`
`Al after 4 weeks storage at 40°C
`
`A2 after 4 weeks storage at 40°C
`
`2
`
`

`

`U.S. Patent
`
`Oct. 20, 2015
`
`Sheet 2 of 3
`
`US 9,161,926 B2
`
`Figure 2. Polarized light images of dapsone in suspension formulations
`
`3
`
`

`

`U.S. Patent
`
`Oct. 20, 2015
`
`Sheet 3 of 3
`
`US 9,161,926 B2
`
`Figure 3. Appearance of formulations with antioxidants or chelating agents over 4 weeks
`
`AS at Initial timepoint
`
`A6 at Initial timepoint
`
`A7 at Initial timepoint
`
`,,..,_
`' - -
`c}_ --~'""~,-.f.
`
`AS after 4 weeks storage at
`40°C
`
`A6 after 4 weeks storage at
`40°C
`
`A7 after 4 weeks
`storage at 40°C
`
`4
`
`

`

`US 9,161,926 B2
`
`1
`TOPICAL DAPSONE AND
`DAPSONE/ADAPLENE COMPOSITIONS AND
`METHODS FOR USE THEREOF
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims the benefit of U.S. Provisional
`Application Ser. No. 61/728,403 filed on Nov. 20, 2012 and
`U.S. Provisional Application Ser. No. 61/770,768 filed on
`Feb. 28, 2013, both of which are incorporated by reference
`herein in their entirety.
`
`FIELD
`
`The present embodiments relate generally to compositions
`useful for treating a variety of dermatological conditions. 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(cid:173)
`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 conditions
`can be complex, and even contradictory. Given this complex-
`ity and unpredictability, medication and other therapies, are
`often developed on a trial-and-error basis in order to deter(cid:173)
`mine the most effective course of treatment for a particular
`patient. The outcome of any particular acne treatment regi(cid:173)
`men greatly varies from patient to patient, as well as through(cid:173)
`out treatment of a particular patient. In addition to the com(cid:173)
`plexity and variability of acne conditions, treatment efficacy
`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 medica(cid:173)
`tions, 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 simultaneously. Another
`factor that negatively affects patient compliance is the cost of
`a drug regiment, which is considerably higher when multiple
`medications are prescribed. In some countries, acne is con(cid:173)
`sidered a cosmetic problem, and acne treatments are not
`covered by insurance plans, thus further increasing patient's
`treatment costs. Certain compositions 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 multiple anti-acne agents can be problem(cid:173)
`atic. Also, these compositions can be difficult 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 60
`that are difficult to classifY or diagnose, in which, neverthe(cid:173)
`less, topical application of agents are known to be effective at
`least in some cases. Examples of such conditions or classes of
`conditions include psoriasis, rosacea and ichthyosis.
`Accordingly, there is a continuing need for compositions 65
`and methods used in a treatment of a variety of skin condi(cid:173)
`tions, such as acne, in which topical application is potentially
`
`2
`effective. The compositions and methods provided 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 ofleprosy. Dapsone and its derivatives are also
`10 effective for treatment of bacterial infections, protozoal
`infections such as malaria, pneumocystis carinii, and plas(cid:173)
`monic infections such as toxoplasmosis.
`Dapsone is also useful as an anti-inflmatory agent. It has
`been used to treat skin diseases characterized by the abnormal
`15 infiltration of neutrophils, such as Dermatitis herpetiformis,
`linear IgA dermatosis, pustular psoriasis, pyoderma gan(cid:173)
`grenosum, acne vulgaris, and Sweet's Syndrome.
`Use of topical compositions of dapsone can be problem(cid:173)
`atic. Topical compositions may act as drying agents for the
`20 skin. They remove essential oils and natural skin softeners
`from the skin thus causing it to be dry, itch and crack. Inclu(cid:173)
`sion of exogeneous skin emollients, oils and the like, how(cid:173)
`ever, causes phase separation and precipitation of dapsone.
`Use of typical emulsifiers does not solve the dapsone precipi-
`25 tation owing to the lowered dapsone solubility and conflicting
`physical characteristics of the phases of the resulting compo(cid:173)
`sition. In particular, topical compositions including dapsone
`and methods are needed that would, for example, exhibit
`improved effectiveness, reduced side effects, or both, when
`30 used in a particular patient with a skin condition. Such
`improved topical compositions including dapsone and meth(cid:173)
`ods 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 treat-
`35 ing a variety of dermatological conditions. Some useful com(cid:173)
`positions include dapsone and/or adapalene in a polymeric
`viscosity builder. Some compositions can be adjusted to opti(cid:173)
`mize the dermal delivery profile of dapsone to effectively
`treat dermatological conditions and improve the efficiency of
`40 pharmaceutical products applied to the skin. Diethylene gly(cid:173)
`col monoethyl ether is a solubilizer for dapsone, thereby
`allowing compositions to be prepared with increased solubi(cid:173)
`lized concentrations of dapsone. As a result, the compositions
`described herein are effective in treating dermatological con-
`45 ditions in a subject in need thereof.
`Moreover, it has been found that use of a polymeric vis(cid:173)
`cosity builder minimizes the intensity of yellowing of the
`composition caused by the increased solubility of dapsone in
`diethylene glycol monoethyl ether. In addition, the polymeric
`50 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).
`In one embodiment, there are provided compositions
`55 including dapsone, a first solubilizing agent which is dieth(cid:173)
`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.
`In one embodiment, there are provided compositions
`including dapsone, a first solubilizing agent which is dieth(cid:173)
`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
`
`5
`
`

`

`US 9,161,926 B2
`
`3
`performed, for example, by administering to a subject in need
`thereof a therapeutically effective amount of a pharmaceuti(cid:173)
`cal composition described herein.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`FIG. 1 presents the impact of an acrylamide/sodium acry(cid:173)
`loyldimethyltaurate copolymer emulsion viscosity builder on
`color change.
`FIG. 2 presents the impact of an acrylamide/sodium acry(cid:173)
`loyldimethyltaurate copolymer emulsion viscosity builder on
`dapsone crystal growth.
`FIG. 3 presents the impact of anti-oxidants and chelating
`agents on color change.
`
`DETAILED DESCRIPTION
`
`4
`plugged with dirt, other cells, tiny hairs, or bacteria. Come(cid:173)
`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
`10 elevation of the skin that is filled with pus. The term "papule"
`is generally used to refer to a small, solid, usually inflamma(cid:173)
`tory 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.
`15 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 bac-
`teria. 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.
`25 It is to be understood that classification of acne into one of the
`subtypes does not mean that the characteristics of the classi(cid:173)
`fied 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(cid:173)
`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. Indi(cid:173)
`vidual 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 adulthood. 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(cid:173)
`ized by appearance of more painful, deep-rooted, inflamed
`lesions, which can result in scarring. Severe acne is charac(cid:173)
`terized 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 communi(cid:173)
`cate under the skin with abscesses and burrowing sinus tracts.
`Some other skin conditions exhibiting acne-like symptoms
`which can be treated by the compositions and methods
`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
`
`It is to be understood that both the foregoing general
`description and the following detailed description are exem(cid:173)
`plary and explanatory only and do not restrict the claims. As 20
`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- 30
`passes human and animal conditions, disorders, or diseases
`affecting skin. Such skin conditions include, but are not lim(cid:173)
`ited to, conditions involving skin inflammation, conditions
`involving sebaceous glands and hair follicles, conditions
`characterized by acneiform symptoms, and conditions 35
`involving skin dryness, skin thickening, skin scaling or skin
`flaking. Skin conditions that can be treated using some com(cid:173)
`positions, products and methods described herein include, but
`are not limited to, acne, rosacea, folliculitis, perioral derma(cid:173)
`titis, photodamage, skin aging, psoriasis, ichtiosis, atopic der- 40
`matitis, treatment of chronic wounds, bed sores, keratosis
`piralis, scars, including surgical and acne scars, sebaceous
`cysts, inflammatory dermatoses, post inflammatory hyper(cid:173)
`pigmentation, eczema, xerosis, pruritis, lichen planus, nodu(cid:173)
`lar prurigo, eczema, and miliaria.
`The term "acne," as used herein, encompasses skin condi(cid:173)
`tions involving acneiform or acne-like symptoms. For
`example, a skin condition characterized by follicular erup(cid:173)
`tions, such as papules and pustules resembling acne, can be
`categorized as acne. It is to be understood that the term "acne" 50
`is not to be limited to diseases and conditions characterized by
`papules and pustules, but can be characterized 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 treatments, and therefore the patient 55
`can exhibit reduced symptoms or be asymptomatic. Never(cid:173)
`theless, continuing treatment of acne can be recommended in
`such a patient in order to reduce the probability of the return
`of the acne symptoms.
`Symptoms of acne or acne-like conditions include, but are 60
`not limited to, the appearance of various skin lesions. The
`term "lesion" is generally used to denote an infected or dis(cid:173)
`eased patch of skin. A lesion can involve an infected seba(cid:173)
`ceous gland. Some lesions are more severe than others.
`Examples of skin lesions are comedones, macules, papules, 65
`pustules, nodules and cysts. The term "comedo" (plural
`"comedones") is used to describe a sebaceous follicle
`
`45
`
`6
`
`

`

`US 9,161,926 B2
`
`20
`
`5
`sometimes involved. A mild degree of eye (ocular) involve(cid:173)
`ment occurs in more than fifty percent of people with rosacea.
`Perioral dermatitis is characterized by the appearance of
`small tiny papules, pustules, red bumps and scaling with
`intense itching. It is usually localized to the surrounding 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 pustules and
`cysts, possibly occurring as a complication resulting from a
`long term antibiotic treatment of acne vulgaris.
`As used herein, the terms "treatment" or "treating" in ref(cid:173)
`erence to a skin condition generally mean "having positive
`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 inhi(cid:173)
`bition of the progression of the skin condition. Treatment
`need not mean that the condition is totally cured. A compo(cid:173)
`sition 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 oflife, or delay, prevent, or inhibit the onset of symp(cid:173)
`toms of a skin condition.
`In one embodiment, there are provided compositions
`including dapsone, a first solubilizing agent which is dieth(cid:173)
`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
`emb~diments, 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 45
`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 monoet(cid:173)
`hyl ether is present at a concentration of about 35% w/w to 50
`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%.
`Id another embodiment, there are provided compositions 55
`further including adapalene. In some embodiments, ada(cid:173)
`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. 60
`Such second solubilizing agents include, but are not limited
`to, PEG 400, lactic acid, dimethyl isosorbide, propylene gly(cid:173)
`col, propylene carbonate, hexylene glycol, isostearyl alcohol,
`benzyl alcohol, diethyl sebacate, and ethanol.
`In certain embodiments, the second solubilizing agent is 65
`propylene glycol. In some embodiments, propylene glycol is
`present at a concentration of about 2% w/w to 8% w/w. In
`
`6
`some embodiments, propylene glycol is present at a concen(cid:173)
`tration of about 3% w/w to 7% w/w. In some embodiments,
`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(cid:173)
`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 embodi-
`10 ments, propylene carbonate is present in the composition at
`about 5% w/w.
`In certain embodiments, the second solubilizing agent is
`ethanol. In some embodiments, ethanol is present at a con(cid:173)
`centration of about 1% w/w to about 5% w/w. In some
`15 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, car(cid:173)
`homer 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
`25 of about 0.85% w/w to about 1.0% w/w.
`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.
`30 Use of a neutralizing agent results in compositions 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
`ethylenediamine tetraacetic acid (EDTA). EDTA is typically
`35 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
`40 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
`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 diethylene
`glycol monoethyl ether is present at a concentration of about
`10% w/w to about 40% w/w.
`
`Embodiment 3
`
`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.
`
`7
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`US 9,161,926 B2
`
`7
`Embodiment 4
`
`8
`Embodiment 16
`
`The composition of embodiment 1, wherein the diethylene
`glycol monoethyl ether is present in the composition at a
`concentration of about 25% w/w.
`
`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 1, wherein the polymeric
`10 viscosity builder is present at a concentration of about 4%
`w/w.
`
`The composition of embodiment 5, wherein the adapalene
`is present at a concentration of about 0.1% w/wto about 0.3% 15
`w/w.
`
`Embodiment 18
`
`The composition of embodiment 1, further comprising
`methyl paraben.
`
`Embodiment 7
`
`Embodiment 19
`
`The composition of embodiment 1 wherein the second 20
`solubilizing agent is selected an alcohol, a glycol, an ester, or
`an ether.
`
`The composition of embodiment 1, further comprising
`Carbomer interpolymer type A, Carbomer interpolymer type
`B, or Carbomer Homopolymer Type C.
`
`Embodiment 8
`
`The composition of embodiment 1, wherein the second
`solubilizing agent is PEG 400, lactic acid, dimethyl isosor(cid:173)
`bide, propylene glycol, propylene carbonate, hexylene gly(cid:173)
`col, isostearyl alcohol, diethyl sebacate, or ethanol.
`
`Embodiment 9
`
`25
`
`30
`
`Embodiment 20
`
`The composition of embodiment 19, wherein the Car(cid:173)
`homer 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.
`
`Embodiment 10
`
`The composition of embodiment 19, wherein the Car(cid:173)
`homer Homopolymer Type C is present at a concentration of
`35 about 0.85% w/w to about 1.5% w/w.
`
`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
`
`Embodiment 22
`
`The composition of embodiment 19, wherein the Car-
`40 bomer interpolymer Type A is present at a concentration of
`about 1% w/w to 2% w/w.
`
`Embodiment 23
`
`45
`
`The composition of embodiment 19, wherein the Car(cid:173)
`homer interpolymer Type B is present at a concentration of
`about 0.1% w/w to about 0.5% w/w.
`
`The composition of embodiment 11, wherein the propy(cid:173)
`lene carbonate is present in the composition at a concentra(cid:173)
`tion of about 5% w/w.
`
`50
`
`Embodiment 24
`
`Embodiment 13
`
`The composition of embodiment 1, further comprising a
`neutralizing agent.
`
`The composition of embodiment 8, wherein the second
`solubilizing agent is ethanol.
`
`55
`
`Embodiment 25
`
`Embodiment 14
`
`The composition of embodiment 24 wherein the neutraliz(cid:173)
`ing agent is NaOH or triethanolamine.
`
`The composition of embodiment 13, wherein the ethanol is
`present in the composition at a concentration of about 3% 60
`w/w.
`
`Embodiment 15
`
`Embodiment 26
`
`The composition of embodiment 1 further comprising a
`chelating agent.
`
`Embodiment 27
`
`The composition of embodiment 1, wherein the polymeric 65
`viscosity builder comprises an acrylamide/sodium acry(cid:173)
`loyldimethyltaurate copolymer.
`
`The composition of embodiment 26, wherein the chelating
`agent is ethylenediamine tetraacetic acid.
`
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`US 9,161,926 B2
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`9
`Embodiment 28
`
`10
`Embodiment 39
`
`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.
`
`The composition of embodiment 38, wherein the propy(cid:173)
`lene glycol is present in the composition at a concentration of
`about 5% w/w.
`
`Embodiment 29
`
`Embodiment 40
`
`The composition of embodiment 37, wherein the second
`The composition of embodiment 27, wherein the ethylene
`diamine tetraacetic acid is present in the composition at about 10 solubilizing agent is propylene carbonate.
`0.03%w/w.
`
`Embodiment 30
`
`Embodiment 41
`
`The composition of embodiment 40, wherein the propy-
`15 lene carbonate is present in the composition at a concentra(cid:173)
`tion of about 5% w/w.
`
`Embodiment 42
`
`The composition of embodiment 1 wherein the composi(cid:173)
`tion 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 compris(cid:173)
`ing administering to a subject in need thereof a therapeuti(cid:173)
`cally effective amount of a composition of embodiment 1.
`
`Embodiment 32
`
`20
`
`25
`
`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 method of embodiment 31 wherein the condition is
`acne vulgaris, rosacea, atopic dermatitis, treatment of
`chronic wounds, bed sores, keratosis piralis, sebaceous cysts, 30
`inflammatory dermatoses, post inflmatory hyperpigmen(cid:173)
`tation, eczema, xerosis, pruritis, lichen planus, nodular pru(cid:173)
`rigo, dermatitis, eczema, or miliaria.
`
`Embodiment 33
`
`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-
`35 taurate copolymer.
`
`The method of embodiment 32 wherein the condition is
`acne vulgaris.
`
`Embodiment 45
`
`Embodiment 34
`
`The composition of embodiment 1, 2, 3, or 4, further com(cid:173)
`prising adapalene.
`
`Embodiment 35
`
`The compos1t10n of embodiment 34, wherein the ada(cid:173)
`palene 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.
`
`The composition of embodiment 1, 2, 3, 4, 34, 35, 36, 37,
`40 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
`
`45
`
`50
`
`55
`
`The composition of embodiment 45,