(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`Internationa] Bureau
`
`(43) International Publication Date
`14 May 2009 (14.05.2009)
`
`PCT
`
`(51) International Patent Classification:
`A61K 31/136 (2006.01) A61K 47/32 (2006.01)
`A61K9/00 (2006.01) A61P17/00 (2006.01)
`A61K9/06 (2006.01) A61P17/10 (2006.01)
`
`(21) International Application Number:
`PCT/US2007/023468
`
`(22) International Filing Date:
`7 November 2007 (07.11.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(71) Applicant (for all designated States except US): QLT
`USA, INC. [US/US]; 2579 Midpoint Drive, Fort Collins,
`CO 80525-4417 (US).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): GARRETT, John
`Steven [US/US]; 7113 Silver Moon Lane, Fort Collins,
`CO 80252 (US).
`
`(74) Agents: STEFFEY, Charles,E. et al.; Schwegman, Lund-
`berg & Woessner, PA, P.O. Box 2938, Minneapolis, Min-
`nesota 55402 (US).
`
`(10) International Publication Number
`WO 2009/061298 Al
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH,
`CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG,
`ES, FT, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL,
`IN, IS, IP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK,
`LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW,
`MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
`PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY,
`TI, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TI, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FT,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL,
`PT, RO, SE, SI, SK, TR), OAPI (BF, BI, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`PubUshed:
`— with international search report
`
`^= (54) Title: TOPICAL TREATMENT WITH DAPSONE IN G6PD-DEFICIENT PATIENTS
`
`Figure 1
`
`(57) Abstract: The present invention provides a pharmaceutical
`carrier system comprising a dermatological composition that is
`a semi-solid aqueous gel, wherein dapsone is dissolved in the
`gel such that the dapsone has the capacity to cross the stratum
`comeum layer of the epidermis, and wherein the composition
`also contains dapsone in a microparticulate state that does
`not readily cross the stratum comeum of the epidermis. The
`present invention also discloses the treatment of dermatological
`conditions in G6PD-def icient patients with the composition,
`while avoiding adverse hematologic effects.
`
`Treatment Period 2: Dapsone gel
`Completed n=26 (81%)
`
`Treatment Period 2: Vehicle
`Completed n=21 (66%)
`
`Safety-evaluable n=31
`
`Safety-evaluable n=25
`
`00
`ON
`
`ON
`
`o
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`1
`
`AMN1004
`
`

`

`WO 2009/061298 PCT7US2007/023468
`
`TOPICAL TREATMENT WITH DAPSONE
`
`IN G6PD-DEFICIENT PATIENTS
`
`5
`
`Background of the Invention
`
`Dapsone is a sulfone with both anti-inflammatory and antimicrobial
`
`properties. The oral formulation of the drug is used to treat leprosy, dermatitis
`
`herpetiformis, and malaria, using typical doses of 100 mg to 300 mg daily, but
`
`10 historically, it was also used to treat severe acne in doses ranging from 50
`
`mg/day to 300 mg/week (Wolf et al., 2002; Ross 1961; Prendiville et al., 1988).
`
`Currently, use of oral dapsone is generally limited to more severe forms of skin
`
`disease, as its use may be associated with hematologic side effects, including
`
`hemolysis and hemolytic anemia that are dose-dependent and occur more
`
`15 frequently with increasing dose (Zhu and Stiller 2001; Jollow et al., 1995).
`
`The mechanism of dapsone-related hemolysis and hemolytic anemia
`
`involves oxidative damage to red blood cells and is associated with the dapsone
`
`hydroxylamine metabolite (Prendiville et al., 1988). Red blood cells are
`
`somewhat protected against oxidative injury and lysis by glutathione reduction, a
`
`20 metabolic pathway that involves the glucose-6-phosphate dehydrogenase
`
`(G6PD) enzyme. Consequently, individuals who are G6PD-deficient are more
`
`sensitive to developing hemolytic anemia after exposure to hemolytic stressors
`
`such as infection, administration of a variety of drugs, including dapsone, or
`
`ingestion of fava beans (Beutler 1994). G6PD deficiency is most prevalent in
`
`25 individuals of African, Southeast Asian, and Middle Eastern heritage, and
`
`because the G6PD enzyme is encoded on the X chromosome, the deficiency is
`
`more common in males. In the United States, a recent study of military
`
`personnel reported the prevalence of G6PD deficiency to be 2.5% in men and
`
`1.6% in women (Chinevere et al., 2006). Amongst racial groups, the prevalence
`
`30 was highest in African American men (12.2%), Asian men (4.3%), and African
`
`American women (4.1%), and lowest in Caucasian men and women (0.3% and
`
`zero, respectively). An early study that compared the effects of oral dapsone
`
`treatment in G6PD-deficient and non-deficient men found that there was a direct,
`
`linear relationship between oral dapsone dose and extent of red blood cell
`
`2
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`WO 2009/061298 PCT7US2007/023468
`2
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`hemolysis in both the normal and deficient groups. The doses causing hemolysis
`
`in G6PD-deficient subjects were approximately half of the doses that caused
`
`hemolysis in subjects with normal G6PD levels (DeGowin et al., 1966).
`
`What is needed is a method of treating dermatological conditions in
`
`5 patients including G6PD-deficient patients without the adverse hematologic
`
`effects associated with oral dapsone administration.
`
`Summary of the Invention
`
`The present invention provides methods to treat glucose-6-phosphate
`
`10 dehydrogenase-deficient patients with dapsone. In one embodiment, the
`
`treatment is directed to dermatological conditions and the treatment is provided
`
`by a topical dapsone composition. The composition may include dissolved
`
`dapsone and microparticulate dapsone. In certain embodiments, the
`
`dermatological condition to be treated is inflammatory acne, non-inflammatory
`
`15 acne or rosacea.
`
`Second medical uses of the dapsone composition and methods of
`
`manufacture using the dapsone composition for treating dermatological
`
`conditions in a glucose-6-phosphate dehydrogenase-deficient patient are also
`
`contemplated by the present invention.
`
`20 The present invention provides a pharmaceutical carrier system
`
`comprising a dermatological composition that is a semi-solid aqueous gel,
`
`wherein dapsone is dissolved in the gel such that the dapsone has the capacity to
`
`cross the stratum comeum layer of the epidermis and become available
`
`systemically, and wherein the composition also contains dapsone in a
`
`25 microparticulate state that does not readily cross the stratum comeum of the
`
`epidermis. The ratio of microparticulate to dissolved dapsone is adjustable, but
`
`is preferably five or less. Second medical uses of the dermatological
`
`composition and methods of manufacture of a medicament for treating
`
`dermatological conditions in a glucose-6-phosphate dehydrogenase-deficient
`
`30 patient using the dermatological composition are also contemplated by the
`present invention.
`
`In some embodiments, the dermatological composition for use in
`
`methods of treating glucose-6-phosphate dehydrogenase-deficient patients
`
`includes a thickening agent; water; a high-boiling, nonionic organic solvent; a
`
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`WO 2009/061298 PCT7US2007/023468
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`preservative; dapsone in a microparticulate and dissolved state; and a base
`
`solution. In one preferred embodiment, the composition includes about 0.5% to
`
`4.0% carbomer; about 53.8% to 84.2% water; about 10% to 30% ethoxydiglycol;
`
`about 0.2% methylparaben; about 5% to 10% dapsone in a microparticulate and
`
`5 dissolved state; and about 0.1% to 2% sodium hydroxide solution. In some
`
`embodiments, the composition includes about 1% carbomer; about 81.8% water;
`
`about 10% ethoxydiglycol; about 0.2% methylparaben; about 5% dapsone in a
`
`microparticulate and dissolved state; and about 2% sodium hydroxide solution.
`
`In another preferred embodiment, the dermatological composition includes about
`
`10 0.85% carbomer; about 66.95% water; about 25% diethylene glycol monoethyl
`
`ether; about 0.2% methylparaben; about 5% dapsone; and about 0.2% sodium
`
`hydroxide. Second medical uses of the dermatological composition and methods
`
`of manufacture of a medicament for treating dermatological conditions in a
`
`glucose-6-phosphate dehydrogenase-deficient patient using the dermatological
`
`15 composition are also contemplated by the present invention.
`
`In certain embodiments, the invention provides a method to treat a
`
`dermatological condition in a glucose-6-phosphate dehydrogenase-deficient
`
`patient comprising applying topically a dermatological gel composition that
`
`includes a semisolid aqueous gel; dapsone dissolved in the gel, wherein the
`
`20 dapsone has the capacity to cross the stratum comeum layer of the epidermis and
`
`become available systemically; and a microparticulate dapsone dispersed in the
`
`gel, wherein the microparticulate dapsone does not cross the stratum comeum of
`
`the epidermis in its microparticulate state. The dermatological condition can
`
`include inflammatory acne, non-inflammatory acne and/or rosacea.
`25 In embodiments where acne is treated, the acne can be non-inflammatory
`acne, inflammatory acne, or both. In some embodiments, the dermatological
`
`dapsone composition is a semisolid aqueous gel. In other embodiments, the
`
`dermatological dapsone composition is a cream or a lotion. In still other
`
`embodiments, the dapsone composition is a suspension, ointment, or spray. In
`
`30 each of these embodiments, the dapsone may exist as a microparticulate form, a
`dissolved form, or both.
`
`In a preferred embodiment, the invention provides a method to treat a
`
`dermatological condition in a glucose-6-phosphate dehydrogenase-deficient
`
`patient by applying a dermatological composition to the condition, wherein the
`
`4
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`WO 2009/061298 PCT7US2007/023468
`4
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`dermatological composition includes dapsone, wherein the method results in
`
`blood plasma levels of dapsone and N-acetyl dapsone below the levels
`
`associated with hemolysis. Second medical uses of the dermatological
`
`composition and methods of manufacture of a medicament for treating
`
`5 dermatological conditions in a glucose-6-phosphate dehydrogenase-deficient
`
`patient using the dermatological composition are also contemplated by the
`
`present invention.
`
`In another preferred embodiment, the invention provides a method to
`
`treat a dermatological condition in a glucose-6-phosphate dehydrogenase-
`
`10 deficient patient by applying a dermatological composition to the condition,
`
`wherein the dermatological composition includes dapsone, and wherein the
`
`method results in blood plasma levels of dapsone and N-acetyl dapsone between
`
`about 0.5|ig/mL and 1.0 jig/mL. Second medical uses of the dermatological
`
`composition and methods of manufacture of a medicament for treating
`
`15 dermatological conditions in a glucose-6-phosphate dehydrogenase-deficient
`
`patient using the dermatological composition are also contemplated by the
`
`present invention.
`
`In another preferred embodiment, the invention provides a method to
`
`treat a dermatological condition in a glucose-6-phosphate dehydrogenase-
`
`20 deficient patient by applying a dermatological composition to the condition,
`
`wherein the dermatological composition includes dapsone, and wherein the
`
`method results in blood plasma levels of dapsone and N-acetyl dapsone of about
`
`1 ng/mL or less. Second medical uses of the dermatological composition and
`
`methods of manufacture of a medicament for treating dermatological conditions
`
`25 in a glucose-6-phosphate dehydrogenase-deficient patient using the
`
`dermatological composition are also contemplated by the present invention.
`
`In another preferred embodiment, the invention provides a method to
`
`treat a dermatological condition in a glucose-6-phosphate dehydrogenase-
`
`deficient patient by applying a dermatological composition to the condition,
`
`30 wherein the dermatological composition includes dapsone, and wherein the
`
`method results in blood plasma levels of dapsone between 0 and about 37 ng/mL
`
`and blood plasma levels of N-acetyl dapsone between 0 and about 50 ng/mL.
`
`Second medical uses of the dermatological composition and methods of
`
`manufacture of a medicament for treating dermatological conditions in a
`
`5
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`

`

`WO 2009/061298 PCT7US2007/023468
`5
`
`glucose-6-phosphate dehydrogenase-deficient patient using the dermatological
`
`composition are also contemplated by the present invention.
`
`In some embodiments, the method of treating a G6PD-deficient patient
`
`with dapsone results in blood plasma levels of dapsone less than about 37 ng/mL
`
`5 and blood plasma levels of N-acetyl dapsone less than about 50 ng/mL. In some
`
`preferred embodiments, the method of treatment does not induce hemolytic
`
`anemia. In some preferred embodiments, the methods do not induce adverse
`
`hematologic events. In still further embodiments, the method is performed for
`about 12 weeks.
`
`10 The invention also provides a method to treat a dermatological condition
`
`in a glucose-6-phosphate dehydrogenase-deficient patient by topically applying a
`
`gel composition of dissolved dapsone and microparticulate dapsone, wherein the
`
`dissolved dapsone crosses the stratum comeum of the epidermis and is absorbed
`
`into the lower two-thirds of the pilosebaceous unit, and the microparticulate
`
`15 dapsone is primarily delivered into the upper third of the pilosebaceous unit,
`
`crossing the stratum comeum of the epidermis only minimally. Second medical
`
`uses of the dermatological composition and methods of manufacture of a
`
`medicament for treating dermatological conditions in a glucose-6-phosphate
`
`dehydrogenase-deficient patient using the gel composition are also contemplated
`20 by the present invention.
`
`The use of a dermatological composition comprising about 0.85%
`
`carbomer; about 66.95% water; about 25% ethoxydiglycol; about 0.2%
`
`methylparaben; about 5% dapsone in a microparticulate and dissolved state; and
`
`about 0.2% sodium hydroxide solution, for the manufacture of a medicament for
`
`25 treating dermatological conditions in a glucose-6-phosphate dehydrogenase-
`
`deficient patient, is also contemplated by the invention.
`
`In a preferred embodiment, the invention also provides a method to treat
`
`a dermatological condition in a patient by topically applying a dermatological
`
`composition including dapsone, wherein the dermatological composition is
`
`30 formulated to result in blood plasma levels of dapsone of less than 1 microgram
`
`per mL in the patient. In some embodiments, the patient is predisposed to
`
`hemolytic anemia. In some embodiments, the method results in blood plasma
`
`levels of dapsone less than about 37 ng/mL and blood plasma levels of N-acetyl
`
`dapsone less than about 50 ng/mL. In still further embodiments, the
`
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`WO 2009/061298 PCT7US2007/023468
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`dermatological composition is a dermatological gel composition of a semisolid
`
`aqueous gel; dapsone dissolved in the gel, wherein the dapsone has the capacity
`
`to cross the stratum comeum layer of the epidermis and become available
`
`systemically; and a microparticulate dapsone dispersed in said gel, wherein the
`
`5 microparticulate dapsone does not cross the stratum comeum of the epidermis in
`
`its microparticulate state. Second medical uses of the dermato logical
`
`composition and methods of manufacture of a medicament for treating
`
`dermatological conditions in patients using the gel composition are also
`
`contemplated by the present invention.
`
`10 Methods for preparing the compositions of the present invention are also
`described.
`
`Brief Description of the Figures
`
`Figure 1. Study subject disposition. G6PD=glucose-6-phosphate
`15 dehydrogenase.
`
`Figure 2. Correlation analysis of the change in hemoglobin versus
`change in bilirubin at week 2 of dapsone gel treatment (r2=0.104; n=52). The
`
`mean bilirubin level was 0.58 mg/dL at baseline and 0.65 mg/dL at week 2. The
`
`mean change from baseline in bilirubin at week 2 (95% confidence limits) was
`
`20 +0.06 mg/dL (0 mg/dL, 0.12 mg/dL) (Patient data was collected in SI units and
`
`converted to conventional units for summary tables. To convert bilirubin mg/dL
`
`to SI units of nmol/L, multiply by 17.1). SI units= Systeme International units.
`
`Figure 3. Correlation analysis of the change in hemoglobin versus
`change in reticulocytes at week 2 of dapsone gel treatment (r2=0.043; n=52).
`
`25 The mean reticulocyte level was 1.30% at baseline and 1.51 % at week 2. The
`
`mean change from baseline in reticulocyte level at week 2 (95% confidence
`limits) was +0.22% (0.11%, 0.32%).
`
`Figure 4. Correlation analysis of the change in hemoglobin versus
`change in haptoglobin at week 2 of dapsone gel treatment (r2=0.027; n=51). The
`30 mean haptoglobin level was 107.9 mg/dL at baseline and 109.1 mg/dL at week
`
`2. The mean change from baseline in haptoglobin at week 2 (95% confidence
`
`limits) was -0.2 mg/dL (-5.3 mg/dL, 5.0 mg/dL) (Patient data was collected in
`
`SI units and converted to conventional units for summary tables. To convert
`
`7
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`WO 2009/061298 PCT7US2007/023468
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`haptoglobin mg/dL to SI units of g/L, multiply by 0.01). SI units= Systeme
`
`International units.
`
`Figure 5. Correlation analysis of the change in hemoglobin versus
`
`change in lactate dehydrogenase (LDH) at week 2 of dapsone gel treatment
`5 (r2<0.001; n=51). The mean LDH level was 175.0 IU/L at baseline and 171.3
`IU/L at week 2. The mean change from baseline in LDH at week 2 (95%
`
`confidence limits) was -3.3 IU/L (-10.0 IU/L, 3.4 IU/L).
`
`10 Definitions
`
`Detailed Description of the Invention
`
`As used herein, "adverse event" means any adverse change in health or
`
`"side-effect" that occurs in a patient who is participating in a study while the
`
`patient is receiving treatment (dermatological composition or vehicle) or within
`
`a pre-specified period of time after their treatment has been completed.
`
`15 As used herein, "cream" refers to an emulsified medicinal or cosmetic
`
`preparation; a semisolid emulsion of either the oil-in-water or the water-in-oil
`
`type, ordinarily intended for topical use.
`
`As used herein, "dapsone" refers to the chemical compound dapsone
`
`having the chemical formula C12H12N2O2S as well as bis(4-
`20 aminophenyl)sulfone, 4,,4'-diaminodiphenyl sulfone and its hydrates, 4,4'-
`sulfonylbisbenzeneamine, 4,4,-sulfonyldianiline, diaphenylsulfone, dapsone
`analogs, and dapsone related compounds. "Dapsone analogs" refers to chemical
`
`compounds that have similar chemical structures and thus similar therapeutic
`
`potential to dapsone such as the substituted bis(4-aminophenyl)-sulfones.
`
`25 "Dapsone related compounds" refers to chemical compounds that have similar
`
`therapeutic potential, but are not as closely related by chemical structure to
`
`dapsone such as the substituted 2,4-diamino-5-benzylpyrimidines.
`
`A "foam" refers to a mass of bubbles of air or other gas entrapped in a
`
`matrix of liquid or solid, especially an accumulation of fine, frothy bubbles
`
`30 formed in or on the surface of a liquid or solid, as from agitation or generated
`under pressure of a gas.
`
`As used herein, the terms "G6PD-deficient" or "G6PD deficiency" refer
`
`to glucose-6-phosphate dehydrogenase (G6PD) levels that are below 7 U/g Hb,
`
`8
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`WO 2009/061298 PCT7US2007/023468
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`which is considered to be the lower limit of normal. As used herein, ^ U/g Hb
`
`is considered "severely" deficient.
`
`As used herein, "gel" refers to a colloid in a more solid form than a
`
`solution; a jelly-like material formed by the coagulation of a colloidal liquid;
`
`5 many gels have a fibrous matrix and fluid filled interstices: gels are viscoelastic
`
`rather than simply viscous and can resist some mechanical stress without
`
`deformation.
`
`As used herein, the term "microparticulate" refers to any solid form of an
`
`active agent, including dapsone, that is not dissolved in the dermatological
`
`10 composition. The microparticulate dapsone described herein may be in the form
`
`of flakes or crystals, and includes a precipitant that results from the addition of
`
`water and the solvent or mixed solvent system containing dapsone. The
`
`microparticulate dapsone may comprise a crystalline precipitant or an
`
`amorphous precipitant.
`15 As used herein, "ointment" refers to a salve or unguent for application to
`the skin, specifically a semisolid medicinal preparation usually having a base of
`
`fatty or greasy material; an ointment has an oil base whereas a cream is water-
`
`soluble. See, The University of Newcastle Dept. of Medical Oncology On-Line
`
`Medical Dictionary flittpV/cancerweb.ncl.ac.uk/omdA December 19, 2003 and
`20 MedLine Plus Medical Dictionary
`
`(http://www.nlm.nih.gov/medlineplus/mplusdictionarv.htmn December 19,
`2003.
`
`The term "topical" as used herein refers to the route of administration of
`
`a dermatological composition that involves direct application to the body part
`
`25 being treated, e.g., the skin. Examples of topical application include application
`
`to the skin of creams, lotions, gels, ointments or other semisolids to rub-on,
`
`solutions to spray, or liquids to be applied by an applicator. Rinse-off
`
`application with washes, cleansers, or shampoos are also examples of topical
`
`application. Typically, areas of the body suitable for application of the
`
`30 dermatological composition include the skin of the face, throat, neck, scalp,
`
`chest, back, ears, and other skin sites where dermatological conditions may
`occur.
`
`As used herein, the term "treat", "treatment", or "treating" refers to the
`
`reduction in number and/or severity of symptoms, including individual skin
`
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`lesions; prevention of the development of symptoms, including skin lesions; or
`
`global improvement in the appearance of symptoms, including skin lesions.
`
`The invention described herein is directed to methods of treating
`
`5 dermatological disorders in G6PD-deficient patients through use of a topical
`
`dapsone formulation. Aczone• gel, 5%, a topical formulation of dapsone, was
`
`developed to deliver therapeutic concentrations of dapsone to the skin. The
`
`United States Food and Drug Administration (US FDA) approved Aczone• gel,
`
`5%, for the treatment of acne vulgaris, but required certain language in the
`
`10 package insert due to the US FDA's concern that this drug carries a significant
`
`risk of serious hematological adverse effects, including hemolysis, in G6PD-
`
`deficient patients.
`
`The US FDA required that the Aczone• gel, 5%, label state that all
`
`patients should be screened for G6PD deficiency prior to initiation of Aczone•
`
`15 treatment, with routine monitoring of complete blood counts and reticulocyte
`
`counts during treatment with Aczone• in those patients identified as having a
`
`history of anemia and predisposition to increased hemolytic effect with dapsone
`
`(e.g., G6PD deficiency). While previous clinical studies did not demonstrate
`
`evidence of clinically significant anemia, an increased reticulocyte count and a
`
`20 decreased hemoglobin level were noted to be associated in a G6PD deficient
`
`patient treated with Aczone• gel, 5% for acne vulgaris.
`
`The methods and compositions of the invention described herein
`
`demonstrate the unexpected result that treatment of G6PD-deficient patients with
`
`the Aczone gel, 5%, formulation does not result in adverse hematological
`25 effects.
`
`Dapsone
`
`Dapsone was first synthesized in 1908 and has been used medically as an
`
`antibiotic and an anti-inflammatory. Dapsone is a bis(4-aminophenyl)sulfone
`30 also known as 4',4,-diaminodiphenyl sulfone, 4,4,-sulfonylbisbenzeneamine, 4,4'-
`sulfonyldianiline, and diaphenylsulfone. Dapsone has been used orally for the
`
`treatment of acne (Ross 1961) and been found to have a minimum inhibitory
`
`concentration with regard to P. acnes of about 1 microgram per milliliter
`(Godowski et al., 2000).
`
`10
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`WO 2009/061298 PCT7US2007/023468
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`
`Dapsone analogs and related compounds have been described in U.S. Pat.
`
`Nos. 4,829,058 and 4,912,112 to Seydel et al. The '058 patent discloses
`
`substituted bis(4-aminophenyl)sulfones useful for inhibiting growth of bacteria,
`
`mycobacteria, and plasmodia. Some of these compounds were also tested against
`
`5 dapsone for toxicity and anti-inflammatory activity (Coleman et al., 1996a). In
`
`the '112 patent, substituted 2,4-diamino-5-benzyl pyrimidines having
`
`antimicrobial activity particularly against mycobacteria are described. Some of
`
`these compounds were also tested against dapsone for toxicity (Coleman et al.,
`
`1996b) and anti-inflammatory activity (Coleman et al., 1997). The teachings of
`
`10 these references in combination with subsequent publications showed that these
`
`analogs and related compounds have activity similar to dapsone and would be
`
`expected to have similar treatment efficacy.
`
`Topical Dapsone Compositions
`
`15 The present invention comprises compositions for application to the skin
`
`of G6PD-deficient patients. The compositions comprise microparticulate
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`dapsone precipitates in adjustable ratios of microparticulate to dissolved
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`dapsone. The invention also comprises methods for preparation of the
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`compositions, and methods for treatment of skin conditions in G6PD-deficient
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`20 patients using the compositions. The advantages of the present invention are
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`appreciated in the treatment of skin conditions or diseases by using topical
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`dapsone, thus minimizing the hematologic effects associated with oral dapsone
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`treatment. The present invention is particularly effective in the treatment of
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`acne. Because of the nature of the microparticulate dapsone in the composition,
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`25 microparticulate dapsone will be retained in or above the stratum comeum and
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`will therefore serve as a reservoir or provide drug action in the supracomeum
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`zone. The dissolved dapsone will pass through the stratum comeum.
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`Topical dapsone formulations have been described in U.S. Pat. No.
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`5,733,572 to Unger et al., and U.S. Pat. Nos. 6,056,954; 6,056,955; 6,254,866;
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`30 6,248,324; and 6,277,399 to Fischetti et al. A topical composition including
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`dapsone for acne treatment has been described in U.S. Pat. Nos. 5,863,560, and
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`6,060,085 to Osborne which are herein incorporated by reference in their
`entirety.
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`11
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`Clinical studies have shown that dapsone gel, 5% (Aczone•; QLT USA,
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`Inc. Fort Collins, Colorado) (dapsone gel), is effective in the treatment of acne
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`vulgaris (Draelos et al., 2007) and results in <1% of the systemic exposure that
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`is seen with typical oral dapsone treatment (Thiboutot et al., 2007).
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`5 Dapsone Topical Gel. In a preferred embodiment, a dermatological
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`condition in a G6PD-deficient patient is treated by topically applying a
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`dermatological composition that is part of a novel pharmaceutical carrier system
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`of a semisolid aqueous gel, wherein the composition exhibits an optimal balance
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`between dissolved dapsone that is available to cross through the stratum
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`10 comeum to become systemically available, and microparticulate dapsone that is
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`retained in or above the stratum comeum to serve as a reservoir or to provide
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`dapsone to the supracomeum zone. The microparticulate dapsone may comprise
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`a crystalline precipitant or an amorphous precipitant.
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`Optimal balance is accomplished by having a semisolid gel carrier
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`15 system in which microparticulate dapsone precipitates are formed in
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`reproducible ratios with respect to the dissolved dapsone. For the composition to
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`have a wide range of applicability, the microparticulate to dissolved dapsone
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`ratio preferably should be no greater than five, at therapeutic levels of applied
`active dapsone.
`20 A composition having a microparticulate to dissolved dapsone ratio of
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`less than two may provide the greatest amount of pharmaceutical available for
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`immediate partition out of the stratum comeum and into the viable epidermis.
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`This should provide minimum reservoir capacity, but may not maintain
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`sustained delivery or provide maximum activity in the supracomeum zone. A
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`25 composition having a microparticulate to dissolved dapsone ratio of two or
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`greater may have a reduced amount of drug available for immediate partition out
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`of the stratum comeum and into the viable epidermis. This provides maximum
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`reservoir capacity, and maintains sustained delivery, providing maximum
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`activity in the supracomeum zone. In an example of a dermatological
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`30 composition of this inventive method, the ratio for microparticulate dapsone to
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`dissolved dapsone should be no greater than 50, preferably no greater than 10,
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`and most preferably no greater than 5. Drug delivery from the
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`microparticulate/dissolved dapsone formulation may be optimized to provide
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`higher levels of drug to the supracomeum zone, while maintaining the level of
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`WO 2009/061298 PCT7US2007/023468
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`drug partitioning out of the stratum comeum and into the viable epidermis,
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`despite 10-fold increases in the amount of pharmaceutical applied to the skin.
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`Thickening agents include polymer thickeners. Polymer thickeners that
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`may be used include those known to one skilled in the art, such as hydrophilic
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`5 and hydroalcoholic gelling agents frequently used in the cosmetic and
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`pharmaceutical industries. Preferably, the hydrophilic or hydroalcoholic gelling
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`agent comprises "CARBOPOL®" (B. F. Goodrich, Cleveland, Ohio),
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`"HYPAN®" (Kingston Technologies, Dayton, N.J.), "NATROSOL®" (Aqualon,
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`Wilmington, Del.), "KLUCEL®" (Aqualon, Wilmington, Del.), or
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`10 "STABILEZE®" (ISP Technologies, Wayne, N.J.). Preferably, the gelling agent
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`comprises between about 0.2% to about 4% by weight of the composition. More
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`particularly, the preferred compositional weight percent range for
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`"CARBOPOL®" is between about 0.5% to about 2%, while the preferred weight
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`percent range for "NATROSOL®" and "KLUCEL®" is between about 0.5% to
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`15 about 4%. The preferred compositional weight percent range for both
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`"HYPAN®" and "STABILEZE®" is between about 0.5% to about 4%.
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`"CARBOPOL " is one of numerous cross-linked acrylic acid polymers
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`that are given the general adopted name carbomer. These polymers dissolve in
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`water and form a clear or slightly hazy gel upon neutralization with a caustic
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`20 material such as sodium hydroxide, potassium hydroxide, triethanolamine, or
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`other amine bases. "KLUCEL®" is a cellulose polymer that is dispersed in water
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`and forms a uniform gel upon complete hydration. Other preferred gelling
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`polymers include hydroxyethylcellulose, hydroxypropylcellulose, cellulose gum,
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`MVA/MA copolymers, MVE/MA decadiene crosspolymer, PVM/MA
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`25 copolymer, or a combination thereof.
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`Preservatives may also be used in this dermatological composition and
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`preferably comprise about 0.05% to 0.5% by weight of the total composition.
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`The use of preservatives assures that if the product is microbially contaminated,
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`the formulation will prevent or diminish microorganism growth. Some
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`30 preservatives useful in this invention include methylparaben, propylparaben,
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`butylparaben, chloroxylenol, sodium benzoate, DMDM Hydantoin, 3-Iodo-2-
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`Propylbutyl carbamate, potassium sorbate, chlorhexidine digluconate, or a
`combination thereof.
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`Titanium dioxide may be used as a sunscreen to serve as prophylaxis
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`against photosensitization. Alternative sunscreens include methyl cinnamate.
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`Moreover, BHA may be used as an antioxidant, as well as to protect
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`ethoxydiglycol and/or dapsone from discoloration due to oxidation. An alternate
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`5 antioxidant is BHT.
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`In one embodiment, the dermatological composition that is applied
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`comprises a semi-solid or gel-like vehicle that may include a polymer thickener,
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`water, preservatives, active surfactants or emulsifiers, antioxidants, sunscreens,
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`a