WO2013138744A1

WO2013138744A1 - Compositions for the treatment of skin disorders

Info

Publication number: WO2013138744A1
Application number: PCT/US2013/032221
Authority: WO
Inventors: Howard Fein; Mindy B. Berlin
Original assignee: M. Alphabet 1, Llc
Priority date: 2012-03-16
Filing date: 2013-03-15
Publication date: 2013-09-19

Abstract

The present invention relates to methods of treating various skin disorders, including common conditions such as psoriasis and more uncommon conditions such as Netherton's syndrome, epidermolytic ichthyosis, lamellar ichthyosis, Mai de Meleda, harlequin ichthyosis, and erythrokeratodermia variablis. The treatment is carried out with topical pharmaceutical compositions that include a first agent, such as a fluorinated corticosteroid (e.g., fluocinonide) and, as a second agent, N-acetylcysteine (NAC), These compositions, in various formulations (e.g., formulated as lotions, gels, ointments, and creams), constitute another aspect of the invention, and can be packaged for sale either individually or in combination. The methods of the invention are not limited to established medical disorders. The compositions described herein can also be used to improve the appearance of the skin where it is aging, dry, red, or cracked (for example). In these instances, in particular, NAC can be formulated and applied without a first agent as described herein.

Description

COMPOSITIONS FOR THE TREATMENT OF SKIN DISORDERS

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U.S. Provisional Application No. 61/611,598, which was filed March 16, 2012.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to methods for treating both common and uncommon skin disorders including the common conditions psoriasis and eczema and the uncommon conditions of epidermolytic and lamellar ichthyosis. More specifically, the invention encompasses compositions and methods for administering effective amounts of fluocinonide and N-acetyl cysteine, or their pharmaceutically acceptable salts, along with processes for making such compositions.

BACKGROUND OF THE INVENTION

Skin disorders can be debilitating to those suffering from them, as patients can experience a range of symptoms from mildly irritating levels of discomfort to medically threatening conditions. The presence of skin lesions or associated infl ammation can also limit the patient's lifestyle choices and their ability to work. Skin disorders are usually difficult to treat and often require long term efforts to control the lesions.

There are many treatments available, but they can be either expensive, hard to administer or have unwanted side effects. Additionally, even when carried out, these treatments may not be successful or may provide only temporary relief. A case on point is the treatment of psoriasis, a chronic disease of unclear pathogenesis, that affects the skin and joints in about 2% of the population in developed countries. Cell proliferation is increased up to about 10 times the normal rate, and patients experience inflamed, scaly and frequently disfiguring skin lesions and may also develop arthritis of the joints in the hands and feet. Typically, in the skin lesions, keratinocytes differentiate abnormally and hyperproliferate. T ceils and neutrophils

characteristically infiltrate psoriatic skin and are directly involved in the inflammatory state of the affected tissue. In addition, skin capillaries typically increase distinctly.

Psoriasis lesions develop in several different characteristic patterns, with plaque psoriasis being the most common. Guttate psoriasis, with raindrop shaped lesions scattered on the trunk and limbs, is the most frequent form in children, while pustular psoriasis is usually localized to the palms and soles. The classical inflammatory lesions vary from discrete erythematous papules and plaques covered with silvery scales to scaly itching patches that bleed when the scales are removed.

As noted, psoriasis can have a significant negative impact on patients. Psoriatic arthritis appears in 10-30% of patients. In addition, psoriatic skin lesions that itch intensely can provoke severe scratching and disfigurement. The various manifestations of the disease make it more than a dermatologic nuisance as it interferes wit many daily activities of the afflicted. As a consequence, the disease also causes considerable psychological morbidity in many patients.

Currently used topical treatments for skin disorders include topical steroids, coal tar compositions, anthralin, Vitamin D compositions, retinoid therapy, exposure to sunshine and other lotions and creams (see, for example, U.S. Patent os. (5,399,108, 6,011,067, 4,788,061, 7,982,008, 7,670,620, 5,296,500, and 6,399,108). Occlusion therapy, which involves wrapping the lesions with coverings and medications, is also commonly tried. Common side effects from such treatments include skin thinning, stretch marks and resistance to medications. Coal tar treatments may make the skin more sensitive to UV rays, and anthralin can irritate or burn skin surrounding the psoriatic lesions. Other topical treatments may cause allergic reactions or skin irritation, which are obviously unwanted when trying to treat skin that is already irritated. Sun therap may cause skin cancers that lead to more serious medical conditions and treatments. Patients may also try a variety of herbal and dietary remedies.

Phototherapy with UVB radiation is another treatment for skin disorders (see, for example, WiPO Publication No. WO 02/055149, U.S. Publication No. 2002/0183811, and Douwes et al., PhotodermatoL Photoimmunol Photomed. 16:25-29, 2000). It may be used alone or in conjunction with topical treatments. The side effects include skin cancer and skin aging. PUVA, a combined psoralen and UVA radiation treatment, has also been used to treat skin disorders. The patient usually takes psoralen by mouth and administers UVA radiation to the skin surface. The short term side effects include nausea and itching and redness of the skin. The long term effects include changes in the skin's pigmentation, premature skin aging, and cataracts.

Systemic medications have also been used in the treatment of skin disorders (see, for example, WIPO Publication No. WO 97/45098, U.S. Patent Nos. 4,721,705 and 6,589,989, Japanese Patent No. JP 6340541 , and Chinese Patent No. CN 11 13795). Steroids have long been used, but steroids have many side effects that limit the persons who can take the steroids and limit the amount of time steroids can be administered. Additionally, there are side effects from taking steroids and from cessation of steroid medications once treatment ends. Other common medications include methotrexate and oral retinoids. Short term side effects from methotrexate treatment include nausea, fatigue, loss of appetite, and mouth sores. Long term use can lead to liver damage and patients taking methotrexate must be closely monitored for this damage. Oral retinoids pose particular problems for women who may become pregnant because retinoids cause birth defects in developing fetuses, Cyclosporine can also treat skin disorders, but it has the side effect of immune suppression, placing the patient at heightened risk of infection.

Therefore, there is still a need for compositions for treating skin disorders in humans that do not have the serious side effects of current therapies and that are safe for patients, particularly when used over a long term, easily handled, and practical to store.

SUMMARY OF THE INVENTION

The present invention relates to compositions and methods for treating various skin disorders (as described further below). The compositions will include at least one first agent and at least one second agent as described herein. The first agent can be a compound of Formula I, such as fluocinonide or its pharmaceutically acceptable salt, and the second agent can be -aeetyl- cysteine (NAC) or its pharmaceutically acceptable salt. When formulated for administration, the compositions will also include one or more physiologically acceptable earners. Methods of making such compositions are also encompassed by the present invention.

Accordingly, in a first aspect, the invention features pharmaceutically or physiologically acceptable compositions that include (a) a first agent that is a fluorinated corticosteroid

conforming to Formula I or an acceptable salt thereof:

where R is H; CO(CH₂)_nCH₃, wherein n is an integer from 0 to 5; or a eycloalkane;

(b) N-acetylcysteine (NAC) or an acceptable salt thereof; and (c) a pharmaceutically or physiologically acceptable carrier or carrier system, wherein the composition is optionally formulated for topical administration. The eycloalkane, which can be substituted or un substituted can conform to:

In one embodiment, the fluorinated corticosteroid is fluocinonide or an acceptable salt thereof. Any of the compositions described above or elsewhere herein can further include: hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclomethasone di propionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluocinonide, fiuosinoione acetonide, flucortine butylester, fluocortolone, flupred- nidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, corto- doxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcmafide, betamethasone an d the balance of its esters, chloropred- nisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, fiucloronide, flunisoli.de, fluorometh alone, fiuperoione, fluprednisoione, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone,

paramethasone, preunisoione, preunisone, beclomethasone dipropionate, triamcinolone, or tixocortol pivalate, or a pharmaceutically or physiologically acceptable salt of any one of the foregoing compounds.

The first agent can be present in an amount constituting from about 0.001 weight % to about 1 weight % of the total weight of the composition; the NAC or an acceptable salt thereof can be present in an amount from about 1 weight % to about 20 weight % of the total weight of the composition; and/or the carrier can be a sugar, a starch, a cellulose, powdered tragacanth, malt, gelatin, talc, cocoa butter or a suppository wax, an oil, a glycol, a polyol, an ester, agar, a buffering agent, alginic acid, pyrogen-free water, isotonic saline, or a mixture thereof. Weight %s and carriers are described further below. We note here that the carrier system can be a solution, emulsion, gel, or solid, and the composition can be formulated for topical administration as a lotion, cream, oil, a stick- or bar-shaped solid, a spray, an ointment, a paste, a mousse, a body wash, or a cosmetic. The present compositions can further include collagen, hyaluronic acid, elastin, a hydrolysate, primrose oil, jojoba oil, epidermal growth factor or a biologically active variant thereof, a soybean saponin, a mucopolysaccharide, a vitamin, or a mixture thereof. With regard to still further ingredients, the present compositions can include a non-steroidal anti -inflammatory agent, an antioxidant, a chelating agent, a retinoid, a benzofuran derivative, or a mixture thereof, in another aspect, the invention features a pharmaceutically or physiologically acceptable composition comprising: (a) a first agent, wherein the first agent isjrydro- cortisorie, hydroxyltriamcmolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclomethasone dipropioiiate, clobetasol valerate, desonide, desoxymetha- sone, deoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenoione, flue loro lone acetonide, fludrocortisone, flumeth- asone pivalate, fluocinonide, fluosinoione acetonide, flucortine butylester, fluocortoione, fiuprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisoione, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clesciriolone, dichlor-isone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperoione, fluprednis-olone, hydrocortisone valerate, hydrocortisone eye lopenty! propionate, hydrocortamate,

meprednisone, paramethasone, preunisolone, preunisone, beclomethasone dipropionate, triamcinolone, or tixocortol pivalate, or a pharmaceutically or physiologically acceptable salt of any one of the foregoing compounds; (b) N -acetylcysteine ( AC) or an acceptable salt thereof; and (c) a pharmaceutically or physiologically acceptable carrier or carrier system, wherein the composition is optionally formulated for topical administration.

In another aspect, the invention features methods for treating a skin disorder or improving the appearance of the skin by administering, to a patient, an effective amount of a topical composition comprising any of the compositions described above or elsewhere herein. The patient may be suffering from (i.e., may have been identified or diagnosed as having): psoriasis, atopic dermatitis, eczema, disseminated superficial actinic porokeratosis, seborrheic dermatitis, allergic contact dermatitis, irritant contact dermatitis, lichen planus, or may have inflamed skin due to a rash, hives, a bum, hemorrhoids, contact with poison ivy or poison oak, an insect sting, a cut, or vitiligo. In other embodiments, the patient may have aging skin, dry skin, itchy skin, red skin, or cracked skin. In other embodiments, the patient can have acquired or congenital icthvosis or may have Netherton's syndrome, epidermolytic ichthyosis, lamellar ichthyosis, Mai de Meieda, harlequin ichthyosis, or erythrokeratodermia variablis.

in another aspect, the present invention features the use of a composition

described herein in the preparation of a medicament for the treatment of a skin disorder or for improving the appearance of the skin.

In another aspect, the present invention features methods of treating a skin

disorder or improving the appearance of the skin by administering, to a patient, an

effective amount of a topical composition comprising (a) NAC or an acceptable salt

thereof and (b) a pharmaceutically or physiologically acceptable carrier or carrier system, wherein the composition is optionally formulated for topical administration.

In another aspect, the present invention features the use of a composition described herein in the preparation of a mediament for the treatment of a skin disorder or for improving the appearance of the skin. The composition can include (a) -aeetylcysteine (NAC) or an acceptable salt thereof (to the exclusion of a "first agent" as described above) and (b) a pharmaceutically or physiologically acceptable carrier or carrier system, wherein the

composition is optionally formulated for topical administration.

In another aspect, the present invention features kits comprising the composition of any of claims 1-10 and instructions for use, wherein the ingredients of the composition are combined with one another or contained within separate containers. In accordance with standard practice, the temis used in this specification generally have their ordinary meanings in the art, wi thin the context of the invention, and in the specifi c context where each term is used. As the same thing can be said in more than one way, alternative language and synonyms may be used for any one or more of the terms discussed herein. A recital of one or more synonyms does not exclude the use of other synonyms.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig, 1 is a line graph illustrating the improvements in patients' skin when treated as described in the Example below.

Fig. 2 is a Table reporting the results of a quali.ty-of-3.ife questionnaire completed by patients as treated in the Example below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compositions and methods for treating various skin disorders and for improving the appearance of the skin. The compositions can include, as a first agent, a fluorinated corticosteroid conforming to Formula I:

CK-OR

where R is H; CO(CH₂)_nCH₃, where n is an integer from 0 to 5; or a cycloalkane, either substituted or unsubstituted, such as:

or

In one embodiment, the corti

In other embodiments, the hydroxyl group of Formula I can be substituted with H or a halogen, such as CI, Fluocinonide has been used topically as an anti-inflarnmatory agent for the treatment of skin disorders such as eczema and seborrhoeic dermatitis {see, for example, U.S. Patent Nos. 6,765,001, 7,220,424, and 7,794,738), Fluocinonide relieves itching, redness, dryness, crusting, scaling, inflammation, and discomfort. In addition to fluocinonide, or as an alternative to fluocinonide or any other compound of Formula I, the present compositions can include, as a first agent, one or more of: hydrocortisone, hydroxyltri.amcmol.one, alpha-methyl

dexamethasone, dexamethasone-phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasorte, deoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenoione, fluclorolone acetonide,

fludrocortisone, flumethasone pivalate, fluosinolone acetonide, flucortine butyiester, fluocortoione, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylpred-nisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocort sone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, cb.loropredni.sone, chiorprednisone acetate, clocortelone, clescinolone, dichlorisone,

difluprednate, flucloronide, flunisolide, fluoro-methalone, fluperolone, fluprediiisolone, hydrocortisone valerate, hydrocortisone cyclopentyl -propionate, hydrocortamate, raeprednisone, parametbasone, preunisolone, preunisone, beclomethasone dipropionate, triamcinolone, tixocortol pivalate, or a pharmaceutically acceptable salt of any of the foregoing. It is to be understood that wherever a given compound can be used (including any of the compounds described herein as suitable first agents and including NAC), a pharmaceutically or

physiologically acceptable salt of that compound can also be used.

Any given compound can include a group that is protected, i.e. , it can include a "^■protecting" group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction (or for other purposes). A wide variety of oxygen and nitrogen protecting groups are known to one of ordinary skill in the art. Non-limiting examples include: C(0)-alkyl, C(0)Ph, C(0)aryi, C¾, C¾- alkyl, CH₂-aikenyI, CH₂Ph, CH₂-aryl, CI¾0-aikyl, CH₂0-aryl, S0₂-alkyl, SQ₂~aryl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, and l ,3-(l , l ,3,3-tetraisopropyldisiloxanylidene).

The effective amount of the first agent (e.g. , a compound conforming to Formula I, such as fluocittonide, or its pharmaceutically acceptable salt) that may be used in the present invention can be from about 0.001 weight % to about 1 weight %, based on a total weight of the

composition (e.g. , from about 0.05 weight % to about 0.5 weight % (e.g., about 0.1 weight %)). The term "weight %" or "wt %" is defined herein to mean the dry weight of a component (any component described herein) divided by the total weight of the composition and multiplied by 100. "About" or "approximately" as used herein with respect to any characteristic generally means within 20% (e.g., within 5-10%, inclusive) of a given value or range. Moreover, the numerical quantities given herein are approximate, meaning that the term "about" or

"approximately" can be inferred if not expressly stated; other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction

conditions used herein should be understood as modified in all instances by the term "about,"

A free base of any given compound (e.g., fluocinonide free base) ma be used in the compositions of the present invention, however, such free bases may be converted into any pharmaceutically or physiologically acceptable salt, including those described in well-known reference texts such as REMINGTON'S PHARMACEUTICAL SCIENCES, Arthur Osol, ed., 1553-93, 1980). Such salts include, but are not. limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include conventional non-toxic salts as well as the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromie, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glyeolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymafeic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

Λ '-Acetylcysteine (NAC): N-Acetyicysteine is cysteine with an acetyl group on the a-amine. -acetylcysteine has the follo

N-Acetylcysteine is used primarily as a mucolytic agent and in the management of paracetamol overdose (see, for example, Kanter et al., Am. J. Health-System Pharmacy 63(19): 1821, 2006; Dawson et al., Med. J. Australia, 150(6): 329-331, 1989; and Tirouvanziam et al., Proc. Natl. Acad. Sci. USA 103(12): 4628-4633, 2006). It is also available over-the-counter as an oral formulation for use as an antioxidant and nutritional supplement. NAC efficiently breaks sulfur- sulfur bonds in mucus, making it especially useful for alleviating the thick mucus often associated with cystic fibrosis. For in vitro studies, epidermal tissue is commonly dissociated with various large molecular weight proteolytic enzymes. However, previous studies have shown that the epidermis can also be dissociated non-enzymatically with low molecular weight thiol-reducing agent (Hentzer and obayasi, Acta Derm. Venereol. 56: 19-25 , 1976). Thiol reducing agents are thought to destabilize the desmosome complex, resulting in epidermal disintegration. Although the compositions of the present invention are not limited to those that exert their effect by any particular mechanism, it appears that NAC converts the oxidized disulfide bonds between proteins to reduced, free thiol groups, leaving the proteins dissociated. We believe this helps shed thickened layers of skin and supports our contention that NAC can be used alone, as a single agent keratolytic, or part of a combination therapy, as described herein. Increased or abnormal disulfide bonds are found in a variety of dermato logic diseases, including (but not limited to) psoriasis (e.g., psoriasis vulgaris and even refractory or hard-to-treat psoriasis), acquired or congenital ichthyosis, atopic dermatitis, and Neterton's Syndrome. We are currently unaware of any NAC-containing topical dermatologic medications. The low molecular weight of NAC makes it a good candidate for use in topical treatments and cosmetic applications. Extracellular disulfide bonds are present in both the dermis, where they cross-link collagen bundles, and in the epidermis, where they help connect epidermal cells to each other.

Effective amounts of NAC or its pharmaceutically acceptable salt that may be used in the present invention are from about 1 weight % to about 20 weight % (e.g., from about 5 weight % to about 15 weight % (e.g., about 10 weight %)).

As with other agents included in the compositions of the invention, N-acetyfcysteine free base may be used, however, the free base may be converted into any pharmaceutically acceptable salt known in the literature, including those described in REMINGTON'S PHARMACEUTICAL SCIENCES (supra). Salts of N AC include, but are not limited to, mineral and organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,

phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfomc, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

Pharmaceutically Acceptable Carriers: A ''pharmaceutically acceptable carrier" is defined herein to mean one or more compatible solid or liquid filler diluents or microencapsulating substances that are suitable for administration to a host, particularly a human host. We may use the terms "pharmaceutically acceptable" and "physiologically acceptable" interchangeably to refer to the various carriers, with a preference for the term "pharmaceutically acceptable" when the carrier is included in a formulation intended to treat a medical disorder, such as psoriasis, and a preference for the term "physiologically acceptable" when the carrier is included in a formulation intended to treat a cosmetic conditions, such as aging, dry, red, or cracked skin. To our knowledge, any conventional carrier ma be used in the compositions of the present invention. The choice of a particular carrier, or a particular combination of carriers, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state. In this regard, the preparation of a suitable composition for a particular mode of administration is well within the scope of one of ordinary skill in the art. Additionally, many of the carriers (which may also be referred to in the art as "excipients") useful in the phannaceutical compositions of this invention are currently commercially available. By way of further illustration, conventional formulation techniques are described in REMINGTON'S

PHARMACEUTICAL SCIENCES, Arthur Osol, ed., 1553-93 (1980) and II. C. Ansel el al, PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS, 7^th Edition, Lippincotl Williams & White, Baltimore, Md. (1999).

The carriers that may be used in the present invention include, but are not limited to, sugars (e.g., lactose, glucose and sucrose); starches (e.g., corn starch and potato starch);

celluloses (e.g., microcrystailine cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate); powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils (e.g., peanut, cottonseed, safflower, sesame, olive, corn, and soybean oils); glycols (e.g., propylene glycol); polyols (e.g., glycerin, sorbitol, mannitol and polyethylene glycol); esters (e.g., ethyl oleate and ethyl laurate); agar; buffering agents (e.g., magnesium hydroxide and aluminum hydroxide); alginic acid; pyrogen- free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate-buffered solutions; other non-toxic compatible substances; or mixtures thereof.

The carriers used in the compositions and methods described herein must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the host (e.g., a human patient). Safe and effective amounts carriers that may be used in the present invention vary widely from about 1 weight % to about 99 weight %, based on a total weight of the composition.

Pharmaceutical and Cosmetic Compositions and Processes for Making Same: Treatment will employ the use of a therapeutically effective amount of a topical pharmaceutical composition comprising fl.uocinoni.de or its pharmaceutically acceptable salt, NAC or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier.

Variations in formulations that include or exclude certain carriers result in a wide variety of compositions that fall within the scope of the present invention. With respect to exclusion, it is to be understood that any of the carriers listed herein can be explicitly excluded from the compositions. For example, any given composition can be free of a sugar (or a parti cular sugar), free of a starch (or a particular starch), free of a cellulose (or a particular cellulose), and so forth. The topical pharmaceutical compositions of the present invention may be made into a wide variety of product types. These include, but are not limited to lotions, creams, oils (e.g. beach oils), sticks, sprays, ointments, pastes, mousses, and cosmetics (e.g. within a foundation, which has the added benefit of tinting the skin). These product types may comprise several types of carrier systems including, but not limited to solutions, emulsions, gels, and solids.

Topical Compositions: The compositions of the present invention can include a first agent as described herein or its pharmaceutically acceptable salt, NAC or its pharmaceutically acceptable salt, and one or more pharmaceutically or physiologically acceptable carriers formulated into lotions or creams for topical administration. To be clear, the present

compositions can include only one agent that qualifies as a first agent or more than one agent (e.g., two or more agents), each of which qualifies as a first agent. In some embodiments, the first agent can be absent, with NAC or its pharmaceutically acceptable salt being the only active ingredient for treatment or cosmetic improvements.

The therapeutically effective amount of the first agent (e.g., a compound conforming to Formula I, such as fluocinonide or its pharmaceutically acceptable salt) that may be used in lotions or creams is from about 0.001 weight % to about. 1 weight %, based on the total weight of the composition (e.g., from about 0.05 weight % to about 0.5 weight % (e.g., about 0.1 weight %)). The therapeutically effective amount of NAC or its pharmaceutically acceptable salt that may be used in lotions or creams is from about 1 weight % to about 20 weight %, based on a total weight of the composition (e.g., from about 5 weight % to about 15 weight % (e.g., about 10 weight %). The therapeutically effective amount of carrier that may be used in lotions or creams is from about I weight % to about 99 weight %, based on a total weight of the composition. The pharmaceutically acceptable carriers or excipients that may be used in lotions or creams include, but are not limited to, those described above (sugars, starches, celluloses, etc.).

If the carrier is formulated as an emulsion (a mixture of two or more liquids that are immiscible), from about 1 weight % to about 10 weight % (e.g., from about 2 weight % to about 5 weigh t %) of the carrier system can be an ermilsifier (a substance such as a surfactant, that stabilizes the emulsion). Emulsifiers may be nonionic, anionic or cationic. Suitable emulsifiers are disclosed in, for example, U.S. Patent Nos. 3,755,560 and 4,421,769 and in McCUTCHEON'S DETERGENTS AND EMULSIFIERS, North American Edition, pages 317-324, 1986). Lotions and creams can be formulated as emulsions as well as solutions. Such lotions and creams can include from about 1 weight % to about 20 weight % (e.g., from about 5 weight % to about 10 weight %, based on a total weight of the composition, of an emollient; from about 25 weight % to about 95 weight %, preferably from about 45 weight % to about 75 weight %, based on a total weight of the composition, of water; and from about 0.1 weight % to about

10 weight %, preferably from about 0.5 weight % to about 5 weight %, based on a total weight of the composition, of an emulsifier. Emollients are materials used for the prevention or relief of dryness, as well as for the protection of the skin.

Single emulsion skin care preparations, such as lotions and creams, of the oil-m-water type and water-in-oil type are well-known in the art and are useful in the present invention.

Multiphase emulsion compositions, such as the water-iii-oil-in-water type, as disclosed in U.S. Patent No. 4,254,105, incorporated herein by reference in its entirety, are also useful in the present invention. In general, such single or multiphase emulsions contain water, emollients and emulsifiers as essential ingredients.

Triple emulsion carrier systems comprising an oil-in -water-in-silicone fluid emulsion composition as disclosed in U.S. Patent No. 4,960,764, incorporated herein by reference in its entirety, are also useful in the present invention.

Other Topical Compositions: The topical compositions below comprise the following: (a) a therapeutically effective amount of fluocinonide or its phamiaceuticallv acceptable salt from about 0.001 weight % to about 1 weight %, based on a total weight of the composition (e.g., from about 0.05 weight % to about 0.5 weight % (e.g., about 0.1 weight %)); (b) a therapeutically effective amount ofN-acetylcysteine or its pharmaceutically acceptable salt from about 1 weight % to about 20 weight %, based on a total weight of the composition (e.g., from about 5 weight % to about 15 weight % (e.g., about 10 weight %)); and (c) a therapeutically effective amount of a pharmaceutically or physiologically acceptable carrier from about 1 weight % to about 99 weight %, based on a total weight of the composition.

The pharmaceutically acceptable carriers or excipients that may be used in the topical compositions are, but not limited to, sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoi and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate-buffered solutions; other non-toxic compatible substances; or mixtures thereof.

The topical pharmaceutical compositions of the present invention may be formulated as solutions, which typically include pharmaceutically or physiologically acceptable aqueous or organic solvents. These solvents have, dispersed or dissolved therein, any active compound (e.g., a first agent as described herein and/or NAC alone), and they possess acceptable safety properties (e.g., irritation and sensitization characteristics). Water is a typical aqueous solvent and can be included in any of the compositions described herein. Examples of suitable organic solvents include: propylene glycol, butylene glycol, polyethylene glycol (200-600),

polypropylene glycol (425-2025), glycerol, 1 ,2,4-butanetrioL sorbitol esters, 1 ,2,6-hexanetriol, ethanol, isopropanol, butanedioi, and mixtures thereof.

Topical compositions of the present invention may also be formulated as a solution comprising an emollient. An example of a composition formulated in this way would be a beach-style oil product. Such compositions can contain from about 2 weight % to about

50 weight %, based on the total weight of the composition, of a topical and acceptable emollient.

Another type of topical composition that may be formulated from a solution system is an ointment. An ointment may comprise a simple base of animal or vegetable oils or semi-solid hydrocarbons (oleaginous). Ointments may also comprise absorption ointment bases which absorb water to form emulsions. Ointment carriers may also be water soluble. An ointment may also comprise from about 2 weight % to about 10 weight %, based on a total weight of the composition of an emollient plus from about 0.1 weight % to about 2 weight %, based on the total weight of the composition of a thickening agent (generally understood as a substance that increases the viscosity of a solution or liquid/solid mixture without substantially modifying its other properties). A more complete disclosure of thickening agents useful herein can be found in Segarin, COSMETICS, SCIENCE AND TECHNOLOGY, 2^nd Edition, Vol. 1, pp. 72-73 (1972). If the topical compositions of the present invention are formulated, for example, as a gel or a cosmetic stick- or bar-shaped solid, a thickening agent from about 0.1 weight % to about 2 weight %, based on a total weigh t of the composition, can be added to the formul ation.

If the topical compositions of the present invention are formulated as an aerosol and applied to the skin as a spray-on, a prope Slant is added to a solution composition. Examples of propellants useful herein include, but are not limited to, the chlorinated, fluorinated and ehloro- fluorinated lower molecular weight hydrocarbons. A more complete disclosure of propellants useful herein can be found in Sagarin, COSMETICS SCIENCE AND TECHNOLOGY, 2^nd Edition, Vol. 2, pp. 443-465 (1972).

The compositions can also be formulated as toilet bars, liquids, pastes, or mousses.

These forms are quite useful in that they can be used to administer or apply a composition as described herein whil e at the same time act as cleansing agents for the skin. One of ordinary skill in the art is readily able to formulate the present compositions into a toilet bar or other bath product, liquid, paste or mousse as a leave-on product after the skin has been washed. As noted, ,the topical compositions of the present invention may also be formulated as makeup products, such as cosmetics {e.g., a foundation or other cosmetic product).

The topical compositions of the present invention can include, in addition to the aforementioned components, a wide variety of additional oil-soluble materials and/or water- soluble materials conventionally used in topical compositions, at their art-established levels. Water-soluble materials include humeetants, proteins and polypeptides, preservatives, and alkaline agents. In addition, any of the present topical compositions can contain conventional cosmetic adjuvants, such as dyes, opacifiers (e.g., titanium dioxide), pigments and perfumes (however, as noted, in some embodiments, compositions can be free of odor-masking materi als).

The topical pharmaceutical compositions of the present invention may also include a safe and effective amount of a penetration enhancing agent. A preferred amount of penetration enhancing agent is from about 1 weight % to about 5 weight %, based on the total weight of the composition. Examples of useful penetration enhancers, among others, are disclosed in U.S. Patent. Nos. 4,537,776, 4,552,872, 4,557,934, 4, 130,667, 3,989,816, 4,017,641 , al l of which are incorporated by reference herein, and European Patent Application 0043738,.

Other conventional skin care product additives may also be included in the compositions of the present invention. For example, a component of the extracellular matrix or a biologically active variant thereof (such as collagen, hyaluronic acid, or elastin), hydrolysates, primrose oil, jojoba oil, epidermal growth factor or a biologically active variant thereof, soybean saponins, mucopolysaccharides, vitamins (e.g., vitamin A, and derivatives thereof, vitamin B₂, biotin, pantothenic, vitamin D, or vitamin E), and/or mixtures thereof may be used. Variations in formulation of these carriers will result in a wide variety of products which fall within the scope of the present invention.

Methods of Treatment: Other aspects of the present invention relate to methods of treating various skin disorders and/or improving the appearance of the skin with a composition described above or elsewhere herein. The disorders that may be treated include psoriasis, atopic dermatitis, eczema, disseminated superficial actinic porokeratosis, seborrheic dermatitis, allergic contact dermatitis, irritant contact dermatitis, lichen planus, and other papulosquamous disease states. In addition, one can treat inflammation (e.g. , inflamed skin) and/or conditions associated with inflammation, rashes, hives, burns, hemorrhoids, poison ivy, insect stings, cuts or similar insults to the skin, vitiligo, aging skin, dry skin, itchy skin, red skin, itchy eczema, and cracked skin. Skin disorders may generally be evidenced by skin elevations and scales, which may be silver}' in appearance. Where a host exhibits, in particular, aging, dry, red, or cracked skin, the present compositions can be applied to improve the cosmetic appearance of the skin. Where there is no diagnosis of a particular disorder and/or where the aim is an improvement in the appearance of the skin, the composition(s) applied may lack a "first agent" as described herein but include AC.

In addition, one can treat less common ailments such as etherton's syndrome, epidermolytic ichthyosis, lamellar ichthyosis, Mai de Meleda, harlequin ichthyosis, and erythro- keratodermia variablis. The compositions described herein can also be used for the treatment of acquired or congenital icthyosis. Any of the methods of the invention can include a step of identifying a host in need of treatment. A "host" is defined herein to mean a mammal and, preferably, a human. The human can be of any age, and even pediatric and elderly hosts can be treated. We may use the terms "host" and "patient" interchangeably. Veterinary applications, at least in certain indications, are clearly anticipated by the present invention. Thus, the present compositions can be administered to domesticated animals (e.g., cats and dogs) or to livestock.

The amount of a given composition and the frequency of its administration can vary widely. Where the amount is "an effective amount" it will be sufficient to bring about a positive modification in the disorder to be treated or in the appearance of the skin (for example, in the event a patient is treated for aging skin) but low enough to avoid serious side effects. It is well within the abili ty of one of ordinary skill in the art. to determine wh ether the ratio of benefit to risk for any given patient or group of patients merits proceeding. Where a patient is suffering from a medical disorder, particularly with severe symptoms, we may refer to the "effective amount" as a therapeutically effective amount of a composition described herein or an active agent within it. Where a patient has a cosmetic issue, the effective amount is an amount (of a composition or an agent therein) that improves the appearance of the skin with respect to that issue. As would be appreciated by one of ordinary skill in the art, effective amounts will vary depending on the particular condition being treated or addressed, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed (depending on, for example, its absorption, inactivation, and excretion rate), the particular formulation utilized, and similar factors.

With the foregoing in mind, we suggest, as non-limiting examples, administration of a topical formulation (i.e., one intended for directly laying on or spreading on outer skin) about once per week to about 10 times daily (e.g., about twice per week to about 4 times daily; about 3 times a week to about 3 times daily; or about once or twice per day). It is to be understood that for any particular patient, specific regimens should be adjusted over time according to the individuals' needs and the professional judgment of the person administering or supervising the administration of the compositions.

In the present methods, the compositions of the invention can be administered in combination or alternation with one or more additional compositions, including those containing other anti-inflammatory agents or antioxidants, chelating agents, retinoids, benzofuran derivatives, or a combination thereof. In general, in combination therapy, effective amounts of two or more agents are administered together, whereas during alternation therapy, an effective amount of each agent is administered serially.

A nti-Inflammatory Agents: An effective amount of an anti-inflammatory agent may be administered in addition to or instead of any a tiinflammatory described above as a first agent in the present compositions and methods. Where a second anti-inflammatory agent is added to the compositions described herein, it may be added in an amount from about 0.1 weight % to about 10 weight % (e.g., from about 0.5 weight % to about 5 weight %, based on the total weight of the composition). The exact amount will depend in large measure on the particular anti-inflammatory agent utilized, since such agents tend to vary widely in potency. Steroidal anti-inflammatory agents that can be used in addition to or instead of a compound of Formula I include but are not limited to corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, bec!omethasone dipropionate, clobetasol valerate, desonide, desoxymethasonc, deoxycorticosterone acetate, dexamethasone, diclilorisone, diflora- sone diacetate, diflucortolone valerate, fluadrenolorie, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, flucortine butylester, fluocortolone, fluprednidene (flupredny!idene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcina- fi.de, betamethasone and the balance of its esters, chloroprednisone, ehiorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethaione, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyelopentylpropionate, hydrocortamate, meprednisone, paramethasone, preunisolone, preunisone, beciomethasone dipropionate, triamcinolone, tixocortol pivalate, and mixtures thereof.

Non-steroidal anti-inflammatory agents can also be administered. The variety of compounds encompassed by this group are well known to one of ordinary skil l in the art. For a detailed description of the chemical structure, synthesis, side effects, and other properties of non- steroidal anti-inflammatory agents, one can consult standard texts, including ANTIINFLAMMATORY AND ANTI-RHEUMATIC DRUGS, K. D. Rainsford, Vol. I-III, CRC Press, Boca. Raton, (1985), and ANTI-INFLAMMATORY AGENTS, CHEMISTRY AND PHARMACOLOGY, 1, R. A. Scherrer, et al., Academic Press, New York (1974).

Specific non-steroidal anti-inflammatory agents that may be used in the compositions of the present invention include, but are not limited to: (!) the oxicams, such as piroxicarn, isoxicam, tenoxicam, sudoxicam, and CP-14,304 ((3Z)-3-[anilino(hydroxy)methylidene]-2- memyi-1 , l-dioxobenzo[e]thiazin-4-one); (2) the salicylates, such as aspirin, disalcid, benoryiate, trilisate, safapryn, solprin, diflunisal, and fendosai; (3) the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; (4) the fenamates, such as mefenamic, meciofenamic, flufenamic, niflumic, and tolfenamic acids; (5) the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and (6) the pyrazoles, such as

phenybutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone.

Mixtures of these non-steroidal anti-inflammatory agents may also be employed, as well as the pharmaceutically acceptable salts and esters of these agents. For example, etofenamate, a flufenamic acid derivative, is particularly useful for topical application.

"Natural" anti-inflammatory agents are also useful in the present invention. For example, one ca also include cand.eli.lla wax, alpha bisabolol, aloe vera, manjistha (extracted from plants in the genus Rubia, particularly Ruhia cordifoli ), and guggai (extracted from plants in the genus Commiphora, particularly Commiphora mukul), or mixtures thereof.

Anti-Oxidants: An effective amount of an anti-oxidant may be added to the compositions of the present invention, preferably from about 0.1 weight % to about 10 weight % (e.g., from about 1 weight % to about 5 weight %, based on a total weight of the composition). Useful anti-oxidants include but are not limited to: ascorbic acid (vitamin C) and its salts, tocopherol (vitamin E), tocopherol sorbate, other esters of tocopherol, but lated hydroxy benzoic acids and their salts, 6- hydroxy-2,5,7,8-tetramethylchroman-2-carboxyiic acid, gallic acid and its alkyl esters, especially propyl gal late, uric acid and its salts and alkyl esters, sorbic acid and its salts, the ascorbyi esters of fatty acids, amines (e.g., Ν, -diethylhydroxyiamine, amino-guanidine), sulfhydryl compounds (e.g., glutathione), and dihydroxy fumaric acid and its salts or mixtures thereof.

Chelating Agents: A safe and effective amount of a chelating agent, which forms a complex with metal ions to inhibit their participation in (or ability to catalyze) chemical reactions, may be added to the compositions of the present invention, preferably from about 0.1 weight % to about 10 weight % (e.g., from about 1 weight % to about 5 weight %, based on a total weight of the composition). One can use, for example, ethylenediaminetetraacetic acid, 2-furildioxime, alkyl phosphate, 1 ,4,7, 10-tetraazacyclododecane-N-N '-N' '- ^{' ' '}-tetraacetic acid, furoic acid, 2- thiophenecarboxylic acid, picolinic acid, desferoxamine, or mixtures thereof.

Retinoids: A safe and effective amount of a retinoid may be added to the compositions of the present invention in varying amounts. For example, a retinoid may be included from about 0.001 weight % to about 2 weight % (e.g., from about 0.01 weight % to about 1 weight, %). The retinoid may be a natural or a synthetic analog of Vitamin A, a retinol-like compound that possesses the biological activity of Vitamin A in the skin, or a geometric isomers or stereoisomer of such compounds. Useful retinoids include, but not limited to, vitamin A, synthetic analogs of vitamin A, all-trans-retinoic acid, 9-cis-retinoic acid, 11-cis-retinoic acid, 13-cis-retinoic acid, 9, 13-di-cis-retinoic acid, retinoic acid, a tetracycline, dapsone, prednisone, estrogen, isotretinoin, adapalene, tretinoin, tazarotene, acitretin, and mixtures thereof.

Benzofuran Derivatives: A safe and effective amount of a benzofuran derivative may be added to the compositions of the present invention, preferably from about 0.01 weight % to about 20 weight % (e.g., from about 0.1 weight % to about 10 weight %). Benzofuran

derivatives that may be used in the compositions and methods of the present invention include, but not limited to, amiodarone, 5-hydroxybenzofuran, 6-hydroxybenzofuran, 2,3-dihydro-6- hydroxybenzofuran, 3-methyl-6-hydroxybenzofuran, 2,3-dimethyl-6-hydroxybenzofuran, 2,3- dihydro-3-methyl-6-hydroxybenzofiiran, 2-methyl-5-hydroxybenzofuran, or mixtures thereof.

As noted, in another aspect, the present invention features processes for the preparation of the compositions described herein, whether intended for therapeutic or cosmetic use. To prepare the compositions, one can add (e.g., by mixing) an effective amount of a first agent (e.g., fluocinonide or its pharmaceutically acceptable salt) to an effective amount of a second agent (e.g., NAC or its pharmaceutically acceptable salt). Depending on the precise formulation and intended route of administration, one of ordinary skill in the art can incorporate one or more pharmaceutically or physiologically acceptable carriers according to conventional compounding techniques to produce a desired composition. Any process may be used as deemed appropriate by one of ordinary skill in the art to prepare a composition having the desired constituents, in desired amounts, and exhibiting the desired effect.

Any of the compositions described herein can include or exclude an odor-masking material. Kits: In another embodiment of the present invention, a kit is provided that comprises a composition comprising fluocinonide or its pharmaceutically acceptable salt and another composition comprising N-acetylcysteine or its pharmaceutically acceptable salt. The kit may also comprise one or more pharmaceutically acceptable carriers. The kit may also comprise packaging materials and instructions. The packaging material may comprise a container for housing the compositions. Thus, the invention encompasses kits including one or more of the agents described herein whether those agents are already fully combined with one another in a preparation suitable for use or whether those agents are in a form intended to be either combined at a later time or administered separately. For example, the kit can include a compound conforming to Formula I (e.g., a fl.uocinonide-containi.ng composition) in a first container and an AC-containifig composition in a second container. The compositions can be combined (e.g., in the palm of the hand) before administration to the skin, or the compositions can be effectively combined by applying one to the skin and then the other to the skin.

EXAMPLE

We performed an open label study involving patients with refractory psoriasis vulgaris. Patients on systemic psoriasis medications were excluded from the study. Eligible patients were instructed to apply a topical combination product containing fluocinoni.de 0.05 wt % and NAC 10 wt % once a day to lesions located on the extensor aspects of the elbows or knees. We then assessed target plaque severity (TPS) after six weeks of treatment^". Our preliminary results indicate a significant (p<0.001) reduction in TPS (see also Fig. 1):

A questionairre regarding quality of life also showed improvement in all categories {see

Fig. 2).

Although certain embodiments and examples have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible, and all such modifications are intended to be encompassed within the below claims of the invention.

WHAT IS CLAIMED IS:

Claims

1. A pharmaceutically or physiologically acceptable composition comprising:

(a) a first agent that is a fluorinated corticosteroid conforming to Formula I or an acceptable salt thereof:

where R is H; CO(CH₂)_nCH₃, wherein n is an integer from 0 to 5; or a cycloalkane;

(b) N -acetylcysteine (NAC) or an acceptable salt thereof; and (c) a pharmaceutically or physiologically acceptable carrier or carrier system, wherein the composition is optionally formulated for topical administration.

2. The composition of claim 1 , wherein the cycloalkane is

or

3. The composition of claim 1, wherein the fluorinated corticosteroid is fluocinonide or an acceptable salt thereof.

4. The composition of claim 1 , wherein the composition further comprises:

hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclornethasone dipropionate, ciobetasol valerate, desonide, desoxymethasone, desoxvcoriicosterone acetate, dexamethasone, dichlonsone, diflorasone diacetaie, diflucort- olone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluocinonide, fiuosinolone acetomde, flucordne bulylester, fluocortolone, f3.upredni.dene (Huprednylidene) acetate, fiurandrenolone, haScmonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fiudrocortisone, difluorosone diacecate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisoiide, fluoromethalone, fluperoione, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, preunisone, beclomethasone dipropionate, triamcinolone, or tixocortol pivalate, or a pharmaceutically or physiologically acceptable salt of any one of the foregoing compounds.

5. The composition of claim 1 , wherein the first agent is present in an amount constituting from about 0.001 weight % to about 1 weight % of the total weight of the composition; the NAC or an acceptable salt thereof is present in an amount from about

1 weight % to about 20 weight % of the total weight of the composition; and/or the carrier is a sugar, a starch, a cellulose, powdered tragacanth, malt, gelatin, talc, cocoa butter or a suppository wax, an oil, a. glycol, a polyol, an ester, agar, a buffering agent, aiginic acid, pyrogen-free water, isotonic saline, or a mixture thereof.

6. The composition of claim 1 , wherein the carrier system is a solution, emulsion, gel, or solid.

7. The composition of claim 1 , wherem the composition is formulated for topical administration as a lotion, cream, oil, a stick- or bar-shaped solid, a spray, an ointment, a paste, mousse, a body wash, or a cosmetic.

8. The composition of claim .1 , further comprising coll agen, hyaluronic acid, eiastin, a hydrolysate, primrose oil, jojoba oil, epidermal growth factor or a biologically active variant thereof, a soybean saponin, a mucopolysaccharide, a vitamin, or a mixture thereof.

9. The composition of claim 1 , further comprising a non-steroidal anti-inflammatory agent, an antioxidant, a chelating agent, a retinoid, a benzofuran derivative, or a mixture thereof.

10. A pharmaceutically or physiologically acceptable composition comprising:

(a) a first agent, wherein the first agent is hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, betamethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenoione, flucioroione acetonide, fludrocortisone, flumethasone pivalate, fluocinonide, fluosinolone acetonide, flucortine butylester, fluocortoione, fluprednidene (fluprednylidene) acetate, flurandrenolone, haicinonide,

hydrocortisone acetate, hydrocortisone butyrate, methylpred isolone, triamcinolone acetonide, cortisone, cortodoxone, fiucetonide, fludrocortisone, diffuorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chioroprednisone, chforprednisone acetate, clocortelone, cleseinolone, dichlorisone, diflu- prednate, flucloromde, flunisolide, fluoromethaione, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, preunisolone, preunisone, beclomethasone dipropionate, triamcinolone, or tixocortol pivalate, or a pharmaceutically or physiologically acceptable salt of any one of the foregoing compounds;

(b) -acetyicysteine (NAC) or an acceptable salt thereof; and

(c) a pharmaceutical ly or physiologically acceptable carrier or carrier system, wherein the composition is optionally formulated for topical administration.

1 1. A method for treating a skin disorder or improving the appearance of the skin, the method comprising administering, to a patient, an effective amount of a topical composition comprising the composition of any of claims 1-10.

12. The method of claim 1 1 , wherein the patient has psoriasis,

13. The method of claim 11, wherein the patient is suffering from atopic dermatitis, eczema, disseminated superficial actinic porokeratosis, seborrheic dermatitis, allergic contact dermatitis, irritant contact demiatitis, lichen planus, or has inflamed skin due to a rash, hives, a bum, hemorrhoids, contact with poison ivy or poison oak, an insect sting, a cut, or vitiligo.

14. The method of claim 11, wherein the patient has aging skin, dry skin, itchy skin, red skin, or cracked skin.

15. The method of claim 11, wherein the patient has acquired or congenital icthyosis.

16. The method of claim 11 , wherein the patient has Netherton's syndrome, epidermolytic ichthyosis, lamellar ichthyosis, Mai de Meleda, harlequin ichthyosis, or eiythrokeratodermia variablis.

17. Use of the composition of any of claims 1-10 in the preparation of a medicament for the treatment of a skin disorder or for improving the appearance of the skin.

18. A method for treating a skin disorder or improving the appearance of the skin, the method comprising administering, to a patient, an effective amount of a topical composition comprising (a) N-acetylcysteine (NAC) or an acceptable salt thereof and (b) a pharmaceutically or physiologically acceptable carrier or carrier system, wherein the composition is optionally formulated for topical administration,

19. Use of a composition in the preparation of a mediament for the treatment of a skin disorder or for improving the appearance of the skin, wherein the composition comprises (a) N-acetylcysteine (NAC) or an acceptable salt thereof and (b) a pharmaceutically or

physiologically acceptable carrier or carrier system, wherein the composition is optionally formulated for topical administration.

20. A kit comprising the composition of any of claims 1-10 and instructions for use, wherein the ingredients of the composition are combined with one another or contained within separate containers.