(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2007/0122435 A1
`Osborne
`(43) Pub. Date:
`May 31, 2007
`
`US 2007.0122435A1
`
`(54) TOPICAL DAPSONE FOR THE TREATMENT
`OF ACNE
`
`(75) Inventor: David W. Osborne, Fort Collins, CO
`(US)
`Correspondence Address:
`SCHWEGMAN, LUNDBERG, WOESSNER &
`KLUTH, P.A.
`P.O. BOX 2938
`MINNEAPOLIS, MN 55402 (US)
`(73) Assignee: QLT USA, INC.
`(21) Appl. No.:
`11/637,645
`(22) Filed:
`Dec. 12, 2006
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 10/081,050, filed on
`Feb. 20, 2002.
`
`Continuation-in-part of application No. 09/236,909,
`filed on Jan. 25, 1999, now Pat. No. 6,620,435, which
`is a continuation of application No. 08/712,454, filed
`on Sep. 11, 1996, now Pat. No. 5,863,560.
`
`Publication Classification
`
`(51) Int. Cl.
`(2006.01)
`A6II 3 L/35
`(2006.01)
`A6IR 8/40
`(52) U.S. Cl. ............................................ 424/401; 514/646
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a method of treating acne by
`topically applying a dermatological composition comprising
`dapsone. In addition to inflammatory lesions, the composi
`tion also treats non-inflammatory acne. The composition is
`formulated to include dapsone in a both a dissolved and
`microparticulate state.
`
`1 of 6
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`Almirall EXHIBIT 2053
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`US 2007/O122435 A1
`
`May 31, 2007
`
`TOPCAL DAPSONE FOR THE TREATMENT OF
`ACNE
`
`FIELD OF THE INVENTION
`0001. The present invention relates to the field of derma
`tology. In particular, the invention is a novel method for
`treating primary non-inflammatory acne or closed come
`dones by topically administering dapsone.
`
`BACKGROUND OF THE INVENTION
`0002 Sebaceous glands are associated with hair follicles
`and secrete an oily Substance called sebum into the upper
`part of the follicles. These glands are found everywhere on
`the human skin, except for the soles and dorsa of the feet and
`the palms. In each gland, a common excretory duct is
`Supplied by Smaller ducts that originate in the acini of the
`gland. As the sebaceous cells move toward the center of the
`gland, lipid synthesis within the cells continues until there is
`a 100 to 150 fold increase in cell volume. The cells then
`rupture and lipid is expelled into the excretory stream of the
`gland, passing through the follicular canal and into the upper
`third of the hair follicle. On the skin of the face, the
`sebaceous glands are the predominant portion of the follicles
`and are called sebaceous follicles.
`0003. The follicular canal contains keratinous material,
`i.e., dead skin cells, from the wall of the canal, sebum from
`the sebaceous glands, and bacteria, predominately Propioni
`bacterium acnes. In the follicular canal of patients with
`acne, these dead skin cells clump together to form a keratin
`plug. This altered pattern of keratinization is the primary
`structural change in the follicular canal that leads to an acne
`lesion.
`0004. When the follicular canal becomes blocked, a
`comedone is formed. The primary manifestation of acne is
`the closed comedone, which are small, circumscribed,
`elevated lesions of the follicle that are often without a visible
`central plug. Closed comedones (whiteheads) are non-in
`flammatory acne lesions. Open comedones (blackheads)
`consist of Small follicular lesions having a central black
`keratin plug as a result of oxidation of melanin pigment.
`Open comedones develop from closed comedones as the
`orifice dilates. The open comedone is not an inflammatory
`lesion unless traumatized, i.e. picked at, by the patient.
`Comedones, either open or closed, are non-inflammatory.
`While the comedone is the primary lesion of acne, come
`dones are not unique to acne since they may be seen in other
`conditions such as senile comedones or trophic skin result
`ing from X-ray therapy.
`0005 Closed comedones are potential precursors to large
`inflammatory lesions. The dead skin cells of the comedone
`are permeated with lipid and P. acnes, and as the follicle
`dilates from the expanding mass of keratin and lipid, inflam
`mation develops along the follicular wall. This can lead to
`follicular wall rupture which extrudes the entire contents of
`the comedone into the dermis, generating a greater inflam
`matory response. Inflammatory lesions can be small papules
`with an encircling inflammatory region or, depending on the
`site and extent of the rupture, a pustule or large tender
`nodule may form. Papules, pustules and nodules are the
`three clinical descriptions for inflammatory acne.
`0006. As summarized by Strauss (J. S. Strauss. (1991).
`“Biology of the Sebaceous Gland and Pathophysiology of
`
`Acne Vulgaris.” Chapter 13 in Pathophysiology of Derma
`tologic Diseases, Second Edition. N. A. Sotor and H. Baden
`eds., McGraw-Hill, New York: pp. 195-210) there are four
`principles of acne therapy: 1) correct the pattern of altered
`keratinization within the follicle; 2) decrease sebaceous
`gland activity; 3) decrease the P. acnes population and/or
`decrease the generation of inflammatory Substances by the
`bacterial population; and 4) produce non-inflammatory
`effects.
`0007 Topical retinoids such as tretinoin primarily func
`tion by correcting altered patterns of keratinization. Oral
`isotretinoin (13-cis retinoic acid) primarily functions by
`decreasing sebaceous gland activity. Antibiotic therapies
`Such as oral minocycline or topical clindamycin primarily
`function by reducing the numbers or activity of P. acnes.
`Furthermore, Steroids can be injected into acne lesions to
`produce an anti-inflammatory effect. However, topically
`applying steroids to acne results in an increase in acne
`lesions.
`0008 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 also known as
`4',4'-diaminodiphenyl sulfone, 4,4'-sulfonylbisbenzeneam
`ine, 4,4'-sulfonyldianiline, and diaphenylsulfone. Dapsone
`has been used orally for the treatment of acne (C. M. Ross,
`Br. J. Dermatol. 73:367, (1961)) and been found to have a
`minimum inhibitory concentration with regard to Pacnes of
`about 1 microgram per milliliter (K. L. Godowski et al., J.
`Invest. Dermatol. 114:862 (2000)).
`0009 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 bac
`teria, mycobacteria, and plasmodia. Some of these com
`pounds were also tested against dapsone for toxicity and
`anti-inflammatory activity (Coleman et al., Environmental
`Toxicology and Pharmacology, 2:389-395 (1996)). In the
`112 patent, substituted 2,4-diamino-5-benzyl pyrimidines
`having antimicrobial activity particularly against mycobac
`teria are described. Some of these compounds were also
`tested against dapsone for toxicity (Coleman et al., J.
`Pharm. Pharmacol., 48:945-950 (1996)) and anti-inflam
`matory activity (Coleman et al., J. Pharm. Pharmacol.,
`49:53-57 (1997)). The teachings of 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.
`0010 Topical dapsone formulations have been described
`in U.S. Pat. No. 5,733,572 to Unger et al., and U.S. Pat. Nos.
`6,056,954; 6,056,955; 6,254,866; 6,248,324; and 6,277.399
`to Fischetti et al. However, these compositions are not used
`to treat acne lesions.
`0011 U.S. Pat. No. 6,200,964 discloses a topical silicone
`gel having salicylic acid, and optionally, a dermatological
`agent such as dapsone. In this formulation, salicylic acid is
`described as the anti-acne agent. Dapsone is not specifically
`included in this composition to treat acne.
`0012 While inflammatory acne lesions are currently
`treated in various ways, effective treatments for non-inflam
`matory acne lesions are lacking. Thus, new treatments for
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`non-inflammatory acne are needed. In particular, a topical
`composition having dapsone is needed for the treatment of
`non-inflammatory acne.
`
`SUMMARY OF THE INVENTION
`0013 The present invention is a method for treating acne
`conditions such as inflammatory and non-inflammatory acne
`by topically applying a dermatological composition that
`includes dapsone. The dermatological composition prefer
`ably includes a mixture of dissolved and microparticulate
`dapsone. Typically, dapsone is delivered using a semisolid
`aqueous gel, but other pharmaceutical carriers such as
`creams, lotions, Solutions, ointments, and sprays may also be
`used. The dermatological composition that is topically
`applied may also include additives Such as preservatives,
`antioxidants, fragrances, colorants, or Sunscreens. Besides
`treating acne, the dermatological composition having dap
`Sone may also be topically applied to prevent non-inflam
`matory acne lesions from progressing to inflammatory acne
`lesions.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`0014. The inventive method treats acne conditions, e.g.,
`inflammatory or non-inflammatory acne, by the topical
`application of a dermatologic composition comprising dap
`Sone. A topical composition including dapsone for acne
`treatment has been described in U.S. Pat. Nos. 5,863,560,
`and 6,060,085 to Osborne which are herein incorporated by
`reference in their entirety. The composition is a combination
`of microparticulate and dissolved dapsone that allows opti
`mal delivery of dapsone to the upper follicle and drug
`penetration to the site of inflammation. As used herein, the
`term “treat”, “treatment’, or “treating refers to the reduc
`tion in number and/or severity of individual acne lesions,
`prevention of the development of acne lesions, or global
`improvement in the appearance of acne lesions.
`0015 The term “topical” as used herein refers to the route
`of administration of a dermatological composition that
`involves direct application to the body part being treated,
`e.g., the skin. Examples of topical application include appli
`cation to the skin of gels 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 dermatological
`composition include the skin of the face, throat, neck, Scalp.
`chest, back, ears, and other skin sites where acne lesions
`may occur.
`0016 P. acnes is a primary factor in the formation of
`papules, pustules, and nodules, the inflammatory lesions of
`acne. The antimicrobial and anti-inflammatory properties of
`dapsone have been well described over the nearly 100 year
`use of the drug, implicating dapsone as a favorable drug
`candidate for the treatment of inflammatory acne. The role
`of P. acnes, while not fully understood, is not considered a
`primary factor in the development of non-inflammatory
`lesions. Thus, it would be unexpected that topical dapsone
`would significantly reduce the number of non-inflammatory
`lesions. However, our experimental data demonstrates that
`the number of non-inflammatory acne lesions are reduced as
`a result of treatment with topical dapsone.
`
`Topical Dapsone Compositions
`0017. By use of the term “dapsone” it is meant the
`chemical compound dapsone having the chemical formula
`CHNOS as well as bis(4-aminophenyl)sulfone, 4',4'-
`diaminodiphenyl sulfone and its hydrates, 4,4'-sulfonylbis
`benzeneamine, 4,4'-sulfonyldianiline, diaphenylsulfone,
`dapsone analogs, and dapsone related compounds. "Dap
`Sone analogs' refers to chemical compounds that have
`similar chemical structures and thus similar therapeutic
`potential to dapsone Such as the Substituted his(4-aminophe
`nyl)-sulfones. “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-benzylpyri
`midines.
`0018. In one embodiment, non-inflammatory acne is
`treated by topically applying a dermatological composition
`comprising dapsone. Preferably, the dermatological compo
`sition is part of a novel pharmaceutical carrier system that is
`a semisolid aqueous gel, wherein the composition exhibits
`an optimal balance between dissolved dapsone that is avail
`able to cross through the stratum corneum to become
`systemically available, and microparticulate dapsone that is
`retained in or above the stratum corneum to serve as a
`reservoir or to provide dapsone to the Supracorneum Zone.
`The microparticulate dapsone may comprise a crystalline
`precipitant or an amorphous precipitant.
`Dapsone Topical Gel
`0019. Optimal balance is accomplished by having a semi
`Solid gel carrier system in which microparticulate dapsone
`precipitates are formed in reproducible ratios with respect to
`the dissolved dapsone. For the composition to have a wide
`range of applicability, the microparticulate to dissolved
`dapsone ratio preferably should be no greater than five, at
`therapeutic levels of applied active dapsone.
`0020. A composition having a microparticulate to dis
`Solved dapsone ratio of less than two may provide the
`greatest amount of pharmaceutical available for immediate
`partition out of the stratum corneum and into the viable
`epidermis. This should provide minimum reservoir capacity,
`but may not maintain Sustained delivery or provide maxi
`mum activity in the Supracorneum Zone. A composition
`having a microparticulate to dissolved dapsone ratio of two
`or greater may have a reduced amount of drug available for
`immediate partition out of the stratum corneum and into the
`viable epidermis. This provides maximum reservoir capac
`ity, and maintains Sustained delivery, providing maximum
`activity in the Supracorneum Zone. In an example of a
`dermatological composition of this inventive method, the
`ratio for microparticulate dapsone to dissolved dapsone
`should be no greater than 50, preferably no greater than 10,
`and most preferably no greater than 5. Drug delivery from
`the microparticulate/dissolved dapsone formulation may be
`optimized to provide higher levels of drug to the Supracor
`neum Zone, while maintaining the level of drug partitioning
`out of the stratum corneum and into the viable epidermis,
`despite 10-fold increases in the amount of pharmaceutical
`applied to the skin.
`0021. In one embodiment, the dermatological composi
`tion that is applied comprises a semi-solid or gel-like vehicle
`that may include a polymer thickener, water, preservatives,
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`active surfactants or emulsifiers, antioxidants, Sunscreens,
`and a solvent or mixed solvent system. The solvent or mixed
`Solvent system is important to the formation of the micro
`particulate to dissolved dapsone ratio. The formation of the
`microparticulate, however, should not interfere with the
`ability of the polymer thickener or preservative systems to
`perform their functions.
`0022 Polymer thickeners that may be used include those
`known to one skilled in the art, Such as hydrophilic and
`hydroalcoholic gelling agents frequently used in the cos
`metic and pharmaceutical industries. Preferably, the hydro
`philic or hydroalcoholic gelling agent comprises “CAR
`BOPOLR” (B.F. Goodrich, Cleveland, Ohio.), “HYPANR”
`(Kingston Technologies, Dayton, N.J.), “NATROSOL(R”
`(Aqualon, Wilmington, Del.), “KLUCELR' (Aqualon,
`Wilmington, Del.), or “STABILEZEOR (ISP Technologies,
`Wayne, N.J.). Preferably, the gelling agent comprises
`between about 0.2% to about 4% by weight of the compo
`sition. More particularly, the preferred compositional weight
`percent range for “CARBOPOL(R) is between about 0.5% to
`about 2%, while the preferred weight percent range for
`“NATROSOLOR) and “KLUCEL(R) is between about 0.5% to
`about 4%. The preferred compositional weight percent range
`for both “HYPANOR) and “STABILEZEOR’ is between about
`0.5% to about 4%.
`0023 “CARBOPOLR” is one of numerous cross-linked
`acrylic acid polymers that are given the general adopted
`name carbomer. These polymers dissolve in water and form
`a clear or slightly hazy gel upon neutralization with a caustic
`material Such as sodium hydroxide, potassium hydroxide,
`triethanolamine, or other amine bases. “KLUCEL(R)' is a
`cellulose polymer that is dispersed in water and forms a
`uniform gel upon complete hydration. Other preferred gel
`ling polymers include hydroxyethylcellulose, hydroxypro
`pylcellulose, cellulose gum, MVA/MA copolymers, MVE/
`MA decadiene crosspolymer, PVM/MA copolymer, or a
`combination thereof Preservatives may also be used in this
`dermatological composition and preferably comprise about
`0.05% to 0.5% by weight of the total composition. The use
`of preservatives assures that if the product is microbially
`contaminated, the formulation will prevent or diminish
`microorganism growth. Some preservatives useful in this
`invention include methylparaben, propylparaben, butylpa
`raben, chloroxylenol, sodium benzoate, DMDM Hydantoin,
`3-Iodo-2-Propylbutyl carbamate, potassium sorbate, chlo
`rhexidine digluconate, or a combination thereof.
`0024 Titanium dioxide may be used as a sunscreen to
`serve as prophylaxis against photosensitization. Alternative
`sunscreens include methyl cinnamate. Moreover, BHA may
`be used as an antioxidant, as well as to protect ethoxydig
`lycol and/or dapsone from discoloration due to oxidation.
`An alternate antioxidant is BHT.
`0025. In one embodiment, the dermatological composi
`tion that is applied includes 0.5% to 4.0% carbomer and
`about 0.5% to 10% dapsone that exists in both a dissolved
`state and a microparticulate state. In another embodiment,
`the dermatological composition comprises about 1% car
`bomer, about 80-90% water, about 10% ethoxydiglycol,
`about 0.2% methylparaben, and about 0.3% to 3.0% dapsone
`including both microparticulate dapsone and dissolved dap
`Sone, and about 2% caustic material. More particularly, the
`carbomer may include “CARBOPOLR, 980 and the caustic
`material may include Sodium hydroxide solution.
`
`In a preferred embodiment, the composition com
`0026.
`prises dapsone and ethoxydiglycol, which allows for an
`optimized ratio of microparticulate drug to dissolved drug.
`This ratio determines the amount of drug delivered, com
`pared to the amount of drug retained in or above the stratum
`corneum to function in the Supracorneum domain. The
`system of dapsone and ethoxydiglycol may include purified
`water combined with “CARBOPOL(R” gelling polymer,
`methylparaben, propylparaben, titanium dioxide, BHA, and
`a caustic material to neutralize the “CARBOPOLR).
`Dapsone Topical Cream or Lotion
`0027. In another embodiment, dapsone may be applied as
`a topical cream or lotion in which dapsone is dissolved or
`dispersed or both partially dissolved and partially dispersed.
`Topical creams or lotions may be either oil-in-water emul
`sions or water-in-oil emulsions. The oil phase may include
`but is not limited to fatty alcohols, acids, or esters such as
`cetyl palmitate, cetyl alcohol, Stearyl alcohol, Stearic acid,
`isopropyl Stearate, glycerol Stearate, mineral oil, white pet
`rolatum, or other oils alone or in combination.
`0028. Emulsifiers that may be added to the composition
`include, but are not limited to, steareth 20, ceteth 20,
`Sorbitan sesquioleate, Sorbitan mono-oleate, propylene gly
`col Stearate, dosium lauroyl sarcosinate, polysorbate 60, or
`combination. Preservatives, antioxidants, fragrances, colo
`rants, sunscreens, thickeners, and other additives required to
`achieve pharmaceutical or cosmetically acceptable or pre
`ferred product may also be included. However, topical
`creams and lotions are not limited to these components since
`one skilled in the art will be aware of additional components
`useful in the formulation of topical creams and lotions.
`Dapsone Topical Solution or Suspension
`0029. In another embodiment dapsone may be applied as
`a solution or Suspension. These are fluid solvent or mixed
`Solvent systems including, but not limited to, water, ethanol,
`propylene glycol, glycerol, polyethylene glycol, ethyl
`acetate, propylene carbonate, n-methyl pyrolidone, trietha
`nolamine, 1,4-butanediol, triacetin, diacetin, dimethyl isos
`orbide alone or in combination. Preservatives, antioxidants,
`fragrances, colorants, Sunscreens, thickeners, Suspending
`agents, enhancers, and other additives required to achieve
`pharmaceutically or cosmetically acceptable or preferred
`product may also be included. Again, topical Solutions or
`Suspensions are not limited to these components, since one
`skilled in the art will be aware of additional components
`useful in the formulation of topical Solutions or Suspensions.
`Other Dapsone Topical Formulations
`0030) Dapsone may also be applied using a pharmaceu
`tical or cosmetic carrier form such as an ointment, roll-on or
`Stick product, micro-emulsion, shake powder, an aerosolized
`spray or mousse, a pump spray or mousse, or bath additive.
`Examples of ointments include essentially non-aqueous
`mixtures of petrolatum, lanolin, polyethylene glycol, plant
`or animal oils, either hydrogenated or otherwise chemically
`modified. An ointment may also contain a solvent in which
`dapsone is either fully or partially dissolved. Additional
`pharmaceutical carriers will be known to those skilled in the
`art and this list should not be considered to be limiting.
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`Method for Preparing the Dapsone Dermatological Compo
`sition
`0031. The present invention also provides methods for
`preparing the dermatological compositions described above.
`In a general form, the method for producing a dermatologi
`cal gel composition having dissolved dapsone and micro
`particulate dapsone precipitates comprises the steps of com
`pletely dissolving dapsone in a solvent or solvent mixture;
`adding and adequately dispersing a polymeric thickener in
`water, and combining the dissolved dapsone with the dis
`persed polymeric thickener. Alternatively, water may be
`slowly added to the dissolved dapsone, followed by the
`addition of a polymeric thickener. Ethoxydigylcol and 1-me
`thyl-2-pyrollidone are preferred solvents for use in the
`topically applied dermatological composition.
`0032. In one preferred embodiment, the method for pre
`paring a topically applied dermatological composition hav
`ing dissolved and microparticulate dapsone comprises the
`steps of forming a homogenous dispersion by stirring puri
`fied water vigorously enough to form a vortex and sifting gel
`polymer into the vortex formed in the water while continu
`ing to stir, forming a pharmaceutical component by dissolv
`ing methyl paraben and propylparaben in ethoxydiglycol by
`mixing to form a solution, and mixing dapsone with the
`Solution until the pharmaceutical is dissolved; mixing the
`pharmaceutical component with the homogenous dispersion
`to form a microparticulate dapsone dispersion; and adding a
`caustic material.
`0033. The order in which reagents are combined may be
`important, depending on the particular reagents necessary
`for the target mixture. For example, after a pharmaceutical
`Such as dapsone is dissolved in a solvent Such as ethoxy
`diglycol water may be slowly added to the dapsone in the
`ethoxydiglycol Solution, or the dapsone in ethoxydiglycol
`Solution may be added to the water with mixing. Adding the
`dapsone in ethoxydiglycol solution to water may result in
`less polydispersity in the size of the microparticulates than
`adding water to the dapsone in ethoxydiglycol Solutions. The
`carbomer is generally dispersed in the water component of
`the formulation, while the remaining ingredients will be
`dissolved or dispersed in whichever of the two components
`are best for dissolving or dispersing the ingredient. For
`example, it is Suggested to dissolve methylparaben, propy
`lparaben, and BHA in ethoxydiglycol. After the ethoxydig
`lycol component and water component are combined, neu
`tralizer is added to formulate the gel.
`Specific Applications of Topical Dapsone
`0034. In one preferred embodiment of the invention, a
`method for treating acne is employed by topically applying
`dapsone. Specifically, the invention includes a method for
`reducing the number of non-inflammatory acne lesions by
`topically applying a dermatological composition comprising
`dapsone. Furthermore, in another embodiment, a method is
`provided for topically applying a dermatological composi
`tion having dapsone to prevent closed comedones (non
`inflammatory acne) from becoming inflamed papules, pus
`tules, or nodules. However, if the follicular canal ruptures,
`dapsone would also help to reduce the resultant inflamma
`tion. Typically, the dermatological composition having dap
`Sone is applied once daily, but may be applied more fre
`quently if desired.
`
`EXAMPLES
`0035. The following examples are provided to show that
`topically applied dapsone has unexpected therapeutic benefit
`in the treatment of non-inflammatory acne lesions. Dapsone
`was expected to reduce the degree of inflammation and the
`number of inflammatory lesions. The known mechanisms of
`dapsone activity did not anticipate an improvement in the
`number of non-inflammatory lesions.
`Example 1
`0036 A 20-year-old white male applied 1% dapsone
`topical gel once daily as part of an open label, pharmaco
`kinetic clinical study. This patient had 115 non-inflamma
`tory lesions (closed comedones) at baseline. The number of
`non-inflammatory lesions decreased to 103 after seven days
`of treatment, 31 non-inflammatory lesions after 24 days, and
`13 non-inflammatory lesions after 21 days of treatment with
`1% dapsone topical gel applied once daily.
`Example 2
`0037. A four week, open label, dose-ranging study was
`completed in 18-39-year-old patients having mild to mod
`erate acne. The number of pustules, papules, comedones,
`and nodules were counted at baseline and after 28 days of
`topical dapsone therapy for each patient. The number of
`papules, pustules, and nodules were combined to give the
`total number of inflammatory lesions while the number of
`comedones provided the total non-inflammatory lesion
`count. Four males and seven females applied 1% dapsone
`topical gel once daily, five males and seven females applied
`1% dapsone topical gel twice daily; seven males and six
`females applied 5% dapsone topical gel once daily; and four
`males and eight females applied 5% dapsone topical gel
`twice daily. The average percent lesion reduction for each of
`the four dosage groups after 28 days of treatment is shown
`in Table 1. These results can be compared to a 0.1%
`Tretinoin cream. (FOI Services, Inc., Gaithersburg, Md.,
`releasable documents for ANDA 75-213). This maximum
`strength topical retinoid produced a 26% (test article) to
`27% (reference article) reduction in non-inflammatory
`lesions after four weeks of treatment.
`
`TABLE 1.
`
`Percent Lesion Reduction
`
`Inflammatory
`
`Non-Inflammatory
`
`1% Dapsone Once Daily Dosing
`1% Dapsone Twice Daily Dosing
`5% Dapsone Once Daily Dosing
`5% Dapsone Twice Daily Dosing
`
`13%
`53%
`48%
`47%
`
`539
`45%
`32%
`39%
`
`Example 3
`0038 Table 2 shows the results from a multicenter,
`double-blind, randomized, parallel-design study in which
`patients were randomized to receive either 3% dapsone
`topical gel, 5% dapsone topical gel, or vehicle control once
`daily for 12 weeks. Inflammatory lesion counts include data
`from Portland, Cheery Creek, Orange County, and Denver
`Center clinical sites, with the number of patients being 20,
`15, and 18 for the 5% dapsone, 3% dapsone, and vehicle
`control groups respectively. Patients were male or female
`
`5 of 6
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`US 2007/O122435 A1
`
`May 31, 2007
`
`aged 13-years or older. This was the first study in which a
`vehicle control was used. Thus, any reduction in non
`inflammatory lesions beyond about 13% is due to the effect
`of topical dapsone.
`
`TABLE 2
`
`Percent Lesion Reduction
`
`Inflammatory
`
`Non-Inflammatory
`
`Once Daily Dosing
`Vehicle
`3% Dapsone Once Daily Dosing
`5% Dapsone Once Daily Dosing
`
`28%
`46%
`45%
`
`13%
`37%
`28%
`
`0039 Those skilled in the art will recognize that while
`specific embodiments have been illustrated and described,
`various modifications and changes may be made without it
`departing from the spirit and scope of the invention.
`1-26. (canceled)
`27. A method for treating acne comprising the step of
`topically applying a dermatological composition to the acne,
`wherein the dermatological composition comprises an active
`agent, and the active agent comprises Dapsone.
`28. The method of claim 27 wherein the dermatological
`composition consists essentially of dapsone in a single
`phase.
`29. The method of claim 27 wherein the acne comprises
`inflammatory acne and non-inflammatory acne.
`
`30. The method of claim 28 wherein the single-phase
`dapsone comprises dissolved dapsone.
`31. The method of claim 30 wherein the dermatological
`composition is a semisolid aqueous gel.
`32. The method of claim 30 wherein the dermatological
`composition is a cream.
`33. The method of claim 30 wherein the dermatological
`composition is a lotion.
`34. The method of claim 30 wherein the dermatological
`composition is a solution.
`35. The method of claim 30 wherein the dermatological
`composition is an ointment.
`36. The method of claim 30 wherein the dermatological
`composition is a spray.
`37. The method of claim 30 wherein the dermatological
`composition further comprises an additive selected from the
`group consisting of a preservative, an antioxidant, a fra
`grance, a colorant, and a Sunscreen.
`38. The method of claim 30 wherein the dermatological
`composition comprises between about 0.03% and about
`10% dapsone.
`39. The method of claim 30 wherein the dermatological
`composition comprises about 0.03% up to about 0.3%
`dapsone.
`40. The method of claim 30 wherein the dermatological
`composition comprises about 0.1% up to about 0.3% dap
`SO.
`
`6 of 6
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`