US 20140212362A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0212362 A1 Pippin (43) Pub. Date: J 11]. 31, 2014

(54) COMPOSITION AND METHOD FOR (60) Provisional application No. 61/540,953, ?led on Sep. TREATMENT OF SYMPTOMS ASSOCIATED 29, 2011. WITH VARIOUS SKIN CONDITIONS _ _ _ _ Publication Classi?cation (71) Applicant: THERACEUTIX, LLC, Exton, PA A61KIIlt. 31/4164 (2006.01) (72) Inventor: Douglas A. Pippin, Chester Springs, PA A61K 45/06 (200601) (Us) C07D 233/64 (2006.01) (52) US. Cl. - _ CPC ...... A61K31/4164 (2013.01); C07D 233/64 (73) Ass1gnee. LEISERACEUTIX, LLC, Exton, PA (201301); A61K 45/06 (201301) USPC ...... 424/59; 514/400; 514/171 (21) Appl. No.: 14/230,494 (57) ABSTRACT Compositions containing imidazole-based compounds, and (22) Filed; Mar, 31, 2014 optionally, colloidal oatmeal, for the treatment, prevention, and management of symptoms, conditions, diseases, and dis Related US. Application Data orders of the skin. Also, methods for the' treatment, preven tion, and management of symptoms, condltlons, d1seases, and (63) Continuation of application No. PCT/US2012/ disorders of the skin using compositions containing imida 057431, ?led on Sep. 27, 2012. zole-based compounds, and optionally, colloidal oatmeal. US 2014/0212362 A1 Jul. 31, 2014

COMPOSITION AND METHOD FOR [0011] Another aspect of the invention relates to a method TREATMENT OF SYMPTOMS ASSOCIATED of suppressing a dermatologic immune response in a patient WITH VARIOUS SKIN CONDITIONS in need thereof, comprising topically administering an effec tive composition comprising the imidazole compound con CROSS-REFERENCE TO RELATED tained in a dermatologically acceptable carrier. APPLICATIONS [0012] Another aspect of the invention relates to a compo [0001] This application is a continuation claiming bene?t sition comprising an imidazole compound of the formula: under 35 U.S.C. §§120 and 365(c) of PCT International Application No. PCT/US2012/057431, ?led Sep. 27, 2012, and claiming bene?t under 35 U.S.C. §119(e) of US. Provi R7 R8 sional Application No. 61/540,953, ?led Sep. 29, 2011. The HO disclosures of PCT International Application No. PCT/ R9 US2012/057431 and US. Provisional Application No. 61/540,953 are incorporated herein by reference in their — R6 entirety. HN / N FIELD OF THE INVENTION

[0002] This invention relates to compositions containing R1 0 imidazole-based compounds, and optionally, colloidal oat meal, and to methods of their use for the treatment, preven tion, and management of symptoms, conditions, diseases, and wherein: disorders of the skin. [0013] R1 is hydrogen, alkyl or aryl; [0014] R6 is OR10 or OC(O)R10; SUMMARY OF THE INVENTION [0015] R7 is ORll or OC(O)R11; [0003] One aspect of the invention relates to a method of [0016] R8 is OR12 or OC(O)R12; and treating, managing, or preventing a dermatological or skin [0017] R9 is hydrogen, CHzOR13 or CHZOC(O)R13; and condition, which comprises topically administering to a sub each of R10, R11, R12 and R13 is independently hydrogen or ject in need thereof a therapeutically or prophylactically lower alkyl, effective composition comprising an imidazole compound of and pharmaceutically, dermatologically, or cosmetically the formula: acceptable salts thereof. [0018] Another aspect of the invention relates to composi tions containing combinations of imidazole-based com R7 R8 pounds and, optionally, colloidal oatmeal, and to methods of HO their use for the treatment, prevention, and management of in?ammatory or immune-mediated symptoms, conditions, R9 diseases, and disorders of the skin. — R6 [0019] Another aspect of the invention relates to combina tions of imidazole-based compounds and, optionally, colloi HN / N dal oatmeal, and to methods of their use for the treatment, prevention, and management of various skin symptoms, con ditions, diseases, and disorders. R1 0 [0020] Another aspect of the invention relates to combina tions of imidazole-based compounds and colloidal oatmeal wherein: and to methods of their use for the treatment, prevention, and [0004] R1 is hydrogen, alkyl or aryl; management of atopic dermatitis, seborrheic dermatitis, con [0005] R6 is ORlo or OC(O)R10; tact dermatitis, cutaneous sarcoidosis, drug induced photo [0006] R7 is ORll or OC(O)R11; sensitivity, ?xed drug eruptions, id reactions, bullous skin [0007] R8 is ORl2 or OC(O)R12; and diseases, discoid lupus erythematosus, subacute cutaneous [0008] R9 is hydrogen, CHzOR13 or CHZOC(O)R13; and lupus, alopecia areata, sea bathers eruptions, psoriasis, each of R10, R11, R12 and R13 is independently hydrogen or dyshidrotic eczema, and pompholyx. lower alkyl, [0021] Another aspect of the invention relates to composi and pharmaceutically, dermatologically, or cosmetically tions and methods for treating in?ammatory and/or immune acceptable salts thereof. mediated dermatoses with imidazole-based compounds and [0009] Another aspect of the invention relates to a method combinations of imidazole-based compounds and colloidal of caring for skin, which comprises topically administering to oatmeal. the skin of a subj ect in need thereof a composition comprising [0022] Another aspect of the invention relates to care, the imidazole compound in an amount and for a time suf? supplement, and pharmaceutical compositions containing cient to effect a change in the skin. imidazole-based compounds, colloidal oatmeal, and other [0010] Another aspect of the invention relates to a method ingredients used to treat disorders of the skin, as well as to of delivering or depositing a bene?t agent onto skin, which compositions suitable for use in personal care applications, comprises topically administering to the skin of a subject a and in particular skin care compositions, which effectively composition comprising the imidazole compound contained deliver and/ or deposit various bene?t agents into and onto the in a dennatologically acceptable carrier. skin. US 2014/0212362 A1 Jul. 31, 2014

[0023] Another aspect of the invention relates to composi which reduces the severity of the disease or disorder, or tions and methods for treating contact dermatitis. retards or slows the progression of the disease or disorder. [0024] These and further aspects of the claimed invention [0031] Unless otherwise indicated, the term “include” has will now be explained in more detail. the same meaning as “include, but are not limited to,” and the term “includes” has the same meaning as “includes, but is not DETAILED DESCRIPTION OF THE INVENTION limited to.” Similarly, the term “such as” has the same mean ing as the term “such as, but not limited to.” De?nitions [0032] Unless otherwise indicated, one or more adjectives [0025] Unless otherwise indicated, the term “alkyl” means immediately preceding a series of nouns is to be construed as a straight chain, branched and/ or cyclic (“cycloalkyl”) hydro applying to each of the nouns. For example, the phrase carbon having from 1 to 20 (e.g., l to 10 or 1 to 4) carbon “optionally substituted A, B, or C” has the same meaning as atoms. Alkyl moieties having from 1 to 4 carbons are referred “optionally substituted A, optionally substituted B, or option to as “lower alkyl.” Examples of alkyl groups include, but are ally substituted C.” not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-bu [0033] It should be noted that a chemical moiety that forms tyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl part of a larger compound may be described herein using a pentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl name commonly accorded it when it exists as a single mol and dodecyl. Cycloalkyl moieties may be monocyclic or mul ecule or a name commonly accorded its radical. ticyclic, and examples include cyclopropyl, cyclobutyl, [0034] It should also be noted that if the stereochemistry of cyclopentyl, cyclohexyl, and adamantyl. Additional a structure or a portion of a structure is not indicated with, for examples of alkyl moieties have linear, branched and/or example, bold or dashed lines, the structure or the portion of cyclic portions (e. g., l-ethyl-4-methyl-cyclohexyl). The term the structure is to be interpreted as encompassing all stereoi “alkyl” includes saturated hydrocarbons as well as alkenyl somers of it. Moreover, any atom shown in a drawing with and alkynyl moieties. unsatis?ed valences is assumed to be attached to enough [0026] Unless otherwise indicated, the terms “manage,” hydrogen atoms to satisfy the valences. “managing” and “management” encompass preventing the [0035] As used herein, the term “bene?t agent” includes recurrence of the speci?ed disease or disorder in a patient who any active ingredient that is to be delivered into and/or onto has already suffered from the disease or disorder, and/or the skin at a desired location, such as a cosmetic, care or lengthening the time that a patient who has suffered from the pharmaceutical agent, and that is capable of providing a cos disease or disorder remains in remission. The terms encom metic, care, or therapeutic effect. pass modulating the threshold, development and/or duration [0036] By “cosmetic agent,” it is meant any ingredient that of the disease or disorder, or changing the way that a patient is appropriate for cosmetically treating, providing nutrients responds to the disease or disorder. to, and/or conditioning the hair, nail, and/or skin via topical [0027] Unless otherwise indicated, the terms “prevent,” application. “preventing” and “prevention” contemplate an action that [0037] By “pharmaceutical agent,” it is mean any drug that occurs before a patient begins to suffer from the speci?ed is either hydrophobic or hydrophilic in nature and appropriate disease or disorder, which inhibits or reduces the severity of for topical use. the disease or disorder. In other words, the terms encompass [0038] As used herein “medicament agents” include those prophylaxis. agents capable of promoting recovery from injury and illness. [0028] Unless otherwise indicated, a “prophylactically [0039] As used herein “pharrnaceutically, dermatologi effective” means suf?cient to prevent a disease or condition, cally, or cosmetically acceptable” means that the ingredients or one or more symptoms associated with the disease or which the term describes are suitable for use in contact with condition, or prevent its recurrence. A prophylactically effec the skin without undue toxicity, incompatibility, instability, tive amount of a compound means an amount of therapeutic irritation, allergic response, and the like. agent, alone or in combination with other agents, which pro [0040] Other than where otherwise indicated, or where vides a prophylactic bene?t in the prevention of the disease. required to distinguish over the prior art, all numbers express The term “prophylactically effective” can encompass a com ing quantities of ingredients herein are to be understood as position that improves overall prophylaxis or enhances the modi?ed in all instances by the term “about”. As used herein, prophylactic ef?cacy of another prophylactic agent. the words “may” and “may be” are to be interpreted in an [0029] Unless otherwise indicated, a “therapeutically open-ended, non-restrictive manner. At minimum, “may” and effective” means suf?cient to provide a therapeutic bene?t in “may be” are to be interpreted as de?nitively including, but the treatment or management of a disease or condition, or to not limited to, the composition, structure, or act recited. delay or minimize one or more symptoms associated with the [0041] As used herein, and in particular as used herein to disease or condition. A therapeutically effective amount of a de?ne the elements of the claims that follow, the articles “a” compound means an amount of therapeutic agent, alone or in and “an” are synonymous and used interchangeably with “at combination with other therapies, which provides a therapeu least one” or “one or more,” disclosing or encompassing both tic bene?t in the treatment or management of the disease or the singular and the plural, unless speci?cally de?ned herein condition. The term “therapeutically effective” can encom otherwise. The conjunction “or” is used herein in both in the pass a composition that improves overall therapy, reduces or conjunctive and disjunctive sense, such that phrases or terms avoids symptoms or causes of a disease or condition, or conjoined by “or” disclose or encompass each phrase or term enhances the therapeutic ef?cacy of another therapeutic alone as well as any combination so conjoined, unless spe agent. ci?cally de?ned herein otherwise. [0030] Unless otherwise indicated, the terms “treat, treat [0042] The description of a group or class of materials as ing” and “treatment” contemplate an action that occurs while suitable or preferred for a given purpose in connection with a patient is suffering from the speci?ed disease or disorder, the invention implies that mixtures of any two or more of the US 2014/0212362 A1 Jul. 31, 2014

members of the group or class are equally suitable or pre speci?c indication to be treated, prevented, or managed, and ferred. Description of constituents in chemical terms refers the age, sex and condition of the patient. The roles played by unless otherwise indicated, to the constituents at the time of such factors are well known in the art, and may be accommo addition to any combination speci?ed in the description, and dated by routine experimentation. One skilled in the art can does not necessarily preclude chemical interactions among adjust the dosage forms to achieve the desired therapeutic the constituents of a mixture once mixed. Steps in any method levels. disclosed or claimed need not be performed in the order [0048] Depending on the speci?c tissue to be treated, addi recited, except as otherwise speci?cally disclosed or claimed. tional components may be used prior to, in conjunction with, [0043] Changes in form and substitution of equivalents are or subsequent to treatment with active ingredients of the contemplated as circumstances may suggest or render expe invention. For example, penetration enhancers may be used to dient. Although speci?c terms have been employed herein, assist in delivering active ingredients to the tissue. such terms are intended in a descriptive sense and not for [0049] Another embodiment of the present invention is purposes of limitation. directed to a method for depositing a bene?t agent onto the skin to a desired location on a human or animal. While the Methods of Treatment frequency and amount of the bene?t agent-containing com [0044] The general form of treatment for dermatoses position to be applied will depend upon, for example, the type according to the invention is chemical therapy by topical and amount of bene?t agent available, the intended usage of administration of the bene?t agent or agents. Topical medi the ?nal composition, i.e. therapeutic versus maintenance regimen, and the sensitivity of the individual user to the cations may be delivered to the affected site by means includ ing but not limited to baths, soaps, shampoos, wet dressings composition, typically the bene?t agent-containing compo sition of the present invention should be topically applied to or soaks, powders, pastes, tinctures, shake lotions, aerosols, affected body parts at regular intervals, and preferably twice foams, medicated tape, transdermal devices, creams, oint daily, in the morning and evening. The composition may be ments, oils, and emulsions. applied more frequently during the initial stages of treatment, [0045] Generally, the composition is topically applied to until the desired effect is achieved, then less frequently when the affected skin areas in a predetermined or as-needed regi maintenance is desired. men to bring about improvement, it generally being the case that gradual improvement is noted with each successive Conditions Treated application. Insofar as has been determined based upon stud ies to date, no adverse side effects are encountered. [0050] The methods according to the invention can be used [0046] In treating atopic dermatitis, psoriasis, eczema, or to treat a variety of skin conditions, which result in in?am any of the conditions or indications disclosed herein, an oint mation or erythema. For example, in?ammation or erythema ment or lotion according to aspects of the invention contain can result from external causes such as sun or wind burn or ing 0.01% to 10% by weight of the imidazole compound and, irritating soaps or cleansers. It is also known that in?amma optionally, 0.01% to 25% of colloidal oatmeal is applied to tion and erythema can be caused from inherent conditions the affected area of the skin. . The upper limit of the imidazole such as rosacea, atopic dermatitis, or allergic skin reactions. compound may preferably be 9%, 8%, 7%, 6%, 5%, 4%, 3%, The method according to the invention can be used to treat 2.5%, 2%, or even 1.5% by weight of the ointment or lotion, in?ammation and/or erythema caused by both external and and the lower limit of the imidazole compound may prefer inherent conditions. ablybe 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, oreven0.5% [0051] Another aspect of the invention relates to combina by weight of the ointment or lotion. Preferably the ointment tions of imidazole-based compounds and colloidal oatmeal or lotion comprises 1.0% by weight of the imidazole com and to methods of their use for the treatment, prevention, and pound. The upper limit of the colloidal oatmeal may prefer management of atopic dermatitis, seborrheic dermatitis, con ably be 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, tact dermatitis, cutaneous sarcoidosis, drug induced photo 2.5%, 2%, or even 1.5% by weight of the ointment or lotion, sensitivity, ?xed drug eruptions, id reactions, bullous skin and the lower limit of the colloidal oatmeal may preferably be diseases, discoid lupus erythematosus, subacute cutaneous 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, or even 0.5% by lupus, alopecia areata, sea bathers eruptions, psoriasis, weight of the ointment or lotion. Preferably the ointment or dyshidrotic eczema, and Pompholyx. This list of examples of lotion comprises 1.0% by weight of the colloidal oatmeal. dermatological conditions, for which the therapy as proposed The patient may be treated, for example, daily for two to four in this application is useful, does not limit the present inven weeks with a dosage amount of 5 mg to 10 mg of imidazole tion to these indications, since there may be other dermato compound and 5 mg to 10 mg of colloidal oatmeal a day. The logical conditions not mentioned here where combinations of topically effective amounts of imidazole compound are typi imidazole-based compounds and colloidal oatmeal may also cally 0.5% to 2% by weight and of the colloidal oatmeal be effective. Thus, further non-limiting examples of condi 0.5%% to 2% by weight in an ointment or lotion and are tions to which the present invention may be applied include: applied one to three times a day for a period of time, typically [0052] (a) dermatologic allergies, such as contact derma weeks, to effectively treat the dermatoses. titis, photoallergic dermatitis; industrial dermatoses [0047] Under certain circumstances, it is desirable to caused by exposure to a variety of compounds used by administer the imidazole compound and colloidal oatmeal industry that are contact irritants; atopic eczema (infan simultaneously with other dermatologically active agents. tile and adult), dermatoses caused by drugs and nummu The precise amount of imidazole compound and colloidal lar eczema; oatmeal used alone or with other dermatologic agents varies [0053] (b) immune-mediated skin diseases, suchbullous depending, for example, on the condition for which the com pemphigoid, pemphigus vulgaris, necrotizing vasculitis, position is administered. The amount, route of administration lupus erythematosus (discoid and systemic), dermatitis and dosing schedule will depend upon factors such as the herpetiformis; US 2014/0212362 A1 Jul. 31, 2014

[0054] (B2) immune, non-immune, or autoimmune urti rosal, quartemium-lS, neomycin sulfate, formaldehyde, carias such as allergic urticaria, chronic idiopathic urti bacitracin, thiuram mix, balsam of Peru, cobalt chloride, caria, solar urticaria, cholinergic urticaria, pressure urti p-phenylenediamine, and carba mix. Other steroid responsive caria, cold urticaria, dermatographia, and pruritic dematoses might include seborrheic dermatitis, diaper rash, urticarial papules and plaques of pregnancy (PUPPP); and bullous skin diseases such as bullous pemphigoid. [0055] (B3) mastocytosis; [0075] Further examples of diseases and disorders include [0056] (c) pruritic dermatoses, such as winter, senile, and ankylosing spondylitis, asthma (e.g., bronchial asthma), essential pruritus, pruritus ani, external otitis, and geni atopic dermatitis, Behcet’s disease, graft-vs-host disease, tal pruritus; Kawasaki syndrome, lupus erythematosus, multiple sclero [0057] (d) vascular dermatoses, such as erythema multi sis, myasthenia gravis, pollinosis, psoriasis, psoriatic arthri forme, erythema nodosum, stasis dermatitis, purpuric tis, rheumatoid arthritis, scleroderma, transplant rejection dermatoses such as thrombocytopenic purpura and (e.g., of organ, cell or bone marrow), type 1 diabetes, and Henoch-Schonlein purpura, ecchymoses, stasis pur uveitis. Additional diseases and disorders include Addison’s pura, primary and secondary telangiectases; Disease, anti-phospholipid syndrome, autoimmune atrophic [0058] (e) seborrheic dermatitis, acne, and rosacea; gastritis, achlorhydra autoimmune, Celiac Disease, Crohn’s [0059] (f) papulosquamous dermatoses: such as psoria Disease, Cushing’s Syndrome, dermatomyositis, Goodpas sis, pityriasis rosea, lichen planus; ture’s Syndrome, Grave’s Disease, Hashimoto’s thyroiditis, [0060] (g) bacterial dermatoses, such as pyoderma, idiopathic adrenal atrophy, idiopathic thrombocytopenia, impetigo, ecthyma, folliculitis, furuncles styes, car Lambert-Eaton Syndrome, pemphigoid, pemphigus vulgaris, buncles, sweat gland infections, erysipelas, erythrasma, pernicious anemia, polyarteritis nodosa, primary biliary cir infected ulcers, and infected eczematoid dermatitis; rhosis, primary sclerosing cholangitis, Raynauds, Reiter’s [0061] (h) systemic bacterial infections with skin mani Syndrome, relapsing polychondritis, Schmidt’s Syndrome, festations, such as scarlet fever, granuloma inguinale, Sjogren’s Syndrome, sympathetic ophthalmia, Takayasu’s chancroid, tuberculosis, leprosy, gonorrhea, rickettsial Arteritis, temporal arteritis, thyrotoxicosis, ulcerative colitis, diseases, actinomycosis, syphilis; and Wegener’ s granulomatosis. [0062] (i) viral skin infection, such as those caused by herpes simplex virus, Kaposi’s varicelliform eruption, [0076] Further indications addressed by the compositions zoster, chickenpox, smallpox, vaccinia, cowpox, warts, and methods of the invention include, for example, immuno molluscum contagiosum, lymphogranuloma venereum, suppression (e.g., employing one or more agents such as exanthematous diseases such as German measles, cyclosporin A, OKT3, FK506, mycophenolate mofetil roseola and erythema infectiosum; (MMF), azathioprine, corticosteroids (such as prednisone), [0063] (j) mycolic skin infections, such as tinea (super antilymphocyte globulin, antithymocyte globulin, and the ?cial fungal infections of the skin in various body sites), like), in?ammatory disease therapy (e.g., employing disease sporotrichosis, North American blastomycosis; modifying agents (such as antimalarials, methotrexate, sul [0064] (k) granulomatous dermatoses, such as sarcoido fasalaZine, mesalamine, azathioprine, 6-mercaptopurine, sis, granuloma annulare, silica induced granulomas; metronidazole, inj ectable and oral gold, D-penicillamine, and the like), corticosteroids, non-steroidal antiin?ammatory [0065] (l) parasitic skin infections, such as scabies, drugs (such as aspirin, sodium salicylate, magnesium salicy pediculosis; late, choline magnesium salicylate, salicylsalicylic acid, ibu [0066] (m) bullous dermatoses; profen, naproxen, diclofenac, di?unisal, etodolac, fenoprofen [0067] (n) exfoliative dermatitis, primary and secondary; calcium, ?uriprofen, piroxicam, indomethacin, ketoprofen, [0068] (o) pigmented dermatoses, such as chloasma ketorolac tromethamine, meclofenamate, meclofenamate (melasma) and vitiligo; sodium, mefenamic acid, nabumetone, oxaproZin, phenyl [0069] (p) collagen diseases, such as lupus erythemato butyl nitrone (PBN), sulindac, tolmetin, and the like), and the sus, scleroderma, dermatomyositis; like), anti-cancer therapy (e.g., employing one or more agents [0070] (q) dermatoses due to internal diseases, such as such as alkylating agents (such as mechlorethamine, Kaposi’s sarcoma, pyoderma gangrenosum associated chlorambuccil, ifosfamide, melphalan, busulfan, carmustine, with ulcerative colitis, ulcers due to diabetes, xantho lomustine, procarbaZine, dacarbaZine, cisplatin, carboplatin, mas; and the like), antimetabolites (such as methotrexate, mercap [0071] (r) diseases of mucous membranes, such as aph topurine, thioguanine ?uorouracil, cytarabine, and the like), thous ulcers; hormonal agents (such as testosterone propionate, ?uoxyme [0072] (s) dermatoses due to physical agents, such as sterone, ?utamide, diethylstilbestrol, ethinyl estradiol, sunbums and radiation; and tamoxifen, hydroxyprogesterone caproate, medroxyprogest [0073] (t) photosensitive dermatoses of the exogenous erone, megestrol acetate, and the like), adrenocorticosteroids type, such as drug-induced photodermatitis, contact der (such as prednisone), aromatase inhibitors (such as amino matitis with photoallergic components, and of the glutethimide), leuprolide, goserelin acetate, biological endogenous-type, such as porphyrias, collagen vascular response modi?ers (such as interferon-.alpha.2a, interferon-. disorders such as lupus erythematosus, dermatomyosi alpha.2b, interleukin-2, and the like), peptide hormone tis, and polymorphous light eruptions. inhibitors (such as octreotide acetate), natural products (such [0074] Contact dermatitis is a steroid responsive condition as vinblastine, vincristine, vinorelbine, paclitaxel, dactino and is caused by plant saps (poison ivy, etc) and chemicals. mycin, daunorubicin, idarubicin, doxorubicin, etoposide, pli About 80% are irritant type while 20% are allergic. There are camycin, mitomycin, mitoxantrone, bleomycin, hydrox over 85,000 chemicals estimated to exist in the modern envi yurea, mitotane, ?udarabine, cladribine, and the like), ronment. Any might cause contact dermatitis. The most com supportive agents (such as allopurinol, mesna, leucovorin, mon allergic sensitizers are nickel sulfate, fragrances, thime erythropoietin, ?lgrastim, sargramostim, and the like), and US 2014/0212362 Al Jul. 31, 2014

the like, anti-microbial therapy (e.g., employing one or more methylbromide, methylnitrate, methylsulfate, mucate, nap agents such as celftriaxone, TMP-SMZ, penicillin, aminogly sylate, nitrate, pamoate, pantothenate, pho sphate/dipho spate, cosides, vancomycin, gentamicin, rifampin, imipenem, clin polygalacturonate, salicylate, stearate, subacetate, succinate, damycin, metronidazole, tetracycline, erythromycin, sul sulfate, tannate, tartrate, teoclate, tosylate and triethiodide. fonamide, streptomycin, ampicillin, isoniazid, pyrazinamide, [0085] Pharmaceutically, dermatologically, or cosmeti ethambutol, and the like), anti-fungal therapy (e.g., employ cally acceptable basic/cationic salts include, and are not lim ing agents such as amphotericin B, griseofulvin, myastatin, ited to aluminum, benzathine, calcium, chloroprocaine, cho ?ucytosine, natamycin, antifungal imidazoles (e.g., clotrima line, diethanolamine, ethylenediamine, lithium, magnesium, zole, miconazole, ketoconazole, ?uconazole, itraconazole, meglumine, potassium, procaine, sodium and zinc. Other and the like), and the like, anti-retroviral therapy (e.g., salts may, however, be useful in the preparation of com employing agents such as protease inhibitors (such as Invi pounds according to this invention or of their cosmetically rase, Ritonavir, Crixivan, and the like), zidovudine, acceptable salts. Organic or inorganic acids also include, and didanosine, zalcitabine, stavudine, viramune, and the like), are not limited to, hydriodic, perchloric, sulfuric, phosphoric, and treatment of cellular proliferative diseases (e.g., onco propionic, glycolic, methanesulfonic, hydroxyethane lytic viral therapy employing naturally occurring and/or sulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic, modi?ed oncolytic viruses such as reovirus, adenovirus, sen cyclohexanesulfamic, saccharinic or tri?uoroacetic acid. eca valley virus, vesicular stomatitis virus, poliovirus, vacina [0086] In particular embodiments, the imidazole com virus, herpes virus and the like), and treatment of opportunis pound is 2-acetyl-4-tetrahydroxybutylimidazole (THI). THI tic infections and malignancies (e.g., anti-AIDS treatment, is a component of caramel color 111 and has been identi?ed as employing agents such as pentamidine, trimethoprim/sul a sphingosine-1-phosphate lyase antagonist. Sphingosine-1 famethoxazole, primaquine, atovaquone, clarithromycin, phosphate (S1P) is a bioactive molecule with effects on mul clofazimine, ethambutol, rifampin, amikacin, cipro?oxacin, tiple organ systems. Sphingosine-1-phosphate lyase is a vita pyrimethamine, amphotericin B, ganciclovir, foscarnet, ?u min B6-dependent enzyme localized in the membrane of the conazole, ketoconazole, acyclovir, and the like). endoplasmic reticulum. Van Veldhoven and Mannaerts, J. Biol. Chem. 266:12502-12507 (1991); Van Veldhoven and Bene?t Agents Mannaerts, Adv. Lipid. Res. 26:69 (1993). The polynucle [0077] A ?rst element of the compositions and methods otide and amino acid sequences of human SP1 lyase and its according to aspects of the invention is an imidazole com gene products are described in PCT Patent Application No. pound of the formula: WO 99/16888. [0087] THI inhibits S1P lyase activity when administered to mice. Schwab, S. et al., Science 309:1735-1739 (2005). R7 R8 Administration of the compound to rats and mice induces HO lymphopenia and causes the accumulation of mature T cells in the thymus. See, e.g., Schwab, supra; Pyne, S. G., ACGC R9 Chem. Res. Comm. 11:108-112 (2000); Gugasyan, R., et al., — R6 Immunology 93(3):398-404 (1998); Halweg, K. M. and Buchi, G., J. Org. Chem. 50:1 134-1136 (1985); US. Pat. No. HN / N 4,567,194 to Kroeplien and Rosdorfer. Still, there are no known reports of THI having an immunological effect in animals other than mice and rats. Although US. Pat. No. R1 0 4,567,194 alleges that THI and some related compounds may be useful as immunosuppressive medicinal agents, studies of the compound in humans have found no immunological wherein: effects. See Thuvander, A. and Oskarsson, A., Fd. Chem. [0078] R1 is hydrogen, alkyl or aryl; Toxic. 32(1):7-13 (1994); Houben, G. F., et al., Fd. Chem. [0079] R6 is ORlo or OC(O)R10; Toxic. 30(9):749-757 (1992). [0080] R7 is ORll or OC(O)R11; [0088] Compounds of the invention may contain one or [0081] R8 is ORl2 or OC(O)R12; and more stereocenters, and can exist as racemic mixtures of [0082] R9 is hydrogen, CHzOR13 or CHZOC(O)R13; and enantiomers or mixtures of diastereomers. This invention each of R10, R11, R12 and R13 is independently hydrogen or encompasses stereomerically pure forms of such compounds, lower alkyl. as well as mixtures of those forms. Stereoisomers may be [0083] The compounds of the preceding formula of the asymmetrically synthesized or resolved using standard tech present invention may also be present in the form of pharma niques such as chiral columns or chiral resolving agents. See, ceutically, dermatologically, or cosmetically acceptable salts e.g., Jacques, J ., et al., Enantiomers, Racemates and Resolu thereof that can be made by conventional techniques. tions (Wiley lnterscience, New York, 1981); Wilen, S. H., et [0084] Pharmaceutically, dermatologically, or cosmeti al., Tetrahedron 33 :2725 (1977); Eliel, E. L., Stereochemistry cally acceptable acidic/anionic salts include, and are not lim of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, ited to acetate, benzenesulfonate, benzoate, bicarbonate, S. H., Tables of Resolving Agents and Optical Resolutions, p. bitartrate, bromide, calcium edetate, camsylate, carbonate, 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, Ind., 1972). This invention further encompasses stereoiso esylate, fumarate, glyceptate, gluconate, glutamate, glycol meric mixtures of compounds disclosed herein. It also lylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, encompasses con?gurational isomers of compounds dis hydrochloride, hydroxynaphthoate, iodide, isethionate, lac closed herein, either in admixture or in pure or substantially tate, lactobionate, malate, maleate, mandelate, mesylate, pure form. US 2014/0212362 A1 Jul. 31, 2014

[0089] Compounds of the invention can be prepared by ever, it is to be understood that the bene?t agents useful herein methods known in the art (e.g., by varying and adding to the may, in some circumstances, provide more than one thera approaches described in Pyne, S. G., ACGC Chem. Res. peutic bene?t or operate via greater than one mode of action. Comm. 11:108-112 (2000); Halweg, K. M. and Buchi, G., J. Therefore, the particular classi?cations provided herein are Org. Chem. 50:1134-1136 (1985)). Compounds can also be made for the sake of convenience and are not intended to limit made by the methods disclosed below and variants thereof, the bene?t agents to the particular application(s) listed. In which will be apparent to those of ordinary skill in the art. addition, the compounds, which are identi?ed below as being [0090] The compositions according to the invention pref suitable for use as bene?t agents, may be used in an amount erably contain the imidazole-based compound in an amount over and above the amount that they may be used for other of 0.001% to 10%, more preferably 0.5% to 2%, and most purposes in the compositions of the invention. preferably about 1% by weight of the composition. The imi dazole-based compound may also preferably be included in [0095] Further bene?t agents useful in the methods and an amount of0.01% to 10%, 0.1% to 10%, 0.1% to 9%, 0.1% compositions of the invention include antipruritics, emol to 8%, 0.1% to 7%, 0.1% to 6%, 0.1% to 5%, 0.2% to 5%, lients, antiseptics, antifungals, antiin?ammatories, immuno 0.3% to 5%, 0.4% to 5%, 0.5% to 5%, 0.5% to 4%, and 0.5% suppressants, psoriasis agents, anti-cancer agents, antibiot to 3% by weight of the composition. ics, antiparasitics, antioxidants, antibacterials, [0091] A further element of preferred compositions and antimicrobials, antiretrovirals, moisturizers, sunscreens, methods according to aspects of the invention is colloidal NSAIDs, hormones, steroids, analgesics, antihistamines, and oatmeal. Oatmeal has been used as a soothing agent to relieve antipyretics. The following chemotherapeutic agents used to itch and irritation associated with various xerotic dermatoses. treat dermatoses are not comprehensive but rather consist of In 1945, a ready to use colloidal oatmeal, produced by ?nely examples of commonly used groups of drugs. The antihista grinding the oat andboiling it to extract the colloidal material, mines added to the topical compositions are typically from became available. Today, colloidal oatmeal is available in the structural classes of ethylenediamines, aminoalkylethers, various dosage forms from powders for the bath to shampoos, and alkylamines. Among the ethylenediamine group are such shaving gels, and moisturizing creams. Currently, the use of antihistamines as antazoline phosphate, clemizole hydro colloidal oatmeal as a skin protectant is regulated by the US. chloride, chlorcyclizine hydrochloride, chlorothen, meth Food and Drug Administration (FDA) according to the Over apheniline hydrochloride, dorastine hydrochloride, methdi The-Counter Final Monograph for Skin Protectant Drug lazine hydrochloride, promethazine hydrochloride, Products issued in June 2003. Its preparation is also standard pyrathiazine hydrochloride, pyrilamine maleate, quinetolate, ized by the United States Pharrnacopeia. thenaldine, thenyldiamine hydrochloride, thonzylamine [0092] The many clinical properties of colloidal oatmeal hydrochloride, tripelennamine, and zolamine hydrochloride. derive from its chemical polymorphism. The high concentra Among the aminoalkylether group are such antihistamines as tion in starches and beta-glucan is responsible for the protec chlorphenoxamine hydrochloride, carbinoxamine maleate, tive and water-holding functions of oat. The presence of dif clemastine, diphenhydramine hydrochloride, diphenylpyra ferent types of phenols confers antioxidant and anti line hydrochloride, doxylamine succinate, and pyroxamine in?ammatory activity. Some of the oat phenols are also strong maleate. Among the alkamine group are such antihistamines ultraviolet absorbers. The cleansing activity of oat is mostly as azatadine maleate, bromdiphenhydramine hydrochloride, due to saponins. Its many functional properties make colloi cyproheptadine hydrochloride, dimethindene maleate, phen dal oatmeal a cleanser, moisturizer, buffer, as well as a sooth indamine tartrate, pheniramine maleate, brompheniramine ing and protective anti-in?ammatory agent. Colloidal oat maleate, dexbrompheniramine maleate, chlorpheniramine meal may act at the site of application to control the osmotic maleate, dex-chlorpheniramine maleate, closiramine, cyc pressure of water with respect to the skin and permits liramine maleate, mianserin hydrochloride, pyrrobutamine adequate water to enter into the stratum comeum. Oatmeal phosphate, terfenadine, and triprolidine hydrochloride. may leave an occlusive ?lm on the skin that serves to hold in Besides the above, some compositions in structural groups, moisture, which protects the skin against irritation and acts as which groups are not primarily antihistamines such as phe an antipruritic. nothiazines, piperidines, and piperazines, have antihista [0093] Colloidal oatmeal includes the powder resulting minic characteristics. These groups include promethazine, from the grinding and further processing of whole oat grain astemizole, fexofenadine, loratadine, desloratadine, terfena meeting United States Standards for Number 1 or Number 2 dine, cetirizine, and meclizin, which are antihistaminic. oats. A suitable colloidal oatmeal has a particle size distribu [0096] Another active ingredient used in the formulations tion as follows: not more than 3 percent of the total particles hereof is the employment of a topical anesthetic. While some exceed 150 micrometers in size and not more than 20 percent of these topical anesthetic compounds are structurally related of the total particles exceed 75 micrometers in size. Examples to the antihistamines in the preceding paragraph, the com of suitable colloidal oatmeals include, but are not limited to, pounds take on a disinct role in preparations described. The “Tech-O” colloidal oatmeals (e. g., Tech-O #11-065 colloidal ?rst group are esters of benzoic acid and diethylaminoethyl oatmeal) available from the Beacon Corporation and colloi alcohols, namely, benzocaine, chloroprocaine, procaine, and dal oatmeals available from Quaker. A USP grade of colloidal tetracaine. Other synthetic anesthetic compounds, which are oatmeal suitable for use in this invention may be obtained not esters of benzoic acid and are pharmacologically grouped under the mark “Tech-O” from Beacon CMP Corporation, together, are bupivacaine, dibucaine, lidocaine, mepivacaine, 611 Spring?eld Road, Kenilworth, N]. 07033. and prilocaine. Besides these two groups, the compounds of [0094] The compositions may further contain one or more etidocaine and pramoxine are also applicable. In one of the bene?t agents or pharmaceutically-acceptable salts thereof. topical spray formulations described below the anesthetic, The bene?t agents useful herein may be categorized by their pramoxine hydrochloride, comprises up to 1.0 percent by therapeutic bene?t or their postulated mode of action. How weight thereof. US 2014/0212362 A1 Jul. 31, 2014

[0097] Corticosteroids are a group of agents used to treat up preparations; vitamins; amino acids and their derivatives; in?ammation of the skin having many different etiologies. herbal extracts; retinoids; ?avenoids; sensates; anti-oxidants; Examples of indications in which systemically administered skin conditioners; hair lighteners; chelating agents; cell tum corticosteroids are employed as therapeutics include psoria over enhancers; coloring agents; pigments; sunscreens; anti sis, erythema nodosum leprosum, discold lupus erythemato edema agents; collagen enhancers; and mixtures thereof. sus, urticaria, different types of pruritis, pemphigus and kel [0107] Examples of suitable anti-edema agents nonexclu oids. Antihistamines are a group of agents having an sively include bisabolol natural, synthetic bisabolol, and mix antipruritic effect. They include alkylamines, phenothiazines, tures thereof. Examples of suitable vasoconstrictors nonex ethylenediamine, ethanolamine, and piperazine. Retinoids clusively include horse chestnut extract, prickly ash, and are synthetic and natural forms of vitaminA, including isotre mixtures thereof. Examples of suitable anti-in?ammatory tinoin and etretinate. Retinoids are used to treat acne vulgaris agents nonexclusively include benoxaprofen, centella asi or rosacea and psoriasis. Antimicrobial compounds include atica, bisabolol, feverfew (whole), feverfew (parthenolide antibiotic, antibacterial, antifungal, antiviral, and antipara free), green tea extract, green tea concentrate, hydrogen per sitic agents. oxide, lycopene including “Lyc-o-Pen” available from [0098] In addition to the imidazole-based compound and LycoRed Natural Products Industries, Ltd., oat oil, chamo colloidal oatmeal, the bene?t agents comprising topical mile, and mixtures thereof. Examples of collagen enhancers preparations used according to the invention may also com nonexclusively include vitamin A, vitamin C, and mixtures prise: thereof. Examples of suitable skin ?rming agent nonexclu [0099] (a) anti pruritic agents, which relieve itching, sively include dimethylaminoethanol (“DMAE”). Examples such as 0.25% menthol, 0.5% phenol, 2% camphor and of suitable antipruritics and skin protectants nonexclusively 2-10% coal tar solutions; include betaglucan, feverfew, soy and derivatives thereof, [0100] (b) keratoplastic agents, which increase the thick bicarbonate of soda, colloidal oatmeal, surfactant based col ness of the horny layer of the skin, such as 1-2% salicylic loidal oatmeal cleanser, Anagallis Arvensis, Oenothera Bien acid; nis, Verbena Of?cinalis, and the like. [0101] (c) emollients, which often soften surface layers [0108] Examples of suitable re?ectants nonexclusively of skin, such as petrolatum, nivea oil and mineral oil; include mica, alumina, calcium silicate, glycol dioleate, gly [0102] (d) antiseptics, which inhibit and/or destroy fungi col distearate, silica, sodium magnesium ?uorosilicate, and and/or bacteria, such as 3% Vioform, 3-10% ammoni mixtures thereof. Suitable ?lm forming polymers include ated mercury, antifungal agents such as Whit?elds oint those that, upon drying, produce a substantially continuous ment, antibiotics such as 3% terramycin, 0.5% neomy coating or ?lm on the skin. Nonexclusive examples of suit cin, 0.1% garamycin and 3% aureomycin; able ?lm forming polymers include acrylamidopropyl trimo [0103] (e) antieczematous agents, which remove oozing nium chloride/acrylamide copolymer; corn starch/acryla and vesicular excretions, such as Burows solution, soaks mide/sodium acrylate copolymer; polyquatemium-10; or packs, 2-5% coal tar solutions and 0.5-2% hydrocor polyquatemium-47; polyvinylmethylether/maleic anhydride tisone; copolymer; styrene/acrylates copolymers; and mixtures [0104] (f) keratolytic agents, which remove or soften the thereof. Commercially available humectants which are horny layer of the skin, such as 4-10% salicylic acid, capable of providing moisturization and conditioning prop 2-4% resorcinol and 4-10% sulfur; and erties to the composition are suitable for use in the present [0105] (g) antiparasitics, which inhibit or destroy infes invention. Examples of suitable humectants nonexclusively tations by parasites, such as Kewell cream for scabies include: water soluble liquid polyols selected from the group and pediculosis and Eurax lotion for scabies. comprising glycerine, propylene glycol, hexylene glycol, [0106] Further examples of suitable bene?t agents include, butylene glycol, pentylene glycol, dipropylene glycol, and but are not limited to: depigmentation agents; re?ectants; ?lm mixtures thereof; polyalkylene glycols; polyethylene glycol forming polymers; humectants; amino acids and their deriva ether of methyl glucose; urea; fructose; glucose; honey; lactic tives; antimicrobial agents; allergy inhibitors; anti-acne acid; maltose; sodium glucuronate; and mixtures thereof. agents; anti-aging agents; anti-wrinkling agents, antiseptics; [0109] Suitable amino acid agents include amino acids analgesics; antitussives; antipruritics; local anesthetics; anti derived from the hydrolysis of various proteins as well as the hair loss agents; hair growth promoting agents; hair growth salts, esters, and acyl derivatives thereof. Examples of such inhibitor agents, antihistamines such as Mandragora Vemalis, amino acid agents nonexclusively include amphoteric amino Tanacetum Parthenium and the like; antiinfectives such as acids such as alkylamido alkylamines, i.e. stearyl acetyl Acacia Catechu, Aloe Barbadensis, Convallaria Majalis, glutamate, capryloyl silk amino acid, capryloyl collagen Echinacea, Eucalyptus, Mentha Piperita, Rosa Canina, Sas amino acids; capryloyl keratin amino acids; capryloyl pea safras Albidum, and the like; in?ammation inhibitors; anti amino acids; cocodimonium hydroxypropyl silk amino acids; emetics; anticholinergics; vasoconstrictors; vasodilators; corn gluten amino acids; cysteine; glutamic acid; glycine; wound healing promoters; peptides, polypeptides and pro hair keratin amino acids; amino acids such as aspartic acid, teins; deodorants and anti-perspirants; medicament agents; threonine, serine, glutamic acid, proline, glycine, alanine, skin emollients and skin moisturizers; skin ?rming agents, cystine, valine, methionine, isoleucine, leucine, tyrosine, hair conditioners; hair softeners; hair moisturizers; vitamins; phenylalanine, cysteic acid, lysine, histidine, arginine, cys tanning agents; skin lightening agents; antifungals such as teine, tryptophan, citrulline; lysine; silk amino acids, wheat Centaurea Cyanus, Kalmia Latifolia and antifungals for foot amino acids; and mixtures thereof. preparations; depilating agents; shaving preparations; exter [0110] Suitable proteins include those polymers that have a nal analgesics; perfumes; counterirritants; hemorrhoidals; long chain, i.e. at least about 10 carbon atoms, and a high insecticides; poison ivy products; poison oak products; burn molecular weight, i.e. at least about 1000, and are formed by products; anti-diaper rash agents; prickly heat agents; make self-condensation of amino acids. Nonexclusive examples of US 2014/0212362 A1 Jul. 31, 2014

such proteins include collagen, deoxyribonuclease, iodized such as green tea, soy, milk thistle, algae, aloe, angelica, bitter corn protein; milk protein; protease; serum protein; silk; orange, coffee, goldthread, grapefruit, hoellen, honeysuckle, sweet almond protein; Wheat germ protein; Wheat protein; Job’s tears, lithospermum, mulberry, peony, puerarua, nice, alpha and beta helix of keratin proteins; hair proteins, such as sa?lower, and mixtures thereof. intermediate ?lament proteins, high-sulfur proteins, ultra [0116] Examples of suitable external analgesics and local high-sulfur proteins, intermediate ?lament-associated pro anesthetics nonexclusively include benzocaine, dibucaine, teins, high-tyrosine proteins, high-glycine tyrosine proteins, benzyl alcohol, camphor, capsaicin, capsicum, capsicum tricohyalin, and mixtures thereof. oleoresin, juniper tar, menthol, methyl nicotinate, methyl [0111] Examples of suitable vitamins nonexclusively salicylate, phenol, resorcinol, turpentine oil, and mixtures include vitamin B complex; including thiamine, nicotinic thereof. acid, biotin, pantothenic acid, choline, ribo?avin, vitamin B6, [0117] Examples of suitable antiperspirants and deodor vitamin B12, pyridoxine, inositol, camitine; vitamins A,C,D, ants nonexclusively include aluminium chlorohydrates, alu E,K and their derivatives such as vitamin A palmitate and minium Zirconium chlorohydrates, and mixtures thereof. pro-vitamins, e.g. (i.e. panthenol (pro vitamin B5) and pan [0118] Examples of suitable counterirritants nonexclu thenol triacetate) and mixtures thereof. sively include camphor, menthol, methyl salicylate, pepper [0112] Examples of suitable antibacterial agents nonexclu mint and clove oils, ichtammol, and mixtures thereof. sively include bacitracin, erythromycin, neomycin, tetracy Examples of suitable in?ammation inhibitors nonexclusively cline, chlortetracycline, benzethonium chloride, phenol, and includes hydrocortisone, Fragaria Vesca, Matricaria mixtures thereof. [0119] Chamomilla, and Salvia O?icinalis. Other well [0113] Examples of suitable skin emollients and skin mois known antipruritic agents include phenol, camphor, menthol, turizers nonexclusively include mineral oil, lanolin, veg hydro-cortisone, hydrocortisone acetate, camphorated meta etable oils, isostearyl isostearate, glyceryl laurate, methyl cresol, phenolated sodium, and mixtures thereof. gluceth-lO, methyl gluceth-20 chitosan, and mixtures [0120] Other preferred bene?t agents nonexclusively thereof. include DMAE, soy and derivatives thereof, colloidal oat [0114] Examples of sunscreen agents nonexclusively meal, sulfonated shale oil, olive leaf, elubiol, 6-(l-piperidi include benzophenones, bomelone, butyl paba, cinnami nyl)-2,4-pyrimidinediamine-3-oxide, ?nasteride, ketocona dopropyl trimethyl ammonium chloride, disodium distyryl Zole, salicylic acid, Zinc pyrithione, coal tar, benzoyl biphenyl disulfonate, paba, potassium methoxycinnamate, peroxide, selenium sul?de, hydrocortisone, sulfur, menthol, butyl methoxydibenzoylmethane, octyl methoxycinnamate, pramoxine hydrochloride, tricetylmonium chloride, oxybenzone, octocrylene, octyl salicylate, phenylbenZimida polyquatemium 10, panthenol, panthenol triacetate, vitamin zole sulfonic acid, ethyl hydroxypropyl aminobenzoate, men A and derivatives thereof, vitamin B and derivatives thereof, thyl anthranilate, aminobenzoic acid, cinoxate, diethanola vitamin C and derivatives thereof, vitamin D and derivatives mine methoxycinnamate, glyceryl aminobenzoate, titanium thereof, vitamin E and derivatives thereof, vitamin K and dioxide, Zinc oxide, oxybenzone, Padimate O, red petrola derivatives thereof, keratin, lysine, arginine, hydrolyzed tum, and mixtures thereof. Further examples of sunscreen Wheat proteins, hydrolyzed silk proteins, octyl methoxycin active agents include, but are not limited to octyl methoxy namate, oxybenzone, minoxidil, titanium dioxide, Zinc diox cinnamate (ethylhexyl p-methoxycinnamate), octyl salicy ide, retinol, erthromycin, tretinoin, and mixtures thereof. late oxybenzone (benzophenone-3), benzophenone-4, men [0121] One preferred type of bene?t agent includes those thyl anthranilate, dioxybenzone, aminobenzoic acid, amyl therapeutic components that are effective in the treatment of dimethyl PABA, diethanolamine p-methoxy cinnamate, ethyl seborrheic dermatitis and psoriasis as well as the symptoms 4-bis (hydroxypropyl) aminobenzoate, 2-ethylhexy l-2-cy associated thereWith. Examples of such suitable bene?ts ano-3,3-diphenylacrylate, homomenthyl salicylate, glyceryl agents nonexclusively include Zinc pyrithione, anthralin, aminobenzoate, dihydroxyacetone, octyl dimethyl PABA, shale oil and derivatives thereof such as sulfonated shale oil, 2-phenylbenZimidazole-5-sulfonic acid, triethanolamine selenium sul?de, sulfur; salicylic acid; coal tar; povidone salicylate, Zinc oxide, and titanium oxide, and mixtures iodine, imidazoles such as ketoconazole, dichlorophenyl imi thereof. dazolodioxalan, Which is commercially available from J ans [0115] Examples of suitable anti-aging agents include, but sen Pharmaceutica, N.V., under the tradename, “Elubiol”, are not limited to inorganic sunscreens such as titanium diox clotrimazole, itraconazole, miconazole, climbazole, tiocona ide and Zinc oxide; organic sunscreens such as octyl-methoxy Zole, sulconazole, butoconazole, ?uconazole, miconazole cinnamates and derivatives thereof; retinoids; vitamins such nitrate and any possible stereo isomers and derivatives as vitamin E, vitamin A, vitamin C, vitamin B, and derivatives thereof; piroctone olamine (Octopirox); selenium sul?de; thereof such as vitamin E acetate, vitamin C palmitate, and ciclopirox olamine; anti-psoriasis agents such as vitamin D the like; antioxidants including beta carotene, alpha hydroxy analogs, e.g. calcipotriol, calcitriol, and tacaleitrol; vitaminA acids such as glycolic acid, citric acid, lactic acid, malic acid, analogs such as esters of vitamin A, e.g. vitamin A palmitate, mandelic acid, ascorbic acid, alpha-hydroxybutyric acid, retinoids, retinols, and retinoic acid; corticosteroids such as alpha-hydroxyisobutyric acid, alpha-hydroxyisocaproic hydrocortisone, clobetasone, butyrate, clobetasol propionate acid, atrrolactic acid, alpha-hydroxyisovaleric acid, ethyl and mixtures thereof. pyruvate, galacturonic acid, glucoheptonic acid, glucohep [0122] Further examples of bene?t agents are emollients, tono l,4-lactone, gluconic acid, gluconolactone, glucuronic skin conditioning agents, humectants, preservatives, antioxi acid, glucuronolactone, glycolic acid, isopropyl pyruvate, dants, perfumes, chelating agents, or mixtures thereof. Emol methyl pyruvate, mucic acid, pyruvic acid, saccharic acid, lients in the composition of the invention function have ability saccaric acid l,4-lactone, tartaric acid, and tartronic acid; beta to remain on the skin surface or in the stratum comeum to act hydroxy acids such as beta-hydroxybutyric acid, beta-phe as lubricants, to reduce ?aking, and to improve the skin nyl-lactic acid, beta-phenylpyruvic acid; botanical extracts appearance. Typical emollients include fatty esters, fatty US 2014/0212362 A1 Jul. 31, 2014

alcohols, mineral oil, polyether siloxane copolymers and the hydrochloride, clemastine, clemastine fumarate, and the like. Examples of suitable emollients include, but are not like), ethylenediamines (e.g., brompheniramine, bro limited to, polypropylene glycol (“PPG”)-15 stearyl ether, mpheniramine maleate, chlorpheniramine, chlorphe PPG- 1 0 acetyl ether, steareth- 10, oleth-8, PPG-4 lauryl ether, niramine maleate, dexchlorpheniramine maleate, tripro vitamin E acetate, PEG-7 glyceryl cocoate, lanolin, cetyl lidine, triprolidine hydrochloride, and the like), alcohol, (e.g., Cetyl Alcohol NF available from Lotioncrafter phenothiaZines (e.g., promethaZine), piperidines (e.g., LLC) octyl hydroxystearate, dimethicone (e.g., Xiameter® hydroxzine, hydroxyZine hydrochloride, terfenadine, PMX-ZOO Silicone Fluid lOOCS available from DoW Com astemizole, azatadine, azatadine maleate, and the like), ing), and combinations thereof. cyproheptadine, cyproheptadine hydrochloride, lorati [0123] Examples of skin conditioning agents include, but dine, carbinoxamine maleate, diphenylpyraline hydro are not limited to, olive leaf, sulfonated shale oil, elubiol, chloride, phenindamine tartrate, tripelennamine hydro 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, ?nas chloride, methdilaZine hydrochloride, trimpraZine teride, ketoconazole, Zinc pyrithione, coal tar, benzoyl per tartrate, and the like; oxide, selenium sul?de, hydrocortisone, pramoxine hydro [0130] immunosuppressants, such as glucocorticoids chloride, tricetylammonium chloride, polyquatemium 10, (methylprednisolone), myelin basic protein (e.g., 7-ca panthenol, panthenol triacetate, vitamin B and derivatives paxone), anti-Fc receptor monoclonal antibodies, thereof, vitamin C and derivatives thereof, vitamin D and hydroorotate dehydrogenase inhibitor, anti-1L2 mono derivatives thereof, vitamin E and derivatives thereof, vitamin clonal antibodies (e.g., CHI-621 and dacliximab), bus K and derivatives thereof, keratin, lysine, arginine, hydro pirone, castanospermine, CD-59 (complement factor lyzed Wheat proteins, hydrolyzed silk proteins, octyl meth inhibitor), 5-lipoxygenase inhibitor (e.g., CMl-392), oxycinnamate, oxybenzone, minoxidil, titanium dioxide, phosphatidic acid synthesis antagonists, ebselen, edel Zinc dioxide, erthromycin, tretinoin, and mixtures thereof. fosine, enlimomab, galaptin, platelet activating factor [0124] Polyhydric alcohols can be utilized as humectants in antagonists, selectin antagonists (e.g., lCAM-4), inter the compositions of the invention. The humectants aid in leukin-10 agonist, macrocylic lactone, methoxatone, increasing the effectiveness of the emollient, reduce scaling, mizoribine, OX-l9, peptigen agents, PG-27, protein stimulate removal of built-up scale and improve skin feel. kinase C inhibitors, phosphodiesterase IV inhibitor, Suitable polyhydric alcohols include, but are not limited to, single chain antigen binding proteins, complement fac glycerol (also known as glycerin), polyalkylene glycols, alky tor inhibitor, sialophorin, sirolimus, spirocyclic lactams, lene polyols and their derivatives, including butylene glycol, 5-hydroxytryptamine antagonist, anti-TCR monoclonal propylene glycol, dipropylene glycol, polypropylene glycol, antibodies, CD5 gelonin and TOK-8801, and the like; polyethylene glycol and derivatives thereof, sorbitol, hydrox [0131] antibacterial agents (e.g., amikacin sulfate, aZtre ypropyl sorbitol, hexylene glycol, 1,3-dibutylene glycol, 1,2, onam, chloramphenicol, chloramphenicol palmitate, 6,-hexanetriol, ethoxylated glycerol, propoxylated glycerol chloramphenicol sodium succinate, cipro?oxacin and mixtures thereof. hydrochloride, clindamycin hydrochloride, clindamy [0125] Examples of suitable preservatives for use in the cin palmitate, clindamycin phosphate, metronidazole, compositions of the invention include the Cl-C4 alkyl para metronidazole hydrochloride, gentamicin sulfate, linco bens and phenoxyethanol (e.g., Microcare® PE available mycin hydrochloride, tobramycin sulfate, vancomycin from Thor Personal Care). Suitable antioxidants include hydrochloride, polymyxin B sulfate, colistimethate butylated hydroxy toluene (BHT), ascorbyl palmitate, buty sodium, colistin sulfate, and the like); lated hydroanisole (BHA), phenyl-[alpha]-naphthylamine, [0132] antifungal agents (e.g., griseofulvin, kelocona hydroquinone, propyl gallate, nordihydroquiaretic acid, vita Zole, and the like); min E or derivatives of vitamin E, vitamin C and derivatives [0133] antiviral agents (e.g., interferon gamma, Zidovu thereof, calcium pantothenic, green tea extracts and mixed dine, amantadine hydrochloride, ribavirin, acyclovir, and the polyphenols, and mixtures thereof. Any fragrance may be like); added to the compositions of the invention for aesthetic pur [0134] antimicrobials (e.g., cephalosporins (e.g., cefazo poses. Suitable fragrances include, but are not limited to, lin sodium, cephradine, cefaclor, cephapirin sodium, eucalyptus oil, camphor synthetic, peppermint oil, clove oil, ceftizoxime sodium, cefoperazone sodium, cefotetan lavender, chamomile and the like. disodium, cefutoxime azotil, cefotaxime sodium, [0126] In certain aspects of this invention, the compositions cefadroxil monohydrate, ceftaZidime, cephalexin, may include a chelating agent. Chelating agents Which are cephalothin sodium, cephalexin hydrochloride monohy useful in the compositions of present invention include eth drate, cefamandole nafate, cefoxitin sodium, cefonicid ylenediamine tetra acetic acid (EDTA) and derivatives and sodium, ceforanide, ceftriaxone sodium, ceftaZidime, salts thereof, dihydroxyethyl glycine, tartaric acid, and mix cefadroxil, cephradine, cefuroxime sodium, and the tures thereof. like), penicillins (e.g., ampicillin, amoxicillin, penicillin [0127] It is also envisioned that the composition of this G benzathine, cyclacillin, ampicillin sodium, penicillin invention could be combined With other agents topical anes G potassium, penicillin V potassium, piperacillin thetics, for example, such as benzocaine or other caine type sodium, oxacillin sodium, bacampicillin hydrochloride, molecules, or even mild steroids such as hydrocortisone for cloxacillin sodium, ticarcillin disodium, aZlocillin enhanced anti-in?ammatory activity. sodium, carbenicillin indanyl sodium, penicillin G [0128] Further bene?t agents useful in the compositions potassium, penicillin G procaine, methicillin sodium, and methods of the present invention include, but are not nafcillin sodium, and the like), erythromycins (e.g., limited to: erythromycin ethylsuccinate, erythromycin, erythromy [0129] antihistamine/antipruritic drugs, such as ethano cin estolate, erythromycin lactobionate, erythromycin lamines (e. g., diphenhydramine, diphenhydramine siearate, erythromycin ethylsuccinate, and the like), tet US 2014/0212362 A1 Jul. 31, 2014 10

racyclines (e.g., tetracycline hydrochloride, doxycy formulations for acne (e.g., nicotinamide, N-547, and cline hyclate, minocycline hydrochloride, and the like), Papulex), growth hormone antagonists (e.g., Octreotide, and the like); Sandostatin, Lanreotide, angiopeptin, BIM-23014, and [0135] antioxidants (e.g., N-acetylcsysteine, Vitamin A, Somatuline), humanized antibodies (e.g., anti-CD4 anti Vitamin C, Vitamin E, .beta.-carotene, EUK-8, ?a body), hydroorotate dehydrogenase inhibitors (e.g., vonoids, glutathione, .alpha.lipoic acid, melatonin, ret Brequinar sodium, bipenquinate, and DuP-785), inols, and the like); ICAM-l inhibitors (e.g., ISIS 939), IL-1 and other [0136] anti-infectives (e.g., miconazole, vidarabine, cytokine inhibitors (e.g., Septanil), IL-1 converting inosine, pranobex, vidarabine, inosine prabonex, cefpi ezyme inhibitors, IL-1 receptor antagonists (e.g., mizole sodium), fradiomycin, and the like); Antril), IL-2 antagonists (e.g., Tacrolimus, Prograf, and [0137] hormones (e.g., androgens (e.g., danazol, test FK-506), IL-2 receptor-targeted fusion toxins osterone cypionate, ?uoxymesterone, ethyltosto sterone, (DAB389IL-2), IL-8 receptors, immunostimulants testosterone enanihate, methyltestosterone, ?uoxymes (e.g., Ihymopentin, and Timunox), immunosuppres terone, testosterone cypionate), estrogens (e.g., estra sants (e.g., XomaZyme-CD5 Plus, cyclosporine, Sand diol, estropipate, conjugated estrogens), progestins immune, SR-31747, anti-CD 11, 18 MAb, Tacrolimus, (e.g., methoxyprogesterone acetate, norethindrone Prograf, FK-506, and FK-507), immunosuppressive acetate), corticosteroids (e.g., triamcinolone, agents targeting FK506 (e.g., immunophilins, betamethasone, betamethasone sodium phosphate, dex VX-10367, and VX-10428), immunotoxins MAb amethasone, dexamethasone sodium phosphate, dexam directed against CD antigen (e.g., XomaZyme-CD5 ethasone acetate, prednisone, methylprednisolone Plus), leukotriene antagonists (e.g., Sch-40120, acetate suspension, triamcinolone acetonide, methyl Wy-50295, and Wy49232), leukotriene B4 antagonists prednisolone, prednisolone sodium phosphate methyl (e.g., SC-41930, SC-50605, SC-48928, ONO-4057, prednisolone sodium succinate, hydrocortisone sodium LB-457, LY-255283, LY-177455, LY-223982, succinate, methylprednisolone sodium succinate, triam LY-223980, and LY-255253), leukotriene synthesis cinolone hexacatonide, hydrocortisone, hydrocortisone inhibitors (MK-886, and L-663536), lipase clearing fac cypionate, prednisolone, ?uorocortisone acetate, tor inhibitors (e.g., 1-docosanol, and lidakol), lipid paramethasone acetate, prednisolone tebulate, predniso encapsulated reducing agent (e.g., Dithranol), liposomal lone acetate, prednisolone sodium phosphate, hydrocor gel (e.g., Dithranol), LO inhibitors (e.g., CD581, tisone sodium succinate, and the like), thyroid hormones CD554, Masoprocol, and Actinex), lithium succinate (e.g., levothyroxine sodium) and the like), and the like; ointments (e.g., lithium salts, and Efalith), LO/CO [0138] psoriasis agents, such as 5-LO inhibitors (e.g., inhibitors (e.g., P-8892, P-8977, CHX-108, and FPL Wy-50295, Wy-49232, Lonapalene, RS-43179, 62064), membrane integrity agonists (e.g., lithium salts, MK-886, L-663536, ETH-615, DUP-654, Zileuton, and Efalith), microtubule inhibitors (e.g., Poso epocarbazolin-A, and A-64077), 5-LO/CO inhibitors phyliotoxin-containing compound, and Psorex), (e.g., BF-397, Tenidap, CP-309, and CP-66248), angio octapeptide somatostatin analogues (e.g., Lanreotide, genesis inhibitors (e.g., platelet factor 4), anticancer angiopeptin, BIM-23014, and Somatuline), oligonucle antibiotic (e.g., AGM-1470, and TNP-470), anti-in?am otides (e.g., ISIS 4730, ISIS 3801, ISIS 1939, and IL-1 matory cytochrome P450 oxidoreductase inhibitors inhibitors), peptide agonists (e.g., octapeptide, and pep (e.g., DuP-630, and DuP-983), antiproliferative com tide T), PKC inhibitors, phospholipase A2 compounds, pounds (e.g., Zyn-Linker), arachidonic acid analogues pospholipase D compounds, photodynamic anticancer (e.g., CD581, and CD554), arachidonic acid antagonists agents (e.g., 5-aminolevulinic acid, and 5-ALA), photo (e.g., Lonopalene, RS-43179, triamcinolone acetonide dynamic therapies (e.g., benzoporphyrin derivative, With penetration enhancer Azone, betamethasone dipro synthetic chlorins, synthetic porphyrins, and EF-9), pionate steroid Wipe, G-202, Halobetasol propionate, photosensitizer (e.g., Por?rmer sodium), PKC inhibitors ultravate, Halometasone, C-48401-Ba, and Sicorten), (e.g., Sa?ngol, and Kynac), platelet activating factor beta-glucan receptor antagonists, betamethasone steroid antagonists (e.g., TCV-309), platelet aggregation inhibi Wipes, calcium metabolic moderators (e.g., Tacalcitol, tors (e.g., CPC-A), prodrug NSAIDs (e.g., G-201), pros Bonealfa, TV-02 ointment, Ro-23-6474, KH-1060, Cal taglandin agonist (e.g., eicosapentaenoic acid +gamma cipotriol, BMS-181161, BMY-30434, Dovonex, and linolenic acid combination, and Efamol Marine), protein Divonex), CD4 binding inhibitors (e.g., PIC 060), cell inhibitors (e.g., SPC-103600, and SPC-101210), protein adhesion compounds (e.g., CY-726,VCAM-1, ELAM kinase C (PKC) inhibitors (e.g., Ro-31-7549, Ro-31 1, and ICAM), cell adhesion inhibitors (e.g., selectin 8161, and Ro-31-8220), protein synthesis antagonists inhibitor, GM-1930), cellular aging inhibitors (e.g., Fac (e.g., Calcitriol, Du-026325, LG-1069, LG-1064,AGN tor X), corticosteroids (e.g., Halobetasol propionate, 190168, Namirotene, and CBS-211A), purine nucleo ultravate, Halometasone, C-48401-Ba, and Sicorten), side phosphorylase inhibitors (e.g., BCX-34), radical cyclosporin analogues (e.g., IMM-125), dihydrofolate formation agonists (e.g., benzoporphyrin derivative), reductase inhibitors (e.g., G-301, dichlorobenzoprim, recombinant antileukoproteinases (e.g., ALP-242), ret methotrexate, and methotrexate in microsponge deliv inoids (e.g., BMY-30123, LG-1069, and LG-1064), ret ery system), E-selectin inhibitors (e.g., ISIS 4730), inoid derivatives (e.g., AGN-190168), rapamycin bind endogenous active form of vitamin D3 (e.g., Calcitriol, ing proteins (FKBP) (e.g., immunophilins, VX-10367, and Du-026325), ?broblast growth factor antagonists and VX-10428), second generation monoaromatic ret (e.g., Saporin mitotoxin, and Steno-Stat), fumagillin inoids (e.g., Acitretin, and Neotigason), soluble IL-1, analogues (e.g., AGM-1470, and TNP-470), G-proteins IL-4 and IL-7 receptors, somatostatin and somatostatin and signal transduction compounds (e.g., CPC-A), gel analogues (e.g., Octreotide, and Sandostatin), steroids, US 2014/0212362 A1 Jul. 31, 2014

(e.g., AGN-191743), streptomyces anulatus isolates Particularly preferred is PEMULEN TR-l (CTFA Designa (e.g., epocarbazolin-A), superoxide dismutase (e.g., tion: Acrylates/10-30 Alkyl Acrylate Crosspolymer). EC-SOD-B), thymidylate synthase inhibitors (e.g., [0143] The composition of the invention may be in the form AG-85, MPl-5002, 5-FU in biodegradable gel-like of an oil-in-water emulsion, a water-in-oil emulsion, or a matrix, 5-FU and epinephrine in biodegradable gel-like dispersion. Liquid form preparations such as lotions or matrix, and AccuSite), topical formulations (e.g., creams include solutions, suspensions, and emulsions, for P-0751, and P-0802), transglutaminase inhibitors, tyr example, water or DMSO/propylene glycol solutions. Liquid phostin EGF receptor kinase blockers (e.g., AG-18, and suspensions suitable for topical use can be made by dispers AG-555),VCAM-1 inhibitors (e.g., ISIS 3801), vitamin ing the ?nely divided active component in an appropriate D analogues (e.g., Ro-23-6474, KH-1060, Calcipotriol, liquid with viscous material, such as natural or synthetic BMS-181 161, BMY-30434, Dovonex, and Divonex), gums, resins, methycellulose, sodium carboxymethylcellu vitamin D3 analogues (e. g., Tacalcitol, 20 Bonealfa, lose, and other well-known suspending agents. TV-02 ointment), and vitamin D3 derivatives (e. g., 1,2 diOH-vitamin D3), and the like; and agents useful for [0144] Also included are solid form preparations which are the treatment of carcinomas (e. g., adriamycin, taxol, intended to be converted, shortly before use, to liquid form interleukin-1, interleukin-2 (especially useful for treat preparations for topical administration. Such liquid forms ment of renal carcinoma), and the like, as well as leu include solutions, suspensions, and emulsions. These prepa prolide acetate, LHRH analogs (such as nafarelin rations may contain, addition to the active component, colo acetate), and the like, which are especially useful for the rants, ?avors, fragrances, stabilizers, buffers, arti?cial and treatment of prostatic carcinoma). natural sweeteners, dispersants, thickeners, solubilizing [0139] The amount of bene?t agent to be included may vary agents, and the like. depending upon, for example, the ability of the bene?t agent [0145] To prepare dermally applicable formulations it is to penetrate through the skin, the speci?c bene?t agent cho possible to use the previously mentioned substances and sen, the particular bene?t desired, the sensitivity of the user to spreadable or liquid hydrocarbons such as Vaseline or paraf?n the bene?t agent, the health condition, age, and skin condition or gels of alkanes and polyethylene, fats and oils of plant or of the user, and the like. In sum, the bene?t agent is used in a animal origin, which may in part also be hydrated, or syn “safe and effective amount,” which is an amount that is high thetic fats such as glycerides of fatty acids C8-C18, as well as enough to deliver a desired skin bene?t or to modify a certain beeswax, cetyl palmitate (e.g., Cutina® CP available from condition to be treated, but is low enough to avoid serious side Cognis/BASF), wool wax, wool wax alcohols, fatty alcohols effects, at a reasonable risk to bene?t ratio within the scope of such as cetyl alcohol, stearyl alcohol, polyethylene glycols of sound medical judgment. molecular weight 200 to 20,000; liquid waxes such as isopro pyl myristate, isopropyl stearate, ethyloleate; emulsi?ers Formulations such as sodium, potassium, ammonium salts of stearic acid or [0140] The compositions of the present invention can be palmitic acid as well as triethalolamine stearate, alkali salts of prepared and administered in a wide variety of topical forms. oleic acid, castor oil acid, salts of sulfurated fatty alcohols For topical formulations of the present invention, dermato such as sodium lauryl sulphate, sodium cetyl sulphate, logically acceptable carriers can be either solid or liquid. The sodium stearyl sulphate, salts of gallic acid, sterols such as compositions of this invention is preferably in the form of cholesterol, partial fatty acid esters of multivalent alcohols topical products that can be applied externally to the skin and such as ethylene glycol monostearate, glycerol monostearate, can be prepared in accordance with conventional techniques pentaerythritol monostearate, partial fatty acid esters of sor known to those of ordinary skill in the art. The carrier may bitan, partial fatty acid esters of polyoxyethylene sorbitan, take a variety of physical forms such as, for example, creams, sorbitol ethers of polyoxyethylene, fatty acid esters of poly dressings, gels, lotions, ointments or liquids. One could also oxyethylene, fatty alcohol ethers of polyoxyethylene, fatty utilize this in a convenient spray applicator. acid esters of saccharose, fatty acid esters of polyglycerol, [0141] Typical carriers include lotions containing water lecithin. and/ or alcohols and emollients such as hydrocarbon oils and [0146] Examples of suitable esters nonexclusively include waxes, silicone oils, hyaluronic acid, vegetable, animal or a branched C5 to C22 alkyl alcohol ester of an aromatic acid, marine fats or oils, glyceride derivatives, fatty acids or fatty a straight-chained or branched C5 to C22 alkyl acid esters of acid esters or alcohols or alcohol ethers, lanolin and deriva optionally ethyoxylated/propoxylated polyols having from tives, polyhydric alcohols or esters, wax esters, sterols, phos about 3 carbon atoms to about 7 carbon atoms, a branched C5 pholipids and the like, and generally also emulsi?ers (non to C22 alkyl alcohol esters of branched polyacids, a branched ionic, cationic or anionic), although some of the emollients or straight-chained C5 to C22 alkyl acid esters of branched inherently possess emulsifying properties. These same gen and/or unsaturated C5 to C22 alkyl alcohols, a branched or eral ingredients can be formulated into a cream rather than a unsaturated C5 to C22 alkyl alcohol esters of an acid selected lotion, or into gels, or into solid sticks by utilization of dif from the group consisting of adipic acid, succinic acid, maleic ferent proportions of the ingredients and/or by inclusion of acid, sebacic acid, and mixtures thereof, polyether inter thickening agents such as gums or other forms of hydrophillic rupted fatty acid esters, benzoic acid ester of heterogeneous colloids. alcohols having from about 8 carbon atoms to about 22 car [0142] The compositions according to the invention pref bon atoms and mixtures thereof with straight-chained or erably contain an effective stabilizing amount of an emulsi branched C5 to C22 alkyl acid esters of optionally ethyoxy ?er. Any emulsi?er that is compatible with the components of lated/propoxylated polyols, benzoic acid esters of heteroge the composition can be employed. Suitable emulsi?ers neous alcohols, and mixtures thereof. Further suitable esters include stearic acid, acetyl alcohol, stearyl alcohol, steareth 2, are disclosed in Us. Pat. No. 6,762,158, the entire disclosure steareth 20, Acrylates/C10-30 alkyl Acrylate Crosspolymer of which is incorporated herein by reference. US 2014/0212362 A1 Jul. 31, 2014

[0147] Antioxidants that may for example be used are glycol-10 methyl glucose ether, ethoxydiglycol, polyethylene sodium metabisulphite, ascorbic acid, gallic acid, gallic acid glycol-6 caprylic/capric glyceride, ethylene glycol monobu alkyl ester, butylhydroxyanisol, nordihydroguaiacic acid, tyl ether, polyethylene glycol-8 caprylic/capric glycerides, tocopherols as well as tocopherols .+-.synergitic substances 3-methoxy-3-methyl-l-butanol, dimethyl isosorbide, and that bind heavy metals through complex formation, for mixtures thereof. Most preferred water dispersible compo example lecithin, ascorbic acid, phosphoric acid). Conserv nents include hexylene glycol, dimethyl isosorbide, polyeth ing agents that may for example be considered are sorbic acid, ylene glycol-6 caprylic/capric glyceride, and mixtures p-hydroxybenzoic acid esters (for example lower alkyl thereof. esters), benzoic acid, sodium benzoate, trichloroisobutyl [0152] A further optional component of the compositions alcohol, phenol, cresol, benzethonium chloride and formalin of the present invention is a volatile or nonvolatile liquid derivatives . silicone. Examples of suitable silicones nonexclusively [0148] Topical dosage forms include, but are not limited to, include the polydimethyl siloxanes and derivatives thereof sprays, aerosols, creams, lotions, ointments, gels, solutions, such as hexamethylsiloxane, dimethicone, dimethiconol, and emulsions, suspensions, or other forms known to one of skill cyclomethicone, with cyclomethicone being preferred. in the art. See, e.g., Remington’s Pharmaceutical Sciences, Examples of suitable cyclomethicones nonexclusively 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & include cyclotetradimethyl siloxane; cyclopentadimethyl 1990); and Introduction to Pharmaceutical Dosage Forms, siloxane, cyclohexadimethyl siloxane, cycloheptadimethyl 4th ed., Lea & Febiger, Philadelphia (1985). See also Cos siloxane, and mixtures thereof. metic Model FormulaeiA Compilation of Model Formulae [0153] Further optional components of the compositions of for the Manufacture of Cosmetic Preparations (Henkel the present invention are polymeric emulsi?ers and/or thick KGaA; 1988), the entirety of which is incorporated herein by eners. Examples of suitable polymeric emulsi?ers nonexclu reference. Transdermal dosage forms include “reservoir sively include polyethylene glycol-30 dipolyhydroxystear type” or “matrix type” patches, which can be applied to the ate, dimethicone copolyol, substituted acrylates, and skin and worn for a speci?c period of time to permit the mixtures thereof. Examples of suitable hydrophilic thicken penetration of a desired amount of active ingredients. Suit ers nonexclusively include carbomers (e.g., Carbopol® able excipients (e.g., carriers and diluents) and other materi UltreZ polymers available from Lubrizol Corp.; also various als that can be used to provide transdermal, topical, and carbomer prodcts available from B. F. Goodrich), acrylate mucosal dosage forms are well known to those skilled in the copolymers, hydroxyethylcellulose modi?ed with cetyl ether pharmaceutical arts, and depend on the particular tissue to groups, polyvinylmethyl ether/maleic anhydride (PVM/MA) which a given pharmaceutical composition or dosage form decadiene crosspolymer, and copolymers and mixtures will be applied. thereof. Examples of suitable acrylate copolymers nonexclu [0149] The pH of the inventive compositions may also be sively include acrylate copolymers available from Rohm & adjusted to improve delivery of one or more active ingredi Haas, acrylates/aminoacrylates copolymer, acrylates/ste ents. In another preferred embodiment, the compositions areth-20 itaconate copolymer, acrylates/ceteth-20 itaconate used in the methods of present invention contain a pH-buff copolymer, acrylates/steareth-20 methacrylate copolymer, ering agent. Preferably, the amount of buffering agent should and copolymers and mixtures thereof. be that which would result in compositions having a pH [0154] The compositions of the present invention may also ranging from about 4.5 to about 8.5, more preferably from optionally contain a stability enhancer for the purpose of about 5.5 to about 8.5, most preferably from about 6.5 to enhancing the stability of the bene?t agent and/ or the aesthet about 8.0. The buffering agent can be any of the known ics of the composition. Generally, the stability enhancer may buffering agents commonly found in topical compositions be selected from a nonionic emulsi?er, an essentially non provided that they are physically and chemically stable with foaming surfactant, or mixtures thereof. Examples of suitable the other ingredients of the composition. Suitable buffering nonionic emulsi?ers include isocetheth-20, oleth-2, mixture agents include organic acids such as, but not intended to be of PEG-40 hydrogenated castor oil and trideceth-9, Polox restricted to, citric acid, malic acid, and glycolic acid. amer 184, laureth-4, sorbitan trioleate, polyoxyethylene-(2) [0150] Similarly, the polarity of a solvent carrier, its ionic oleyl ether, sorbitan stearate, cetearyl glucoside, glyceryl ole strength, or tonicity can be adjusted to improve delivery. ate, trideceth-9, polyethylene glycol-40 hydrogenated castor Compounds such as stearates may also be added to pharma oil, and mixtures thereof. ceutical compositions or dosage forms to advantageously [0155] Examples of suitable essentially non-foaming sur alter the hydrophilicity or lipophilicity of one or more active factants include non-foaming nonionic surfactants such as ingredients so as to improve delivery. In this regard, stearates sucrose esters, e.g., sucrose cocoate, sucrose stearate and can serve as a lipid vehicle for the formulation, as an emul mixtures thereof. By “essentially non-foaming,” it is meant sifying agent or surfactant, and as a delivery-enhancing or that the surfactant, when used with the composition of the penetration-enhancing agent. Different salts, hydrates or sol present invention, has a column height of less than about 20 vates of the active ingredients can be used to further adjust the mm as determined by the Ross-Miles Foam Generation Test. properties of the resulting composition. See 18 (I.) Oil & Soap 99-102 (1941)(“Ross-Miles Test”), [0151] The topical compositions of the present invention which is incorporated by reference herein. The composition may contain a water dispersible component, which is prefer may either be rinseable with water or may be wiped-off. ably a water soluble solvent. As used herein, the term “water Preferably, the essentially non-foaming surfactants are used dispersible component” shall mean a material that produces a in embodiments wherein the composition is rinseable with uniform, clear or hazy, mixture when combined with at least water. a weight equivalent of water. Examples of suitable water [0156] The composition may also optionally contain a dispersible components nonexclusively include polyethylene foaming surfactant. The foaming surfactant may be non glycol 400, hexylene glycol, propylene glycol, polypropylene ionic, cationic, amphoteric, or anionic. By “foaming,” it is US 2014/0212362 A1 Jul. 31, 2014

meant that the surfactant, when used with the composition of thereof. The formulations may contain surfactants, antioxi the present invention, has a column height of foam greater dants, and stabilizers such as benzoic acid, sorbic acid, para than about 20 mm as determined by the Ross-Miles Test. bens, butylated hydroxyanisole (BHA), butylated hydroxy [0157] Preservatives for the formulations herein are ben toluene (BHT), vitamin E, sarcosonates, and the like. zoic acid and derivatives thereof, namely, butylparaben, eth [0162] The bene?t agents can also be combined with astrin ylparaben, methylparaben, propylparaben, sodium benzoate, gents such as witch hazel, aluminum acetate, aluminum sul and mixtures thereof. Typical use of benzoic-acid-derived fate, zinc oxide, zinc acetate, sodium bicarbonate, and preservative is a mixture of methylparaben comprising up to calamine. One of the functions of the formulations when 0.3 percent by weight of the treating composition and propy applied to contact dermatitis is to remove the irritant material lparaben comprising up to 0.1 percent by weight of the treat from the skin. This requires astringent activity, and the addi ing composition. Other useful preservatives include alcohol, tion of aluminum acetate, zinc oxide, zinc acetate, sodium benzalkonium chloride, benzethonium chloride, benzyl alco bicarbonate, calamine, witch hazel, zinc carbonate, and alu hol, bronopol, cetrimide, chlorhexidine, chlorobutanol, chlo minum hydroxide may be employed to enhance this physical rocresol, cresol, glycerin, imidurea, phenol, phenoxyethanol, property. phenylethyl alcohol, phenylmercuric acetate, phenylmercu [0163] A preferred carrier material includes water, glyc ric borate, phenylmercuric nitrate, potassium sorbate, propy erin, cetyl palmitate, mineral oil, caprylic/capric triglyceride, lene glycol, sodium propionate, sorbic acid and thimerosal. octyldodecanol, cetyl alcohol, glyceryl stearate, colloidal oat [0158] Among the inactive ingredients are surfactants and ?our, dimethicone, PEG-40 stearate, carbomer, sodium emulsifying agents. These ingredients take on importance as hydroxide, phenoxy ethanol, caramel III coloring, DMDM the use thereof improves absorption, coverage, appearance, hydantoin, and iodopropynyl butylcarbamate. and feel of the product. Some suitable emulsifying agents are [0164] Glycerin, also called glycerol, acts as a humectant, acacia, anionic emulsifying wax, carbomer, carboxymethyl skin protectant, and solvent present in all natural lipids (fats), cellulose, cetostearyl alcohol, cetyl alcohol, cholesterol, whether animal or vegetable. Whether natural or synthetic, diethanolamine, glyceryl monostearate, hydrous lanolin, glycerin is a humectant and extremely hygroscopic, meaning hydroxyethyl cellulose, hydroxypropyl cellulose, hydrox it readily absorbs water from other sources, attracting water ypropyl methylcellulose, lanolin, lanolin alcohols, lecithin, from the environment and from the lower layers of skin (der methylcellulose, mineral oil and lanolin alcohols, monobasic mis) and increasing the amount of water in the surface layers sodium phosphate, monoethanolamine, nonionic emulsify of skin. Another aspect of glycerin’s bene?t is that it is a ing wax, oleic acid, poloxamer, polyoxyethylene alkyl ethers, skin-identical ingredient, meaning it is a substance found polyoxyethylene castor oil derivatives, polyoxyethylene sor naturally in skin. In that respect it is one of the many sub bitan fatty acid esters, polyoxyethylene stearates, propylene stances in skin that help maintain the outer barrier and prevent glycol alginate, sodium lauryl sulfate, sorbitan esters, stearic dryness or scaling. The Food and Drug Administration (FDA) acid, triethanolamine, and xanthan gum. Frequently mixtures includes glycerin on its list of direct food additives considered of complimentary surfactants are used in a given formulation. Generally Recognized As Safe (GRAS), and on its list of [0159] Suitable anionic surfactants are lauryl sulfates, approved indirect food additives. Glycerin is also an FDA including sodium lauryl sulfate, triethanolamine lauryl sul approved active ingredient in Over-the-Counter (OTC) skin fate, and ammonium lauryl sulfate; laureth sulfates,including protectant drug products and ear drying products, and it is an sodium laureth sulfate, triethanolamine laureth sulfate, and approved demulcent for the eyes. ammonium laureth sulfate; sarcosines, including lauryl sar [0165] Cetyl palmitate acts as an emollient, acting as a cosine, and sodium lauryl sarcosinate; sulfosuccinates, lubricant on the skin’ s surface, which gives the skin a soft and including disodium oleamine sulfosuccinate, and sodium smooth appearance. The palmitates generally are esters of dioctyl sulfosuccinate; and docusate sodium. The cationic palmitic acid and ethylhexyl, cetyl, or isopropyl alcohol. In surfactants are benzalkonium chloride, benzethonium chlo cosmetics and personal care products, they all function as ride, and cetrimide. The nonionic surfactants are glyceryl skin conditioning agents and emollients. The palmitates are monooleate, polyvinyl alcohol, sorbitan esters, povidone, ef?cient opaci?ers in cream and lotion shampoos. Isopropyl crospovidone, polyoxyethylene fatty alcohols, polyoxyethyl Palmitate also functions as a binder. The safety of the palmi ene sorbitol esters, and alkanolamides. Additionally, ampho tates has been assessed by the Cosmetic Ingredient Review teric detergents such as betaines, sultaines, and imidazo (CIR) Expert Panel. The CIR Expert Panel evaluated the linium derivatives are used, and particularly ingredients such scienti?c data and concluded that Ethylhexyl Palmitate, Cetyl as cocamidopropyl betaine and sodium lauraminopropionate. Palmitate and Isopropyl Palmitate were safe as cosmetic [0160] In ointment and cream preparations, emollients ingredients. In 2001, the CIR Expert Panel considered avail form a vehicle to carry the active ingredients to the site of the able new data on Ethylhexyl, Cetyl and Isopropyl Palmitate immune response and the associated dermatitis. The emol and reaf?rmed the above conclusion. lient group from which these carriers are selected include [0166] Light mineral oil acts as an emollient, skin pro allantoin, cetostearyl alcohol, cetyl esters wax, cocoa butter, tectant, and solvent. Mineral oil functions as an emollient skin cholesterol, dimethicone, glycerin, glyceryl monostearate, conditioning agent, an occlusive skin protectant, and as a isopropyl myristate, isopropyl palmitate, kaolin, lecithin, solvent. The FDA permits the use of mineral oil as an active light mineral oil, mineral oil, mineral oil and lanolin alcohols, ingredient in the following OTC drug product categories: petrolatum, and petrolatum and lanolin alcohols. anorectal drugs, skin protectants, and ophthalmic emollients. [0161] The carrier can be any suitable aqueous dispersion [0167] Caprylic/capric triglyceride (CAS No. 124-07-2) material, cream, lotion, or ointment, which may include, for acts as a moisturizer, viscosity modulator, inactive carrier, example hydrocolloids, plasdone, methyl cellulose, hydrox and stabilizer. Caprylic/capric triglyceride is an oily liquid ypropyl cellulose, lanolin, mineral oil, petroleum jelly, poly made from coconut oil. It is used in cosmetics and other alkylene glycols such as polyethylene glycols, or mixtures personal care products, such as face creams, lipstick, eye US 2014/0212362 A1 Jul. 31, 2014

makeup and foundations. It can also be used in perfumes, [0170] Glyceryl stearate (CAS Nos. 11099-07-3, 31566 moisturizers and sunscreens. It is found naturally in foods but 31-1) may act as an emulsi?er, humectant, lubricant, or sol can also be made by industrial processes. Caprylic/capric vent. As an emulsi?er it assists in forming neutral, stable triglyceride has a number of useful properties in the formu emulsions; it is also a solvent, humectant, and consistency lation of cosmetics and, in particular, face creams. Caprylic/ regulator in water-in-oil and oil-in-water formulations. It is capric triglyceride creates a barrier on the skin’s surface, typically derived from palm kernel or soy oil for cosmetic use. decreasing the amount of moisture lost through the skin, Glyceryl stearate helps to form emulsions by reducing the functioning not only to prevent dryness in skin, but also as a surface tension of the substances to be emulsi?ed. The safety skin conditioning agent. It provides a slippery feeling and of Glyceryl Stearate has been assessed by the Cosmetic Ingre promotes dispersion of pigments in various colored cosmet dient Review (CIR) Expert Panel. The CIR Expert Panel evaluated the scienti?c data and concluded that Glyceryl ics. Caprylic/capric triglycerides have a low viscosity. This Stearate was safe for use in cosmetics and personal care property allows it to alter the thickness of a particular cos products. The CIR Expert Panel reviewed chronic studies of metic product. Adding caprylic/capric triglycerides to thick glyceryl stearate that showed no adverse effects on reproduc face creams helps thin them out to the desired thickness. tion, and no carcinogenic effects. Human exposure studies of Caprylic/capric trigylceride does not readily oxidize. It is products containing glyceryl stearate and glyceryl stearate particularly useful as a stabilizer of emulsions. This property SE, as well as clinical experience, have shown these com is particularly useful in facial creams and other cosmetic pounds to be non-sensitizing, non-phototoxic and non-pho products, helping to give them a longer shelf life. The Food tosensitizing. If they are made from plants, glyceryl stearate and Drug Administration lists caprylic/capric triglyceride as and glyceryl stearate SE may be used in cosmetics and per Generally Recognized As Safe, or GRAS, for use as a direct sonal care products marketed in Europe according to the food additive. In addition, caprylic/capric triglyceride has general provisions of the Cosmetics Directive of the Euro been assessed by the Cosmetic Ingredient Review Expert pean Union. Ingredients made from animal sources must Panel, which evaluated the scienti?c data and concluded, and comply with the European Union animal by-products regu reaf?rrned in 2001, that it was safe as it was being used at that lations. A suitable material is available from Protameen time. Similarly suitable triglyceride materials include Chemicals Inc. under the trade name “Protachem GMS-450.” medium-chain triglyceride oil (CAS 65381-09-1) available as MCT oil from Acme-Hardesty Oleochemicals. [0171] Colloidal oat ?our (CAS No. 281 -672-4) may act as a moisturizer, skin protectant, pH buffer, and anti-in?amma [0168] Octyldodecanol (CAS No. 5333-42-6; Tegosoft® tory agent, and may have anti-irritant and anti-in?ammatory G20 available from Evonik) acts as a stabilizer, emulsi?er, properties. As a skin protectant, colloidal oatmeal tempo lubricant, and solvent. Octyldodecanol helps to form emul rarily protects injured or exposed skin from harmful or annoy sions and prevent an emulsion from separating into its oil and ing stimuli, and may therefore provide relief to the skin. liquid components. These ingredients also reduce the ten Oatmeal has been used for centuries as a soothing agent to dency of ?nished products to generate foam when shaken. relieve itch and irritation associated with various xerotic der When used in the formulation of skin care products, octyl matoses. In 1945, a ready to use colloidal oatmeal, produced dodecanol acts as a lubricant on the skin surface, which gives by ?nely grinding the oat and boiling it to extract the colloidal the skin a soft, smooth appearance. The safety of Octyldode material, became available. Today, colloidal oatmeal is avail canol and related ingredients has been assessed by the Cos able in various dosage forms from powders for the bath to metic Ingredient Review (CIR) Expert Panel. The CIR Expert shampoos, shaving gels, and moisturizing creams. Panel evaluated the scienti?c data and concluded that octyl [0172] Currently, the use of colloidal oatmeal as a skin dodecanol was safe for use in cosmetics and personal care protectant is regulated by the US. Food and Drug Adminis products. In 2004, the CIR Expert Panel considered available tration (FDA) according to the Over-The-Counter Final new data on octyldodecanol and reaf?rmed the above conclu Monograph for Skin Protectant Drug Products issued in June sion. Octyldodecanol may be used in cosmetics and personal 2003. Its preparation is also standardized by the United States care products marketed in Europe according to the general Pharmacopeia. The many clinical properties of colloidal oat provisions of the Cosmetics Directive of the European Union. meal derive from its chemical polymorphism. The high con [0169] Cetyl alcohol (CAS No. 36653-82-4) acts as an centration in starches and beta-glucan is responsible for the emollients, thickeners, and emulsi?er. Cetyl alcohol and the protective and water-holding functions of oat. The presence other fatty alcohols keep an emulsion from separating into its of different types of phenols confers antioxidant and anti oil and liquid components. These ingredients are also used to in?ammatory activity. Some of the oat phenols are also strong alter the thickness of liquid products and to increase foaming ultraviolet absorbers. The cleansing activity of oat is mostly capacity or to stabilize foams. The safety of cetyl alcohol has due to saponins. Its many functional properties make colloi been assessed by the Cosmetic Ingredient Review (CIR) dal oatmeal a cleanser, moisturizer, buffer, as well as a sooth Expert Panel. The CIR Expert Panel evaluated the scienti?c ing and protective anti-in?ammatory agent. data and concluded that this fatty alcohol was safe for use as [0173] The Food and Drug Administration (FDA) reviewed a cosmetic ingredient. In 2005, the CIR Expert Panel consid the safety and ef?cacy of colloidal oatmeal and approved its ered available new data on cetearyl alcohol and the other fatty use as an active ingredient in Over-the-Counter (OTC) skin alcohols and reaf?rrned the above conclusion. If they are protectant drug products at a minimum concentration of derived from plants, cetearyl, cetyl, isostearyl, myristyl and 0.007%, or 0.003% when used in combination with mineral behenyl alcohols may be used in cosmetics and personal care oil. When used as a skin protectant in an OTC skin protectant products marketed in Europe according to the general provi drug product, this ingredient must be called colloidal oat sions of the Cosmetics Directive of the European Union. meal. The Cosmetic Ingredient Review (CIR) has deferred Ingredients of animal origin must comply with European evaluation of this ingredient because the safety has been Union animal by-products regulations. assessed by FDA. This deferral of review is according to the US 2014/0212362 A1 Jul. 31, 2014

provisions of the CIR Procedures. Avena Sativa (Oat) Kernel therefore the addition of a suitable preservative system is Meal and colloidal oatmeal may be used in cosmetics and advisable. The safety of the Carbomer has been assessed by personal care products marketed in Europe according to the the Cosmetic Ingredient Review (CIR) Expert Panel. The CIR general provisions of the Cosmetics Directive of the Euro Expert Panel evaluated the scienti?c data and concluded that pean Union. carbomer polymers were safe as ingredients in cosmetics and [0174] Dimethicone (CAS No. 9006-65-9) may act as a personal care products. In 2001, as part of the scheduled moisturizer and emollient. Dimethicone is a silicone based re-evaluation of ingredients, the CIR Expert Panel considered polymer that forms a protective barrier on the skin to help available new data on carbomer polymers and reaf?rmed the retain moisture. Dimethicone’s oil-like consistency also above conclusion. gives it emollient properties. The Food and Drug Administra [0177] The CIR Expert Panel reviewed acute oral studies tion (FDA) reviewed the safety of dimethicone and approved showing that carbomer polymers have low toxicities when its use as a skin protectant active ingredient in over-the ingested. Minimal skin irritation and no to moderate eye counter (OTC) drug products. The safety of Dimethicone has irritation were observed. Subchronic feeding studies with a been assessed by the Cosmetic Ingredient Review (CIR) carbomer polymer resulted in lower than normal body Expert Panel. The CIR Expert Panel evaluated the scienti?c weights, but no abnormal changes were observed in the data and concluded that these ingredients were safe for use in organs. Some gastrointestinal irritation and marked pigment cosmetics. Dimethicone, methicone, and the related poly deposition within speci?c cells in the liver, called Kupffer mers may be used in cosmetics and personal care products cells, were seen in studies with carbomer. Clinical studies marketed in Europe according to the general provisions of the with carbomers showed that these polymers have low poten Cosmetics Directive of the European Union. The World tial for skin irritation and sensitization at concentrations up to Health Organization Joint FAO/WHO Expert Committee on 100%. A carbomer polymer demonstrated low potential for Food Additives has established an acceptable daily intake phototoxicity and photo-contact allergenicity. The Car level for Dimethylpolysiloxane (Dimethicone) of 0 to 1.5 bomers may be used in cosmetics and personal care products mg/kg body weight. marketed in Europe according to the general provisions of the [0175] PEG-40 stearate (CAS No. 9004-99-3) may act as Cosmetics Directive of the European Union. an emulsi?er. PEG-40 stearate typically functions as a cleans [0178] Sodium Hydroxide (CAS No. 1310-73-2) may ing agent, but also helps keep ingredients solubilized. Suit function as a pH modulator, an alkali used to neutralize acids able materials include a PEG-40 stearate available from Lipo in maintenance of pH of the cream. The Food and Drug Chemicals Inc. under the trade name “Lipopeg® 39S.”The Administration (FDA) includes sodium hydroxide on its list safety of the PEG stearates has been assessed by the Cosmetic of substances af?rmed as Generally Recognized as Safe Ingredient Review (CIR) Expert Panel. The CIR Expert Panel (GRAS) for direct addition to food. Sodium hydroxide, as evaluated the scienti?c data and concluded that PEG-2, -6, -8, well as calcium hydroxide, is also approved as an indirect -12, -20, -32, -40, -50, -100 and -150 stearates are safe for use food additive for use as a defoaming agent in the manufacture in cosmetics and personal care products. In 2002, as part of of paper and paperboard used as food packaging. Sodium the scheduled re-evaluation of ingredients, the CIR Expert hydroxide is listed in the Cosmetics Directive of the European Panel considered available new data on the PEG Stearates and Union (see Annex III) and may be used at the following reaf?rmed the above conclusion. In the CIR Safety Review, concentrations and pH values: 5% by weight in nail cuticle the PEG stearates, whose average number of ethylene oxide solvents, 2% by weight in hair straighteners for general use, monomers range from 2 to 150, were nonlethal at levels up to 4.5% by weight in hair straighteners for professional use, up 10 g/kg. They gave evidence of only minimal skin irritation to a pH 12.7 in depilatories, and up to pH 11 in other uses as and minimal eye irritation when tested at 100%. PEG-8, -40 a pH adjuster. The nail cuticle solvents and the general use and -100 stearates produced no signi?cant changes in growth, hair straighteners containing these ingredients must be histopathologic observations or hematologic values in long labeled “contains alkali, avoid contact with eyes, can cause term feeding studies. Multiple generation studies of PEG-8 blindness, keep out of reach of children.” The professional and -40 stearates were negative for effects on reproduction. hair straighteners must be labeled “for professional use only, Clinical studies on the PEG stearates indicated that these avoid contact with eyes, can cause blindness.” Depilatories ingredients were neither irritants nor sensitizers at concentra containing these ingredients must include the following on tions of 25% or greater. There was no evidence of phototox the label: “Keep out of reach of children, avoid contact with icity or photosensitization of PEG-2 or -8 stearates. Because eyes.” the smaller PEG stearates were not photosensitizing the CIR [0179] Phenoxy ethanol (CAS No. 9004-78-8) may act as a Expert Panel did not expect the larger ingredients to be pho preservative, anti-oxidant, or anti -microbial. Phenoxyethanol tosensitizing. The CIR Expert Panel concluded that safety is used as a preservative in cosmetics. Phenoxyethanol pre data on individual PEG stearates were suf?cient for a decision vents or retards microbial growth, and thus protects cosmetics regarding the safety of the entire group. and personal care products from spoilage. It may also be used [0176] Carbomer polymers may act a thickeners and for in fragrances. Phenoxyethanol is usually synthesized for mulation stabilizers. Carbomers are synthetic polymers of commercial use but it can also be found naturally in products varying molecular weights that can be used to thicken sus such as green tea. The CIR Expert Panel reviewed safety data pend and stabilize cosmetic formulations. Requiring very low on phenoxyethanol and noted that it was practically nontoxic concentrations, carbomers are often used to adjust the viscos via oral and dermal administration. In a subchronic oral study, ity of cosmetic preparations. They dry quickly and are not increased weights of some organs were noted when high ?lm forming. Carbomers as an ingredient family resist bac doses of phenoxyethanol were administered. The doses in this terial attack and do not readily support mold growth. Under study were considered to be much higher than those resulting normal conditions, gels prepared with sodium carbomer nei from use of cosmetics and personal care products containing ther prevent nor promote the growth of microorganisms; phenoxyethanol. In dermal laboratory studies, phenoxyetha US 2014/0212362 A1 Jul. 31, 2014

nol did not cause any birth defects. Phenoxyethanol was not sonal care products and concluded that it was safe to a great mutagenic. In clinical studies, phenoxyethanol was neither a majority of consumers but has limited the concentration to primary nor a cumulative irritant, it did not cause delayed 0.2% free formaldehyde due to the skin sensitivity of some hypersensitivity, and was it nonphototoxic. Phenoxyethanol individuals to this agent. The amount of DMDM hydantoin is listed as 2-Phenoxyethanol in Annex VI, Part 1 (preserva required to preserve a product (less than 1%) does not expose tive which cosmetic products may contain) of the Cosmetics the consumer to concentrations of formaldehyde above the Directive of the European Union and may be used in concen 0.2% limit for formaldehyde recommended by the CIR trations up to 1%. Expert Panel. [0180] Caramel Coloring III (CAS No. 8028-89-5) is a [0183] DMDM hydantoin, called dimethylol, dimethylhy coloring agent derived from heating edible sugar. In cosmet dantoin [1 ,3-Bis(hydroxymethyl)-5 ,5 -dimethylimidazoli ics and personal care products, caramel is used in the formu dine-2,4-dione], is listed in Annex VI, Part I (preservatives lation of a wide variety of product types as a coloring agent. which cosmetics products may contain) of the Cosmetics The Food and Drug Administration (FDA) includes caramel Directive of the European Union and may be used in cosmet on its list of substances considered Generally Recognized As ics and personal care products at a maximum concentration of Safe (GRAS) as a multipurpose food substance. FDA also 0.6%. If the concentration of released formaldehyde exceeds lists caramel as a color additive exempt from certi?cation. 0.05% in the ?nished product it must be labeled “contains Caramel is determined to be safe foruse in coloring cosmetics formaldehyde.” and personal care products, including products applied to the [0184] Iodopropynyl Butylcarbamate (CAS No. 55406-53 lips and area of the eye. The Cosmetic Ingredient Review 6) may function as a preservative, anti-microbial, and anti (CIR) has deferred evaluation of this ingredient because the fungal. The active ingredient of this product, IPBC, is recog safety has been assessed by FDA. This deferral of review is nized by the CTFA in the USA for use in cosmetic and according to the provisions of the CIR Procedures. Caramel personal care products and listed by the EU as an approved functions as a colorant in cosmetics and personal care prod cosmetic preservative. IPBC-II is a colorless to light yellow, ucts. To be used as a colorant in the United States, caramel clear viscous liquid at room temperature. It is a unique and must comply with FDA manufacturing requirements. For cost effective preservative that provides a high level of anti example, only certain food-grade acids, alkalis, and salts may microbial activity. It is remarkably pro?cient in inhibiting the be used to assist carmelization, in amounts consistent with growth of yeasts and molds. IPBC is compatible with essen good manufacturing practice. Caramel is listed in Annex IV, tially all cosmetic ingredients, such as surfactants, emulsi? Part I (coloring agent allowed for use in cosmetic products) of ers, proteins and herbal extracts. the Cosmetics Directive of the European Union and may be used without restriction when purity requirements included in Methods of Preparation food regulations are ful?lled. [0185] The compositions in general are prepared from the [0181] DMDM Hydantoin (e.g., Glydant® Plus available imidazole compound and colloidal oatmeal, as well as any from Lonza) may function as a preservative and anti-micro other desired bene?t agents. If desired additional ingredients bial. It is used as an antimicrobial formaldehyde releaser such as surfactants and emulsifying agents, antihistamines, preservative with the trade name Glydant. DMDM hydantoin topical anesthetics, topical antipruritics, astringents, and is an organic compound belonging to a class of compounds emollients may be added. The ingredients may be added in known as hydantoins. It is used in the cosmetics industry and such steps and amounts and processing varied as to create a found in products like shampoos, hair conditioners, hair gels spray, cream, gel, ointment, or lotion. and skin care products. DMDM hydantoin works as a preser [0186] The advantages of the invention and speci?c vative because the released formaldehyde makes the environ embodiments of the skin care compositions prepared in ment less favorable to the microorganisms. The Cosmetic Ingredient Review (CIR) Expert Panel has evaluated DMDM accordance with the present invention are illustrated by the hydantoin and concluded that it was safe to a great majority of following examples. It will be understood, however, that the invention is not con?ned to the speci?c limitations set forth in consumers but has limited the concentration to 0.2% free the individual examples, but rather de?ned within the scope formaldehyde due to the skin sensitivity of some individuals of the appended claims. to this agent. A study found “[a]n increase in the use of DMDM hydantoin in cosmetic products will also inevitably EXAMPLES increase the risk of cosmetic dermatitis in consumers allergic to formaldehyde. Example 1 [0182] The CIR Safety Review determined DMDM hydan toin is poorly absorbed from the skin. In a laboratory study, [0187] A topical formulation containing 100 mg of THI in oral exposure to DMDM hydantoin did not result in any 10 g ofbase cream was prepared as follows. To 1.0 g ofbase adverse effects. The CIR Expert Panel noted that DMDM cream (water, glycerin, mineral oil, cetyl palmitate, caprylic/ hydantoin is a formaldehyde donor in aqueous media. They capric triglyceride, octyldodecanol, cetyl alcohol, glyceryl attributed positive results in some in vitro mutagenicity stud stearate, colloidal oat ?our, dimethicone, PEG-40 stearate, ies to formaldehyde release. In these studies, the concentra carbomer, sodium hydroxide, phenoxy ethanol, caramel III tions of DMDM hydantoin tested were higher than those used coloring, DMDM hydantoin, iodopropynyl butylcarbamate) in cosmetic and personal care products, likely resulting in was added 100 mg of THI (CAS No. 94944-70-4) portion much higher concentrations of formaldehyde than found in wise with levigation of the powder between additions. A products. Clinical studies revealed some observations of skin smooth cream was obtained by levigation in a marble mortar irritation which could also be related to the release of form and pestle. A dime-sized portion of the levigated material was aldehyde from DMDM hydantoin. The CIR Expert Panel has then incorporate geometrically with similar-sized portions of reviewed the safety of formaldehyde in cosmetics and per base and mixed thoroughly. Geometric mixing with addi US 2014/0212362 A1 Jul. 31, 2014

tional cream base was repeated until 9.9 g of base was incor following the treatment protocol of Example 2 using only the porated, yielding a 1.0% THI cream. Examination of the 0.5% concentration lotion, the subject rated the severity of cream on a mixing plate suggested the THI was at least excema after treatment as 0. partially dissolving in the cream base. Application of the ?nished cream to the skin left no residue. Example 4

Example 2 Test Case for Psoriasis [0193] The subject is a 63-year-old Caucasian male, appar Eczema/Psoriasis Lotion Treatment ently in otherwise good health, suffering from psoriasis over a portion of the subject’s chest and lower back. The subject [0188] The treatment test regime consists of three concen had been suffering from moderate to severe psoriasis in these trations ranging from 0.5% to 2% of the active ingredient areas for more than 40 years and was able to obtain only THI. Affected areas are documented with before and after moderate relief during that time from a variety of treatments photos and notes of observations from each step in the treat including UV radiation, and at the time immediately prior to ment regime are recorded. Three lotions respectively contain the treatment according to the protocol of Example 2 had been ing 0.5% (Disc “A”), 1.0% (Disc “B”), and 2% (Disc “C”) by taking methotrexate orally and applying Daivonet or weight of THI are used in the treatment test. Daivonex ointments topically. Following the treatment pro tocol of Example 2 for two weeks and three weeks concluding Stande Application Protocol with the 2.0% concentration lotion substantially relieved the subject’s psoriatic symptoms. [0189] The area to which the lotion is to be applied to is cleaned before starting treatment. The lotion from Disc “A” is What is claimed: applied to just cover the affected area twice a day, once in 1. A method of treating, managing, or preventing a derma morning and once again in evening. Any physical changes tological or skin condition, which comprises topically admin observed are noted; the treatment is discontinued if redness istering to a subject in need thereof a therapeutically or pro occurs. This regime is continued for one week. If the desired phylactically effective bene?t agent comprising an imidazole effect is realized at this concentration, applications at 0.5% compound of the formula: concentration are continued without moving on to the next higher concentration. The treatment is discontinued if redness R7 R8 occurs. [0190] At the start of week two if no observed relief is HO noticed with 0.5% lotion from Disc “A”, treatment is begun R9 with 1.0% lotion from Disc “B”. The application regime just described is repeated substituting the 1.0% lotion from disc — R6 “B” for one week. If the desired effect is realized at 1.0% HN / N concentration, the applications are continued at this concen tration without moving on to the next higher concentration. Any physical changes observed are noted; the treatment is R1 0 discontinued if redness occurs. [0191] At the start of week three if no observed relief is noticed with 1.0% lotion from Disc “B”, treatment is begun wherein: with 2.0% lotion from Disc “C”. The application regime just R1 is hydrogen, alkyl or aryl; described is repeated substituting the 2.0% lotion from disc R6 is ORlo or OC(O)R10; “C” for one week. If the desired effect is realized at 2.0% R7 is ORll or OC(O)R11; concentration, the applications are continued at this concen R8 is ORl2 or OC(O)R12; and tration. Any physical changes observed are noted; the treat R9 is hydrogen, CH2OR13 or CHZOC(O)R13; and each of ment is discontinued if redness occurs. R10, R11, R12 and R13 is independently hydrogen or lower alkyl, and pharmaceutically acceptable salts and Example 3 solvates thereof, and pharmaceutically, dermatologically, or cosmetically Test Case for Excema acceptable salts thereof. 2. The method of claim 1, wherein the imidazole com [0192] The subject is a 10-year-old Caucasian male, in pound is 2-acetyl-4-tetrahydroxybutylimidazole. otherwise excellent health, suffering from excema over a 3. The method of claim 1, wherein the dermatological or portion of the subject’s thighs. The subject rated the severity skin condition is an immune-mediated skin condition. of the excema before treatment according to the protocol of 4. The method of claim 3, wherein the immune-mediated Example 2 as 9 on a scale of 0 to 10, where 0 represents no skin condition is atopic dermatitis, seborrheic dermatitis, psoriasis or excema, and 10 represents extremely bad psoria contact dermatitis, cutaneous sarcoidosis, drug induced pho sis or excema. The subject had been previously treated with tosensitivity, ?xed drug eruptions, id reactions, bullous skin locoid lipid oil and hyderm topical hydrocortisone treatments diseases, discoid lupus erythematosus, subacute cutaneous with little to moderate success. The subject rated the effec lupus, alopecia areata, sea bathers eruptions, or psoriasis. tiveness of the locoid lipid oil as 2 and of the hyderm cream as 5. The method of claim 1, for treating, managing, or pre 4 on a scale of 1 to 5, where 1 represents an extremely useful venting the symptoms or diseases of atopic dermatitis, seb treatment, and 5 represents no change in symptoms. After orrheic dermatitis, contact dermatitis, cutaneous sarcoidosis, US 2014/0212362 A1 Jul. 31, 2014

drug induced photosensitivity, ?xed drug eruptions, id reac and pharmaceutically, dermatologically, or cosmetically tions, bullous skin diseases, discoid lupus erythematosus, acceptable salts thereof, contained in a dermatologically subacute cutaneous lupus, alopecia areata, sea bathers erup acceptable carrier. tions, or psoriasis. 13. A composition comprising colloidal oatmeal and an 6. The method of claim 1, wherein the dermatological or imidazole compound of the formula skin condition is an in?ammatory or immune-mediated der matosis. 7. The method of claim 6, wherein the in?ammatory or R7 R8 immune-mediated dermatosis is atopic dermatitis. HO 8. The method of claim 6, wherein the in?ammatory or R9 immune-mediated dermatosis is a papulosquamous dermato sis. — R6 9. The method of claim 8, wherein the papulosquamous HN / N dermatosis is psoriasis. 10. The method of claim 1, wherein the subject is a mam mal or fowl. R1 0 11. The method of claim 10, wherein the mammal is a human, canine, feline, bovine, or ovine. 12. A method of caring for skin, delivering or depositing a wherein: bene?t agent onto skin, or suppressing a dermatologic R1 is hydrogen, alkyl or aryl; immune response in a patient in need thereof, which com R6 is ORlo or OC(O)R10; prises topically administering to the skin of a subject in need R7 is ORll or OC(O)R11; thereof a bene?t agent comprising an imidazole compound of R8 is ORl2 or OC(O)R12; and the formula: R9 is hydrogen, CH2OR13 or CHZOC(O)R13; and each of R10, R11, R12 and R13 is independently hydrogen or lower alkyl, R7 R8 and pharmaceutically, dermatologically, or cosmetically acceptable salts thereof, contained in a dermatologically HO acceptable carrier. R9 14. The composition of claim 13, in the form of a spray, cream, gel, lotion, or ointment. — R6 15. The composition of claim 13, wherein the carrier com HN / N prises one or more excipients selected from the group con sisting of surfactants, solvents, tonicity modi?ers, thickeners, emulsi?ers, preservatives, dispersants, buffers, stabilizers, R1 0 fragrances, colorants, and ?avorings. 16. The composition of claim 13, wherein the bene?t agent further comprises one or more compounds or compositions wherein: selected from the group consisting of antipruritics, emol R1 is hydrogen, alkyl or aryl; lients, antiseptics, antifungals, antiin?ammatories, immuno R6 is ORlo or OC(O)R10; suppressants, psoriasis agents, anti-cancer agents, antibiot R7 is ORll or OC(O)R11; ics, antiparasitics, antioxidants, antibacterials, R8 is ORl2 or OC(O)R12; and antimicrobials, antiretrovirals, moisturizers, sunscreens, R9 is hydrogen, CH2OR13 or CHZOC(O)R13; and each of NSAle, hormones, steroids, analgesics, antihistamines, and R10, R11, R12 and R13 is independently hydrogen or antipyretics. lower alkyl,