US006482839B1 (12) United States Patent (10) Patent N0.: US 6,482,839 B1 Thornfeldt (45) Date of Patent: Nov. 19, 2002

(54) PYRIDINE-THIOLS FOR TREATMENT OFA 5,686,489 A 11/1997 Yu et al...... 514/557 FOLLICULAR DERMATOSIS OTHER PUBLICATIONS (75) Inventorr Carl R- Thornfeldt, Nampa, ID (US) CA 1191233716, Martin et al., Jul., 1993* _ _ CA 99:10733, FDA Monograph, Dec., 1982* (73) Asslgnee: Qellegy Pharmaceutlcals’ Inc” Foster A. Bernard Ackerman, Histologic Diagnosis of In?amma C1ty> CA (Us) tory Skin Diseases, Library of Congress Cataloging in . _ . . . _ Publicatin Data, pp. 640—663, 668—672 (1995). ( * ) Nonce' Sub]eCt_tO any ((iilsglalmeéi the fiermgf “31; T. Sakamoto et al., “Shampoos containing vitamin EAcetate Patent 15 sexéenbe (sir a Juste un er and Dandruff—Controlling Agents,” chemical Abstracts U50 1 4( ) Y0 ays- (Oct. 24, 1986) 106, Abstract 106155622. (21) Appl. N0.: 09/145,822 * Cited by examiner (22) Filed; Sep_ 2, 1998 Primary Examiner—EdWard J. Webman (74) Attorney, Agent, or Firm—ToWnsend and Townsend Related US. Application Data and Crew, LLP (63) Continuation-in-part of application No. l~3CT/US98/11270, (57) ABSTRACT SL651 ’ gililaoioilligfufflfgggpm of apphcw This invention provides compositions and methods for treat (60) Provisional application No. 60/047,360, ?led on Jun. 2, meat of 5km and_ mucous mempremqs Suffenng from a 1997, provisional application No, 60/056,282, ?led on Sep, follicular dermatosis. The compositions mclude one or more 3, 1997, Provisiona1 aPPliCatiOIl N9 69/058,752, ?led 0n pyridine-thiols and tautomers With attached metallic moi gigi (131312923 arllggpgovlslonal apphcanon NO‘ 60/056290’ eties. Administration of the compounds to aging skin and p' ’ ' mucous membranes in topical formulations, either as the (51) Int. Cl.7 ...... A61K 31/4402; A61P 17/00; only active ingredient or in combination With other known A61P 17/ 10 active ingredients to treat a follicular dermatosis. Additional (52) US. Cl...... 514/345; 514/859 compositions for treating follicular dermatosis contain one (58) Field of Search ...... 514/354, 859, or mere sul?des and oxides of these same meeenie iene, 514/345 either alone or in combination With other molecules. Topical formulations containing both a pyridine-thiol and tautomers 56 References Cited With attached metallic moiet y and a metallic sul?de and/or metallic oxide effectively treat skin and mucous membranes U.S. PATENT DOCUMENTS suffering from a follicular dermatosis. 4,307,089 A 12/1981 Melloh et al...... 424/245 5,284,649 A 2/1994 Juneja ...... 424/67 16 Claims, N0 Drawings US 6,482,839 B1 1 2 PYRIDINE-THIOLS FOR TREATMENT OF A scription and over-the-counter markets for years to treat FOLLICULAR DERMATOSIS dandruff and seborrheic dermatitis. The difference betWeen the tWo markets is that the prescription product has a much CROSS-REFERENCE TO RELATED higher concentration of the selenium sul?de. These products APPLICATIONS are generally considered to be more effective than Zinc pyrithione because of documented superior anti-microbial This application is a continuation-in-part of PCT Patent activity. Application No. PCT/US98/11270, Which designates the United States and Was ?led Jun. 2, 1998, and of US. patent A topical product for Wound healing, hair groWth and to application Ser. No. 09/089,302, ?led Jun. 1, 1998, both of ?rm and improve elasticity of skin utiliZes copper bound to 10 Which applications claim bene?t of US. Provisional Patent a three amino acid peptide. Strontium has been reported to Application Serial No. 60/047,360, ?led Jun. 2, 1997, and treat stinging/burning due to neurogenic in?ammation but No. 60/056,282, ?led Sep. 3, 1997. This application also can be associated With bone deposition and marroW sup claims bene?t of US. Provisional Patent Application Serial pression. Multiple enZymes are knoWn to require metallic No. 60/058,752, ?led Sep. 12, 1997 and No. 60/056,290, ions as cofactors or are needed as catalysts. Several other ?led Sep. 3, 1997. Each of these applications is incorporated 15 metals currently are or have been in the past used a human herein by reference for all purposes. disease medicines. Arsenic Was a major topical treatment for psoriasis prior to the advent of corticosteroids. Gallium BACKGROUND OF THE INVENTION formulations injected intravenously are used in human medi cal diagnostic tests. Copper and silver salts are the active 1. Field of the Invention 20 ingredients in topical products for cleansing and deodoriZing This invention pertains to the ?eld of treating and pre stomas and burns. venting signs and symptoms of aging, acneiform follicular Use of these metallic compounds as therapeutic com diseases, mucocutaneous diseases, and neoplasia. pounds Would be expected to have serious draWbacks 2. Background because several, including nickel, chromium, and cobalt, are Therapeutic products comprising metallic moieties have 25 potent contact sensitiZers of the skin and mucous mem been used for many years for a variety of skin diseases. branes. Iron is a potent oxidant inducing cell damage. These medications have continued to be used to treat one or Bromine often induces a characteristic dermatosis knoWn as several skin diseases. For example, Zinc pyrithione (Zinc bromoderma. High calcium levels in the stratum corneum pyridine-2-thiol-1-oxide) is a therapeutic molecule that is inhibit normal barrier formation and desquamation. 30 used as the active ingredient in the most Widely distributed Chronologically aged (intrinsic aging) mucocutaneous commercially available medicated shampoos for treatment surfaces shoW a slight atrophy of the epidermis With of dandruff and seborrheic dermatitis. In the past year, this straightening of the rete pegs thus Weakening the dermal/ compound has been introduced by tWo companies in a epidermal junction measured by a decrease in the threshold topical leave-on product to treat scalp psoriasis. Zinc for suction bullae. There is a moderate decrease in the 35 pyrithione has multiple mechanisms of action including number of Langerhans cells. Dryness of the skin is a antiproliferative, keratolytic, astringent, antibacterial and common phenomenon. In the dermis there is loWer cellu anti-yeast properties. Zinc undecylenate has also been used larity and a decrease in elastic ?bers and thus in skin as an antifungal agent. Zinc oxide has also had a long history elasticity. Capillaries are also fragile as evidenced by bruis as a sunblock and skin protectant especially for the diaper 40 ability. Collagen metabolism is sloWer, and there is a pro area. Zinc lactate (0.15%) is one component of a prescrip gressive loWering in concentration of glycosaminoglycans. tion product Which also comprises erythromycin (2%) in a Wrinkling occurs, but it tends to be in the form of ?ne topical therapy for acne vulgaris. Wrinkles that disappear temporarily With stretching. There is US. Pat. No. 4,307,089 discusses a formulation that a decreased ability to mount in?ammatory response and an increase in the time of healing after injury. contains Zinc pyrithione and/or its tautomeric form com 45 bined With undecylenic acid and the use of the formulation Photoaging induces deep Wrinkles not erased by to treat dandruff. US. Pat. No. 5,284,649 discusses the use stretching, pigmentary alterations With areas of hyper- and of heavy metal salts of hydroxypyridine thiones and their hypopigmentation (actinic lentigines and leukodermas), and tautomeric forms, including Zinc, Zirconium, cadmium, tin, a variety of benign, premalignant, and malignant neoplasms. magnesium, sodium, calcium, aluminum and potassium 50 The dermis shoWs evidence of chronic in?ammation With pyrithione, as human deodorants. increased cellularity and enlarged ?broblasts. Elastotic Zinc is an essential mineral for animal cell groWth and degeneration occurs in Which parts of the upper dermis is regeneration due to its integral structural role in certain occupied by a basophilic ?brous material separating the enZymes especially proteases including carboxypeptidase A. dermis from the epidermis. This “grenZ” Zone is interpreted Furthermore, the deoxyribonucleic acid (DNA) contains 55 as a repair area. Glycosaminoglycan concentrations are Zinc ?nger binding domains utiliZed in transcription thus increased, While elastin concentration is increased and regulating gene activity. This element also functions as an arranged in atypical clumps. Collagen ?bers are fragmented. enZyme activator, a coenZyme, and an antioxidant. Zinc and Psoriasis is the most commonly occurring papulosqua other bivalent ions including cobalt, copper, nickel, and mous disease of the skin and mucous membranes. It is a manganese inhibit the binding of triiodothyronine to its 60 multi-factorial condition With epidermal hyperproliferation, nuclear receptor. Zinc, selenium, vanadium, and chromium scaling and marked epidermal and dermal in?ammation. all have documented insulin mimetic activity. The lesions predominantly occur on knees, elboWs, scalp, Selenium is a knoWn antioxidant utiliZed as an immune genitalia and buttocks. These plaques are characteriZed by modulator in naturpathic and lay medicine. Its major mecha sharply demarcated erythema With thick, White, micaceous nism of action is via covalent binding to the key 65 scale. The majority of patients Will be infected With a variety detoxi?cation/antioxidant enZyme glutathione peroxidase. of micro-organisms, most commonly Staphylococcus Multiple selenium sul?de shampoos have been on the pre aureus, although beta-hemolytic Streptococcus has been US 6,482,839 B1 3 4 known to induce guttate psoriasis. This disease may occur at cular triad Which is characteriZed by sebaceous gland cysts, all age groups, last a lifetime and involve localized to and abscesses, ?stulas and scarring of the scalp, aXilla, Wide-spread areas of the body. Other diseases Within this perineum, and crural folds induced by a combined multio papulosquamous group include among others lichen planus, rganism infection of the several pathogens listed above. pityriasis rubra pilaris, pityriasis rosea and other pityriases. These are dif?cult diseases to control and/or cure but pro Psoriasis is reportedly treated effectively With topical prod longed use of systemic retinoids are curative in most patients ucts containing only Zinc pyrithione and Zinc pyrithione With if they can tolerate the myriad of adverse reactions, some of clobetasol, a corticosteroid. Which may have life-long sequelae. EcZematous dermatitis is characteriZed by poorly demarcated, erythematous, scaly, vesicular, Weeping, Rosacea is a chronic disease of the primarily area of the ?ssured, crusted patches associated With severe itching. face characteriZed by a heightened vascular response. It Atopic, seborrheic and nummular dermatitis are the most begins as a prominent intermittent ?ushing/blushing Which common types. The lesions of atopic dermatitis occur on the becomes permanent folloWed by telangectasias. Papules and face, neck and ?eXural surfaces. Patients suffering from pustules often occur but no comedos develop. It occurs most ecZematous dermatitis are usually also heavily infected With commonly in Women over 30 years of age With type I or type Staphylococcus aureus and less frequently With Streptococ 15 II skin. Topical and systemic antibiotics and topical corti cus pyogenes. costeroids are commonly used for treatment coupled With Seborrheic dermatitis may mimic mild psoriasis. These dietary manipulation and sunlight protection but complete lesions appear as erythematous patches With yelloWish, remissions are uncommon and recurrences are the rule even greasy scales. Classic sites of involvement include scalp, With temporary cessation of therapy. Current therapy con eyebroWs, paranasal chin folds, glabella, ears, presternal and sists of antiin?ammatory broad spectrum antimicrobials interscapular areas of the trunk. Dandruff is a localiZed, mild administered topically or orally. Antioxidants are also ben form of this disease. Rarely, the seborrheic dermatitis may e?cial. involve the entire body producing an eXfoliative erythro Folliculitis is a pustular in?ammatory disease induced by derma. Pityrosporum ovale yeast has been shoWn to occur in usually one but otherWise possibly multiple pathogenic at least 75% of patients af?icted With this disease. These 25 microbes including Staphylococcus aureus, beta hemolytic ecZematous diseases are treated With topical and systemic Streptococcus, and Pityrosporum ovale. Current therapy corticosteroids, antipruritics, antibiotics, tar, immunosupres sives and psoralens plus ultraviolet A light and ultraviolet B consists of the appropriate antimicrobial administered, usu light With varying degrees of success. ally systemically, With a topical keratolytic and antimicro bial or keratolytic Washes. Ichthyoses are a group of chronic, scaling conditions that are divided into tWo large groups-the non-in?ammatory Pseudofolliculitis barbae af?icts 83% of black males as retention hyperkeratotic diseases and the in?ammatory Well as any male of any race Who has naturally curly hair. hyperproliferative hyperkeratotic diseases. The latter group This disease results from the curly hair puncturing the skin includes ten subtypes such as congenital ichthyosiform inducing an in?ammatory foreign body reaction and becom ing a portal for infection. The current therapy Which is rather erythroderma, lamellar ichthyosis and epidermolytic hyper 35 keratosis. The tWo retention hyperkeratotic diseases include unsatisfactory has consisted of topical acne vulgaris therapy. ichthyosis vulgaris and X-linked ichthyosis. These dis?gur The most effective treatment is alloWing beard groWth. ing ichthyotic diseases respond only moderately to systemic A need eXists for methods and compositions that are and topical retinoids, alpha hydroXy acids and greases. effective in preventing and/or reversing signs and symptoms Certain sub-types of all of these epithelial diseases listed of aging and for treating acneiform follicular diseases, as above may af?ict the mucous membrane, but most lesions Well as in?ammatory and scaly diseases. The present inven are on the skin. tion ful?lls these and other needs. Acne vulgaris is a multifactorial disease occurring in SUMMARY OF THE INVENTION teenagers and young adults, With in?ammatory and nonin ?ammatory comedos on the face and upper trunk. The 45 The present invention provides methods and composi disease prerequisite is sebaceous gland dysfunction acti tions for treating various skin and mucous membrane vated by androgens. For some reason as yet unknown, conditions, including signs and symptoms of aging, skin hypercorni?cation in the gland ori?ce occurs blocking nor diseases, follicular dermatosis, papulosquamous or ecZema mal mobility of skin and follicle microorganisms. The tous dermatitis, ichthyotic diseases, and the like. The com restricted environment stimulates release of lipases by Pro positions of the invention include as an active ingredient one pionobacterium acnes (an anaerobic corynebacterium). Sta or more metal ions associated With a pyridine thiol, or a phylococcus epidermidis or S. aureus, certain gram negative tautomer of a pyridine thiol. Alternatively, or in addition to bacteria, and Pitrosporum ovale (a yeast) may also be the pyridine thiol, the compositions can include a metal opportunistic organisms infecting up to 35% of patients With oXide or a metal sul?de as an active ingredient. In some acne vulgaris. Damage to the gland structure and surround 55 embodiments, the compositions also include one or more ing tissue by the lipases results in in?ammatory papules, additional compounds that are effective in treating the pustules and cysts. The comedos are free of pathogenic disorder or signs and symptoms of aging. microbes. In some, the disease is only manifest as these The methods of the invention involve treating the muco nonin?ammatory lesions but all patients With in?ammatory cutaneous conditions by topically applying to an affected lesions have some comedos. Major treatments consist of oral area of the mucocutaneous tissue a therapeutically effective and topical antibiotics and retinoids, topical salicylic acid amount of a topical formulation such as are described herein. and other hydroXy acids, other keratolytics, and benZoyl Typically, the topical formulation Will contain one or more peroXide administered topically, oral antiandrogens, higher of a metal ion associated With a compound selected from the estrogen birth control pills, and nonsteroidal antiin?amma group consisting of a pyridine-thiol and a tautomer of a tory agents including sulfones. 65 pyridine-thiol, and/or a metal oXide or metal sul?de. Acne conglobata, hidradenitis suppurativa, and acne kel Thus, in some embodiments, the invention provides com oidalis nuchae are the three components of dissecting folli positions that can be used to treat or prevent signs and US 6,482,839 B1 5 6 symptoms of aging. These topical formulations can contain symptoms of various conditions of mucocutaneous tissues. (a) a metal ion associated With a compound selected from the The compositions of the invention contain one or more group consisting of a pyridine-thiol and a tautomer of a active compounds that are metal ions complexed With either pyridine-thiol; and (b) one or more compounds Which are pyridine thiols or are metal sul?des or metal oxides. The effective in treating symptoms of aging of mucocutaneous compositions are typically applied to skin or mucous mem tissue. In other embodiments, the topical formulations con branes to prevent or treat the aging symptoms, Which can be tain (a) a metal cation and an anion selected from the group a result of chronologic (intrinsic) aging or photoaging. consisting of an oxide and a sul?de; and (b) one or more compounds Which are effective in treating symptoms and This invention also provides methods and compositions signs of aging of mucocutaneous tissue. for treating signs and symptoms of various diseases. These 10 The invention also provides methods for treating or diseases, Which include papulosquamous and ecZematous preventing symptoms and signs of aging by topically apply diseases and disorders of corni?cation, including ichthyoses, ing to an affected area of the mucocutaneous tissue a are successfully reversed by administering topical formula therapeutically effective amount of a topical formulation tions comprising one or more pyridine-thiols With attached containing: (a) a metal ion associated With a compound metallic ion combined With one or more knoWn FDA selected from the group consisting of a pyridine-thiol and a 15 approved or -alloWed therapeutic compounds for these dis tautomer of a pyridine-thiol; and (b) a metal oxide or a metal eases and/or one or more Cosmetic and Toiletry Association sul?de. alloWed excipients and/or cosmeceutical compounds. Additional embodiments of the invention provide com A. Therapeutic and Anti-Aging Compounds and positions and methods for treating in?ammatory and/or Formulations scaly diseased skin, adnexal and mucous membranes. These compositions generally include one or more pyridine-thiols, The compounds of the invention include pyridine-thiols, or tautomeric forms thereof, that are attached to one or more as Well as tautomers of the pyridine thiols, that are associ metallic ions. In additional embodiments, the compositions ated With a metal ion. In other embodiments, the compounds include one or more oxides or sul?des of the metallic ions. of the invention are metal ions associated With a sul?de ion These compounds can be present as the only active 25 or an oxide ion. In still other embodiments, the formulations ingredient, or can be combined With one or more compounds of the invention include combinations of the pyridine-thiol selected from the group of other FDA-approved prescription oxides and sul?des and tautomers thereof. The Zinc and/or OTC-monographed, FDA-alloWed non-prescription pyrithione and selenium pyrithione combination are pre therapeutic compounds and/or excipients and/or nutrients ferred. Furthermore, this invention includes metallic sul?des and/or cosmeceuticals. and metallic oxides in combination as Well as With pyridine In some embodiments, one or more of the pyridine thiols thiol With attached metallic ion or its tautomers. Selenium With attached metallic ion are combined With one or more sul?de With Zinc pyrithione is preferred. Preferred non sul?des and oxides of the metallic ions in topical formula metallic compounds are 1-hydroxy-pyridine-thiol and tions that are useful for treating these epithelial diseases. 2-hydroxy-pyridine-thiol With the oxides and sul?des most Furthermore, these latter formulations can additionally com 35 preferred. Examples of these most preferred species include prise one or more compounds effective in treating the signs Zinc pyrithione and selenium pyrithione. and symptoms of these diseases. The metal ions that can be included in the compounds of These embodiments do not include topical formulations the invention are, for example, Zinc, Zirconium, vanadium, that include Zinc pyrithione or selenium sul?de as the only titanium, tin, strontium, sodium, silver, scandium, active ingredients for treatment of psoriasis, dandruff and potassium, nickel, manganese, magnesium, iron, seborrheic dermatitis or formulations that include Zinc germanium, gallium, copper, cobalt, chromium, calcium, pyrithione and clobetasol as the only active ingredients for cadmium, bromine, and arsenic. Zirconium, Zinc, vanadium, treating psoriasis. titanium, strontium, sodium, silver, selenium, potassium, DETAILED DESCRIPTION manganese, magnesium, gallium, copper, calcium, and 45 arsenic are preferred. Zinc, strontium, silver, selenium and DEFINITIONS copper are most preferred. The term “therapeutically effective amount” or “effective 1. Pyridine Thiols amount” is used herein to denote any amount of a topical In some embodiments, the formulations of the invention formulation Which Will cause a substantial improvement in include pyridine-thiols and/or tautomers of the pyridine a disease condition (such as a subsidence of a lesion, for thiols. Examples of suitable pyridine thiols include, but are example) When applied to the affected area. A single appli not limited to, Zinc pyrithione, selenium pyrithione, silver cation can be suf?cient, or the formulation can be applied pyrithione, and copper pyrithione. Zinc pyridine-2-thiol-1 repeatedly over a period of time. The amount Will vary With oxide (pyrithione) is a preferred pyridine thiol. The formu the condition being treated, the stage of advancement of the lations of the invention further include combinations of tWo condition, and the type and concentration of formulation 55 or more of these pyridine-thiols, With Zinc pyrithione and applied. Appropriate amounts in any given instance Will be selenium pyrithione being a preferred combination. readily apparent to those skilled in the art or capable of These organometallic compounds typically exist as bis determination by routine experimentation. adducts. For example, in a preferred embodiment, the A “cosmeceutical” is a product, typically non empirical formula is C1OH8N2OS2Zn. The synthesis of bis prescription, that is utiliZed in the cosmetic industry Which (2-pyridylthio)Zinc 1,1‘dioxide (i.e., Zinc pyridine-2-thiol-1 produces measurable structural changes in the skin and oxide) is outlined in British Patent No. 761,171 and US. Pat. mucous membranes. Nos. 3,236,733 and 3,281,366 all of Which are incorporated herein by reference. DESCRIPTION OF THE PREFERRED 2. Metal Sul?des and Oxides EMBODIMENTS 65 The invention also provides formulations in Which an The present invention provides methods and composi oxide or a sul?de anion is combined With a metallic ion. tions that are useful for treating or preventing signs and These oxides and sul?des can also be present in a formu US 6,482,839 B1 7 8 lation that also includes one or more metal ions associated monochloroacetic, and dichloracetic, tetrahydroxypentanoic With pyridine thiols as described above. The sul?des and and hexahydroxyheptanoic acids, glucoconolactone, oxides of the metallic ions that have activity against the tocopherol, retinol, retinaldehyde, tretinoin, isotretinoin, signs and symptoms of aging and other conditions of the vitamin D analogs, glucocorticosteroids, colchicine, mucocutaneous tissue include, for example, any combina dapsone, ibuprofen, ketoprofen, ketorolac, piroxicam, tion of a sul?de or an oxide moiety associated With a metal indomethacin, serine, alanine, glycine, phenol, arginine, as set forth above. Preferred examples of these metals that thymol, menthol, eucalyptol, resorcinol, methyl resorcinol, can be combined With the oxides and sul?des include, for hexyl resorcinol, 3-hydroxy butyric acid, 4-hydroxyvaleric example, Zirconium, Zinc, vanadium, titanium, sodium, acid, epigallocatechingallate, and esters, ethers, amides, silver, selenium, potassium, manganese, magnesium, 10 analogs, derivatives, aldehydes, isomers and salts thereof. gallium, copper, and arsenic. Zinc oxide, Zinc sul?de, stron These compounds are typically present in the topical for tium oxide, strontium sul?de, silver oxide, silver sul?de, mulation at a concentration of about 0.5% to about 30% by selenium oxide, selenium sul?de, copper oxide, and copper Weight. sul?de are most preferred. Particularly preferred compounds b. Follicular Dermatoses include selenium sul?de and Zinc oxide. 15 The compositions of the invention are also useful for 3. Formulations for Speci?c Diseases and Conditions treating skin and mucous membranes that are suffering from The formulations of the invention are useful for treating a follicular dermatosis. These compositions contain a thera and preventing a Wide variety of conditions of the mucocu peutically effective amount of one or more pyridine thiols, taneous tissues. Examples of suitable formulations for vari or tautomeric forms thereof, to Which is attached one or ous conditions are described beloW. 20 more metallic ions, including those described above. The a. Signs and Symptoms of Aging compositions can also include, in place of or in addition to The compositions of the invention are useful for treating the pyridine thiol, one or more metallic ions that are attached and preventing signs and symptoms of aging, Which to an anion. Preferred anions include oxide and sul?de ions. includes chronologic aging as Well as photoaging. Signs or For example, these compositions can include a therapeu symptoms of aging include, for example, Wrinkling, irregu 25 tically effective amount of a dermatologic/cosmeceutical lar pigmentation, laxity, inelasticity, fragility, ?ne lines, formulation that contains from about 0.01% to about 30.0% roughness, poor Wound healing, and neoplasia. by Weight of one or more active ingredients such as a) a Preferred compositions for this application include topical compound that comprises a hydroxypyridine thione, or a formulations that contain about 0.001% to about 60% by tautomeric form thereof, attached to one or more metallic Weight pyridine thiol, pyridine thiol tautomer, metal sul?de, 30 ions; and/or b) a metallic ion attached to an anion selected or metal oxide. Particularly preferred compositions are topi from the group consisting of an oxide and a sul?de. The cal formulations that contain about 0.1% to about 5% by metallic ions that are suitable for use in the formulations Weight of Zinc pyrithione, silver pyrithione, selenium include, for example, Zinc, Zirconium, vanadium, titanium, pyrithione, or copper pyrithione. One example of a preferred tin, silver, scandium, sodium, selenium, potassium, nickel, topical formulation contains about 2.5% by Weight Zinc 35 magnesium, manganese, iron, gallium, germanium, copper, pyrithione. cadmium, calcium, chromium, cobalt, bromine, arsenic, and Additional preferred compositions are topical formula aluminum. tions that contain from about 0.025% to about 20% by Examples of preferred dermatologic/cosmeceutical for Weight metal oxide or metal sul?de. Particularly preferred mulations contain from about 0.15% to about 4.0% by topical formulations contain from about 0.1% to about 5% 40 Weight of a compound that includes a heavy metal (e.g., by Weight Zinc oxide or selenium sul?de. One example of a Zinc, Zirconium, vanadium, titanium, silver, selenium, preferred topical formulation contains about 0.2% by Weight sodium, potassium, magnesium, manganese, copper, of selenium sul?de. gallium, arsenic or aluminum) attached to a The compositions of the invention can also contain, in 1-hydroxypridine thione oxide, a 2-hydroxypridine thione addition to one or more of the above compounds, one or 45 oxide, a 1-hydroxypyridine thione sul?de, or a more additional compounds that are effective in treating 2-hydroxypyridine thione sul?de. signs or symptoms of aging. These additional compounds In some embodiments, the invention provides composi include, for example, alpha-, beta-, gamma- and poly tions that are particularly useful for treating follicular der hydroxy and keto acids, tretinoin, isotretinoin, retinol, matoses such as acne vulgaris, acne conglobata, acne kel retinaldehyde, ascorbic acid, tocopherol, dicarboxylic acids, 50 oidalis nuchae, acne necroticans miliaris disseminata, lactones of hydroxy acids, kojic acids, linoleic and other rosacea, hidradenitis suppurativa, folliculitis, and pseudo carboxylic acids, compounds With a phenol ring as the folliculitis barbae. Preferred compositions for this applica primary active structure, derivatives of phenol, chloroacetic tion contain a therapeutically effective amount of a acids, corticosteroids, nonsteroidal anti-in?ammatory dermatologic/cosmeceutical formulation that contains from agents, sulfones, catechins and other antioxidants, amino 55 about 0.05% to about 10.0% by Weight of a compound that acids and other minerals, and esters, amides, salts, analogs, has one or more heavy metallic ions attached to a aldehydes, isomers, and derivatives thereof. The additional 1-hydroxypyridine-thiol or a 2-hydroxypyridine-thiol. Pre compound is typically present in the topical formulation at ferred metallic ions include, for example, Zinc, Zirconium, a concentration of about 0.01% to about 99.9% by Weight. titanium, tin, sodium, selenium, scandium, silver, potassium, Other examples of additional compounds that can be 60 manganese, magnesium, gallium, germanium, copper, present in the compositions of the invention include, but are cadmium, bromine, arsenic and aluminum. Other preferred not limited to, salicylic, benZilic, malic, citric, tartaric, compositions include about 0.25% by Weight of one or more tropic, glucuronic, mandelic, benZoic, acetic, formic, of Zinc pyrithione, Zirconium pyrithione, titanium fumaric, oxalic, propanoic, succinic, galactonic, pyrithione, silver pyrithione, selenium pyrithione, copper galacturonic, glucoronic, glyceric, mucic, succharic, 65 pyrithione, and aluminum pyrithione. tartaronic, allolactic, phenyllactic, pyruvic, glycolic, lactic, The compositions of the invention for use in treating linoleic, linolenic, aZelaic, kojic, ascorbic, trichloroacetic, follicular dermatoses can also include one or more addi US 6,482,839 B1 9 10 tional biologically active compounds Which have activity in Preferably, these compositions also include one or more the skin or mucous membranes. These compounds include, additional compounds such as, for example, anti for example, keratolytics, hydroxyacids, anti-in?ammatory in?ammatory, antimicrobial, immunosuppressive, agents, antimicrobials, immunosuppressives, carboxylic and chemotherapeutic, antiproliferative, antioxidant, keratolytic, amino acids, phenolics, retinoids, antioxidants, minerals, humectant, surfactant, emulsi?er, and nutrient compounds, vitamins and their lactones, analogs, isomers, salts, esters, and lactones, esters, amides, isomers, analogs and deriva amides and derivatives thereof. These additional biologi tives thereof. Examples of therapeutic compounds that can cally active compounds can include, for example, salicylic, be included in the compositions include therapeutic com malic, citric, tartaric, pyruvic, glycolic, lactic, kojic, and pounds such as dapsone, meselamine, sulfasalaZine, aZelaic acids, gluconolactone, serine, undecylenic acid, 10 sulfacetamide, colchicine, calcipotriene, calcipitriol, resorcinol, thymol, menthol, phenol, eucalyptol, sulfur, ketoprofen, indomethacin, piroxicam, ketorolac, clindamycin, erythromicin, griseofulvin, sulfacetamide, triamcinolone, ?urandrenolide, prednicarbate, halcinonide, metronidiZole, cipro?oxan, o?oxan, chloramphenicol, alclometasone, hydocortisone, desonide, amcinonide, glucocorticoids, piroxicam, ketoprofen, ketorolac, ?uocinonide, di?orasone, betamethasone, dexomethasone, indomethacin, ketoconaZole, terbena?ne, nafti?ne, 15 desoximetasone, ?uticasone, mometisone, ?uocinolone, cicloprix, benZoyl peroxide, bacitracin, mupirocin, cyclosporin, rapamycin, tacrolimus, erythromycin, polymixin, gramicidin, chloroxylenol, benZylkonium clindamycin, lincomycin, vancomycin, cipro?oxacin, chloride, benZethonium chloride, tobramycin, gentamicin, o?oxacin, nor?oxacin, doxycycline, meclomycin, minocycline, tetracycline, silver salts, copper complexes, tetracycline, minocycline, methotrexate, mercaptopurine, tretinoin, isotretinoin, retinaldehyde, adapalene, taZorotene 20 hydroxyurea, aZathioprine, bleomycin, nitrogen mustard, vitamins A, C, E and D and their lactones, analogs, esters, carmustine, anthralin, tretinoin, etretinate, acitretin, amides, isomers, salts, and derivatives thereof. isotretinoin, adapalene, taZarotene, metronidaZole, One example of a preferred formulation contains about terbeni?ne, ketoconaZole, oxiconaZole, sulconoZole, 0.25 % by Weight Zinc pyrithione, and about 2.0% by Weight ?uconaZole, itraconaZole, griseofulvin, cicloprix, salicylic acid. Another example of a preferred formulation 25 clotrimiZole, econaZole, miconaZole, aZelaic acid, benZoyl contains about 2.5% by Weight selenium sul?de, and about peroxide, gramicidin, bacitracin, polymixin, nystatin, 2.0% by Weight salicylic acid. tobramycin, gentamicin, chloramphenicol, amphotericin, c. KeratiniZing Epithelial Diseases and Disorders dicloxacillin, carbenicillin, amoxicillin, cephalexin, The compounds and formulations of the invention also ce?xime, cefuroxime, cephadroxil, mupirocin, resorcinol, include those that are useful for topical treatment of kera 30 salicylic acid, sulfur, glycols, alcohols, carboxylic acids, tiniZing epithelial diseases and disorders. These composi sulfoxides, hydroxy acids, keto acids, terpenes, vitamins A, tions typically include therapeutically effective amounts of C, E, D, and the analogs, amides, isomers, derivatives, esters an active ingredient Which can be one or more pyridine and salts thereof. thiols With an attached metallic ion, or one or more metallic Preferred compositions include those having about 0.05 to oxides or metallic sul?des. The formulations can also 35 10.0% by Weight of one or more of selenium sul?de, Zinc include one or more additional compounds, such as pre oxide and titanium dioxide, along With an additional thera scription and over-the-counter therapeutic compounds, cos peutic compound. One example of a preferred composition meceutical compounds, and excipient compounds. for these applications contains about 0.25% by Weight of d. Papulosquamous, EcZematous, Ichthyotic and In?amma selenium sul?de, and about 0.05% by Weight of di?orasone tory Adnexal Diseases 40 acetate. Another example of a preferred composition con The compositions of the invention are also useful for the tains about 2.5% by Weight of selenium sul?de, and about topical treatment of skin and mucous membranes suffering 2.0% by Weight of salicylic acid. from a papulosquamous, ecZematous, ichthyotic and in?am For treatment of diseases such as psoriasis, lichen planus, matory adnexal diseases. Such diseases include, but are not atopic dermatitis, seborrheic dermatitis and ichthyoses, pre limited to, psoriasis, lichen planus, pityriasis rubra pilaris, 45 ferred dermatologic/cosmeceutical formulations contain pityriasis rosea and other pityriases, contact dermatitis, from about 0.05% to about 10.0% by Weight of a compound seborrheic dermatitis, atopic dermatitis, ichthyosis vulgaris, selected from the group consisting of Zirconium pyrithione, acquired ichthyosis, x-linked ichthyosis, congenital primary Zinc pyrithione, titanium pyrithione, selenium pyrithione, ichthyoses including lamellar ichthyosis, congenital ichthy sodium pyrithione, potassium pyrithione, magnesium osiform erythroderma, epidermolytic hyperkeratosis, severe 50 pyrithione, gallium pyrithione, copper pyrithione and alu xerosis, acne vulgaris, acne conglobata, acne keloidalis minum pyrithione; and an additional therapeutic compound. nuchae, acne necroticans milliaris disseminata, hidradenitis One example of a preferred formulation contains about suppurativa, folliculitis, rosacea, and pseudofolliculitis bar 0.25% by Weight of Zinc pyrithione and/or selenium bae. pyrithione; and about 2.0% by Weight of salicylic acid. Preferred compositions for treating these diseases include 55 Another example of a preferred formulation contains about dermatologic/cosmeceutical formulations that have from 0.25% by Weight of Zinc pyrithione and/or selenium about 0.001% to about 99.999% by Weight of an active pyrithione and about 1.0% by Weight of clindamycin phos ingredient such as (a) one or more compounds selected from phate. the group consisting of l-hydroxypyridine thiols and 4. Formulations and Dosages 2-hydroxypyridine thiols attached to a metallic ion, or (b) 60 Typically, the compositions described herein Will be in the one or more compounds selected from the group consisting form of a topical formulation for delivering the active of metal oxides and sul?des. The metals in these formula ingredient. The formulation Will typically contain the anti tions can be, for example, one or more of Zirconium, Zinc, aging compound in concentrations that range from about vanadium, titanium, tin, sodium, silver, selenium, scandium, 0.001% to about 60.0% by Weight, With about 0.025% to potassium, nickel, manganese, magnesium, iron, 65 about 20.0% by Weight preferred, and about 0.1% to about germanium, gallium, copper, cobalt, calcium, chromium, 5.0% by Weight the most preferred. The formulations gen cadmium, bromine, arsenic, and aluminum. erally also include a non-toxic, pharmaceutically and/or US 6,482,839 B1 11 12 cosmeceutically acceptable carrier. See, e.g., DRUG: to the nature of the base include soft paraf?n, aluminum FACTS AND COMPARISONS, Published by Facts and stearate, cetostearyl alcohol, propylene glycol, polyethylene Comparisons, AWolters KluWer Company (1997) and Der glycols, Woolfat, hydrogenated lanolin, beesWax, and the matological Formulations: Percutaneous Absorption, Barry like. Lotions can be formulated With an aqueous or oily base (ed.), Marcel Dekker Inc. (1983). and Will, in general, also include one or more of the The local absorption and efficacy of the compounds can folloWing: stabiliZing agents, emulsifying agents, dispersing be further enhanced by incorporating an appropriate amount agents, suspending agents, thickening agents, coloring of an excipient Which can alloW increased penetration of, or agents, perfumes, and the like. PoWders can be formed With assist in the delivery of therapeutic molecules across, the the aid of any suitable poWder base, e. g., talc, lactose, starch, stratum corneum permeability barrier of the skin. Many of and the like. Drops can be formulated With an aqueous base these penetration enhancing molecules are knoWn to those or non-aqueous base, and can also include one or more trained in the art of topical formulation. Examples include dispersing agents, suspending agents, solubiliZing agents, humectants such as urea and glycols such as propylene and the like. glycol, alcohols including ethanol, fatty acids such as oleic The ointments, pastes, creams and gels also can contain acid, surfactants such as isopropyl myristate and sodium 15 excipients, such as animal and vegetable fats, oils, Waxes, lauryl sulfate, pyrrolidones, glycerol monolaurate, paraffins, starch, tragacanth, cellulose derivatives, polyeth sulfoxides, terpenes including menthol, amines, amides, ylene glycols, silicones, bentonites, silicic acid, talc and Zinc alkanes, alkanols, Orgelase and Water. Vegetable oils or oxide, or mixtures thereof. PoWders and sprays also can botanical oils containing high unsaturated fatty acids, eg contain excipients such as lactose, talc, silicic acid, alumi safflower oil, olive oil, avocado oil, Wheat germ oil, etc. or num hydroxide, calcium silicates and polyamide poWder, or other chemicals can also facilitate absorption and delivery of mixtures of these substances. Solutions of active compound compounds. can be converted into aerosols or sprays by any of the knoWn Pharmaceutically and cosmeceutically acceptable carriers means routinely used for making aerosol inhalant pharma Will include Water, saline, buffers, and other compounds ceuticals. In general, such methods comprise pressuriZing or described, e.g., in the Merck Index, Merck & Co., RahWay, 25 providing a means of pressuriZing a container of the N.J. See, also, Bioreversible Carriers in Drug Design, solution, usually With an inert carrier gas, and passing the Theory and Application, Roche (ed.), Pergamon Press, pressuriZed gas through a small ori?ce. Sprays can addi (1987). Various considerations are described, e.g., in Gilman tionally contain customary propellants, such as chloro?uo et al. (eds) (1990) Goodman and Gilman’s: The Pharmaco rohydrocarbons and volatile unsubstituted hydrocarbons, logical Bases of Therapeutics, 8th Ed., Pergamon Press; such as butane and propane. Novel Drug Delivery Systems, 2nd Ed., Norris (ed.) Marcel Multiple inactive ingredients are generally incorporated Dekker Inc. (1989), and Remington’s Pharmaceutical in topical formulations to improve cosmetic acceptability, Sciences, the full disclosures of Which are incorporated and are optional ingredients in the formulations of this herein by reference. For standard dosages of conventional invention. Examples of ingredients are emulsi?ers, pharmacological agents, see, e.g., Physicians Desk Refer 35 humectants, surfactants, preservatives, fragrances, coloring ence (1997 Edition); and American Medical Association agents, emollients, and ?llers. (1997) Drug Evaluations (Subscriptions). The topical pharmaceutical compositions can also include The compounds of the invention can be administered in a one or more preservatives or bacteriostatic agents, e.g., variety of forms. These include, for example, solid, semi methyl hydroxybenZoate, propyl hydroxybenZoate, solid and liquid dosage forms, such as tablets, pills, chlorocresol, benZalkonium chlorides, and the like. The poWders, liquid solutions or suspensions, liposomes, nasal/ topical pharmaceutical compositions also can contain other aerosoliZed dosage forms, implants, injectable and infusible active ingredients such as antimicrobial agents, particularly solutions. These agents can also be incorporated into various antibiotics, anesthetics, analgesics, and antipruritic agents. cosmetic and toiletry formulations (See, e.g., Flick E. W. One example of a topical formulation contains, in addi Cosmetic and Toiletry Formulations, 2nd Ed., Noyes 45 tion to the active agent, light mineral oil, sorbitol solution, Publications, 1989). The preferred form depends on the hydroxyoctacosanyl hydroxystearate, methoxy PEG-22/ intended mode of administration and therapeutic or cosmetic dodecyl glycol copolymer, stearoxytrimethylsilane and application. stearic alcohol, dimethicone 50 cs, fragrance, Dosage forms for the topical administration of the com methylparaben, edetate disodium, quarterium-15, butylates positions of the invention include various mixtures and hydroxytoluene, citric acid (monohydrate) and puri?ed combinations that can be applied topically and Will permit Water. even spreading and absorption into the cutaneous and The dosage of a speci?c active compound of the invention mucosal surfaces. Examples include sprays, mists, aerosols, depends upon many factors that are Well knoWn to those lotions, creams, solutions, gels, ointments, pastes, unguents, skilled in the art, for example, the particular compound; the emulsions and suspensions. The active compound can be 55 condition being treated; the age, Weight, and clinical con mixed under sterile conditions With a cosmeceutically or dition of the recipient patient; and the experience and pharmaceutically acceptable carrier, and With any judgment of the clinician or practitioner administering the preservatives, buffers, or propellants Which may be required. therapy. An effective amount of the compound is that Which Topical preparations can be prepared by combining the provides either subjective relief of symptoms or an objec active compounds With conventional pharmaceutical and/or tively identi?able improvement as noted by the clinician or cosmeceutical diluents and carriers commonly used in topi other quali?ed observer. The dosing range varies With the cal dry, liquid, cream and aerosol formulations. Ointment compound used, the route of administration and the potency and creams can, for example, be formulated With an aqueous of the particular compound. or oily base With the addition of suitable thickening and/or Because the active compounds of the invention are each gelling agents. Such bases can include Water and/or an oil 65 effective alone, the compositions can be essentially free of such as liquid paraffin or a vegetable oil such as peanut oil other agents that are effective against symptoms on muco or castor oil. Thickening agents Which can be used according cutaneous membranes. In some embodiments, hoWever, the US 6,482,839 B1 13 14 compositions include additional agents that are known, immunosuppressives, corticosteroids, antimicrobials, reported, or suspected to display, a therapeutic or anti-aging chemotherapeutics, vitamin D analogs and retinoids. The activity. In the case of anti-aging compositions, such mol preferred compounds include dapsone, meselamine, ecules include, for example, keratolytics such as hydroxy sulfasalaZine, sulfacetamide, silver sulfadiaZine, colchicine, acids and their lactones, ketoacids, phenolics, amino acids, calcipotriene, calcipitriol, ibuprofen, ?ubiprofen, carboxylic acids, antioxidants, vitamins A, C, E, certain ketoprofen, indomethacin, piroxicam, ketorolac, nutrients, metallic elements, anti-in?ammatory agents, and chloroquine, quinacrine, hydroxy-chloroquine, the esters, amides, aldehydes, salts, analogs, isomers and triamcinolone, ?urandrenolide, prednicarbate, halcinonide, derivatives thereof. Some examples of speci?c anti-aging alclometasone, hydocortisone, desonide, amcinonide, active ingredients that can be additionally incorporated into 10 ?uocinonide, di?orasone, betamethasone, dexamethasone, desoximetasone, ?uticasone, mometisone, ?uocinolone, formulations of this invention include, for example, alpha-, cyclosporin, ascomycin, rapamycin, tacrolimus, beta-, gamma- and poly-hydroxy and keto acids as Well as erythromycin, clindamycin, lincomycin, vancomycin, tretinoin, retinol, retinaldehyde, ascorbic acid, tocopherol, cipro?oxacin, o?oxacin, nor?oxacin, doxycycline, dicarboxylic acids, lactones of hydroxy acids, kojic acids, meclomycin, tetracycline, minocycline, methotrexate, other carboxylic acids, including linoleic, compounds With a 15 mercaptopurine, hydroxyurea, aZathioprine, bleomycin, phenol ring as the primary active structure, derivatives of cyclophosphamide, S-?uorouracil, cis-platinin, phenol, chloroacetic acids, corticosteroids, nonsteroidal chlorambucil, nitrogen mustard, carmustine, doxorubicin, anti-in?ammatory agents, sulfones, catechins and other daonorubicin, anthralin, transretinoic acid, etretinate, antioxidants, amino acids and other minerals, and the esters, acitretin, isotretinoin, adapalene, taZarotene, metronidaZole, amides, salts, analogs, aldehydes, isomers, and derivatives terbeni?ne, ketoconaZole, oxiconaZole, sulconoZole, thereof. ?uconaZole, itraconaZole, griseofulvin, cicloprix, The excipients that can be used in the formulations of the clotrimiZole, econaZole, miconaZole, aZelaic acid, benZoyl invention are typically compounds Whose inclusion is peroxide, gramicidin, bacitracin, polymixin, nystatin, alloWed by the Cosmetic, Toiletry and Fragrance Associa tobramycin, gentamicin, chloramphenicol, amphotericin, tion and that increase penetration of or assist in the delivery 25 dicloxacillin, carbenicillin, ampicillin, amoxicillin, of therapeutic molecules across the stratum corneum per amoxicillin-clavulanate, cephalexin, ce?xime, cefuroxime, meability barrier. There are many of these penetration cephadroxil, and mupirocin. The FDA over-the-counter enhancing molecules knoWn to those trained in the art of monograph alloWed therapeutic compounds for dandruff, topical formulations. Examples are humectants such as urea psoriasis and seborrheic dermatitis include hydrocortisone, and glycols, including propylene glycol and polyethylene resorcinol, salicylic acid, and sulfur in addition to Zinc glycol, alcohols such as ethanol, fatty acids such as oleic and pyrithione and selenium sul?de Which are included in this linoleic acids, alpha-hydroxy acids such as lactic acid and invention. The preceding list of the approved prescription glycolic acids, surfactants such as isopropyl myristate and and OTC therapeutic compounds for epithelial diseases is sodium lauryl sulfate, pyrollidones, glycerol monolaurate, for example only and is not intended to be all inclusive for oleyl alcohol, sulfoxides, terpenes, phenolics including men 35 the FDA-approved and FDA-monographed compounds. thol and resorcinol, amines, amino acids, alkanes, alkanols, The compounds of the invention Which are effective in Water and Orgelase. Many of these compounds have recently treating and/or preventing signs and symptoms of aging and been shoWn to produce a measurable anatomic and/or physi epithelial diseases can also be used in conjunction With ologic change, including anti-aging effects, in the keratiniZ anti-in?ammatory and other therapeutic agents. Examples of ing epithelia giving rise to the term “cosmeceuticals”. This anti-in?ammatory agents include, for example, concentrated class of compounds includes alpha-, beta- and gamma in?ammation modi?ers as described in commonly assigned hydroxy acids, chloracetic acids, carboxylic acids, US. patent application Ser. No. 09/087,744, ?led on May phenolics, vitamins A, C, and E, catechins and other 29, 1998. antioxidants, amino acids, corticosteroids and nonsteroidal This invention does not include topical formulations that antiin?ammatory agents and their lactones, esters, amides, 45 contain Zinc pyrithione or selenium sul?de as the only active salts, analogs, isomers, and derivatives thereof. The pre ingredient to treat psoriasis, dandruff and seborrheic ferred cosmeceutical compounds incorporated into this dermatitis, or Zinc pyrithione and clobetasol to treat psoria invention include salicylic, epigallocatechin gallate, ancic, s1s. mandelic, benZoic, acetic, formic, fumaric, oxalic, mucic, propanoic, succinic, glyceric, linoleic, trichloroacetic, B. Methods for Treating or Preventing Signs and saccharic, tartaronic, galactonic, galacturonic, glucuronic, Symptoms of Aging and Epithelial diseases tetra-hydroxypentanoic and hexahydroxy heptanoic, malic, The invention also provides methods for treating signs citric, tartaric, pyruvic, glycolic, lactic, linolenic, stearic, and symptoms of aging of the skin and mucosal membranes, palmitic, myristic, oleic, aZelaic and kojic acids, as Well as methods for treating epithelial diseases such as gluconolactone, resorcinol, hexylresorcinol, 55 those described herein. The treatments involve administer methylresorcinol, retinol, retinaldehyde, tocopherol, ing an effective amount of a compound of the invention as alanine, glycine, serine, arginine, thymol, phenol, 4-hydroxy described herein, typically as a topical formulation. The valeric acid, menthol, eucalyptol, and trichloroacetic, formulations of this invention are generally applied to the bichloroacetic, and nochloroacetic acids. The nutrients locally affected diseased or abnormal skin and/or mucous include vitamins, minerals, fats, proteins, carbohydrates, membranes. These formulations include various mixtures Water and oxygen. The proceeding list is for examples only and combinations that can be applied topically and Will and is not intended to be all inclusive of knoWn cosmeceu permit even spreading and absorption into the cutaneous and tical compounds. mucosal surfaces. Examples include sprays, mists, aerosols, The FDA approved prescription therapeutic compounds lotions, creams, solutions, gels, ointments, pastes, unguents, that can be included in the formulations of the invention for 65 emulsions and suspensions. treating epithelial diseases such as those described herein To treat or prevent an aging-related condition of the skin include, for example: nonsteroidal antiin?ammatory agents, or mucosal membrane, a composition that contains one or US 6,482,839 B1 15 16 more of the compounds described herein is administered to diminution of ?ne Wrinkling, irregular pigmentation, and the skin or mucosal membrane in an amount effective to improved skin texture. modulate the condition. An effective amount can be deter mined by applying the compositions containing the com Example 5 pounds of the invention to test animal models. The methods described herein ?nd use in the treatment Formulation C and/or prevention of a variety of signs and symptoms of Formulation C Was prepared by dissolving 25 milligrams aging. Such signs and symptoms against Which the methods of selenium sul?de (Sigma: St. Louis, M0.) in 100 milliliters are effective include, but are not limited to, Wrinkling, of 60% ethanol, 25% propylene glycol, and 15% Water to irregular pigmentation, laxity, inelasticity, fragility, 10 make a 2.5% by Weight selenium sul?de solution. Each roughness, poor Wound healing, and neoplasia. application Was performed as in Example 1 above. Also provided are methods for treating or preventing diseases such as acneiform follicular diseases, in?ammation, Example 6 and scaly diseases. These methods also involve topical application of an effective amount of the compounds and 15 Application formulations of the invention to affected areas of the skin TWo middle aged males suffered from skin aging expe and/or mucocutaneous membranes. Again, an effective rienced de?nite improvement in all signs With tWice daily amount can be determined by applying the compositions to application of Formulation C for 16 Weeks. test animals and human subjects. It Will also be readily apparent to those skilled in the art. The amount Will vary Example 7 With the condition being treated, the siZe, number and distribution of the lesions and the type and concentration of Application the formulation applied. Three patients suffering from frequently recurrent facial EXAMPLES 25 seborrheic dermatitis and moderate signs of aging applied Formulation C tWice daily for sixteen Weeks. There Was The folloWing examples are offered to illustrate, but not complete clearing of the dermatitis Within four Weeks, and to limit the present invention. no recurrences during the sixteen Week period. All patients experienced improved texture, decreased roughness, and Example 1 30 diminished ?ne Wrinkles. Formulation A Example 8

A 0.25% Zinc pyrithione lotion Was produced by dissolv Formulation D ing 2.5 mg of Zinc-1-hydroxypyridine-2-thione (Sigma: St. Louis, M0.) in 100 milliliters of 60% ethanol, 25% propy 35 A 0.25% Zinc pyrithione lotion Was produced by dissolv lene glycol and 15% Water. This emulsion Was designed to ing 2.5 mg of Zinc-1-hydroxypyridine-2-thione (Sigma: St. be thoroughly shaken prior to topical application to affected Louis, M0.) in 100 milliliters of 60% ethanol, 25% propy mucocutaneous surface. Once applied, Formulation A Was lene glycol, and 15% Water. This emulsion Was to be alloWed to dry for 3 to 5 minutes; glycerin Was then applied thoroughly shaken prior to topical application to diseased sparingly to cover the Whole surface. 40 skin. Example 2 Example 9 Application Application 45 Three middle aged patients af?icted With mild acne vul Three teenage patients af?icted With acne vulgaris char garis With about 10 in?ammatory lesions on each side of the acteriZed by in excess of 20 in?ammatory papules and face and moderate ?ne Wrinkling, irregular pigmentation, pustules Were treated With Formulation D tWice daily for and loss of elasticity Were treated With Formulation A tWice tWelve Weeks. All patients experienced signi?cant but not daily for 12 Weeks. All patients experienced complete clear complete clearing. The average improvement Was 56% ing of the acne lesions and noticeable decrease in the degree decrease in the number of in?ammatory lesions and 45% and number of Wrinkles and pigmentation With improvement decrease in comedos. in elasticity. Example 10 Example 3 55 Application Formulation B TWo middle age patients af?icted With rosacea experi Formulation AWas adjusted to Formulation B by adding enced marked improvement after nine Weeks of using For 5 mg of salicylic acid (Sigma: St. Louis, M0.) by Weight to mulation D tWice daily to their face. make a 0.5% solution. Each application Was performed as in 60 Example 1 above. Example 11 Example 4 Application Application TWo middle age men suffering from pseudofolliculitis 65 barbae Were treated With Formulation D for nine Weeks. TWo middle aged patients Were treated With Formulation Both experienced >50% decrease in the number of in?am B tWice daily for 16 Weeks. Both experienced a noticeable matory lesions. US 6,482,839 B1 17 18 Example 12 Example 21 Application Formulation H Three adults afflicted with acne necroticans miliaris dis This product Was prepared by dissolving 25 mg of sele seminata applied Formulation D tWice daily for nine Weeks. nium pyrithione and 10 mg of clindamycin phosphate, All observed >50% decrease in the number of tender lesions. (Sigma; MilWaukee, Wis.) in 100 mL of 60% ethanol, 25% propylene glycol, and 15% Water to make a 2.5% by Weight Example 13 selenium pyrithione and 1.0% by Weight clindamycin phos Formulation E phate solution. 10 Formulation E Was produced by adding 20 mg of salicylic Example 22 acid (Sigma: St. Louis, Mo.) to Formulation D to make a 2.0% by Weight salicylic acid solution. Application Example 14 TWo patients suffering With oral lichen planus resistant to 15 other topical therapies experienced complete clearing of all Application lessons With tWice daily application of formulation H for TWo teenagers Were treated With Formulation E tWice tWelve Weeks. daily for tWelve Weeks. Both experienced an average of 92% clearing of in?ammatory acne lesions. Example 23 20 Example 15 Formulation I Formulation F Formulation I Was prepared by dissolving 0.2% by Weight (20 mg) selenium sul?de and 0.05% by Weight (5 mg) Formulation F Was prepared by dissolving 25 milligrams di?orasone acetate (Sigma; MilWaukee, Wis.) in 100 mL of of selenium sul?de (Sigma: St. Louis, M0 in 100 milliliters 25 60% ethanol, 25% propylene glycol and 15% Water. of 60% ethanol, 25% propylene glycol, and 15% Water to make a 2.5% by Weight selenium sul?de solution. Example 24 Example 16 Application Application 30 Three patients suffering from recurrent atopic dermatitis TWo middle aged males suffering from recurrent pityre Were treated With Formulation I tWice daily. Complete sporum folliculitis experienced complete clearing With tWice clearing of the dermatitis Was achieved Within tWo Weeks daily application of Formulation F for 23 and 26 days and no recurrences developed over the following four respectively. months. 35 It is understood that the examples and embodiments Example 17 described herein are for illustrative purposes only and that Formulation G various modi?cations or changes in light thereof Will be suggested to persons skilled in the art and are to be included A 0.25% Zinc pyrithione lotion Was produced by dissolv Within the spirit and purvieW of this application and scope of ing 25 mg. of Zinc pyrithione (Sigma; Milwaukee, Wis.) in 40 the appended claims. All publications, patents, and patent 60% ethanol, 25% propylene glycol and 15% Water. 2% applications cited herein are hereby incorporated by refer salicylic acid by Weight Was added. This emulsion Was ence for all purposes. thoroughly shaken prior to topical application to the affected What is claimed is: mucocutaneous surface. Once applied it Was alloWed to dry 1. A method for the treatment of skin and mucous mem for up to ?ve minutes folloWed by application of glycerin. 45 branes suffering from rosacea, folliculitis or pseudofollicu Example 18 litis barbae, said method comprising applying to an affected area a therapeutically effective amount of an active ingre Application dient selected from the group consisting of: (a) one or more pyridine-thiols, or tautomeric forms Three patients suffering With psoriasis Were treated With 50 Formulation G tWice daily for six Weeks. TWo patients thereof, to Which is attached a metallic ion; and experienced complete clearing of the lesions and one (b) one or more members selected from the group con improved by over 50%, according to a standard grading sisting of sul?des and oxides attached to a metallic ion. scale. 2. The method of claim 1, Wherein said formulation is 55 applied topically to skin or mucous membranes in a formu Example 19 lation selected from the group consisting of sprays, mists, Application aerosols, solutions, lotions, gels, creams, ointments, pastes, unguents, emulsions and suspensions. TWo patients suffering from facial seborrheic dermatitis 3. The method of claim 1, Wherein the method comprises Were treated With Formulation G tWice daily. Both experi 60 applying to the affected area a therapeutically effective enced complete clearing Within tWo Weeks of use. amount of a dermatologic/cosmeceutical formulation com Example 20 prising from about 0.01% to about 30.0% by Weight of an active ingredient selected from the group consisting of: Application (a) a compound that comprises a hydroxypyridine thione, TWo patients suffering from x-linked ichthyosis Were or a tautomeric form thereof, attached to a metallic ion treated With formulation G tWice daily. The lesions of both (b) a metallic ion attached to an anion selected from the completely cleared Within four Weeks. group consisting of an oxide and a sul?de, US 6,482,839 B1 19 20 wherein the metallic ion is selected from the group 9. The method of claim 8, Wherein the additional derma consisting of Zinc, Zirconium, vanadium, titanium, tin, tologically active compound is selected from the group silver, scandium, sodium, selenium, potassium, nickel, consisting of: salicylic, malic, citric, tartaric, pyruvic, magnesium, manganese, iron, gallium, germanium, glycolic, lactic, kojic, and aZelaic acids, gluconolactone, copper, cadmium, calcium, chromium, cobalt, bromine, serine, undecylenic acid, resorcinol, thymol, menthol, arsenic and aluminum. phenol, eucalyptol, sulfur, clindamycin, erythromycin, 4. A method for the treatment of skin and mucous mem griseofulvin, sulfacetamide, metronidiZole, cipro?oxan, branes suffering from rosacea, folliculitis or pseudofollicu o?oxan, chloramphenicol, glucocorticoids, piroxicam, ketoprofen, ketorolac, indomethacin, ketoconaZole, litis barbae, said method comprising applying to an affected terbina?ne, nafti?ne, cicloprix, benZoyl peroxide, area a therapeutically effective amount of a dermatologic/ 10 bacitracin, mupirocin, polymixin, gramicidin, cosmeceutical formulation, Wherein said dermatologic/ chloroxylenol, benZylkonium chloride, benZethonium cosmeceutical formulation comprises from about 0.15% to chloride, tobramycin, gentamicin, minocycline, tetracycline, about 4.0% by Weight of a compound that comprises a heavy silver salts, copper complexes, tretinoin, isotretinoin, metal selected from the group of Zinc, Zirconium, vanadium, retinaldehyde, adapalene, taZorotene, vitamins A, C, E and titanium, silver, selenium, sodium, potassium, magnesium, 15 D and their lactones, analogs, esters, amides, isomers, salts, manganese, copper, gallium, arsenic and aluminum, Wherein and derivatives thereof. the heavy metal is attached to a moiety selected from the 10. The method of claim 4, Wherein said formulation is group of 1-hydroxy-2-pyridine thione and 2-pyridinethiol applied topically to skin or mucous membranes in a formu 1-oxide. lation selected from the group consisting of sprays, mists, 5. A method for the treatment of skin and mucous mem 20 aerosols, solutions, lotions, gels, creams, ointments, pastes, branes suffering from rosacea, folliculitis or pseudofollicu unguents, emulsions and suspensions. litis barbae, said method comprising applying to an affected 11. The method of claim 4, Wherein the follicular derma area a therapeutically effective amount of a formulation tosis is selected from the group of rosacea, hidradenitis comprising: suppurativa, folliculitis, and pseudofolliculitis barbae. 25 12. The method of claim 4, Wherein the formulation (a) one or more members selected from the group con comprises about 0.25% by Weight of a compound selected sisting of sul?des and oxides attached to a metallic ion, from the group consisting of Zinc pyrithione, Zirconium and pyrithione, titanium pyrithione, silver pyrithione, selenium (b) one or more compounds that have dermatological pyrithione, copper pyrithione, and aluminum pyrithione. activity in the skin and mucous membranes. 13. The method of claim 12, Wherein said formulation 6. The method of claim 1, said method comprises apply 30 comprises an additional dermatologically active compound ing to the affected area a therapeutically effective amount of selected from the group consisting of keratolytics, a dermatologic/cosmeceutical formulation comprising from hydroxyacids, anti-in?ammatory agents, antimicrobials, about 0.05% to about 10.0% by Weight of a compound that immunosuppressives, carboxylic and amino acids, comprises one or more heavy metallic ion selected from the phenolics, retinoids, antioxidants, minerals, vitamins and group of Zinc, Zirconium, titanium, tin, sodium, selenium, 35 their lactones, analogs, isomers, salts, esters, amides and scandium, silver, potassium, manganese, magnesium, derivatives thereof. gallium, germanium, copper, cadmium, bromine, arsenic 14. The method of claim 5, Wherein said formulation is and aluminum, attached to a moiety selected from the group applied topically to skin or mucous membranes in a formu consisting of 1-hydroxy-2-pyridine thione and lation selected from the group consisting of sprays, mists, 2-pyridinethiol 1-oxide. 40 aerosols, solutions, lotions, gels, creams, ointments, pastes, 7. The method of claim 6, Wherein the formulation unguents, emulsions and suspensions. comprises about 0.25% by Weight of a compound selected 15. The method of claim 5, Wherein the therapeutically from the group consisting of Zinc pyrithione, Zirconium effective amount of the formulation comprises from about pyrithione, titanium pyrithione, silver pyrithione, selenium 0.01% to about 30.0% by Weight of the active ingredient. pyrithione, copper pyrithione, and aluminum pyrithione. 45 16. The method of claim 5, Wherein compound (b) is 8. The method of claim 1, Wherein said formulation selected from the group consisting of keratolytics, comprises an additional dermatologically active compound hydroxyacids, anti-in?ammatory agents, antimicrobials, selected from the group consisting of keratolytics, immunosuppressives, carboxylic and amino acids, hydroxyacids, anti-in?ammatory agents, antimicrobials, phenolics, retinoids, antioxidants, minerals, vitamins and immunosuppressives, carboxylic and amino acids, 50 their lactones, analogs, isomers, salts, esters, amides and phenolics, retinoids, antioxidants, minerals, vitamins and derivatives thereof. their lactones, analogs, isomers, salts, esters, amides and derivatives thereof.