US 2005O214328A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0214328A1 Zeldis et al. (43) Pub. Date: Sep. 29, 2005 (54) METHODS OF USING AND COMPOSITIONS Publication Classification COMPRISING IMMUNOMODULATORY COMPOUNDS FOR THE TREATMENT AND (51) Int. Cl." ......................... A61K 39/08; A61K 38/21; MANAGEMENT OF SKIN DISEASES OR A61K 35/78; A61K 31/19; DSORDERS A61K 31/59 (52) U.S. Cl. ..................... 424/239.1; 424/769; 424/85.4; 514/159; 514/557; 514/559; (76) Inventors: Jerome B. Zeldis, Princeton, NJ (US); 514/12: 514/588 Robert J. Hariri, Florham Park, NJ (57) ABSTRACT (US) Methods of treating, preventing, correcting and/or managing Correspondence Address: skin diseases or disorders characterized by Overgrowths of JONES DAY the epidermis, keratoses, Scleroderma, cutaneous vasculitis, 222 EAST 41ST ST acne or wrinkles are disclosed. Specific embodiments NEW YORK, NY 10017 (US) encompass the administration of an immunomodulatory compound, or a pharmaceutically acceptable Salt, Solvate, (21) Appl. No.: 11/085,905 hydrate, Stereoisomer, clathrate, or prodrug thereof, alone or in combination with a Second active agent. Specific Second (22) Filed: Mar. 22, 2005 active ingredients are capable of affecting or inhibiting cell Related U.S. Application Data growth or proliferation, removing or improving acne Scars, or reducing or correcting wrinkle lines. Pharmaceutical (60) Provisional application No. 60/554,923, filed on Mar. compositions, Single unit dosage forms, and kits Suitable for 22, 2004. use in methods of the invention are also disclosed. Patent Applicat US 2005/0214328A1 US 2005/0214328A1 Sep. 29, 2005 METHODS OF USING AND COMPOSITIONS actinic keratoses has been reported in fair, redheaded, and COMPRISING IMMUNOMODULATORY blonde patients who burn frequently and tan poorly. Stuart COMPOUNDS FOR THE TREATMENT AND J. Salasche, J. Am. Acad. Dermatol. 2000, 42:S4-7. No Sex MANAGEMENT OF SKIN DISEASES OR predilection has been found, except that Sun exposure tends DISORDERS to be higher in males due to more exposure from outside activities. One of the most important factors in determining 0001. This application claims the benefit of U.S. provi the expression of actinic keratoses is age. Epidemiologic sional application No. 60/554,923, filed Mar. 22, 204, the Studies indicate that actinic keratoses increase in prevalence entirety of which is incorporated herein by reference. with advancing age. Id. at S5. The age of occurrence is related to the skin type and amount of Sun damage. Thus, 1. FIELD OF THE INVENTION while actinic keratosis can occur in patients aged 20-30 0002 This invention relates to methods of treating, pre years, it is more common in patients aged 30-60 years. Venting and managing keratoses, Scleroderma, cutaneous vasculitis, skin diseases or disorders characterized by over 0008 Seborrheic keratosis, also known as seborrheic growths of the epidermis, acne or wrinkles, which comprise wart or Senile wart, is a benign tumor commonly found in the administration of an immunomodulatory compound advanced and middle-aged persons. Merck Index, 1999 (17" alone or in combination with known therapeutics. The ed.), 841. A familial predisposition is apparent with an invention also relates to pharmaceutical compositions and autosomal inheritance. Seborrheic keratosis also may be a dosing regimens. consequence of inflammatory dermatoses or malignancies. It is typically characterized by a raised papular lesion of 2. BACKGROUND OF THE INVENTION variable color from light to dark brown. Seborrheic keratosis may be smooth or wartlike with visible pitting. Common 0003 2.1. Types of Skin Diseases Sites include the face, trunk, and extremities. Id. A variant known as dermatosis papulosa nigra occurs over the fore 0004 2.1.1 Keratosis head and malar regions of individuals with black skin, 0005 Keratosis refers to a diverse group of skin diseases occurs at an earlier age, and is Smaller and Smoother than or disorders characterized by lesions on the epidermis variants in perSons with fairer skin. Irritated Seborrheic marked by the presence of circumscribed Overgrowths of the keratosis is one Subtype, characterized by a predominance of horny layer of the skin. Specific types of keratosis include, basal cells with whorling sheets of Squamous cells. All but are not limited to, actinic keratosis, seborrheic keratosis, Seborrheic keratoses are characterized by varying degrees of keratoacanthoma, keratosis follicularis (Darier disease), acanthosis, papillomatosis, hyperkeratosis, and hyperpig inverted follicular keratosis, palmoplantar keratoderma mentation of the basal cells. Id. (PPK, also known as keratosis palmaris et plantaris), kera tosis pilaris, and stucco keratosis. Stedman, Medical Dic 0009. Another type of keratosis is inverted follicular tionary, 1990, 25" ed., 823. keratosis, which is believed to be an inflammatory variant of Seborrheic keratosis. It is commonly found on the faces and 0006 Actinic keratosis is also known as senile keratosis, Sun-exposed areas of elderly patients. Typically, this lesion keratosis Senilis, Verruca Senilis, plana Senilis, Solar kerato is located on the upper eyelid. The lesion tends to be single sis or keratodemma. Stedman, Medical Dictionary, 1990, and present as a papule or nodule. The hallmarks of this 25 ed., 823; and Clay J. Cockerell, J. Am. Acad. Dermatol. lesion are the plentiful Squamous eddies. A papillomatous 2000, 42:S11-7. Actinic keratosis is characterized by scaly, and acanthotic appearance is found. The margins are discrete red, epidermal lesions that can develop into malignant and lack the inflammatory component found in keratoacan non-melanoma skin cancer. Steven R. Feldman et al., J. Am. thoma (eMedicine Website, benign skin lesions). Acad. Dermatol. 1999, 40:43-7. Lesions typically have an erythematous base covered by Scale (hyperkeratosis). Steven 0010 Another type of keratosis is keratoacanthoma, R. Feldman et al., J. Am. Acad. Dermatol. 1999, 40:43-7. which is characterized by round, firm, usually flesh-colored Actinic keratoses are characterized by disordered epidermal nodules with Sharply sloping borders and a characteristic differentiation. The epidermis in actinic keratoses may be center crater containing keratinous material. Merck Index, atrophic or of normal thickness, or it may be of increased 1999 (17" ed.), 842. Its rapid growth rate is frequently thickness with proliferation of abnormally differentiated adequate to allow the clinician to distinguish keratoacan epithelium extending into the papillary dermis. With time, thoma from malignancy because it grows much more actinic keratoses may develop into invasive cutaneous horns quickly than carcinoma. Id. It tends to occur in males more or skin cancers. Richard G. Glogau, J. Am. Acad. Dermatol. often than in females, with a male-to-female ratio of 3-4:1. 2000, 42:S23-4. Keratoacanthoma appears to be a product of the infundibu lum of the hair follicle, and various infections have been 0007 Actinic keratosis can be caused by carcinogens and implicated in its occurrence, including viral Sources. Also, UV light exposure, and occurs chiefly in Sun-exposed areas mineral oil and tar products historically have had Some of the face, ears, forearms, and dorsum of hands. Lynn A. importance, although the most common denominator Drake et al., J. Am. Acad. Dermatol. 1995, 32:95-8. How appears to be Sun exposure. Id. ever, it may occur on any area that is chronically or repeatedly exposed to the Sun, Such as the back, chest, and 0011 Keratosis follicularis, also known as Darier disease legs. The Specific effect of ultraViolet radiation on the tumor (DD) or Darier-White disease, is a dominantly inherited Suppressor gene p53 Suggests a cause-effect relationship genodermatosis that is characterized by hyperkeratotic pap between ultraViolet radiation and the earliest mutations Seen ules in Seborrheic regions and various nail abnormalities. in actinic keratoses. David J. Leffell, J. Am. Acad. Dermatol. Burge S M, J. Am. Acad. Dermatol., 1992, 27(1): 40-50. 2000, 42:S18-22. Moreover, a genetic predisposition for Abnormal cell-cell adhesion and aberrant epidermal kerati US 2005/0214328A1 Sep. 29, 2005 nization are its primary features. The majority of DD mucosal Surface. At this location, the virus remains latent in patients have a clear family history of the disease. The the cell as a circular episome. AS the epidermal cells pattern of inheritance is consistent with an autosomal domi differentiate and migrate to the Surface, the virus is triggered nant condition. The first skin lesions typically occur in to undergo replication and maturation. The process of Virus teenage years and are frequently associated with pruritus. replication alters the character of the epidermis, resulting in Heat, humidity, stress, sunlight and UVB rays have been cutaneous or mucosal excrescences known as warts. shown to exacerbate this condition. Even though the Severity 0018 Human papilloma viruses (HPVs) are grouped of DD fluctuates over time, DD is a chronic unremitting broadly into cutaneous and mucosal types, based on the condition. clinical location of the resulting lesion. Although Some 0012 Another type of keratosis is palmoplantar kerato overlap exists, most papilloma viruses have distinct ana derma (PPK, also known as keratosis palmaris et plantaris), tomic predilections, infecting only certain epidermal Sites, which constitutes a heterogeneous group of disorders char Such as Skin or genital mucosa. A