(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`3 September 2009 (03.09.2009)
`
`(10) International Publication Number
`WO 2009/108147 Al
`
`(51) International Patent Classification:
`A61K 8/02 (2006.01)
`
`(21) International Application Number:
`PCT/US2008/002549
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`27 February 2008 (27.02.2008)
`
`English
`
`English
`
`(71) Applicant (for all designated States except US): QLT
`USA, INC. [US/US]; 2579 Midpoint Drive, Fort Collins,
`CO 80525-441 7 (US).
`
`(72) Inventor; and
`(for US only): GARRETT, John
`(75) Inventor/Applicant
`Steven [US/US]; 7 113 Silver Moon Lane, Fort Collins,
`CO 80252 (US).
`
`AO, 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, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IS, JP, 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, TJ, 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, TJ,
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), OAPI
`(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR,
`NE, SN, TD, TG).
`
`(74) Agents: STEFFEY, Charles E. et al; Schwegman, Published:
`Lundberg & Woessner, PA, P.O. Box 2938, Minneapolis,
`— with international search report (Art. 21(3))
`Minnesota 55402 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`
`(54) Title: DAPSONE TO TREAT ROSASCEA
`
`(57) Abstract: The methods described herein provide
`treatment of rosacea using topical formulations of dapsone.
`The methods also provide treatment of rosacea with topical
`dapsone in combination with other active agents, including
`metronidazole. The methods avoid negative hematologic
`side effects,
`including hemolysis and hemolytic anemia,
`that are associated with oral administration of dapsone.
`
`EG. 11
`
`Almirall, LLC
`Exhibit 2001
`Page 1
`
`

`

`DAPSONE TO TREAT ROSACEA
`
`Background of the Invention
`
`Rosacea is a dermatological syndrome affecting approximately 14
`
`million Americans. It is characterized by flushing of the skin, erythema,
`
`inflammatory papules and pustules, edema, telangiectasia, ocular symptoms and
`
`rhinophyma. To date, the etiology of rosacea is unknown and there is no clearly
`
`recognized cure (Bikowski and Goldman, 2004; Stone and Chodosh, 2004).
`
`Four subtypes and one variation of rosacea have been defined. The
`
`subtypes are papulopustular rosacea, erythematotelangiectatic rosacea,
`
`phymatous rosacea, and ocular rosacea; the rosacea variation is granulomatous
`
`rosacea. Some patients may have features of more than one subtype
`
`simultaneously, and differences in severity occur within each subtype.
`
`Management of rosacea is difficult because of the complexity of the
`
`syndrome and the sensitivity of rosacea-affected skin. Various therapies,
`
`including topical application of metronidazole, azelaic acid, sodium
`
`sulfacetamide/sulfur preparations, and antibiotics including erythromycin,
`
`clindamycin and tetracycline, are used in the management of rosacea with
`
`varying rates of success. Systemic therapy with oral tetracyclines,
`
`metronidazole and isotretinoin is also employed in the management of rosacea
`
`(Buechner, 2005). Dapsone antibiotic is effective for treating rosacea redness,
`
`facial flushing, papules and pustules when administered orally; however, the side
`
`effect profile makes the risMienefit ratio too high for most rosacea sufferers
`
`(Nase, 2005).
`
`What is needed are safe, effective treatments for the management of
`rosacea symptoms.
`
`Summary of the Invention
`
`The invention is directed to the treatment of rosacea. The invention
`
`includes a method to treat rosacea by topically administering a pharmaceutical
`
`composition of dapsone and a pharmaceutically acceptable carrier to a patient.
`
`In preferred embodiments, the rosacea is papulopustular rosacea. In other
`
`embodiments, the rosacea is ocular rosacea. The invention is also directed to the
`
`Almirall, LLC
`Exhibit 2001
`Page 2
`
`

`

`treatment of ocular disorders. The invention includes a method to treat an ocular
`
`disease or disorder by topically administering a pharmaceutical composition of
`
`dapsone and a pharmaceutically acceptable carrier.
`
`In some embodiments, the dapsone of the topical composition is entirely
`
`dissolved in the carrier; or partially dissolved and partially microparticulate; or
`
`may be present as an emulsion, suspension or colloid. In an entirely dissolved
`
`state, dapsone exists completely in solution in the solvent, with no solid dapsone
`
`present. If the dapsone is partially dissolved and partially microparticulate, a
`
`portion of the dapsone is present in solution and a portion of the dapsone is
`
`present in a solid form. A dapsone emulsion includes two immiscible,
`
`unblendable substances wherein one substance (the dispersed phase) is dispersed
`
`in the other (continuous phase). The dapsone can be part of the dispersed phase
`
`or part of the continuous phase of the emulsion. A dapsone suspension is a
`
`heterogenous fluid containing solid particles of dapsone dispersed throughout a
`
`fluid. A dapsone colloid is a homogenous mixture of dispersed dapsone
`
`particles that are distributed evenly and stably throughout the continuous phase.
`
`In certain embodiments, the pharmaceutical composition is a lotion, gel,
`
`ointment, cream, emulsion, suspension, spray, or cleanser. In a preferred
`
`embodiment, the pharmaceutical composition is a semisolid aqueous gel. The
`
`semisolid aqueous gel includes a thickening agent, water, a solvent, preservative,
`
`microparticulate dapsone, dissolved dapsone, and caustic materi al hi a
`
`preferred embodiment, the caustic material is a base agent. In a preferred
`
`embodiment, the composition exhibits an optimal balance between dissolved
`
`dapsone that is available to cross through the stratum corneum of the epidermis
`
`and be absorbed into the lower two-thirds of the pilosebaceous unit; 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, crossing the
`
`stratum corneum of the epidermis only minimally as a solid. The solid
`
`microparticulate dapsone reservoir is slowly dissolved in body fluids before it is
`
`delivered through the stratum corneum. In preferred embodiments, the dapsone
`
`makes up about 0.5% to 10% of the pharmaceutical composition. The
`
`microparticulate dapsone can be a crystalline precipitate or an amorphous
`
`precipitate. Antioxidants, fragrance, colorants, sunscreens, or combinations
`
`thereof may also be present in the topical composition. In preferred
`
`Almirall, LLC
`Exhibit 2001
`Page 3
`
`

`

`embodiments, the dapsone composition comprises about 5% dapsone, about
`
`0.85% carbomer 980, about 25% diethylene glycol monoethyl ether (DGME),
`
`about 0.2% methylparaben, about 0.2% sodium hydroxide, and about 68.75%
`
`purified water.
`The methods described herein include the treatment of papulopustular
`
`rosacea by applying the dapsone composition once or twice daily. In preferred
`
`methods the dapsone composition is applied twice daily. The methods
`
`additionally include the use of the dapsone pharmaceutical composition alone or
`
`in combination with other pharmaceutical compositions for rosacea, including
`
`topical and systemic treatments. The treatments are administered simultaneously
`
`or sequentially and include oral metronidazole, isotretinoin, tetracyclines
`
`including doxycycline, and topical metronidazole, azelaic acid, sodium
`
`sulfacetamide/sulfur preparations, and antibiotics including erythromycin,
`
`clindamycin and tetracycline. In some embodiments, the dapsone and other
`
`pharmaceutical are present in the same composition. In other embodiments, the
`
`dapsone and other pharmaceutical are present in separate compositions. In
`
`preferred embodiments, the dapsone pharmaceutical composition is applied
`
`topically in the AM and a separate metronidazole composition is applied
`
`topically in the PM, or vice versa.
`
`In some embodiments, the patient has mild to severe papulopustular
`
`rosacea. In some embodiments, the patient has mild to moderate papulopustular
`
`rosacea. In other embodiments, the patient has moderate to severe
`
`papulopustular rosacea. In preferred embodiments, the rosacea is moderate to
`
`severe papulopustular rosacea. In some embodiments, the patient has at least ten
`
`papulopustular lesions before treatment, or preferably at least twenty
`
`papulopustular lesions before treatment. In a preferred embodiment, the number
`
`of papulopustular rosacea lesions is reduced by administering the dapsone
`
`composition topically. In some embodiments, the methods described herein
`
`result in blood plasma levels of dapsone of less than about 100 ng/mL.
`
`In some embodiments, the patient has an Investigator's Global
`
`Assessment score of 3 or higher before treatment. In some embodiments,
`
`treatment results in a mean reduction of at least 13 papulopustular lesions. In
`
`some embodiments, treatment results in a mean reduction of at least 43 % of the
`papulopustular lesions.
`
`Almirall, LLC
`Exhibit 2001
`Page 4
`
`

`

`Brief Description of the Figures
`Figure 1 shows the mean change from baseline in inflammatory lesion
`
`counts in the intent to treat (ITT) population having > 10 inflammatory lesions
`
`(papules and/or pustules) above the mandibular line.
`
`Figure 2 shows the mean percent change from baseline in inflammatory
`
`lesion counts in the ITT population having > 10 lesions (ITT).
`
`Figure 3 shows mean change from baseline in inflammatory lesion
`
`counts for subjects with <20 lesions.
`
`Figure 4 shows mean percent change from baseline in inflammatory
`
`lesion counts for subjects with <20 lesions.
`
`Figure 5 shows the mean change from baseline in lesion counts for the
`
`subgroup of subjects with > 20 lesions.
`
`Figure 6 shows mean percent change from baseline in inflammatory
`
`lesion counts for subjects with > 20 lesions.
`
`Figure 7 shows the Investigator's Global Assessment (IGA) success rate
`
`over the course of the study in the intent to treat (ITT) population having > 10
`
`inflammatory lesions.
`
`Figure 8 summarizes the Investigator's Global Assessment (IGA) success
`
`rate at week 12 in the intent to treat (ITT) population having > 10 inflammatory
`
`lesions.
`
`Figure 9 shows the Investigator's Global Assessment (IGA) success rate
`
`over the course of the study in subjects with <20 inflammatory lesions.
`
`Figure 10 shows the Investigator's Global Assessment (IGA) success rate
`
`over the course of the study in subjects with > 20 lesions.
`
`Figure 11 summarizes the Investigator's Global Assessment (IGA)
`
`success rate at week 12 for the subgroup of subjects with > 20 lesions.
`
`Detailed Description of the Invention
`
`Definitions
`
`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.
`
`Almirall, LLC
`Exhibit 2001
`Page 5
`
`

`

`As used herein, the term "colloid" refers to a homogenous mixture of two
`
`separate phases. The dispersed phase is made of tiny particles or droplets that
`
`are distributed evenly throughout the continuous phase. Colloids are stable
`
`mixtures and the dispersed phase generally does not settle out of the mixture.
`
`As used herein, "dapsone" refers to the chemical compound dapsone
`having the chemical formula Ci2H 2N2O2S as well as bis(4-
`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.
`
`"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.
`
`As used herein, the term "emulsion" describes a mixture of two
`
`immiscible, unblendable substances. The dispersed phase is dispersed in the
`
`continuous phase. For example, oil and water will form an emulsion when
`
`mixed together. In the compositions described herein, 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 petrolatum, or other oils alone or in combination. Surfactants
`
`may be present in the emulsion to increase kinetic stability. Suitable emulsifiers
`
`that may be added to the compositions described herein include, but are not
`
`limited to, steareth 20, ceteth 20, sorbitan sesquioleate, sorbitan mono-oleate,
`
`propylene glycol stearate, dosium lauroyl sarcosinate, polysorbate 60, or
`combinations.
`
`As used herein, "gel" refers to a colloid in a more solid form than a
`
`solution. A gel is also a jelly-like material formed by the coagulation of a
`
`colloidal liquid. 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 "mild rosacea" refers to papulopustular rosacea
`
`that includes mild erythema and several small papules/pustules.
`
`Almirall, LLC
`Exhibit 2001
`Page 6
`
`

`

`As used herein, the term "moderate rosacea" refers to papulopustular
`
`rosacea that includes moderate erythema, with several small or large
`
`papules/pustules, and up to two nodules.
`
`As used herein, the term "severe rosacea" refers to papulopustular
`
`rosacea that includes severe erythema and numerous small and/or large
`
`papules/pustules, and up to several nodules.
`
`As used herein, the term "microparticulate" refers to any solid form of an
`
`active agent (dapsone) that is not dissolved in the topical composition. The
`
`microparticulate described herein may be in the form of flakes or crystals, and
`
`includes a precipitate of dapsone that results from the addition of water and the
`
`solvent or mixed solvent system. The microparticulate may comprise a
`
`crystalline precipitate or an amorphous precipitate.
`
`As used herein, the term "ointment" means a semisolid, oil-based topical
`
`formulation. 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 an active agent is either fully or partially dissolved.
`
`As used herein, "pharmaceutically acceptable carrier" refers to a
`
`pharmaceutically acceptable solvent, suspending agent or vehicle for delivering
`
`an active agent to a patient. Pharmaceutically acceptable carriers are nontoxic to
`
`the cell or patient being exposed thereto at the dosages and concentrations
`
`employed. Often, the physiologically acceptable carrier is an aqueous pH
`
`buffered solution. Pharmaceutically acceptable carriers are readily available to
`
`the public. Suitable pharmaceutical carriers are described in Remington's
`
`Pharmaceutical Sciences, Mack Publishing Company, a standard reference text
`
`in this field. Pharmaceutically acceptable carriers may include antiadherents,
`
`binders, coatings, disintegrants, fillers, diluents, colorants, glidants, lubricants,
`
`and preservatives. Suitable carrier materials for topical preparations are
`
`glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid
`
`waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and
`
`cellulose derivatives. In a preferred embodiment, the pharmaceutically
`
`acceptable carrier includes ethoxydiglycol, also known as diethylene glycol
`
`monoethyl ether (DGME).
`
`Almirall, LLC
`Exhibit 2001
`Page 7
`
`

`

`As used herein, the term "suspension" refers to a heterogenous fluid
`
`containing solid particles dispersed throughout. The suspended phase or
`
`suspensoid is dispersed throughout the liquid in a moderately finely divided
`
`state, but not so finely divided as to acquire the stability of a colloidal system.
`
`The suspended phase will eventually settle out of the suspension.
`
`The term "topical" or "topical surface" as used herein refers to the route
`
`of administration of a composition that involves direct application to the surface
`
`of the body being treated. Topical application may be to the skin, or to a mucous
`
`membrane, also called mucosa, lining all body passages that communicate with
`
`the exterior such as the respiratory, genitourinary, and alimentary tracts, and
`
`having cells and associated glands that secrete mucous. Topical application may
`
`be to mucous membranes of nose, mouth, eye, eyelid inner surface, etc., or may
`
`be to the surface of intact or compromised skin. Examples of topical application
`
`include application of gels or other semisolids to rub-on, solutions to spray, or
`
`liquids to be applied by an applicator, for example, as eye drops. Rinse-off
`
`application with washes, cleansers, or shampoos are also examples of topical
`
`application. Areas of the body especially suitable for application of the
`
`composition described herein include sites where rosacea symptoms may be
`
`present, including the skin of the face, scalp, ears and neck, and the eyes.
`
`As used herein, the term "treat", "treatment", or "treating" refers to the
`
`reduction in number and/or severity of individual rosacea lesions, prevention of
`
`the development of rosacea symptoms including papulopustular lesions, or
`
`global improvement in the appearance of rosacea. Success of treatment may be
`
`indicated by a reduction from baseline in the raw number of papulopustular
`
`inflammatory lesions, by a percent reduction from baseline in papulopustular
`
`inflammatory lesions, or by an improvement from baseline in an Investigator's
`
`Global Assessment (IGA) score.
`
`Methods of Treatment
`
`The method of the invention described herein treats rosacea conditions,
`
`e.g., papulopustular, erythematotelangiectatic, phymatous, and ocular rosacea,
`
`by the topical application of a composition comprising dapsone and a
`
`pharmaceutically acceptable carrier. The composition is applied as needed to
`
`relieve rosacea symptoms. In some embodiments, the composition is applied
`
`Almirall, LLC
`Exhibit 2001
`Page 8
`
`

`

`every other day. In some embodiments, the composition is applied once daily.
`
`In some embodiments, the composition is applied twice daily. In certain
`
`embodiments, the composition is applied for at least one week, at least two
`
`weeks, at least three weeks, at least four weeks, at least five weeks, at least six
`
`weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least ten
`
`weeks, at least eleven weeks, or at least twelve weeks. In some preferred
`
`embodiments, the composition is applied for at least twelve weeks. In other
`
`preferred embodiments, the composition is applied for at least six months, at
`
`least nine months, or at least a year.
`
`Rosacea
`
`Rosacea is a multifactorial chronic disorder that most often affects the
`
`skin of the central face including the nose, forehead, cheeks, and chin. Rosacea
`
`usually affects fair-skinned people 30 to 50 years of age who tend to blush or
`
`flush easily. Four subtypes of rosacea are described: papulopustular,
`
`erythematotelangiectatic, phymatous, and ocular (Wilkin et al. 2002; Bikowski
`
`and Goldman, 2004). Granulomatous rosacea is considered to be a part of the
`
`spectrum of rosacea, but is referred to as a variant, rather than a subtype, of
`
`rosacea (Khokhar and Khachemoune 2004).
`
`Papulopustular rosacea is characterized by persistent central facial
`
`erythema with transient, central facial papules, pustules or lesions of both types.
`
`In preferred embodiments, mild to severe papulopustular rosacea is treated. In a
`
`more preferred embodiment, moderate to severe papulopustular rosacea is
`
`treated. Erythematotelangiectatic rosacea is characterized by flushing and
`
`persistent central facial erythema, with or without telangiectasia. Phymatous
`
`rosacea is characterized by thickening skin, irregular surface nodularities, and
`
`enlargement, which may occur on the nose, chin, forehead, cheeks or ears.
`
`Ocular rosacea is characterized by a foreign body sensation in the eye, burning
`
`or stinging, dryness, itching, ocular photosensitivity, blurred vision,
`
`telangiectasia of the sclera or other parts of the eye, or periorbital edema.
`
`Granulomatous rosacea is characterized by noninflammatory, hard, brown,
`
`yellow or red cutaneous papules; or nodules of uniform size (Bikowski and
`
`Goldman, 2004).
`
`In a recent study of clinical patterns of rosacea, papules and pustules
`
`were found in 83% and 67% of a sample of 108 rosacea patients, respectively
`
`Almirall, LLC
`Exhibit 2001
`Page 9
`
`

`

`(Sibenge and Gawkrodger, 1992). In the papulopustular subtype of rosacea,
`
`patients typically present with persistent central facial erythema with transient
`
`papules or pustules or both. Symptoms of burning, stinging, and dry skin are
`
`common (Wilkin et al. 2002; Dahl 2004). Other symptoms include flushing,
`
`erythema, and telangiectasia. While the exact pathogenesis of rosacea is
`
`unknown, inflammatory and vascular components are believed to be important in
`
`its pathogenesis.
`
`The methods of the invention described herein include treatment of
`
`papulopustular rosacea lesions. In certain embodiments, the treatment of rosacea
`
`lesions results in a decrease or reduction from the baseline number of lesions by
`
`at least 2 lesions, at least 3 lesions, at least 4 lesions, at least 5 lesions, at least 6
`
`lesions, at least 7 lesions, at least 8 lesions, at least 9 lesions, at least 10 lesions,
`
`at least 11 lesions, at least 12 lesions, at least 13 lesions, at least 14 lesions, at
`
`least 15 lesions, at least 16 lesions, at least 17 lesions, at least 18 lesions, at least
`
`19 lesions, at least 20 lesions, at least 30 lesions, at least 40 lesions, or more than
`
`40 lesions. In certain embodiments, the treatment of rosacea lesions results in a
`
`percentage decrease or reduction of lesions from baseline of at least 20%, at least
`
`25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least
`
`55%, at least 60%, at least 65%, at least 70%, at least 75%, or more than 75%.
`
`About half of all rosacea sufferers also have some involvement of the
`
`eyes, known as ocular rosacea (Starr and McDonald, 1969). Eye problems may
`
`precede the common skin-related rosacea symptoms though it more common for
`
`the skin symptoms to appear first (Borrie, 1953). Ocular rosacea symptoms
`
`include dry eyes or tearing, redness, burning, pain, a gritty feeling in the eye,
`
`scales and crusts on the eyelids, sensitivity to light and blurry vision (Jenkins
`
`1979).
`
`Blepharitis, which includes inflammation of eyelashes or lid margins, is
`
`commonly seen in ocular rosacea. Blepharitis often results in red, itchy, burning
`
`eyes and lashes as well as scales and crusts on the eyelids. Sties, which are
`
`infections of eyelash follicles, may be present. Ocular rosacea sufferers may
`
`also have chalazia or meibomitis, characterized by enlarged, inflamed or plugged
`
`meibomian glands (which normally lubricate the eyelids). Scleritis and
`
`episcleritis, which are inflammatory conditions of the white outer coating of the
`
`Almirall, LLC
`Exhibit 2001
`Page 10
`
`

`

`eye (sclera) and connective tissue between the conjunctiva and sclera (episclera)
`
`may also be present in ocular rosacea.
`
`Keratitis and iritis, which are infections or inflammation of the cornea
`
`and iris, respectively, may also be present in patients with ocular rosacea. These
`
`conditions may result in severe eye pain, blurry vision, formation of pus, and
`
`sensitivity to light. In severe ocular rosacea, ulcers may be present at the border
`
`of the cornea and sclera. This corneal ulceration, if untreated, may lead to
`
`perforation of the eye, a potentially blinding complication.
`
`Management of rosacea is difficult because of the complexity of the
`
`syndrome and the sensitivity of rosacea-affected skin. Various therapies,
`
`including topical application of metronidazole, azelaic acid, sodium
`
`sulfacetamide/sulfur preparations, and antibiotics including erythromycin,
`
`clindamycin and tetracycline, are used in the management of rosacea with
`
`varying rates of success. Systemic therapy with oral tetracyclines,
`
`metronidazole and isotretinoin is also employed in the management of rosacea
`
`(Buechner, 2005). Oral dapsone antibiotic is effective for treating rosacea
`
`redness, facial flushing, papules and pustules; however, the side effect profile
`
`makes the risk/benefit ratio too high for most rosacea sufferers (Nase, 2005).
`
`Ocular Indications
`
`In addition to ocular rosacea, other ocular diseases may be treated with
`
`the topical dapsone compositions of the present invention. These diseases may
`
`be associated with inflammation, infection or other pathologies and the ocular
`
`involvement may be a primary or secondary manifestation of the disease or
`
`disorder. These diseases and disorders include conjunctivitis; scleritis including
`
`nodular scleritis secondary to Sweet's syndrome; vasculitis including
`
`autoimmune vasculitis and retinal vasculitis of Eales1disease; uveitis including
`
`granulomatous uveitis and panuveitis; ocular cicatrical pemphigoid; ocular
`
`leprosy; ocular manifestations of arachnid evenomation, Behcet disease, linear
`
`IgA disease, relapsing polychondritis, peripheral keratitis, tuberculosis, Hodgkin
`
`lymphoma, non-Hodgkin lymphoma, T-cell lymphoma and Reiter's syndrome;
`
`tumors of the eyelids; erythema elevatum diutinum; eyelid manifestations of
`
`erosive lichen planus; and Pneumocystis carinii choroiditis associated with
`
`AIDS. The topical dapsone compositions of the present invention may be
`
`particularly formulated for treatment of ocular conditions. These formulations
`
`Almirall, LLC
`Exhibit 2001
`Page 11
`
`

`

`will be known to those of skill in the art and include drops, gels, ointments,
`
`cleansers and other topical formulations.
`
`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
`
`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).
`
`Dapsone analogs and related compounds have been described in U.S. Pat.
`
`Nos. 4,829,058 and 4,912,1 12 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
`
`dapsone for toxicity and anti-inflammatory activity.
`
`In the 1112 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., 1996) and anti
`
`inflammatory activity (Coleman et al., 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.
`
`Currently, use of oral dapsone is generally limited, as its use may be
`
`associated with hematologic side effects, including hemolysis and hemolytic
`
`anemia that are dose-dependent and occur more 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).
`
`Topical Dapsone Compositions
`
`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. 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.
`
`Almirall, LLC
`Exhibit 2001
`Page 12
`
`

`

`The topical compositions described herein include dapsone and a
`
`pharmaceutically acceptable carrier. The carriers described herein are media
`
`useful for topical delivery of dapsone and optionally any additional active
`
`agents. These media, which are preferably organic or organic/aqueous mixtures,
`
`may be formulated as eye drops, lotions, gels, ointments, creams, sprays,
`
`washes, cleansers, shampoos, roll-on or stick products, micro-emulsions, shake
`
`powders, aerosolized sprays or mousse, and bath additives. Additional
`
`pharmaceutical carriers will be known to those skilled in the art and this list
`
`should not be considered to be limiting.
`
`The dapsone of the topical composition may be entirely dissolved in the
`
`carrier; partially dissolved and partially microparticulate; or may be present as an
`
`emulsion, suspension or colloid. In an entirely dissolved state, dapsone exists
`
`completely in solution in the solvent, with no solid dapsone present. If the
`
`dapsone is partially dissolved and partially microparticulate, a portion of the
`
`dapsone is present in solution and a portion of the dapsone is present in a solid
`
`form. A dapsone emulsion includes two immiscible, unblendable substances
`
`wherein one substance (the dispersed phase) is dispersed in the other (continuous
`
`phase). The dapsone can be part of the dispersed phase or part of the continuous
`
`phase of the emulsion. A dapsone suspension is a heterogenous fluid containing
`
`solid particles of dapsone dispersed throughout a fluid. A dapsone colloid is a
`
`homogenous mixture of dispersed dapsone particles that are distributed evenly
`
`and stably throughout the continuous phase.
`
`Pharmaceutical carriers are pharmaceutically acceptable media for
`
`delivering active agent(s) to a patient. Pharmaceutically acceptable carriers
`
`include solvents, suspending agents or other vehicles that are nontoxic to the
`
`patient being exposed thereto at the dosages and concentrations employed.
`
`Pharmaceutical carriers of the compositions described herein will solubilize
`
`dapsone and any additional active agent(s) in whole or in part. Excipients
`
`present in the pharmaceutically acceptable carrier may include antiadherents,
`
`binders, coatings, disintegrants, fillers, diluents, colorants, glidants, lubricants,
`
`and preservatives.
`
`In some embodiments, the topical compositions include a pharmaceutical
`
`carrier, dapsone, and an additional active pharmaceutical agent or agents. As
`
`described above, these dual agent compositions may be formulated as lotions,
`
`Almirall, LLC
`Exhibit 2001
`Page 13
`
`

`

`gels, ointments, creams, sprays, washes, cleansers, shampoos, roll-on or stick
`
`products, micro-emulsions, shake powders, aerosolized sprays or mousse, and
`
`bath additives. The dapsone and additional active pharmaceutical agent(s) of the
`
`topical composition may be entirely dissolved; partially dissolved and partially
`
`microparticulate; or may be present as an emulsion, suspension or colloid as
`
`described above. Suitable additional active pharmaceutical agents are disclosed,
`
`e.g., in Physician's Desk Reference (PDR), Medical Economics Company
`
`(Montvale, NJ), (53rd Ed.), 1999; Mayo Medical Center Formulary, Unabridged
`
`Version, Mayo Clinic (Rochester, MN), January 1998; Merck Index, An
`
`Encyclopedia of Chemicals, Drugs, and Biologicals, ( 1lth Ed.), Merck & Co.,
`
`Inc. (Rahway, NJ), 1989; and references cited therein.
`
`Additional active pharmaceutical agents include, but are not limited to,
`
`anti-inflammatory agents, keratolyses, anti-infectives and acidic compounds.
`
`Anti-inflammatory agents, including corticosteroids, relieve inflammation
`
`including swelling, itching, and redness of the skin. Keratolytics are agents that
`
`soften skin cells and ease the flaking and peeling process. Examples include
`
`salicylic acid and urea. Anti-infectives including antibiotics, antifungals and
`
`antiseptics combat bacteria, fungi,