Compositions and methods for topical treatment

Abstract

Provided is a method for treating a subject with a skin disorder, skin disease, or skin condition comprising topically administering a composition comprising a calcimimetic compound and a pharmaceutically acceptable carrier. Also provided is a topical composition comprising a mixture of a calcimimetic compound and a pharmaceutically acceptable carrier wherein the composition is useful to treat patients by the disclosed methods.

Description

[0001] COMPOSITIONS AND METHODS FOR TOPICAL TREATMENT

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 580,553, filed September 5, 2023, which is incorporated by reference herein in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates generally to the fields of skin cellular biology, calcium signaling pathways, and diseases, disorders, or conditions associated with the skin. More specifically, the invention relates to topical compositions and methods of treating subjects for skin disorders, skin diseases, or skin conditions with calcimimetic compounds.

[0006] BACKGROUND OF THE INVENTION

[0007] Hailey-Hailey disease (HHD) is a rare, autosomal dominant genodermatosis characterized by painful, crusted plaques and erosions favoring intertriginous skin. The disease has a relapsing-remitting course and few effective treatments.

[0008] The underlying pathophysiology of HHD is a variant of the ATP2C1 gene, which encodes the SPCA1 calcium pump on the Golgi complex. The resultant dysregulated intracellular calcium handling manifests histologically as poor cell-to-cell adhesion and acantholysis.

[0009] Improved options for treatment of HHD and other skin conditions and disorders are needed.

[0010] SUMMARY OF THE INVENTION

[0011] One aspect of the present invention provides a method of treating a skin disorder, skin disease, or skin condition in a subject (e.g., a human subject), comprising topically administering to the subject a composition comprising a therapeutically effective amount of a calcimimetic compound and a pharmaceutically acceptable carrier, thereby treating the said skin disorder, disease, or condition in the subject.

[0012] In one aspect of the present invention, the skin disorder, skin disease, or skin condition is selected from Hailey-Hailey Disease, Psoriasis, Pyoderma gangreonsum, Darier disease, erosive pustular dermatosis of the scalp, diabetic foot wounds, wound healing, erythrodermic autosomal recessive lamellar ichthyosis, nonerythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant lamellar ichthyosis, bullous congenital ichthyosiform erythroderma, palmoplantar keratosis, erythrokeratodermia variabilis, verrucous epidermal nevi, pityriasis rubra pilaris, Netherton syndrome, idiopathic vulgaris, ichthyosis vulgaris, monilethrix, keratosis piliaris, bullous ichthyosiform erythroderma, nonbullous congenital ichthyosis, Sjogren-Larsson syndrome, erythrokeratodermica variabilis, hyperkeratosis lenticularis perstans, eythrokeratodermia figurate variabilis, mutilating keratosis of Vohwinkel, Harlequin ichthyosis, and Tay's syndrome. In a particular aspect of the present invention, the skin disorder, skin disease, or skin condition is Hailey -Hailey Disease.

[0013] In one aspect of the present invention, the skin disorder, skin disease, or skin condition is unresponsive to steroid treatment.

[0014] In one aspect of the present invention, the subject is not suffering from hyperparathyroidism or parathyroid carcinoma.

[0015] In one aspect of the present invention, the carrier comprises a topical carrier. In another aspect of the present invention, the carrier is non-aqueous. In another aspect the topical carrier comprises a water-in-oil emulsion, cream, liquid, gel, oil, paste, ointment, suspension, foam, lotion, oil-in-water emulsion, water-in-oil-in-water emulsion, water-in- silicone emulsion, spray or serum carrier. In one aspect of the present invention, the topical carrier comprises a petroleum based vehicle (e.g., petrolatum).

[0016] In one aspect of the present invention, the calcimimetic compound is provided in the topical carrier in an amount of from about 0.5%, about 1%, or about 2%, to about 4%, about 5%, or about 6% by weight of the carrier. In another aspect of the present invention, the calcimimetic compound is provided in the topical carrier in an amount of about 3% by weight of the carrier.

[0017] In one aspect of the present invention, the administering to a subject comprises applying the composition to the subject on areas of the skin with erythematous plaques, hyperpigmentation, erosions, wounds, and / or inflammation.

[0018] In one aspect of the present invention, the administering to a subject comprises administering the composition on a limb, the back, and / or on the chest of the subject.

[0019] Another aspect of the present invention provides a method of stimulating the epidermal CaSR signaling pathway, promoting keratinocyte differentiation and proliferation, and / or restoring keratinocyte’ s ability to organize intercellular junctions and regulate intracellular calcium signaling, comprising topically administering to the subject an effective amount of a composition comprising a therapeutically effective amount of a calcimimetic compound and a pharmaceutically acceptable carrier.

[0020] Another aspect of the present invention provides a method of stimulating the epidermal CaSR signaling pathway, comprising topically administering to the subject a calcimimetic compound which acts as a positive allosteric modulation of the CaSR, promoting E-cadherin signaling, resulting in an assembly of cell junctions, actin reorganization, and (MAPK)- mediated keratinocyte differentiation and proliferation.

[0021] Another aspect of the present invention provides a topical composition comprising a mixture of a calcimimetic compound and a pharmaceutically acceptable carrier, which may be used to treat subjects with a skin disorder, skin disease, or skin condition.

[0022] Another aspect of the present invention provides the use of a topical composition as taught herein for treating a subject with a skin disorder, skin disease, or skin condition. In one aspect of the invention, the composition is used for treating a skin lesion. In one aspect of the invention, the composition is applied to said subject one, two, three, or four times a day. In another aspect of the present invention, the subject is treated by administering about 0.1, about 0.25, or about 0.3 gram, to about 0.5, about 0.75 or about 1 gram of the composition to the affected skin area twice a day.

[0023] In one aspect of the present invention, the composition is provided and / or packaged as a multi-dose composition. For example, the composition may be provided or packaged as a multi-dose amount of about 0.5 gram to about 50 grams.

[0024] Another aspect of the present invention provides the use of a topical composition as taught herein for treating a subject with a skin disorder, skin disease, or skin condition by applying said composition for 5, 6, 7, 8, 9, 10, 11, or 12 or more days to the affected area.

[0025] In one aspect of the present invention, the composition comprises one or more additional active agents. In another aspect of the invention, the additional active agent is an antioxidant, a sunscreen, a sun protectant, a sunblock, a skin-lightening agent, an antiinflammatory agent, an antifungal, an antibiotic, an antiseptic, an anti-acne agent, or a combination of two or more thereof.

[0026] In one aspect of the present invention, the antioxidant is vitamin E, Coenzyme Q10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol, grape seed extract, Oregon grape root (Mahonia aquifolium) extract, pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, Tocopherol, Dunaliella Salina Extract, or a combination of two or more thereof. In one aspect of the present invention, the skin-lightening agent is hydroquinone, monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol, retinoids, soy proteins, alpha-hydroxy acids, trichloroacetic acid, salicylic acid, hydroquinone-beta-D- glucopyranoside, paper mulberry, glabridin, 4-isopropylcetchol, aleosin, N-acetyl-4-S- cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexaminc acid, undecylenoyl phenylalanine, an alpha MSH antagonist, phytic acid, or a combination of two or more thereof.

[0027] In one aspect of the present invention, the anti-inflammatory agent is selected from salicylic acid, acetylsalicylic acid, methyl salicylate, aspirin, ibuprofen, naproxen, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide; leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin; and other anti-inflammatory agents including, but not limited to, methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone. The anti-inflammatory agent may also be selected from corticosteroids, such as, but not limited to, flurandrenolide, clobetasol propionate, halobetasol propionate, fluticasone propionate, betamethasone dipropionate, betamethasone benzoate, betamethasone valerate, desoximethasone, dexamethasone, diflorasone diacetate, mometasone furoate, amcinodine, halcinonide, fluocinonide, fluocinolone acetonide, desonide, triamcinolone acetonide, hydrocortisone, hydrocortisone acetate, fluoromethalone, prednisone, methylprednisolone, and predinicarbate.

[0028] In one aspect of the present invention, the ani-acne agent is one or more selected from the group consisting of salicylic acid; 5-octanoyl salicylic acid; resorcinol; retinoids such as retinoic acid and its derivatives; sulfur-containing D and L amino acids other than cysteine; lipoic acid; antibiotics and antimicrobials such as benzoyl peroxide, octopirox, tetracycline, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorobanilide, azelaic acid, phenoxyethanol, phenoxypropanol, phenoxisopropanol, ethyl acetate, clindamycin and melclocycline; flavonoids; and bile salts such as scymnol sulfate, deoxycholate and cholate.

[0029] In one aspect of the present invention, the composition further comprises one or more of a solvent, a film former, a preservative, a viscosity increasing agent, a fragrance, a surfactant, a chelating agent, a humectant, a permeation enhancer, and an excipient In one aspect of the present invention, use of the composition results in re- epithelialization of the affected area.

[0030] In one aspect of the present invention, use of the composition decreases the level of erythematous plaques or hyperpigmentation in a subject by about 5%, by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, by about 90%, or by about 100%.

[0031] BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG. 1A and FIG. IB show before and after treatment images, respectively, of a large, crusted, erythematous plaque present on the patient’s right lateral chest. The patient noted complete resolution of the lesion with only residual hyperpigmentation after five days of twice- daily application of cinacalcet. This photograph was taken seventeen days after the patient noted resolution of the lesion (twenty-seven days after the FIG. 1 A photograph was taken).

[0033] FIG. 2 is a schematic of calcium-sensing receptor (CaSR) calcium signaling in keratinocytes, and portrays on the left side that keratinocytes in Hailey-Hailey Disease demonstrate acantholysis, actin stress fibers, and cytoplasmic dissolution of adherens junction (AJ) and desmosome components. Without wishing to be bound by theory, the right side of the figure depicts the proposed action mechanism of cinacalcet. Positive allosteric modulation of the CaSR promotes E-cadherin signaling, resulting in an assembly of cell junctions, actin reorganization, and mitogen-activated protein kinase (MAPK)-mediated keratinocyte differentiation proliferation. The CaSR and SPCA1 interact with each other at the trans-Golgi network.

[0034] DETAILED DESCRIPTION OF EMBODIMENTS

[0035] The present invention now will be described hereinafter with reference to the accompanying drawings and examples, in which embodiments of the invention are shown. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. Thus, the invention contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention. Hence, the following descriptions are intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations, and variations thereof.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0037] All publications, patent applications, patents and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and / or paragraph in which the reference is presented.

[0038] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a composition comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0039] As used in the description of the invention and the appended claims, the singular forms "a," "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0040] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0041] The term "about" as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified value as well as the specified value. For example, "about X" where X is the measurable value, is meant to include X as well as variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of X. A range provided herein for a measurable value may include any other range and / or individual value therein. The term "comprise," "comprises" and "comprising" as used herein, specify the presence of the stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0042] As used herein, the term "therapeutically effective amount" or "effective amount" can refer to that amount of a pharmaceutical composition that results in amelioration of symptoms (e.g., reduction in skin plaques, erosions, lesions, or wounds) in a subject. A therapeutically relevant effect relieves to some extent one or more symptoms of a disease or condition or returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or condition.

[0043] As used herein, the terms "treating" or "treatment" of a condition or disease can include: (1) inhibiting the disease or condition, i.e., arresting, delaying or reducing the development of the disease or condition and its symptoms; or (2) relieving the disease or condition, i.e., causing regression of the disease or condition and its clinical symptoms.

[0044] As used herein, the terms "subject" and "patient" are used interchangeably herein and refer to both human and nonhuman animals. A subject of this invention can be any subject that is susceptible to a disorder that can benefit by the methods and compositions of the present invention and / or can be treated for a disorder by the methods and compositions of the present invention. In some embodiments, the subject of any of the methods of the present invention is a mammal. The term "mammal" as used herein includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, and the like), etc. Human subjects include neonates, infants, juveniles, and adults. As a further option, the subject can be a laboratory animal and / or an animal model of disease. In some preferred embodiments, the subject is a human. The subject may be of any gender, any ethnicity and any age.

[0045] The term "administering" or "administered" as used herein is meant to include topical, parenteral and / or oral administration, all of which are described herein. Parenteral administration includes, without limitation, intravenous, subcutaneous and / or intramuscular administration (e.g., skeletal muscle or cardiac muscle administration). It will be appreciated that the actual method and order of administration will vary according to, inter alia, the particular preparation of compound(s) being utilized, and the particular formulation(s) of the one or more other compounds being utilized. The optimal method and order of administration of the compositions of the invention for a given set of conditions can be ascertained by those skilled in the art using conventional techniques and in view of the information set out herein. In some preferred embodiments, the composition is topically administered to the patient.

[0046] The term “topically administering” or “topically administered” refers to applying the composition directly to an area of the body such as the skin (e.g., to the affected area of the skin).

[0047] In accordance with good clinical practice, the compounds / compositions can be administered at a dose that will produce effective beneficial effects without causing undue harmful or untoward side effects, i.e., the benefits associated with administration outweigh the detrimental effects. In some embodiments, more than one administration e.g., two, three, four or more administrations) by one or more same and / or different routes of administration, may be employed to achieve the desired level of effect (e.g., a therapeutically effective amount) over a period of various intervals, e.g., daily, weekly, monthly, yearly, etc.

[0048] The term "pharmaceutically acceptable" as used herein means that the compound, carrier, or composition is suitable for administration to a subject to achieve a treatment described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.

[0049] The term “calcimimetic compound” as used herein refers to a compound that may act as a positive allosteric modulator of the epidermal Calcium-sensing receptor (CaSR) on the plasma membrane, Golgi, and endoplasmic reticulum of keratinocytes. CaSRs located on keratinocytes regulate intracellular calcium signaling, keratinocyte differentiation, and form complexes with calcium-regulating proteins and the SPCA1 pump on the Golgi. “Calcimimetic compound” includes, but is not limited to:

[0050] Cinacalcet;

[0051] Etelcalcetide;

[0052] NPS 467 (N-(3 -phenylpropyl)- 1 -(3 -methoxyphenyl)ethylamine);

[0053] NPS 568 (N-(3-(2-chlorophenyl)propyl)-l-(3-methoxyphenyl)ethylamine);

[0054] 4M (N-(3 -(2-fluorophenyl)propyl)- 1 -(3 -methoxyphenyl)ethylamine);

[0055] 4N / 40) (N-(3-(3-fluorophenyl)propyl)-l-(3-methoxyphenyl)ethylamine);

[0056] 4P / 4Q (N-(3-(4-fluorophenyl)propyl)-l-(3-methoxyphenyl)ethylamine);

[0057] 4V (N-(3-(2-(trifluoromethyl)phenyl)propyl)-l-(3-methoxyphenyl)ethylamine);

[0058] 4W (N -(3 -(3 -(trifluoromethyl)phenyl)propyl)- 1 -(3 -methoxyphenyl)ethylamine); and

[0059] 6X / 6Y (N-(3-(3-chlorophenyl)propyl)-l-(3-methoxyphenyl)ethylamine); or a pharmaceutically acceptable salt thereof. See, e.g. US Patent No. 6,031,003. Without wishing to be bound by theory, the calcimimetic compound binding may promote interaction between CaSR on the Golgi membrane and the SPCA1 calcium pump, which may restore keratinocytes’ ability to organize intercellular junctions, and may promote keratinocyte differentiation and proliferation, thereby altering dysfunctional calcium signaling.

[0060] The term “Cinacalcet” as used herein refers to a calcimimetic compound that has the empirical formula C22H22F3N and has the structural formula: may be provided as a pharmaceutically acceptable salt (e.g., hydrochloride salt).

[0061] Cinacalcet increases the calcium-sensing receptors’ sensitivity, allowing activation by extracellular calcium. Currently, cinacalcet is used for treating patients with chronic kidney disease on dialysis who have secondary hyperparathyroidism and patients with parathyroid carcinoma who have hypercalcemia. See, e.g., US Patent No. 8,183,415 B2. In one aspect of the present invention, the subject is not suffering from hyperparathyroidism or parathyroid carcinoma.

[0062] The term “pharmaceutically acceptable carrier” as used herein refers to any type of vehicle suitable for aiding in administration of a compound of the invention to the patient. A suitable pharmaceutically acceptable carrier for a topical composition may include, but is not limited to, ointments, salves, gels, creams, lotions, sprays, shampoos, patches, or foams as is generally known by those in the art. In some embodiments, the carrier is a petroleum-based vehicle (e.g., petrolatum). In some embodiments, the carrier is non-aqueous.

[0063] “Cosmetically acceptable” means suitable for cosmetic applications, including topical application of the compositions disclosed herein in the absence of significant adverse side effects upon application of the composition or compounds disclosed herein. Other applications include skin care applications, including but not limited to lotions, cream, cleansing creams or lotions, soaps and other cleansers, antiperspirant and / or deodorants, makeup products, such as face powders, foundations, rouge, eye shadow, mascara, eyeliner or lipstick, sun protection products, such as sunscreen or other UV-protective cosmetics, lotions or creams, hairdressing products, such as shampoo, rinses, or treatment setting agents. The phrases “pharmaceutically acceptable” and “cosmetically acceptable” are not meant to imply mutual exclusiveness in all applications. In some embodiments, a composition may be both “pharmaceutically acceptable” and “cosmetically acceptable,” dependent upon the need and course of action of the compositions disclosed herein.

[0064] “Pharmaceutically acceptable salt” refers to a salt of a compound disclosed herein that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l -carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-m ethylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. In some embodiments, a “pharmaceutically acceptable salt” may also be used in conjunction with cosmetically acceptable compositions.

[0065] “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a disclosed compound is administered. In some embodiments, a “pharmaceutically acceptable vehicle” may also be used in conjunction with cosmetically acceptable compositions.

[0066] The term “skin disorder, skin disease, or skin condition” as used herein is meant to include, without limitation, any infections or conditions associated with and / or exhibiting physiological signs and symptoms including keratinization skin disorders, erythematous or painful plaques, erosions, wounds, lesions, or inflammation of the skin. Skin disorders, diseases, or conditions include, but are not limited to, Hailey-Hailey Disease, Psoriasis, Pyoderma gangreonsum, Darier disease, erosive pustular dermatosis of the scalp, diabetic foot wounds, wound healing, erythrodermic autosomal recessive lamellar ichthyosis, nonerythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant lamellar ichthyosis, bullous congenital ichthyosiform erythroderma, palmoplantar keratosis, erythrokeratodermia variabilis, verrucous epidermal nevi, pityriasis rubra pilaris, Netherton syndrome, idiopathic vulgaris, ichthyosis vulgaris, monilethrix, keratosis piliaris, bullous ichthyosiform erythroderma, nonbullous congenital ichthyosis, Sjogren-Larsson syndrome, erythrokeratodermica variabilis, hyperkeratosis lenticularis perstans, eythrokeratodermia figurate variabilis, mutilating keratosis of Vohwinkel, Harlequin ichthyosis and Tay's syndrome.

[0067] In some embodiments, the skin disorder, skin disease, or skin condition is unresponsive to steroid treatment.

[0068] In some embodiments, the subject is not suffering from hyperparathyroidism or parathyroid carcinoma.

[0069] In some embodiments, topical administration of the calcimimetic compound reduces erythematous plaques or hyperpigmentation by about 10%, by about 15%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, by about 50%, by about 55%, by about 60%, by about 65%, by about 70%, by about 75%, by about 80%, by about 85%, by about 90%, by about 95% or by about 100%.

[0070] In some embodiments, use of the topical composition reduces erythematous plaques or hyperpigmentation by about 10%, by about 15%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, by about 50%, by about 55%, by about 60%, by about 65%, by about 70%, by about 75%, by about 80%, by about 85%, by about 90%, by about 95% or by about 100%.

[0071] The term “non-aqueous composition” as used herein is meant a composition which is effectively free of water and does not contain water that has been deliberately added. A “nonaqueous composition” as used herein preferably has less than 0.5% by weight of water based on the total weight of the composition, more preferably less than 0.2% by weight of water, most preferably less than 0.1% by weight of water based on the total weight of the composition.

[0072] The term “substantially non-aqueous” as used herein refers to a composition comprising less than 5% by weight, more preferably less than 4.5% by weight, of water based on the total weight of the composition.

[0073] The term “aqueous composition” is meant a composition comprising at least 5% by weight of water based on the total weight of the composition. Preferably, the aqueous composition comprises at least 10%, or at least 15% by weight of water based on the total weight of the composition. The aqueous composition may comprise at least 35%, or at least 40% by weight based on the total weight of the composition. For aqueous compositions, preferably the percentage of water is from 5% to 90% by weight, and more preferably from 5% to 50% by weight and most preferably from 8% to 20% by weight based on the total weight of the composition.

[0074] In one embodiment of the present invention there is provided an aqueous composition suitable for topical application comprising a continuous phase and at least one discontinuous phase, said composition comprising at least one polyaphron dispersion, at least one calcimimetic compound and optionally at least one additional active agent such as a corticosteroid. In this embodiment preferably the composition comprises at least 5%, more preferably at least 6%, more preferably still at least 8% by weight of water based on the total weight of the composition.

[0075] In some embodiments, the aqueous composition suitable for topical application comprises from 60 to 95% by weight of discontinuous phase, and from 5 to 40% by weight of continuous phase based on the total weight of the composition, wherein preferably the composition comprises from 5 to 40%, or from 5 to 30%, or from 8 to 20% by weight of water based on the total weight of the composition, wherein discontinuous phase and / or the continuous phase comprise at least one calcimimetic compound and optionally at least one additional active agent such as a corticosteroid and at least one surfactant. In one embodiment, the aqueous composition suitable for topical application comprises from 70 to 90% by weight of discontinuous phase, and from 10 to 30% weight of continuous phase based on the total weight of the composition, wherein preferably the composition comprises at least from 5 to 30%, or from 8 to 20% by weight of water based on the total weight of the composition, wherein discontinuous phase and / or the continuous phase comprise at least one calcimimetic compound and optionally at least one additional active agent such as a corticosteroid and at least one surfactant.

[0076] In some embodiments, the concentration of the calcimimetic compound in the topical compositions comprising the calcimimetic compound are about 0.01%, 0.03%, 0.05%, 0.08%, 0.1%, 0.25%, 0.5%, 1%, 2%, 3%, 4% , 5% , 6%, 7%, 8%, 9% or 10% w / w. In some embodiments, concentrations in the topical compositions of this invention are about 0.1%, about 1%, about 2% or about 3% w / w of the calcimimetic compound, about 5% of the calcimimetic compound, about 10% the of the calcimimetic compound, or higher. In another embodiment, the concentration of the calcimimetic compound is from 0.01% or 0.1% to 10% or 15% w / w; from 0.1%, 0.5% or 1.5% w / w to 2%, 3% or 5% w / w; or from 1%, 3% or 5% to 8%, 10% or 15% w / w.

[0077] In some embodiments, the frequency of administration is once daily, twice daily, weekly, bi-weekly or monthly. In one embodiment, administration frequencies of the topical compositions of this invention are once daily or twice daily.

[0078] In some embodiments, frequency of administration can be gradually decreased over time and maintained at a steady dose suitable for long-term — six months, 1 year, 5 years, 10 years or more, up to lifelong administration to control the symptoms of a skin disease. For example, dosage administration can begin at from twice a day, to once a day, to two times a week, to once a week, to once every two weeks or less frequent than once every two weeks.

[0079] In some embodiments, the pharmaceutical carriers or vehicles suitable for preparation of the compositions provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. In some embodiments, the resulting composition may be a lotion, a solution, a suspension, an emulsion or the like and is formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, sprays, patches, foams, sebum control products or any other formulation suitable for topical administration. The preferred compositions are the cream, the lotion, the gel and the foam.

[0080] Kits containing the compositions of this invention, optionally including instructions for administration are provided. Additionally, provided herein are kits containing the abovedescribed combinations and optionally instructions for administration by topical, transdermal, or other routes, depending on the single composition or two separate compositions to be delivered.

[0081] The compositions provided herein can be packaged as articles of manufacture containing packaging material, a composition provided herein, and a label that indicates that the composition is for treating a skin disease and is formulated for topical delivery. In one aspect of the present invention, the composition is provided and / or packaged as a multi-dose composition.

[0082] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. Examples of pharmaceutical packaging materials include, but are not limited to bottles, tubes, containers, application syringes or dual chamber application syringes and any packaging material suitable for the selected formulation and intended mode of administration and treatment. In some embodiments, the composition further comprises an additional active ingredient. Suitable active ingredients include, but are not limited to botanicals, nutraceuticals, cosmeceuticals, therapeutics, pharmaceuticals, antimicrobials, steroidal hormones, antidandruff agents, anti -acne components, sunscreens, sunblocks, sun protectants, antibiotics, antivirals, antifungals, steroids, antiseptics, analgesics, antitumor drugs, skin conditioning agents, etc.

[0083] In a further embodiment, also included are topical formulations that comprise a composition for cosmetic or dermatological use, which composition comprises a cosmetically and / or dermatologically effective amount of the combination stated above, wherein the like acting agent is a cosmetically active agent. More particularly, the like-acting agent is a skin lightening or skin bleaching compound. In some embodiments, the skin lightening or skin bleaching compound is hydroquinone, kojic acid, ascorbic acid, magnesium ascorbyl phosphate or ascorbyl glucosamine, or mixtures thereof.

[0084] In another embodiment of the combination described above, the additional pharmaceutical or cosmetic agent is a skin care active agent. In some embodiments, the skin care active agent is an abrasive, an absorbent, an astringent, an aesthetic component, such as fragrances, pigments, colorings / colorants, essential oils, skin sensates, astringents and other aesthetic components, an antioxidant, a free-radical scavenging agent, a reducing agent, a sequestrant, a skin bleaching or lightening agent, a skin conditioning agent, for example humectants and emollients, a skin soothing agent, a skin healing agent, such as pathenol and derivatives, aloe vera, pantothenic acid, allantoin, bisbolol, dipotassium glycyrrhizinate, skin treating agents, vitamins and derivatives, such as a retinoid, or mixtures thereof. In some embodiments, the retinoid is retinol, retinal, retinol esters, retinyl propionate, retinoic acid, retinyl palmitate, or mixtures thereof.

[0085] In other embodiments, the composition comprises one or more anti oxi dant(s). Nonlimiting examples of antioxidants include niacinamide, vitamin E, Coenzyme Q10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol, genistein, and pycnogenol. Other embodiments include phenols and phenolic acids (guaiacol, hydroquinone, vanillin, gallic acids and their esters, protocatechuic acid, quinic acid, syringic acid, ellagic acid, salicylic acid, nordihydroguaiaretic acid (NDGA), eugenol); curcumins, tocopherols (including tocopherols (alpha, beta, gamma, delta) and their derivatives, such as tocopheryl-acylate (e.g., -acetate, - laurate, myristate, -palmitate, -oleate, -linoleate, etc., or an y other suitable tocopheryl-lipoate), tocopheryl-POE-succinate; Dunaliella Salina Extract; trolox and corresponding amide and thiocarboxamide analogues; ascorbic acid and its salts, isoascorbate, alkylascorbic acids, ascorbyl esters (e.g., 6-o-lauroyl, myristoyl, palmitoyl-, oleoyl, or linoleoyl-L-ascorbic acid, etc.). Also useful are oxidized compounds, such as sodium bisulphite, sodium metabisulphite, thiourea; chelating agents, such as EDTA (e.g., disodium EDTA), EGTA, desferral; transferrin, lactoferrin, ferritin, cearuloplasmin, haptoglobion, heamopexin, albumin, glucose, ubiquinol- 10; enzymatic antioxidants, such as superoxide dismutase and metal complexes with a similar activity, including catalase, glutathione peroxidase, and less complex molecules, such as betacarotene, bilirubin, uric acid; flavonoids (flavones, flavonols, flavonones, flavanonals, chacones, anthocyanins), N-acetylcystein, mesna, glutathione, thiohistidine derivatives, triazoles; tannines, cinnamic acid, hydroxycinnamatic acids and their esters (coumaric acids and esters, caffeic acid and their esters, ferulic acid, (iso-)chlorogenic acid, sinapic acid). Also included are extracts, including but not limited to plant extracts or cell extracts containing antioxidants, including grape seed extract, pomegranate extract, spice extracts (e.g., from clove, cinnamon, sage, rosemary, mace, oregano, allspice, nutmeg); oat flour extracts, such as avenanthramide 1 and 2; thioethers, dithioethers, sulphoxides, tetralkylthiuram disulphides and extracts from other plant derived material. Also included is carnosic acid, carnosol, carsolic acid; rosmarinic acid, rosmaridiphenol, gentisic acid, ferulic acid; phytic acid, steroid derivatives (e.g., U74006F); tryptophan metabolites (e.g., 3 -hydroxy kynurenine, 3- hydroxyanthranilic acid), and organochalcogenides.

[0086] In other embodiments, the composition comprises at least one additional skin lightening agent. Non-limiting examples of skin-lightening agents are selected from the group of hydroquinone, licorice extract (e.g., Glycyrrhiza Glabra (licorice) root extract), an alpha MSH antagonist (e.g. undecylenoyl phenylalanine), phytic acid, monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol, retinoids (e.g., tretinoin, adapalene), soy proteins, alpha-hydroxy acids (e.g., glycolic acid), trichloroacetic acid, salicylic acid, hydroquinone-beta-D-glucopyranoside, paper mulberry, glabridin, 4-isopropylcetchol, aleosin, N-acetyl-4-S-cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, and tranexaminc acid.

[0087] In other embodiments, the composition comprises at least one botanical ingredient and / or extract. Non-limiting examples of botanical extracts are selected from the group arbutin, alpha-arbutin, deoxyarbutin, aloesin, flavonoids, isoflavones (e.g., 6,7,4'-trihydroxyisoflavone, glycitein, daidzein, genistein), flavonones (e.g., hesperidin, eriodictyol, and naringenin), flavonols, p-coumaric acid, gentisic acid, licorice extracts (e.g., glabridin, liquiritin, glabrene, isoliquiritigenin licuraside, isoliquiritin, licochalcone A), niacinamide, yeast derivatives, polyphenols, (e.g., proanthocyanidins, procyanidins, ellagic acid), ammonium glycyrrhizinate, icariin, piceid, salidroside, epigallocatechin-3 -gallate, glycyrrhiza cinnamic aid, cinnamic acid, sophorcarpidine, aloe vera extract, alaria esculenta extract, alfalfa extract, algae extract, althaea extract, angelica extract, apple extract, arnica extract, ascorbyl palmitate, avocado oil, babassu palm tree fruit, balm mint extract, bamboo extract, bergamot oil, betula extract, bilberry, birch leaf extract, bisabolol, blackcurrant extract, black raspberry seed oil, bladderwrack extract, blue-green algae, blue malva extract, borage seed oil, boswellia serrata, buddleja davidii extract, buckthorn, buckwheat seed extract, burdock root extract, burdock, butcher's broom, calendula, calendula extract, camellia oil, capsaicin, carrageenan extract, carrot extract, cascara sagrada, castor oil, cayenne, cedarwood, chamomile, chamomile extract, chamomile oil, chaparral extract, chaste tree berry extract, chia seed oil, chickpea seed extract, chlorella, chrysanthellis, cinnamon bark, citrus extract, clover, clover blossom extract, clover extract, clover flower oil, cocoa extract, cocoa seed butter, codonopsis, coleus forskohlli, coriander, corn oil, cottonseed oil, couch grass, crambe abyssinica seed extract, cranberry protein, crithmum maritimum extract, cupuacu, cypress oil, dandelion, dandelion extract, dong quai, Dunaliella Salina extract, Echinacea angustifolia purpurea, echium plantagineum, elderberry, esculin, eucalyptus, evening primrose oil, fennel, ferula foetida root extract, flaxseed oil, fucoidan extract, garcinia cambogia, garlic, geranium extract, geranium oil, ginger, ginger root extract, ginkgo biloba, ginseng, ginseng extract, glucosamine, golden seal extract, gotu kola, grapefruit extract, grapeseed, grapeseed extract, grapeseed oil, green tea, green tea extract, guarana, guggul gum extract, gymnesa Sylvestre, hazel oil, hawthorn, holarrhena antidysenterica extract, honeysuckle extract, hops extract, horse chestnut, horsetail extract, hybrid safflower oil, hydrolyzed soy protein, imperata cylindrical root extract, ivy leaf extract, jasmine oil, jojoba oil, juniper oil, kelp, kiwi seed fruit oil, kukui nut oil, lactic acid, lactospore, laminaria digitata, lavandin oil, lavender, lavender oil, lavender extract, L-carnitine, lecithin, lemon balm, lemon extract, lemon fruit extract, lemon oil, lemon verbena botanical plant essence, lemongrass extract, licorice extract (e.g., Glycyrrhiza Glabra (licorice) root extract), lime oil, linden extract, lycium barbarum fruit extract, lysate extract, lysine, maca root, macadamia oil, magnesium ascorbyl phosphate, Mahonium aquifolium (Oregon grape root) extract, maitake extract, mallow extract, maracuja, marrubium vulgare extract, marshmallow, manila oil, matricaria oil, meadowsweet. Melissa extract, menthol, milk thistle, moms alba root extract, mulberry extract (e.g., mulberroside F, gallic acid, quercetin, linoleic acid, palmitic acid), nettle extract, nettle root, nori sea lettuce, nutmeg oil, oat amino acids, oat extract, oat kernel meal, oligophycocorail (sea algae) extract, olive oil, olive leaf extract, squalene (e.g., olive squalen), orange blossom, orange oil, orange fruit extract, orange peel extract, orchid extract, panax ginseng extract, pansy extract, panthenol, papaya enzyme, passion fruit oil, patchouli oil, pea extract, pea protein, peach extract, peanut oil, pecan oil, pepper, peppermint, peppermint oil, perilla seed oil, pine leaf oil, pineapple enzyme, plankton extract, plantain extract, polygonum fagopyrum seed extract, pomegranate extract, pomegranate seed oil, portulaca extract, psyllium, pumpkin seed oil, raspberry extract, red clover, red clover extract, red marine algae extract, reishii, resveratrol, retinyl palmitate, rice bran oil, rhodiola, rhubarb, rice protein, Rosa roxburghii fruit extract, rose geranium botanical plant essence, rosehip extract, rosemary, sccharomyces boulardii, safflower oil, sage, sage extract, sambucus Canadensis extract, sandalwood, turmeric (Curcuma longa root) extract, Bulbine frutescens extract, Bulbine frutescens gel, and phytessence wakame (sea kelp).

[0088] In yet other embodiments, the composition comprises at least one sunscreen, sun protectant or sunblock agent. Such agents may be classified into five groups based upon their chemical structure: para-amino benzoates; salicylates; cinnamates; benzophenones; and miscellaneous chemicals including menthyl anthralinate and digalloyl trioleate. Inorganic sunscreens may also be used including titanium dioxide, zinc oxide, iron oxide and polymer particles such as those of polyethylene and polyamides. Specific suitable sunscreen agents include, for example: p-aminobenzoic acid, its salts and its derivatives (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); Anthranilates (i.e., o-aminobenzoates; methyl, menthyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters); Salicylates (amyl, phenyl, benzyl, menthyl, glyceryl, and dipropylene glycol esters); Cinnamic acid derivatives (methyl and benzyl esters, alpha-phenyl cinnamonitrile; butyl cinnamoyl pyruvate); Dihydroxycinnamic acid derivatives (umbelliferone, methylumbelliferone, methylaceto- umbelliferone); Trihydroxycinnamic acid derivatives (esculetin, methylesculetin, daphnetin, and the glucosides, esculin and daphnin); Hydrocarbons (diphenylbutadiene, stilbene); Dib enzal acetone and benzalacetophenone; Naphtholsulfonates (sodium salts of 2-naphthol- 3,3-disulfonic and of 2-naphthol-6,8-disulfonic acids); Dihydroxynaphthoic acid and its salts; o- and p-Hydroxybiphenyldisulfonates; Coumarin derivatives (7-hydroxy, 7-methyl, 3- phenylyll); Diazoles (2-acetyl-3 -bromoindazole, phenyl benzoxazole, methyl naphthoxalole, various aryl benzothiazoles); Quinine salts (bisulfate, sulfate, chloride, oleate, and tannate); quinoline derivatives (8-hydroxyquinoline salts, 2-phenylquinoline); Hydroxy- or methoxy substituted benzophenones; Uric and vilouric acids; Tannnic acid and its derivatives (e.g., hexaethyl ether); (Butyl carbityl) (6-propyl piperonyl)ether; Hydroquinone; Benzophenones (Oxybenzene, Sulisobenzone, Dioxybenzone, Benzoresorcinol, 2, 2', 4,4'-

[0089] Tetrahydroxybenzophenone, 2,2'-Dihydroxy-4,4'-dimethoxybenzophenone, Octabenzone; 4- Isopropyhldibenzoylmethane; Butylmethoxydibenzoylmethane; Etocrylene; and 4-isopropyl- di-benzoylmethane; titanium dioxide, iron oxide, zinc oxide, and mixtures thereof. Other cosmetically-acceptable sunscreens and concentrations (percent by weight of the total cosmetic sunscreen composition) include diethanolamine methoxy cinnamate (10% or less), ethyl- [bis(hydroxypropyl)]aminobenzoate (5% or less), glyceryl aminobenzoate (3% or less), 4- isopropyl dibenzoylmethane (5% or less), 4-methylbenzylidene camphor (6% or less), terephthalylidene dicamphor sulfonic acid (10% or less), and sulisobenzone (also called benzophenone-4, 10% or less). Yet other cosmetically-acceptable sunscreens and concentrations (reported as a percentage by weight of the total cosmetic sunscreen composition, and referring to the final percentage of the sunscreen) include: aminobenzoic acid (also called para-aminobenzoic acid and PABA; 15% or less; a UVB absorbing organic sunscreen), avobenzone (also called butyl methoxy dibenzoylmethane; 3% or less, a UVA I absorbing organic sunscreen), cinoxate (also called 2-ethoxyethyl p-methoxycinnamate; 3% or less, a UVB absorbing organic sunscreen), dioxybenzone (also called benzophenone-8; 3% or less, a UVB and UVA II absorbing organic sunscreen), homosalate (15% or less, a UVB absorbing organic sunscreen), menthyl anthranilate (also called menthyl 2-aminobenzoate; 5% or less, a UVA II absorbing organic sunscreen), octocrylene (also called 2-ethylhexyl-2-cyano-3,3 diphenylacrylate; 10% or less, a UVB absorbing organic sunscreen), octyl methoxy cinnamate (7.5% or less, a UVB absorbing organic sunscreen), octyl salicylate (also called 2-ethylhexyl salicylate; 5% or less, a UVB absorbing organic sunscreen), oxybenzone (also called benzophenone-3; 6% or less, a UVB and UVA II absorbing organic sunscreen), padimate O (also called octyl dimethyl PABA; 8% or less, a UVB absorbing organic sunscreen), phenylbenzimidazole sulfonic acid (water soluble; 4% or less, a UVB absorbing organic sunscreen), sulisobenzone (also called benzophenone-4; 10% or less, a UVB and UVA II absorbing organic sunscreen), titanium dioxide (25% or less, an inorganic physical blocker of UVA and UVB), trolamine salicylate (also called triethanolamine salicylate; 12% or less, a UVB absorbing organic sunscreen), and zinc oxide (25% or less, an inorganic physical blocker of UVA and UVB).

[0090] In still other embodiments, the composition comprises at least one anti-acne agent. Suitable anti-acne agents may include salicylic acid; 5-octanoyl salicylic acid; resorcinol; retinoids such as retinoic acid and its derivatives; sulfur-containing D and L amino acids other than cysteine; lipoic acid; antibiotics and antimicrobials such as benzoyl peroxide, octopirox, tetracycline, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorobanilide, azelaic acid, phenoxyethanol, phenoxypropanol, phenoxisopropanol, ethyl acetate, clindamycin and melclocycline; flavonoids; and bile salts such as scymnol sulfate, deoxycholate and cholate.

[0091] In yet still other embodiments, the composition comprises at least one antiinflammatory agent. Suitable anti-inflammatory agents include, but are not limited to, nonsteroidal anti-inflammatory drugs such as salicylic acid, acetylsalicylic acid, methyl salicylate, aspirin, ibuprofen, naproxen, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide; leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin; and other anti-inflammatory agents including, but not limited to, methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone. Additional anti-inflammatories useful in topical applications include corticosteroids, such as, but not limited to, flurandrenolide, clobetasol propionate, halobetasol propionate, fluticasone propionate, betamethasone dipropionate, betamethasone benzoate, betamethasone valerate, desoximethasone, dexamethasone, diflorasone diacetate, mometasone furoate, amcinodine, halcinonide, fluocinonide, fluocinolone acetonide, desonide, triamcinolone acetonide, hydrocortisone, hydrocortisone acetate, fluoromethalone, prednisone, methylprednisolone, and predinicarbate.

[0092] In yet still other embodiments, the composition comprises at least one skin conditioning agents. Suitable skin conditioning agents include, but are not limited to, butylene glycol and ethylhexylglycerin.

[0093] In one embodiment, the composition contains one or more of the following additional active ingredients: Retinol, Niacinamide, Tetrahexyl decyl Ascorbate, Licorice root extract, Resorcinol, and ethyl linoleate. In another embodiment, the composition comprises from about 0.1% to about 0.75%, from about 0.05% to about 1.0%, or from about 0.01% to about 2% Retinol. In another embodiment, the composition comprises from about 2.0% to about 8.0%, from about 1% to about 10%, or from about 0.5% to about 15.0% Niacinamide. In another embodiment, the composition comprises from about 1.0% to about 5.0%, from about 0.5% to about 8.0%, or from about 0.1% to about 15% Tetrahexyldecyl Ascorbate. In another embodiment, the composition comprises from about 0.001% to about 0.5%, from about 0.0005% to about 1.0% or from about 0.0001% to about 2% Licorice root extract. In another embodiment, the composition comprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01% to about 10.0% Resorcinol. In another embodiment, the composition comprises from about 0.1% to about 3.0%, from about 0.05% to about 5.0%, or from about 0.01% to about 10.0% ethyl linoleate.

[0094] One aspect of the disclosed embodiments extends to a formulation that comprises a combination of a calcimimetic compound, additional active agent(s), and a carrier. In some embodiments, the active agent is selected from an antioxidant or a skin-lightening agent. In specific embodiments, the calcimimetic compound and active agents are administered in the form of a pharmaceutical or cosmetic composition. Such compositions can be prepared by procedures well known in the pharmaceutical and cosmetic arts. The compositions disclosed herein can contain a cosmetically or pharmacologically acceptable carrier. Such carriers are compatible with skin, nails, mucous membranes, tissues and / or hair, and can include any conventionally used cosmetic or pharmacological carrier. The compositions disclosed herein can be in any form suitable for topical application, including aqueous, aqueous-alcoholic or oily solutions, lotion or serum dispersions, aqueous, anhydrous or oily gels, emulsions obtained by dispersion of a fatty phase in an aqueous phase (O / W or oil in water) or, conversely, (W / O or water in oil), microemulsions or alternatively microcapsules, microparticles or lipid vesicle dispersions of ionic and / or nonionic type. These compositions can be prepared according to conventional methods. Other than the agents disclosed, the amounts of the various constituents of the compositions are those conventionally used in the art. These compositions in particular constitute protection, treatment or care creams, milks, lotions, gels or foams for the face, for the hands, for the limbs, for the back, for the chest, for the body and / or for the mucous membranes, or for cleansing the skin. The compositions can also consist of solid preparations constituting soaps or cleansing bars.

[0095] In some embodiments, the compositions disclosed herein are administered in an effective amount to treat a skin disorder, skin disease, or skin condition. Examples of routes of administration include, but are not limited to, oral, buccal, inhalation, intradermal, subcutaneous, transmucosal, transdermal, or topical administration. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0096] Pharmaceutically or cosmetically appropriate vehicles for such formulations include, for example, lower aliphatic alcohols, polyglycols (e.g., glycerol or polyethylene glycol), esters of fatty acids, oils, fats, silicones, and the like. Such preparations can also include preservatives (e.g., p-hydroxybenzoic acid esters) and / or antioxidants (e.g., ascorbic acid and tocopherol). See also Dermatological Formulations Percutaneous absorption, Barry (Ed.), Marcel Dekker Incl, 1983.

[0097] In other embodiments, the composition further comprises at least one of water, a preservative, a surfactant, an emulsifier, a conditioner, an emollient, a wax, an oil, a polymer, a thickener (viscosity increasing agent), a fixative, a colorant, a humectant, a moisturizer, a stabilizer, a diluent, a solvent and a fragrance.

[0098] In one embodiment, the composition further comprises at least one preservative. Suitable preservatives include, but are not limited to, potassium sorbate, acids, alcohols, glycols, parabens, quatemary-nitrogen containing compounds, isothiazolinones, aldehyde- releasing compounds and halogenated compounds. Illustrative alcohols include phenoxyethanol, isopropyl alcohol, and benzyl alcohol; illustrative glycols include propylene, butylene and pentylene glycols; illustrative parabens include (also known as parahydroxybenzioc acids) methyl, propyl and butyl parabens; illustrative quaternary nitrogen containing compounds include benzalkonium chloride, Quartenium 15; illustrative isothiazoles include methylisothiazoline, methychlorolisothiazoline; illustrative aldehyde releasing agents include DMDM hydantion, imiadolidinyl urea and diazolidinyl urea; illustrative antioxidants include butylated hydroxytoluene, tocopherol and illustrative halogenated compounds include triclosan and chlorohexidene digluconate. Examples of preservatives useful for the purpose of the present disclosure can be found in Steinberg, D. “Frequency of Use of Preservatives 2007”. Cosmet. Toilet. 117, 41-44 (2002) and, “Preservative Encyclopedia” Cosmet. Toilet. 117, SO- 96 (2002). In addition, enzyme preservative systems such as those described in the article by Ciccognani D. Cosmetic Preservation Using Enzymes, in “Cosmetic and Drug Microbiology”, Orth DS ed., Francis & Taylor, Boca Raton, Fla. (2006) can also be effective for use with the composition of the present disclosure.

[0099] In one embodiment, the composition further comprises at least one occlusive. Suitable occlusives include, but are not limited to, capryllic / capric triglycerides, and the like.

[0100] In one embodiment, the composition further comprises at least one emollient. Suitable emollients include, but are not limited to, cetyl ethylhexanoate, mineral oils, lanolin, petrolatum, capric / caprylic triglyceraldehydes, cholesterol, silicones such as dimeticone, cyclometicone, almond oil, jojoba oil, avocado oil, castor oil, sesame oil, sunflower oil, coconut oil and grape seed oil, cocoa butter, olive oil aloe extracts, fatty acids such as oleic and stearic, fatty alcohols such as cetyl and hexadecyl, diisopropyl adipate, hydroxybenzoate esters, benzoic acid esters of C9-i5-alcohols, isononyl iso-nonanoate, ethers such as polyoxypropylene butyl ethers and polyoxypropylene cetyl ethers, and Ci2-i5-alkyl benzoates, and mixtures thereof.

[0101] In one embodiment, the composition further comprises at least one film formers. Suitable film formers include, but are not limited to, polyacrylate-13, Opadry II® or similar materials, e.g., such as those described in U.S. Pat. No. 4,802,924, incorporated herein by reference, may be used as a film former.

[0102] In yet other embodiments, the calcimimetic compound formulated for transdermal administration. Transdermal formulations may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the calcimimetic compound is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the calcimimetic compound. The rate of absorption may be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Alternatively, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[0103] Transdermal formulations described herein may be administered using a variety of devices which have been described in the art. For example, such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144.

[0104] The transdermal dosage forms described herein may incorporate certain pharmaceutically acceptable excipients which are conventional in the art. Transdermal drug delivery systems are topically administered medicaments and may be in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate. The components of transdermal devices include: (1) polymer matrix or matrices, (2) the drug, (3) permeation enhancers and (4) other excipients.

[0105] The polymer controls the release of the drug from the device. Useful polymers for transdermal devices include, but are not limited to Natural Polymers (e.g., Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch, etc.); Synthetic Elastomers (e.g., Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieine rubber, Neoprene, etc.); and Synthetic Polymers (e.g., Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy, etc.)

[0106] Solvents increase penetration possibly by enclosing the polar pathway and / or by fluidizing lipids. Examples include water alcohols (e.g., methanol and ethanol); alkyl methyl sulfoxides (e.g., dimethyl sulfoxide, alkyl homologs of methyl sulfoxide dimethyl acetamide and dimethyl formamide); pyrrolidones (e.g., 2 pyrrolidone, N-methyl, 2-purrolidone); laurocapram (Azone), miscellaneous solvents (e.g., propylene glycol, glycerol, silicone fluids, isopropyl palmitate).

[0107] Surfactants may enhance polar pathway transport, especially of hydrophilic drugs. The ability of a surfactant to alter penetration is a function of the polar head group and the hydrocarbon chain length. Anionic surfactants include, but are not limited to, Dioctyl sulphosuccinate, Sodium lauryl sulphate, and Decodecylmethyl sulphoxide. Nonionic surfactants include, but are not limited to, Pluronic F127, and Pluronic F68. Bile salts include, but are not limited to, Sodium ms taurocholate, Sodium deoxycholate, and Sodium taurogly cocholate. Others include, for example, Propylene glycol-oleic acid and 1,4-butane diol-linoleic acid, urea, N,N-dimethyl-m-toluamide, calcium thioglycolat, anticholinergic agents, eucalyptol, di-o-methyl-P-cyclodextrin and soyabean casein.

[0108] The fastening transdermal devices to the skin may be done by using a pressure sensitive adhesive which can be positioned on the face of the device or in the back of the device and extending peripherally.

[0109] In addition, transdermal formulations can include additional components such as, but not limited to, gelling agents, creams and ointment bases, and the like. In some embodiments, the transdermal formulation further includes a woven or non-woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin. In other embodiments, the transdermal formulations described herein maintain a saturated or supersaturated state to promote diffusion into the skin Compositions disclosed herein may be formulated in conventional manner using one or more pharmaceutically or cosmetically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the calcimimetic compound and optional combination agents. Proper formulation is dependent upon the route of administration chosen and standard therapeutic practice. As used herein, the term “pharmaceutically or cosmetically acceptable carrier” means an inert, nontoxic solid or liquid filler, diluent or encapsulating material, not reacting adversely with the active compound or with the subject. Suitable carriers are well known, and include water, saline, aqueous dextrose, sugar solutions, ethanol, glycols and oils, including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil and mineral oil. In other embodiments, an agent or combination of agents of the instant embodiments can be formulated in an oleaginous hydrocarbon base, an anhydrous absorption base, a water-in-oil absorption base, an oil-in-water water-removable base and / or a water-soluble base. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., polysorbate-80, isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0110] Compositions can also contain adjuvants common to the cosmetic and dermatological fields, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preserving agents, antioxidants, solvents, fragrances, fillers, sunscreens, odor-absorbers and dyestuffs. The amounts of these various adjuvants are those conventionally used in the fields considered and, for example, are from about 0.01% to about 20% of the total weight of the composition. Depending on their nature, these adjuvants can be introduced into the fatty phase, into the aqueous phase and / or into the lipid vesicles.

[0111] The compositions may be in the form of tablets, capsules, skin patches, inhalers, eye drops, nose drops, ear drops, suppositories, creams, ointments, injectables, hydrogels and into any other appropriate formulation known to one of skill in the art. For oral administration the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with acceptable excipients or carriers such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolae); or wetting agents (e.g., sodium lauryl sulphate). Tablets may be coated using methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with acceptable excipients or carriers such as suspending agents (e.g., sorbitol syrup cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p- hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.

[0112] Topical compositions disclosed herein may be in the form of a viscous liquid, solution, suspension, liposomal formulations, gel, jelly, cream, lotion, ointment, suppository, foam, aerosol spray aqueous or oily suspensions or solutions, emulsions, or emulsion ointments. Topical formulation for application to skin may include ointments, lotions, pastes, creams, gels, drops, suppositories, sprays, liquids, powders, shampoos, and transdermal patches. In one embodiment, a topical composition is provided which includes a topical carrier. For example, thickeners, diluents, emulsifiers, dispersing aids or binders may be used as needed. The topical carrier is selected so as to provide the composition in the desired form, e.g., as a liquid, lotion, cream, paste, gel, powder, or ointment, and may be comprised of a material of either naturally occurring or synthetic origin. Examples of suitable topical carriers for use herein include water, alcohols and other nontoxic organic solvents, glycerin, mineral oil, silicone, petroleum jelly, lanolin, fatty acids, vegetable oils, parabens, aloe vera, waxes, and the like.

[0113] Ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

[0114] Lubricants which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0115] Thickeners (viscosity increasing agents) which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, polyacrylate-13, polyisobutene, Acetamide MEA; acrylamide / ethalkonium chloride acrylate copolymer; acrylamide / ethyltrimonium chloride acrylate / ethalkonium chloride acrylate copolymer; acrylamides copolymer; acrylamide / sodium acrylate copolymer; acrylamide / sodium acryloyldimethyltaurate copolymer; acrylates / acetoacetoxyethyl methacrylate copolymer; acrylates / beheneth-25 methacrylate copolymer; acrylates / C10-C30 alkyl acrylate crosspolymer; acrylates / ceteth-20 itaconate copolymer; acrylates / ceteth-20 methacrylate copolymer; acrylates / laureth-25 methacrylate copolymer; acrylates / palmeth-25 acrylate copolymer; acrylates / palmeth-25 itaconate copolymer; acrylates / steareth-50 acrylate copolymer; acrylates / steareth-20 itaconate copolymer; acrylates / steareth-20 methacrylate copolymer; acrylates / stearyl methacrylate copolymer; acrylates / vinyl isodecanoate crosspolymer; acrylic acid / acrylonitrogens copolymer; adipic acid / methyl DEA crosspolymer; agar; agarose; alcaligenes polysaccharides; algin; alginic acid; almondamide DEA; almondamidopropyl betaine; aluminum / magnesium hydroxide stearate; ammonium acrylates / acrylonitrogens copolymer; ammonium acrylates copolymer; ammonium acryloyldimethyltaurate / vinyl formamide copolymer; ammonium acryloyldimethyltaurate / VP copolymer; ammonium alginate; ammonium chloride; ammonium polyacryloyldimethyl taurate; ammonium sulfate; amylopectin; apricotamide DEA; apricotamidopropyl betaine; arachidyl alcohol; arachidyl glycol; arachis hypogaea (peanut) flour; ascorbyl methylsilanol pectinate; astragalus gummifer gum; attapulgite; avena sativa (oat) kernel flour; avocadamide DEA; avocadamidopropyl betaine; azelamide MEA; babassuamide DEA; babassuamide MEA; babassuamidopropyl betaine; behenamide DEA; behenamide MEA; behenamidopropyl betaine; behenyl betaine; bentonite; butoxy chitosan; caesalpinia spinosa gum; calcium alginate; calcium carboxymethyl cellulose; calcium carrageenan; calcium chloride; calcium potassium carbomer; calcium starch octenylsuccinate; C20-40 alkyl stearate; canolamidopropyl betaine; capramide DEA; capryl / capramidopropyl betaine; carbomer; carboxybutyl chitosan; carboxymethyl cellulose acetate butyrate; carboxymethyl chitin; carboxymethyl chitosan; carboxymethyl dextran; carboxymethyl hydroxyethylcellulose; carboxymethyl hydroxypropyl guar; carnitine; cellulose acetate propionate carboxylate; cellulose gum; ceratonia siliqua gum; cetearyl alcohol; cetyl alcohol; cetyl babassuate; cetyl betaine; cetyl glycol; cetyl hydroxyethylcellulose; chimyl alcohol; cholesterol / HDI / pullulan copolymer; cholesteryl hexyl dicarbamate pullulan; citrus aurantium dulcis (orange) peel extract; cocamide DEA; cocamide MEA; cocamide MIPA; cocamidoethyl betaine; cocamidopropyl betaine; cocamidopropyl hydroxysultaine; coco-betaine; coco- hydroxysultaine; coconut alcohol; coco / oleamidopropyl betaine; coco- Sul taine; cocoyl sarcosinamide DEA; cornamide / cocamide DEA; cornamide DEA; croscarmellose; crosslinked toc / Z / w / glucose / sodium glutamate ferment; cyamopsis tetragonoloba (guar) gum; decyl alcohol; decyl betaine; dehydroxanthan gum; dextrin; dibenzylidene sorbitol; diethanolaminooleamide DEA; diglycol / CHDM / isophthalates / SIP copolymer; dihydroabietyl behenate; dihydrogenated tallow benzylmonium hectorite; dihydroxyaluminum amino acetate; dimethicone / PEG-10 crosspolymer; dimethicone / PEG-15 crosspolymer; dimethicone propyl PG-betaine; dimethylacrylamide / acrylic acid / polystyrene ethyl methacrylate copolymer; dimethylacrylamide / sodium acryloyldimethyltaurate crosspolymer; disteareth-100 IPDI; DMAPA acrylates / acrylic acid / acrylonitrogens copolymer; erucamidopropyl hydroxysultaine; ethylene / sodium acrylate copolymer; gelatin; gellan gum; glyceryl alginate; glycine soja (soybean) flour; guar hydroxypropyltrimonium chloride; hectorite; hyaluronic acid; hydrated silica; hydrogenated potato starch; hydrogenated tallow; hydrogenated tallowamide DEA; hydrogenated tallow betaine; hydroxybutyl methylcellulose; hydroxy ethyl acryl ate / sodium acryloyldimethyl taurate copolymer; hydroxyethylcellulose; hydroxyethyl chitosan; hydroxyethyl ethylcellulose; hydroxyethyl stearamide-MIPA; hydroxylauryl / hydroxymyristyl betaine; hydroxypropylcellulose; hydroxypropyl chitosan; hydroxypropyl ethylene diamine carbomer; hydroxypropyl guar; hydroxypropyl methylcellulose; hydroxypropyl methylcellulose stearoxy ether; hydroxypropyl starch; hydroxypropyl starch phosphate; hydroxypropyl xanthan gum; hydroxystearamide MEA; isobutylene / sodium maleate copolymer; isostearamide DEA; isostearamide MEA; isostearamide mIPA; isostearamidopropyl betaine; lactamide MEA; lanolinamide DEA; lauramide DEA; lauramide MEA; lauramide MIPA; lauramide / myristamide DEA; lauramidopropyl betaine; lauramidopropyl hydroxysultaine; laurimino bispropanediol; lauryl alcohol; lauryl betaine; lauryl hydroxysultaine; lauryl / myristyl glycol hydroxypropyl ether; lauryl sultaine; lecithinamide DEA; linoleamide DEA; linoleamide MEA; linoleamide MIPA; lithium magnesium silicate; lithium magnesium sodium silicate; macrocystis pyrifera (kelp); magnesium alginate; magnesium / aluminum / hydroxide / carbonate; magnesium aluminum silicate; magnesium silicate; magnesium trisilicate; methoxy PEG-22 / dodecyl glycol copolymer; methylcellulose; methyl ethylcellulose; methyl hydroxyethylcellulose; microcrystalline cellulose; milkamidopropyl betaine; minkamide DEA; minkamidopropyl betaine; MIPA-myri state; montmorillonite; Moroccan lava clay; myristamide DEA; myristamide MEA; myristamide MIPA; myristamidopropyl betaine; myristamidopropyl hydroxysultaine; myristyl alcohol; myristyl betaine; natto gum; nonoxynyl hydroxyethylcellulose; oatamide MEA; oatamidopropyl betaine; octacosanyl glycol isostearate; octadecene / MA copolymer; oleamide DEA; oleamide MEA; oleamide MIPA; oleamidopropyl betaine; oleamidopropyl hydroxysultaine; oleyl betaine; olivamide DEA; olivamidopropyl betaine; oliveamide MEA; palmamide DEA; palmamide MEA; palmamide MIPA; palmamidopropyl betaine; palmitamide DEA; palmitamide MEA; palmitamidopropyl betaine; palm kernel alcohol; palm kernelamide DEA; palm kernelamide MEA; palm kernelamide MIPA; palm kernelamidopropyl betaine; peanutamide MEA; peanutamide MIPA; pectin; PEG-800; PEG-crosspolymer; PEG-150 / decyl alcohol / SMDI copolymer; PEG-175 diisostearate; PEG-190 distearate; PEG-15 glyceryl tristearate; PEG-140 glyceryl tristearate; PEG-240 / HDI copolymer bis-decyltetradeceth-20 ether; PEG-100 / IPDI copolymer; PEG- 180 / laureth-50 / TMMG copolymer; PEG-10 / lauryl dimethicone crosspolymer; PEG-15 / lauryl dimethicone crosspolymer; PEG-2M; PEG-5M; PEG-7M; PEG-9M; PEG-14M; PEG-20M; PEG-23M; PEG-25M; PEG-45M; PEG-65M; PEG-90M; PEG-115M; PEG-160M; PEG- ISOM; PEG-120 methyl glucose trioleate; PEG-180 / octoxynol-40 / TMMG copolymer; PEG- 150 pentaerythrityl tetrastearate; PEG-4 rapeseedamide; PEG-150 / stearyl alcohol / SMDI copolymer; phaseolus angularis seed powder; polianthes tuberosa extract; polyacrylate-3; polyacrylic acid; poly cyclopentadiene; polyether-1; polyethylene / isopropyl maleate / MA copolyol; polyglyceryl-3 disiloxane dimethicone; polyglyceryl-3 polydimethylsiloxyethyl dimethicone; polymethacrylic acid; polyquaternium-52; polyvinyl alcohol; potassium alginate; potassium aluminum polyacrylate; potassium carbomer; potassium carrageenan; potassium chloride; potassium palmate; potassium polyacrylate; potassium sulfate; potato starch modified; PPG-2 cocamide; PPG-1 hydroxy ethyl caprylamide; PPG-2 hydroxy ethyl cocamide; PPG-2 hydroxyethyl coco / isostearamide; PPG-3 hydroxyethyl soyamide; PPG-14 laureth-60 hexyl dicarbamate; PPG-14 laureth-60 isophoryl dicarbamate; PPG-14 palmeth-60 hexyl dicarbamate; propylene glycol alginate; PVP / decene copolymer; PVP montmorillonite; pyrus Cydonia seed; pyrus malus (apple) fiber; rhizobian gum; ricebranamide DEA; ricinoleamide DEA; ricinoleamide MEA; ricinoleamide MIPA; ricinoleamidopropyl betaine; ricinoleic acid / adipic acid / AEEA copolymer; rosa multiflora flower wax; sclerotium gum; sesamide DEA; sesamidopropyl betaine; sodium acrylate / acryloyldimethyl taurate copolymer; sodium acrylates / acrolein copolymer; sodium acrylates / acrylonitrogens copolymer; sodium acrylates copolymer; sodium acrylates crosspolymer; sodium acrylate / sodium acrylamidomethylpropane sulfonate copolymer; sodium acrylates / vinyl isodecanoate crosspolymer; sodium acrylate / vinyl alcohol copolymer; sodium carbomer; sodium carboxymethyl chitin; sodium carboxymethyl dextran; sodium carboxymethyl beta-glucan; sodium carboxymethyl starch; sodium carrageenan; sodium cellulose sulfate; sodium chloride; sodium cyclodextrin sulfate; sodium hydroxypropyl starch phosphate; sodium isooctylene / MA copolymer; sodium magnesium fluorosilicate; sodium oleate; sodium palmitate; sodium palm kernelate; sodium polyacrylate; sodium polyacrylate starch; sodium polyacryloyldimethyl taurate; sodium polygamma-glutamate; sodium polymethacrylate; sodium polystyrene sulfonate; sodium silicoaluminate; sodium starch octenyl succinate; sodium stearate; sodium stearoxy PG-hydroxyethylcellulose sulfonate; sodium styrene / acrylates copolymer; sodium sulfate; sodium tallowate; sodium tauride acrylates / acrylic acid / acrylonitrogens copolymer; sodium tocopheryl phosphate; solanum tuberosum (potato) starch; soyamide DEA; soyamidopropyl betaine; starch / acrylates / acrylamide copolymer; starch hydroxypropyltrimonium chloride; stearamide AMP; stearamide DEA; stearamide DEA- distearate; stearamide DIBA-stearate; stearamide MEA; stearamide MEA-stearate; stearamide MIPA; stearamidopropyl betaine; steareth-60 cetyl ether; steareth-100 / PEG-136 / HDI copolymer; stearyl alcohol; stearyl betaine; sterculia urens gum; synthetic fluorphlogopite; tallamide DEA; tallow alcohol; tallowamide DEA; tallowamide MEA; tallowamidopropyl betaine; tallowamidopropyl hydroxysultaine; tallowamine oxide; tallow betaine; tallow dihydroxyethyl betaine; tamarindus indica seed gum; tapioca starch; TEA-alginate; TEA- carbomer; TEA-hydrochloride; trideceth-2 carboxamide MEA; tridecyl alcohol; triethylene glycol dibenzoate; trimethyl pentanol hydroxyethyl ether; triticum vulgare (wheat) germ powder; triticum vulgare (wheat) kernel flour; triticum vulgare (wheat) starch; tromethamine acrylates / acrylonitrogens copolymer; tromethamine magnesium aluminum silicate; undecyl alcohol; undecylenamide DEA; undecylenamide MEA; undecyl enamidopropyl betaine; welan gum; wheat germamide DEA; wheat germamidopropyl betaine; xanthan gum; yeast betaglucan; yeast polysaccharides and zea mays (com) starch.

[0116] In some embodiments, one function of the carrier is to enhance skin penetration of the active ingredients. Permeation enhancers are compounds which promote skin permeability by altering the skin as a barrier to the flux of a desired penetrant. These may be classified as solvents, surfactants and miscellaneous chemicals. Suitable carriers are well known to skilled practitioners, and include liposomes, ethanol, dimethylsulfoxide (DMSO), petroleum jelly (petrolatum), mineral oil (liquid petrolatum), water, deimethylformamide, dekaoxyethylene- oleylether, oleic acid, 2 -pyrrolidone, Azone® brand penetration enhancer (Upjohn), biologically acceptable glycols, diglycols, polyglycols; alkyoxy C2-C8 alcohols, ethoxydiglycol and dimethyl isosorbide. A skin penetration enhancer may be included at concentrations ranging from 5% to 95%, preferably 5% to 10% of the total composition.

[0117] In other embodiments, the compositions are free of skin penetrants.

[0118] In other embodiments, the compositions are alcohol-free.

[0119] In a further embodiment of the combinations described above, a topical formulation is prepared that comprises a composition for cosmetic or dermatological use, which composition comprises a cosmetically and / or dermatologically effective amount of the combination stated above.

[0120] In one embodiment, the compositions are in a form suitable for application to the skin including, but not limited to, lotions, ointments, creams, sprays, spritzes, aqueous or aqueous- alcoholic mixture gels, mousses, patches, pads, masks, moistened clothes, wipes, solid sticks, clear sticks, lip sticks, aerosol creams, anhydrous powders, talcs, tonics, oils, emulsions or bath salts.

[0121] In another embodiment, the composition also contains irritation-mitigating additives to minimize or eliminate the possibility of skin irritation or skin damage resulting from the chemical compound to be administered, or other components of the composition. Suitable irritation-mitigating additives include for example: tocopherols, monoamine oxidase inhibitors (e.g., 2-phenyl-l -ethanol), glycerin, salicylates, ascorbates (e.g., tetrahexyl decyl ascorbate), ionophores (e.g., monensin), amphiphilic amines, ammonium chloride, N-acetylcysteine, capsaicin, and / or chloroquine.

[0122] The present invention is further described in the following non-limiting examples.

[0123] EXAMPLES

[0124] Example 1: Improvement of Hailey-Hailey Disease with Topical Cinacalcet Ointment

[0125] A woman in her fifties (Patient 2) with biopsy-proven Hailey-Hailey Disease (HHD) presented with a two-week history of a painful area on the right lateral chest. She was taking prednisone, lOmg, daily and had not used any topical medications. Examination demonstrated a large, crusted, erythematous plaque on the right chest that was consistent with an HHD flare (FIG. 1A and Table 1). Previous flares were treated unsuccessfully with methotrexate, mycophenolate mofetil, cyclosporine, glycopyrrolate, oral antibiotics, topical corticosteroids, topical calcineurin inhibitors, and topical antibiotics. Patient 2 elected to initiate treatment with a compounded topical ointment comprising cinacalcet, 3%, in a petrolatum-based vehicle (Aquaphor brand hydrophilic petrolatum, manufactured by Beiersdorf Pharmaceuticals). After applying 0.25 g twice daily for 5 days, she noted complete resolution of the lesion, with only remnant hyperpigmentation. Two weeks later, she developed new areas of HHD on the left arm and left chest. She applied between 0.25 to 0.5 g of the ointment twice daily, stopping after 12 days when she ran out of the medication. During treatment, she observed rapid improvement on the left chest and gradual improvement on the left arm. She denied local adverse effects or symptoms of hypercalcemia. Baseline and post-treatment laboratory values were within normal limits for intact parathyroid hormone, ionized calcium, and phosphorus.

[0126] Two additional middle-aged patients (Patients 1 and 3) with history of HHD presented with painful erosive plaques on their backs or lower abdomen. (Table 1). Similar to Patient 2, previous treatment attempts with steroids were unsuccessful. The patients were treated with topical cinacalcet similarly to Patient 2. Results demonstrated improvement and / or healing of areas affected with the painful erosive plaques as demonstrating by re-epithelialization of the affected areas.

[0127] Table 1: Clinical Response Summary of Hailey -Hailey Disease Patients

[0128] Hailey-Hailey disease is a rare, autosomal dominant genodermatosis characterized by painful, crusted plaques and erosions favoring intertriginous skin. The disease has a relapsingremitting course and few effective treatments. The underlying pathophysiology of HHD is a variant of the ATP2C1 gene, which encodes the SPCA1 calcium pump on the Golgi complex. The resultant dysregulated intracellular calcium handling manifests histologically as poor cell- to-cell adhesion and acantholysis.

[0129] The assembly and function of cytoskeletal and adhesion molecules is critical for establishing cell-to-cell contacts between keratinocytes, as demonstrated by the acantholysis seen in HHD following their disruption. Immunoelectron microscopy of HHD keratinocytes demonstrates cytoplasmic dissolution of components of the adherens junction (E-cadherin, P- catenin) and desmosomes (desmoglein, plakoglobin). Prominent actin stress fibers, which transmit mechanical tension, have been observed with confocal laser scanning microscopy of affected keratinocytes. Research suggests that the epidermal CaSR promotes E-cadherin- mediated assembly of the aforementioned adherens junction, reorganization of actin- cytoskeletal networks, and promotion of keratinocyte differentiation and proliferation via the mitogen-activated protein kinase pathway. E-cadherin signaling has also been implicated in desmosome assembly. Altogether, these events promote cell-to-cell adhesion and wound healing.

[0130] Without wishing to be bound by theory, the patient’s improvement with treatment with topical cinacalcet may be due to stimulation of the epidermal CaSR signaling pathway, thereby restoring the ability of keratinocytes to organize intercellular junctions (FIG. 2). Interactions between cinacalcet-bound CaSR on the Golgi membrane and defective SPCA1 may also alter the dysfunctional calcium signaling in HHD keratinocytes.

[0131] The epidermal calcium-sensing receptor (CaSR) represents a novel target for pathogenesis directed therapy for HHD. The CaSR is best known for its presence in parathyroid tissue. Calcimimetics, such as oral cinacalcet, are used in hyperparathyroidism, for which they act as positive allosteric modulators of the parathyroid CaSR to decrease serum parathyroid hormone and calcium levels. The instant topical composition is thought to treat HHD by stimulating the epidermal CaSR signaling pathway, thereby restoring the ability of keratinocytes to organize intercellular junctions (FIG. 2). Interactions between cinacalcet- bound CaSR on the Golgi membrane and defective SPCA1 may also alter the dysfunctional calcium signaling in HHD keratinocytes.

[0132] The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

THAT WHICH IS CLAIMED IS:

1. A method for treating a subject for a skin disorder, skin disease, or skin condition comprising topically administering to the subject a composition comprising a therapeutically effective amount of a calcimimetic compound and a pharmaceutically acceptable carrier.

2. The method of claim 1, wherein the calcimimetic compound is cinacalcet, a cinacalcet derivative, or a salt thereof.

3. The method of claim 1 or claim 2, wherein the carrier comprises a topical carrier.

4. The method of any preceding claim, wherein the carrier is non-aqueous.

5. The method of any preceding claim, wherein the carrier comprises a water-in- oil emulsion, cream, liquid, gel, oil, paste, ointment, suspension, foam, lotion, oil-in-water emulsion, water-in- oil- in- water emulsion, water-in-silicone emulsion, spray or serum carrier.

6. The method of any preceding claim, where in the carrier comprises a petroleum based vehicle.

7. The method of claim 6, where in the petroleum based vehicle comprises petrolatum.

8. The method of any preceding claim, wherein the calcimimetic compound is provided in the carrier in an amount of from about 0.5%, about 1%, or about 2%, to about 4%, about 5%, or about 6% by weight of the carrier.

9. The method of any preceding claim, wherein the calcimimetic compound is provided in the carrier in an amount of about 3% by weight of the carrier.

10. The method of any preceding claim, wherein the administering comprises applying the composition to the subject on areas of the skin with erythematous plaques, hyperpigmentation, erosions, wounds, and / or inflammation.

11. The method of any preceding claim, wherein the administering is carried out 1 time a day, 2 times a day, 3 times a day, or 4 times a day.

12. The method of any preceding claim, wherein the skin disorder, skin disease, or skin condition is selected from Hailey-Hailey Disease, Psoriasis, Pyoderma gangreonsum, Darier disease, erosive pustular dermatosis of the scalp, diabetic foot wounds, wound healing, erythrodermic autosomal recessive lamellar ichthyosis, nonerythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant lamellar ichthyosis, bullous congenital ichthyosiform erythroderma, palmoplantar keratosis, erythrokeratodermia variabilis, verrucous epidermal nevi, pityriasis rubra pilaris, Netherton syndrome, idiopathic vulgaris, ichthyosis vulgaris, monilethrix, keratosis piliaris, bullous ichthyosiform erythroderma, nonbullous congenital ichthyosis, Sjogren-Larsson syndrome, erythrokeratodermica variabilis, hyperkeratosis lenticularis perstans, eythrokeratodermia figurate variabilis, mutilating keratosis of Vohwinkel, Harlequin ichthyosis, and Tay's syndrome.

13. The method of any preceding claim, wherein the skin disorder, skin disease, or skin condition is Hailey-Hailey Disease.

14. The method of any preceding claim, wherein the subject is not suffering from hyperparathyroidism or parathyroid carcinoma.

15. The method of any preceding claim, wherein the skin disorder, skin disease, or skin condition is unresponsive to steroid treatment.

16. The method of any preceding claim, wherein the administering is carried out by applying about 0.1, about 0.25, or about 0.3 gram, to about 0.5, about 0.75 or about 1 gram of the composition to the affected area twice a day.

17. The method of any preceding claim, wherein the administering is carried out for 5, 6, 7, 8, 9, 10, 11, 12 days, or more days.

18. The method of any preceding claim, wherein the composition further comprises one or more additional active agent(s).

19. The method of claim 18, wherein the additional active agent(s) is an antioxidant, a sunscreen, a sun protectant, a sunblock, a skin lightening agent, an antiinflammatory agent, an antifungal, an antibiotic, an antiseptic, an anti-acne agent, or a combination of two or more thereof.

20. The method of claim 19, wherein the antioxidant is present and is vitamin E, Coenzyme Q10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol, grape seed extract, Oregon grape root (Mahonia aquifolium) extract, pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, Tocopherol, Dunaliella Salina Extract, or a combination of two or more thereof.

21. The method of claim 19 or claim 20, wherein the skin lightening agent is present and is hydroquinone, monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol, retinoids, soy proteins, alpha-hydroxy acids, trichloroacetic acid, salicylic acid, hydroquinone- beta-D-glucopyranoside, paper mulberry, glabridin, 4-isopropylcetchol, aleosin, N-acetyl-4-S- cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexaminc acid, undecylenoyl phenylalanine, an alpha MSH antagonist, phytic acid, or a combination of two or more thereof.

22. The method of any one of claims 19-21, wherein the anti-inflammatory agent is present and is salicylic acid, acetylsalicylic acid, methyl salicylate, aspirin, ibuprofen, naproxen, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide; leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin; and other anti-inflammatory agents including, but not limited to, methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone. Additional anti-inflammatories useful in topical applications include corticosteroids, such as,but not limited to, flurandrenolide, clobetasol propionate, halobetasol propionate, fluticasone propionate, betamethasone dipropionate, betamethasone benzoate, betamethasone valerate, desoximethasone, dexamethasone, diflorasone diacetate, mometasone furoate, amcinodine, halcinonide, fluocinonide, fluocinolone acetonide, desonide, triamcinolone acetonide, hydrocortisone, hydrocortisone acetate, fluoromethalone, prednisone, methylprednisolone, predinicarbate, or a combination of two or more thereof.

23. The method of any one of claims 19-22, wherein the anti-acne agent is present and is one or more selected from the group consisting of salicylic acid; 5-octanoyl salicylic acid; resorcinol; retinoids such as retinoic acid and its derivatives; sulfur-containing D and L amino acids other than cysteine; lipoic acid; antibiotics and antimicrobials such as benzoyl peroxide, octopirox, tetracycline, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 3,4,4'- trichlorobanilide, azelaic acid, phenoxyethanol, phenoxypropanol, phenoxisopropanol, ethyl acetate, clindamycin and melclocycline; flavonoids; and bile salts such as scymnol sulfate, deoxycholate and cholate.

24. The method of any preceding claim, wherein the composition further comprises a solvent, a film former, a preservative, a viscosity increasing agent, a fragrance, a surfactant, a chelating agent, a humectant, a permeation enhancer, an excipient, or a combination of two or more thereof.

25. The method of any preceding claim, wherein the topically administering to the subject comprises administering the composition on a limb, the back, and / or on the chest of the subject.

26. The method of any preceding claim, wherein said method results in re- epithelialization of the affected area and / or decreases the level of erythematous plaques or hyperpigmentation by about 5%, by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, by about 90%, or by about 100%.

27. A topical composition comprising a mixture of a calcimimetic compound and a pharmaceutically acceptable carrier.

28. The composition of claim 27, wherein the topical composition is for use in treating subjects with a skin disorder, skin disease, or skin condition; optionally for use in treating a skin lesion.

29. The composition of claim 27 or claim 28, wherein the calcimimetic compound is cinacalcet, a cinacalcet derivative, or a salt thereof.

30. The composition of any one of claims 27-29, wherein the carrier comprises a topical carrier.

31. The composition of any one of claims 27-30, wherein the carrier is nonaqueous.

32. The composition of any one of claims 27-32, wherein the carrier comprises a water-in-oil emulsion, cream, liquid, gel, oil, paste, ointment, suspension, foam, lotion, oil-in- water emulsion, water-in- oil- in- water emulsion, water-in-silicone emulsion, spray or serum carrier.

33. The composition of any one of claims 27-32, wherein the carrier comprises a petroleum-based vehicle.

34. The composition of claim 33, where in the petroleum based vehicle comprises petrolatum.

35. The composition of any one of claims 27-34, wherein the calcimimetic compound is provided in the carrier in an amount of from about 0.5%, about 1%, or about 2%, to about 4%, about 5%, or about 6% by weight of the carrier.

36. The composition of any one of claims 27-35, wherein the calcimimetic compound is provided in the topical carrier in an amount of about 3% by weight of the carrier.

37. The composition of any one of claims 27-36, wherein the composition is penetrant-free; preferably wherein the composition is alcohol-free.

38. The composition of any one of claims 27-37, wherein the composition further comprises one or more additional active agent(s).

39. The composition of claim 38, wherein the additional active agent(s) is an antioxidant, a sunscreen, a sunprotectant, a sunblock, a skin lightening agent, an antiinflammatory agent, an antifungal, an antibiotic, an antiseptic, an anti-acne agent, or a combination of two or more thereof.

40. The composition of claim 39, wherein the antioxidant is present and is vitamin E, Coenzyme Q10, idebenone, lycopene, green tea polyphenols, silybin, resveratrol, grape seed extract, Oregon grape root (Mahonia aquifolium) extract, pomegranate extract, genistein, pycnogenol, curcumin, curcuminoids, Tocopherol, Dunaliella Salina Extract, or a combination or two or more thereof.

41. The composition of claim 39 or claim 40, wherein the skin lightening agent is present and is hydroquinone, monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol, retinoids, soy proteins, alpha-hydroxy acids, trichloroacetic acid, salicylic acid, hydroquinone- beta-D-glucopyranoside, paper mulberry, glabridin, 4-isopropylcetchol, aleosin, N-acetyl-4-S- cycteaminylphenol, N-propionyl-4-S-cysteaminylphenol, N-acetyl glucosamine, tranexaminc acid, undecylenoyl phenylalanine, an alpha MSH antagonist, phytic acid, or a combination of two or more thereof.

42. The composition of any one of claims 39-41, wherein the anti-inflammatory agent is present and is salicylic acid, acetylsalicylic acid, methyl salicylate, aspirin, ibuprofen, naproxen, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide; leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin; and other anti-inflammatory agents including, but not limited to, methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone; or is a corticosteroid, such as flurandrenolide, clobetasolpropionate, halobetasol propionate, fluticasone propionate, betamethasone dipropionate, betamethasone benzoate, betamethasone valerate, desoximethasone, dexamethasone, diflorasone diacetate, mometasone furoate, amcinodine, halcinonide, fluocinonide, fluocinolone acetonide, desonide, triamcinolone acetonide, hydrocortisone, hydrocortisone acetate, fluoromethalone, prednisone, methylprednisolone, predinicarbate, or a combination of two or more thereof.

43. The composition of any one of claims 39-42, wherein the anti-acne agent is present and is one or more selected from the group consisting of salicylic acid; 5-octanoyl salicylic acid; resorcinol; retinoids such as retinoic acid and its derivatives; sulfur-containing D and L amino acids other than cysteine; lipoic acid; antibiotics and antimicrobials such as benzoyl peroxide, octopirox, tetracycline, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 3,4,4'- trichlorobanilide, azelaic acid, phenoxyethanol, phenoxypropanol, phenoxisopropanol, ethyl acetate, clindamycin and melclocycline; flavonoids; and bile salts such as scymnol sulfate, deoxycholate and cholate.

44. The composition of any one of claims 27-43, further comprising one or more of a solvent, a film former, a preservative, a viscosity increasing agent, a fragrance, a surfactant, a chelating agent, a humectant, a permeation enhancer, and an excipient.

45. The composition of any one of claims 27-44, wherein the composition is a multi-dose composition.

46. The composition of any one of claims 27-45, wherein in the composition is provided in an amount of about 0.5 gram to about 50 grams.

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