Dim compositions containing additional therapeutic agent

Abstract

Provided herein, in some embodiments, is a composition for use in treating a skin condition, such as an inflammatory' or infectious skin condition. In some embodiments, the composition comprises a first component comprising a substituted or unsubstituted, diindolylmethane; and a second component comprising at least one supplemental (or additional) therapeutic agent, wherein the composition is essentially free of substituted or unsubstituted retinoid, compounds, wherein the composition is essentially free of CYP450 enzyme modulators, wherein the composition is essentially free of probiotic agents, and w herein the composition is essentially free of anti-protozoal agents.

Description

DIM COIMPOSITIONS CONTAINING ADDITIONAL THERAPEUTIC AGENTBACKGROUND OF THE DISCLOSURE

[0001] Diindovlymethane (DIM) is a component of Indole-3-carbinol (I3C) found in members of the Brassica family. Most notably broccoli, kale, and cauliflower.SUMMARY OF THE DISCLOSURE

[0002] Provided herein, in some embodiments, is a composition for use in treating a skin condition, such as an inflammatory or infectious skin condition. In some embodiments, the composition comprises a first component comprising a substituted or unsubstituted diindolylmethane; and a second component comprising at least one supplemental (or additional) therapeutic agent, wherein the composition is essentially free of substituted or unsubstituted retinoid compounds, wherein the composition is essentially free of CYP450 enzyme modulators, wherein the composition is essentially free of probiotic agents, and wherein the composition is essentially free of anti-protozoal agents.

[0003] In some embodiments, the additional therapeutic agent selected from one or more of, a substituted or unsubstituted azelaic acid compound, an oral contraceptive compound, sulphur, a sulphur-containing compound, a substituted or unsubstituted salicylic acid compound, a substituted or unsubstituted resorcinol compound, a plant product, a mineral, a peroxide (such as benzoyl peroxide), a vitamin, and a neutraceutical product.

[0004] In some embodiments, the excluded substituted or unsubstituted retinoid compounds include substituted or unsubstituted first-generation retinoids, substituted or unsubstituted second-generation retinoids, and substituted or unsubstituted third -generation retinoids.

[0005] In some embodiments, the excluded substituted or unsubstituted first-gene ration retinoids include substituted or unsubstituted retinols, substituted or unsubstituted retinals. substituted or unsubstituted tretinoins, substituted or unsubstituted isoretinoins, and substituted or unsubstituted alitretinoins.

[0006] In some embodiments, the excluded second-generation retinoids include substituted or unsubstituted etretinates and substituted or unsubstituted acitretins.

[0007] In some embodiments, the excluded third-generation retinoids include substituted or unsubstituted tazarotenes, substituted or unsubstituted bexarotenes, and substituted or unsubstituted adapalenes.

[0008] In some embodiments, the first component comprises a diindolylmethane of Formula 1 :R olylFormula 1wherein the R groups are independently selected from hydrogen atoms and Ci-Ce hydrocarbon substituents; and wherein the indolyl groups are independently selected from indole-3 -yl and indole- 2-yl groups; and wherein the indolyl groups are unsubstituted, or are substituted with one or more Ci-Cf, hydrocarbon substituents.

[0009] In some embodiments, the first component comprises a substituted or unsubstituted3,3 ’diindolylmethane. of Formula 2, or a substituted or unsubstituted 2,2 ’diindolylmethane, of Formulawherein the R groups are independently selected from hydrogen atoms, and Ci-Ce hydrocarbon substituents.

[0010] In some embodiments, the first component comprises a 3,3 ’diindolylmethane, of Formula 4 or a 2,2’diindolylmethane, of Formula 5:

[0011] In some embodiments, the first component comprises 3,3 ’diindolylmethane.

[0012] In some embodiments, the first component is in a form suitable for providing a daily substituted or unsubstituted diindolylmethane dosage of up to 1500 mg or less. In some embodiments, the first component is in a form suitable for providing a daily substituted or unsubstituted diindolylmethane dosage of about 10 mg to about 750 mg.

[0013] In some embodiments, the substituted or unsubstituted diindolylmetbane is adapted for increased bioavailability. In some embodiments, the substituted or unsubstituted diindolylmetbane is microencapsulated. In some embodiments, the first component comprises one or more lipophilic compounds selected from vitamin E and phosphatidylcholine. In some embodiments, the substituted or unsubstituted diindolylmetbane is BR-DIM,

[0014] In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is in the form of a tablet or capsule.

[0015] In some embodiments, the composition is formulated for topical administration. In some embodiments, the composition is in the form of a gel. cream, ointment, or a liquid.

[0016] In some embodiments, the first and second components are combined into one dosage form. In some embodiments, the first and second components are in separate dosage forms.

[0017] In some embodiments, the first component is in a form suitable for providing a daily substituted or unsubstituted diindolylmetbane dosage of about 10 mg to about 750 mg.

[0018] In some embodiments, the first component is in a form suitable for providing a daily substituted or unsubstituted diindolylmetbane dosage of about 150 mg to about 650 mg, about 250 mg to about 550 mg, about300 mg to about 500 mg, about 400 mg to about 450 mg, or about 500 mg.

[0019] In some embodiments, the first component is present in a dose which is a fraction of the daily dose, preferably a half of the daily dose, or a quarter of the daily dose.DETAILED DESCRIPTION OP THE DISCLOSURE

[0020] The present application discloses a pharmaceutical composition or kit comprising a substituted or unsubstituted diindolylmetbane (DIM) for use in treating skin diseases or conditions. In some embodiments, the composition comprises one or more other components in addition to the substituted or unsubstituted DIM in order to enhance the pharmaceutical effect of the substituted or unsubstituted DIM.Certain Definitions

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which tire claimed subject matter belongs. In the event that there is a plurality of definitions for terms herein, those in tills section prevail.

[0022] It is to be understood that the foregoing general description and the following detailed description are exemplaiy and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that use of "or" means "and / or” unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes", and "included” is not limiting.

[0023] As used herein, the term “about” is used synonymously with the term “approximately.” Illustratively, the use of the term “about” with regard to a certain therapeutically effective pharmaceutical dose indicates that values slightly outside the cited values, e.g., plus or minus 0.1% to 10%, are also effective and safe.

[0024] The term "patient", "subject" or "individual" are used interchangeably. As used herein, they refer to individuals suffering from a disorder, and the like, encompasses mammals and non-mammals. None of the terms require that tire individual be under the erne and / or supervision of a medical professional. Mammals are any member of the Mammalian class, including but not limited to humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In some embodiments of the methods and compositions provided herein, the individual is a mammal. In preferred embodiments, the individual is a human.

[0025] The terms "treat," "treating" or "treatment," and other grammatical equivalents as used herein, include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis. The terms further include achieving a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual is still be afflicted with tlie underlying disorder. For prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0026] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery' of compounds or compositions to the desired site of biological action. These methods include, but are not limited to topical routes, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in tlie art are familiar with administration techniques that can be employ ed with the compounds and methods described herein.

[0027] The term "acceptable" as used herein, with respect to a formulation, composition or ingredient, means having no persistent detrimental effect on the general health of the individual being treated.

[0028] The term "pharmaceutically acceptable" as used herein, refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0029] The term “DIM” as used herein, refers to a substituted or unsubstituted diindolylmethane compound.

[0030] The term “BR-DIM” or “BioResponse DIM” as used herein, refers to an unsubstituted DIM, provided by BioResponse LLC.

[0031] The term “maximum concentration” or Cmax as used herein, refers to the Cmax refers to the maximum (or peak) serum concentration that the substituted or unsubstituted diindolylmethane achieves in the plasma after it has been administrated and prior to the administration of a second dose.

[0032] The term “time to maximum concentration” or Tmax as used herein, refers to the time at which the Cmax is observed.

[0033] The term “area under the curve” or AUC or AUCo-inf as used herein, refers to the area under the curve, also known as the definite integral, in a plot of concentration of drug in blood plasma against time.

[0034] The term “unit dose” as used herein, refers to an amount of substituted or unsubstituted diindolylmethane contained in one discreet pharmaceutical dosage form. Examples of pharmaceutical dosage form that contains a unit dose include but are not limited to a tablet, a capsule, a buccal tablet, a sub-lingual tablet, an orally -disintegrating tablet, an effervescent tablet, a lollipop, a lozenge, a troche, a liquid solution or suspension, powder or liquid or solid crystals packed within a single tablet or capsule, a cream, a gel, an ointment, a lotion.

[0035] ©IM

[0036] As such, provided herein, in one embodiment, are methods and compositions for use in treating skin conditions, such as inflammatory skin conditions, wherein the composition comprises a first component, optionally a second component, wherein the first component comprises a substituted or unsubstituted diindolylmethane (DIM), and the second component comprises a substituted or unsubstituted retinoid compound. In some embodiments, are provided kits containing the compositions for use in treating skin conditions, such as inflammatory skin conditions, as described herein. In some embodiments, the DIM is a substituted or an unsubstituted DIM. In some embodiments, the retinoid compound is a substituted or an unsubstituted retinoid compound. In some embodiments, tire DIM is BioResponse DIM (BR-DIM). In some embodiments, the DIM is any compound comprising a diindolylmethane group. In some embodiments, the DIM lias the following structure (Formula 1):Formula 1 wherein the R groups are be the same or different substituents. In some embodiments, the R substituents comprise any organic group and / or one or more atoms from any of groups III A, IVA, VA, VIA or VIIA of the Periodic Table, such as a B, Si, N, P, O, or S atom or a halogen atom (e.g., F, Ci, Br or I).

[0037] In some embodiments, the R substituent comprises an organic group. In some embodiments, the organic group comprises a hydrocarbon group. In some embodiments, the hydrocarbon group comprises a straight chain, a branched chain or a cyclic group. In some additional embodiments, the hydrocarbon group comprises an a li phatic or an aromatic group. In some additional embodiments, the hydrocarbon group comprises a saturated or an unsaturated group.

[0038] In some embodiments, the hydrocarbon comprises an unsaturated group comprising one or more alkene functionalities and / or one or more alkyne functionalities. In some embodiments, the hydrocarbon comprises a straight or branched chain group comprising one or more primary, secondary and / or tertiary alkyl groups. In some embodiment, the number of carbon atoms in the hydrocarbon group is between 1-40. In some embodiments, the hydrocarbon group is a lower hydrocarbon. In some embodiments, the number of carbo a atom in the lower hydrocarbon is between 1 and 6. In some additional embodiments, the hydrocarbon group is a higher hydrocarbon. In some embodiments, the number of hydrocarbons in the higher hydrocarbon is higher than 7. In some embodiments, the number of carbon atoms in the higher hydrocarbon is between 7 and 40.

[0039] In some embodiments, the hydrocarbon comprises a cyclic group comprising an aromatic ring, an aliphatic ring, a heterocyclic group, and / or fused ring derivatives of these groups. In some embodiments, the cyclic group comprises a benzene, a naphthalene, an anthracene, an indene, a fluorene, a pyridine, a quinoline, a thiophene, a benzothiophene, a furan, a benzofuran, a pyrrole, an indole, an imidazole, a thiazole, and / or an oxazole group, as well as regioisomers of the above groups. In some embodiments, the number of atoms in the ring of the cyclic group is between 3 and 10. In some embodiments, the number of atoms in the ring of the cyclic group is 3, 4, 5, 6, or 7.

[0040] In some embodiments, the cyclic groups comprising beteroatoms described above, as well as any of the other groups defined above, further comprise one or more heteroatoms from any of groups II1.A, IVA, VA, VIA or VITA of the Periodic Table, such as a B, Si, N, P, O, or S atom or a halogen atom (e.g.. F, Cl, Br or I).

[0041] In some embodiments, the R substituent comprises one or more of any of the common functional groups in organic chemistry, such as hydroxy groups, carboxylic acid groups, ester groups, ether groups, aldehyde groups, ketone groups, amine groups, amide groups, imine groups, thiol groups, thioether groups, sulphate groups, sulphonic acid groups, and phosphate groups etc. In someembodiments, the substituent comprises one or more derivatives of any of the common functional groups in organic chemi stry, such as hydroxy groups, carboxylic acid groups, ester groups, ether groups, aldehyde groups, ketone groups, amine groups, amide groups, imine groups, thiol groups, thioether groups, sulphate groups, sulphonic acid groups, and phosphate groups etc. Exemplary derivatives include but are not limited to, carboxylic acid anhydrydes and carboxylic acid halides.

[0042] In some embodiments, any R substituent comprises a combination of two or more of the substituents and / or functional groups defined above.

[0043] In some embodiments, the R substituents are selected from hydrogen atoms and Ci-Ce hydrocarbon substituents such as Ci-Cv alkyl groups (e.g,. methyl, ethyl, propyl, isopropyl, and butyl groups). In some embodiments, both R substituents are hydrogen atoms.

[0044] In some embodiments, the indolyl groups in formula 1 are the same or different. In some embodiments, both indolyl groups are indole-3-yI groups. In some embodiments, both indolyl groups are indole-2 -yl groups. In some embodiments, one indolyl group is indole-3 -yl and the other indolyl group is indole-2 -yl. In some embodiments, the indolyl groups comprise same or different substituents. In some embodiments, the indolyl groups are unsubstituted, such that all substituents are hydrogen atoms. In some embodiments, the indolyl groups are substituted with one or more of any of the R substituents defined above. In some embodiments, the substituents are selected from hydrogen atoms and C) -Cf; hydrocarbon substituents such as Cs-Cv, alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, and butyl groups).

[0045] In some embodiments, the composition comprises a first component comprising a substituted or unsubstituted 3,3’diindolylmetharie. of Formula 2. In some embodiments, the composition comprises a first component comprising a substituted or unsubstituted 2,2’diindolylmethane, of Formula 3.

[0046] In some embodiments, the composition comprises a first component comprising a 3,3’diindolylmethane. of Formula 4. In some embodiments, the composition comprises a first component comprising a 2,2’diindolylmethane, of Formula 5.Formula 4Formula 5Additional Therapeutic Agents

[0047] In some embodiments, the second component has a beneficial effect supplementary to and / or complementaiy to the effect of the first component. In some embodiments, the second component is selected from an antibiotic compound, a substituted or unsubstituted azelaic acid compound, an oral contraceptive compound, sulphur, a sulphur-containing compound, a substituted or unsubstituted salicylic acid compound, a substituted or unsubstituted resorcinol compound, a plant product, a mineral, a vitamin, and a neutraceutical product, and wherein the second component is not a retinoid compound.

[0048] Other agents that are used in the embodiments disclosed herein, either alone or in combination with other therapeutic agents, include anti-apoptotic agents, including caspases, INK inhibitors (by way of example only CEP / KT-75I5, AS601245, SPC9766 and SP600125), antioxidants, NSAIDs, neuroprotectants, glutamate modulators, interleukin 1 modulators, interleukin- 1 antagonists, including tumor necrosis factor-a coverting enzyme (TACE) and caspases, retinaldehyde modulator, notch modulator, gamma secretase modulator, thalidomide, latanoprost (Xalatan®) for reducing internal pressure and combinations thereof.Antibiotic Agents

[0049] In some embodiments, the second component has a beneficial effect supplementary to and / or complementaiy to the effect of the first component.

[0050] Antibiotic agents useful for the treatment of skin disorders, e.g., inflammatory skin diseases, is suitable for use in the formulations and methods disclosed herein. In certain embodiments, the antibiotic agents are antibiotic small molecules. Typically, antibiotic small molecules are of relatively low molecular weight, e.g., less than 1 ,000, or less than 600-700, or between 300-700 molecular weight. In some embodiments, the antibiotic agent is a protein, a peptide, an antibody, a carbohydrate, an inorganic molecule, or an organic molecule,

[0051] In some embodiments, the antibiotic is an aminoglycoside. Examples of aminoglycoside antibiotics include and are not limited to amikacin, gentamicin, kanamycin, neomycin, netilmicin,streptomycin, tobramycin, paromycin or the like. In some embodiments, the antibiotic is an ansamycin. Examples of ansamycins include and are not limited to geldanamvcin, berbimycin or the like. In some embodiments, the antibiotic is a carbacephem. Examples of carbecephems include and are not limited to loracarbef or the like. In some embodiments, the antibiotic is a carbapenem. Examples of carbapenems include and are not limited to ertapenem, doripenem, imipenem (cilostatin), meropenem or the like. In some embodiments, the antibiotic is a ceplialosporin (including, for example, first, second, third, fourth or fifth generation cephalosporins). Examples of cephalosporins include and are not limited to cefaclor, cefamandole, cefotoxin, cefprozii, cefuroxime, cefixime, cefdinir, cefditoren. cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobirprole or the like. In some embodiments, the antibiotic is a glycopeptide. Examples of glycopeptides include and are not limited to vancomycin or the like. In some embodiments, the antibiotic is a macrolide antibiotic. Examples of macrolides include and are not limited to azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, or the like. In some embodiments, the antibiotic is a monobactam. Examples of monobactams include and are not limited to aztreonam or the like. In some embodiments, the antibiotic is a penicillin. Examples of pencillins include and are not limited to amoxicillin, ampicillin, azociling, carbenicillin, cioxacillin, dicioxacillin, flucioxacillin, mezlocillin, meticillin, nafcillin, oxacillin, peperacillin, ticarcillin or the like. In some embodiments, the antibiotic is a polypeptide. Examples of polypeptide antibiotics include and are not limited to bacitracin, colistin, polymyxin B or the like. In some embodiments, the antibiotic is a quinolone. Examples of quinolones include and are not limited to ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nonfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, AL-15469A, AL-38905 or the like. In some embodiments, the antibiotic is a sulfonamide. Examples of suflonamides include and are not limited to afenide, prontosil, sulfacetamide, sulfamethiazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, cotrimoxazole or the like. In some embodiments, the antibiotic is a tetracycline antibiotic. Examples of tetracyclines include and are not limited to demeclocycline, doxycycline, minocycline, oxytetracycline, tetravcline or the like. In some embodiments, the antibiotic is an oxazolidinone antibiotic. Examples of oxazolidinone antibiotics include and are not limited to linezoiid or the like. In some embodiments, the antibiotic is arsogebanubem chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezoiid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin, dalfopristin, rifampicin, thamphenicol, tinidazole or the like.

[0052] Antibacterial agents include amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, geldanmycin, herbimycin. loracarbef, ertapenem. doripenem, imipenem. cilastatin, meropenem, cefadroxil, cefazolin. cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, defprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, teicoplanin,vancomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, aztreonam, amoxicillin, ampicillin, azlocillin, carbenicillin, cioxacillin, dicloxacillm, flucloxacillin, mezlocillin, meticillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcilian, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovfloxacin, mafenide, prontosil, sulfacetamide, suifamethizole, sulfanimiiimde, sulfsaiazine, sulfsi oxazole, trimethoprim, demeclocycline, doxycycline, minocycline, oxtetracycline, tetracycline, arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid. linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin. pyrazinamide, quinuspristin / dalfopristin, rifampin, tinidazole, and combinations thereof.

[0053] In some embodiments, an antibiotic compatible with the compositions described herein is a broad spectrum antibiotic. In some embodiments, an antibiotic compatible with the compositions described herein is effective in treating infections that are resistant to other classes of antibiotics. For example, in some instances, vancomycin is effective in treating infections caused by methicillin resistant staphyloccocus aureus bacteria. In some embodiments, intratympanic admnistration of an antibiotic composition described herein reduces the risk of development of antibiotic resistance that is seen with systemic treatments.

[0054] In specific embodiments, an antibiotic used in compositions or devices described herein is ciprofloxacin (Cipro). In specific embodiments, an antibiotic used in compositions or devices described herein is gentamicin. In specific embodiments, an antibiotic used in compositions or devices described herein is a penicillin. In specific embodiments, an antibiotic used in compositions or devices described herein is streptomycin.

[0055] In some embodiments, an antibiotic agent is a peptide or a lantibiotic including, by way of example, Maximin H5, Denncidin, Cecropins, andropin, moricin, ceratotoxin and melittin, Magainin, dermaseptin, bombinin, brevinin-1, esculentins and buforin II, CAP 18, LL37, abaecin, apidaecins, prophenin, indolicidin, brevinins, protegrin, tachyplesins, defensins, drosomycin, alamethicin, pexiganan orMSI-78, and other MSI peptides like MSI-843 andMSI-594, polyphemusin, Class I II and III bacterocins like: colicin, pyocin, klebicin, subtilin, epidermin, herbicolacin, brevicin, halocin, agrocin, alveicin, carnocin, curvaticin, divercin, enterocin, enterolysin, erwiniocin, glycinecin, lactococin, lacticin, leucoccin, mesentericin, pediocin, plantaricin, sakacin, sulfolobicin, vibriocin, warnerinand, nisin or the like.Immunomodulating agents,4 n ti - TNF A gen ts

[0056] Contemplated for use with the formulations disclosed herein are agents which reduce or ameliorate symptoms or effects as a result of an autoimmune disease and / or inflammatory disorder. Accordingly, some embodiments incorporate the use of agents which block the effects of TNF-a,including anti-TNF agents. By way of example only, anti-TNF agents include protein-based therapeutics, such as etanercept (ENBREL®), infliximab (REMICADE5), adalimumab (HUMIRA®) and golimumab (CNTO 148), and small molecule therapeutics, such as TACE inhibitors, IKK inhibitors or calcineurin inhibitors or combinations thereof.

[0057] Infliximab and adalimumab are anti-TNF monoclonal antibodies, and etanercept is a fusion protein designed to bind specifically to the TNF protein. All are currently approved for use in the treatment of rheumatoid arthritis. Golimumab. which is currently in Phase 3 clinical trials for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, is a fully -humanized anti-TNF- alpha IgGl monoclonal antibody that targets and neutralizes both the soluble and the membranebound form of TNF-a. Other antagonists to TNF, by way of example only, include TNF receptors (pegylated soluble TNF receptor type 1; Amgen); TNF binding factors (Onercept; Scrono); TNF antibodies (US Patent App. No. 2005 / 0123541; US Patent App. No. 2004 / 0185047); single domain antibodies against the p55 TNF receptor (US Patent App. No. 2008 / 00088713); soluble TNF receptors (US Patent App. No. 2007 / 0249538); fusion polypeptides binding to TNF (US Patent App. No.2007 / 0128177); and flavone derivatives (US Patent App. No. 2006 / 0105967), all of which are incorporated by reference for such disclosure. The use of onercept, a soluble TNF p55 receptor, was discontinued in 2.005. Three phase-III clinical trials reported patients diagnosed with fatal sepsis. A risk to benefit analysis was subsequently performed, resulting in the discontinuation of the clinical trials. As discussed above, the embodiments herein specifically contemplate the use of anti-TNF agents which have been previously shown to have limited or no systemic release, systemic toxicity, poor PK characteristics of combinations thereof.

[0058] Although etanercept, infliximab and adalimumab are currently approved systemic therapies for use in rheumatoid arthritis, these anti-TNF agents are not without serious adverse side effects. It is contemplated that the localized application of the anti-TNF agents to the target for treatment of autoimmune and / or inflammatory disorders will result in the reduction or elimination of these adverse side effects experienced with systemic treatment. Moreover, localized treatment with the anti-TNF agents contemplated herein will also reduce the amount of agent needed for effective treatment of the targeted disorder,

[0059] Etanercept is a dimeric fusion protein consisting of the extracellular ligand -bind! ng portion of tiie human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG 1. The Fc component of etanercept contains the CH2 domain, the CH3 domain and hinge region, but not the CHI domain of IgGl . Etanercept is a recombinant protein consisting of 934 amino acids, with an apparent molecular weight of approximtately 150 kilodaltons. Etanercept binds specifically to tumor necrosis factor (TNF), and acts by inhibiting the interaction of TNF with cell surface TNF receptors. Serious side effects with etanercept have been reported with systemic administration, including serious infections and sepsis that resulted in fatalities. Other side effectsobserved upon intravenous administration of etanercept include contraction of tuberculosis; onset or exacerbation of central nervous system disorders, including mental status changes, transverse myelitis, optic neuritis, multiple sclerosis and seizures resulting in permanent disability; adverse hematologic events, including pancytopenia, aplastic anemia with fatal outcomes, blood dyscrasias, persistent fever, bruising, bleeding and pallor, neutropenia and cellulitis. Treatment with etanercept may also result in the formation of autoantibodies, which may develop into a lupus-like syndrome, as well as development of malignant disorders. Moreover, over one-third of patients systemically treated with etanercept experience injection site reactions including mild to moderate erythema and / or itching, pain and / or swelling. Injection site bleeding and bruising lias also been observed. Other side effects from the systemic administration of etanercept include headache, nausea, rhinitis, dizziness, pharyngitis, cough., asthenia, abdominal pain, rash, peripheral edema, respiratory' disorder, dyspepsia, sinusitis, vomiting, mouth ulcer, alopecia and pneumonitis. Infrequent side effects include heart failure, myocardial infarction, myocardial ischemia, hypertension, hypotension, deep vein thrombosis, thrombophlebitis, cholecystitis, pancreatitis, gastrointestinal hemorrhage, bursitis, polymyositis, cerebral ischemia, depression, dyspnea, pulmonary embolism, and membranous glomerulonephropathy in rheumatoid arthritis patients. Varicella infections, gastroenteritis, depression / personality disorder, cutnaeous ulcer, esophagitis / gastritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and post-operative wound infection was also seen in juvenille rheumatoid arthiritis patients.

[0060] Infliximab is a chimeric human-mouse IgGlK monoclonal antibody with an approximate molecular weight of 149 kilodaltons. Infliximab binds specifically to TNFa with an association constant of 10IUM1. Infliximab is produced by a recombinant cell line cultured by continuous perfusion. Infliximab acts to neutralize the binding activity’ of TNFa by inhibiting binding of TNF to its cell surface receptors. Serious side effects as a result of systemic intravenous infusions or injections have been reported with the use of infliximab, including fatal sepsis and serious infections. Cases of histoplasmosis, listeriosis, pneumocystosis and tuberculosis have also been observed. Hypersensitivity, including urticaria, dyspnea and hypotension have occurred upon treatment with infliximab. Infusion reactions include cardiopulmonary' reactions (primarily chest pain, hypotension, hypertension or dyspnea), pruritus, and combined reactions. Oilier hypersensitivity symptoms include fever, rash, headache, sore throat, myalgias, polyarthraligias, hand and facial edema and / or dysphagia, anaphylaxis, convulsions, erythematous rash, latyngeal / pharyngeal edema and severe bronchospasm. Neurologic adverse events include optic neuritis, seizure and new onset or exacerbation and / or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis. The formation of autoantibodies have also been observed, including symptoms suggestive of a lupus-like syndrome following treatment. Other serious adverse events include worsening rheumatoid arthrtis, rheumatoid nodules, abdominal hernia, asthenia, chest pain, diaphragmatichernia, pancytopenia, splenic infarction, splenomegaly, syncope, cerebral hypoxia, convulsions, dizziness, encephalopathy, hemiparesis, spinal stenosis, upper motor neuron lesion, ceruminosls, endophthalmitis, and other infrequent-occurring side effects.

[0061] Adalimumab is a recombinant human IgGl monoclonal antibody specific for human TNF. Adalimumab was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgGLK constant regions, and consists of 1330 amino acids with a molecular weight of approximately 148 kilodaltons. Adalimumab binds specifically to TNF-a and blocks its interaction with both the p55 and p75 TNF cell surface receptors. Adalimumab also lyses TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-p). Serious side effects from systemic administration have been reported with the intravenous administration or injection of adalimumab, including fatal sepsis and serious infections, including upper respiratory infections, bronchitis, urinary tract infections, pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas cellulitis, diverticulitis, py elonephritis, tuberculosis, and invasive opportunitistic infections caused by histoplasma, aspergillus and nocardia. Other serious adverse reactions were neurologic events, including confusion, multiple sclerosis, paresthesia, subdural hematoma, and tremor, and the development of malignancies, including lymphoma development. The formation of autoantibodies has also been observed, including symptoms suggestive of a lupus-like syndrome following treatment. The most common adverse reaction was injection site reactions, with 20% of patients developing erythema and / or itching, hemorrhage, pain and / or swelling. Other adverse events as a result of systemic administration of adalimumab include clinical flare reaction, rash and pneumonia. Other adverse events included sinusitis, flu syndrome, nausea, abdominal pain, hypercholesterolemia, hyperlipidemia, hematuria, increased alkaline phosphatase levels, back pain, hypertension, as well as more infrequent serious adverse events, including pain, pelvic pain, thorax pain, arrthythmia, atrial fibrillation, cardiovascular disorder, congestive heart failure, coronary artery disorder, heart arrest, hypertensive encelphalopathy, myocardial infact, palpitation, pericardial effusion, pericarditis, syncope, tachycardia, vascular disorders, and other disorders.Calcineurin Inhibitors

[0062] Calcineurin inhibitors are a group of structurally diverse small molecule immunomoduiators which function through the inhibition of calcineurin function. Calcineurin is a calcium-activated protein phosphatase which catalyses the dephosphorylation of cytoplasmic NFAT. Upon dephosphorylation, NFAT migrates to tire nucleus and forms a regulatory’ complex involved in the transcription of cytokines, such as TNF-LJ, IL -2, IL-3 and IL-4. Inhibition of calcineurin function blocks the dephosphorylation event and subsequent cytokine transcription. An unusual aspect of calcineurin inhibition is that cyclosporine, tacrolimus and pimecrolimus are required to form a complex with an immunophilin for the Inhibitory properties to be realized (Schreiber et al, Immunol.Today (1992), 13:136-42; Liu et al. Cell (1991), 66:807-15). For cyclosporine the immunophilin is cvclopbilin; tacrolimus and pimecrolimus bind to the FK506-binding protein (FKJBP).cyclosporine A

[0063] Cyclosporine is an 11 -residue cyclic peptide produced as a metabolite of the fungus Beauveria nivea and has the chemical name cycIo[[(E)-(2S,3R,4R)-3-hydroxy-4-rnethyl-2- (metiiylamino)-6-octenoyl]-L-2-aminobutyiyl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl- L-leucyl-L-aianyi-D-alanyl-N-metliyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L -valyl. It is provided in several formulations for both systemic or local administration. Sandimmune'® provides cyclosporine in three different formulations: soft gelatin capsules, an oral solution or a formulation for injection. Sandimmune® is indicated for prevention of organ rejection in kidney, liver or heart transplants. Neoral® and Gengraf® provide cyclosporine in two formulations: soft gelatin capsules and an oral solution. They are indicated for prevention of organ rejection in kidney, liver or heart transplants, for treatment of patients with severe active, rheumatoid arthritis, or for treatment of severe psoriasis. Compared to Sandimmune®, Neoral® and Gengraf® provide increased bioavailability of cyclosporine. Restasis® provides cyclosporine in an ophthalmic emulsion formulation. It is indicated to increase tear production in patients with reduced tear production due to ocular inflammation associated with keratoconjunctivitis sicca.

[0064] Tacrolimus, also known as FK-506 or fujimy cin, is a 23-membered macrolide natural product produced by Streptomyces tsukubaensis and has the chemical name [3S-[3R*[E(1S*,3S*,4S*)], 4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]- 5,6,8,l l,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4~hydroxy-3- medioxycyclohexyl)-l-methyiethenyl]-14,16-dimethoxy -4, 10, 12, 18-tetramethyl-8-(2 -propenyl)- 15,19-epoxy-3H-pyrido [2,1-39c] [ 1 ,4] oxaazacyclo tricosine- 1 ,7,20,21 (4H,23H)-tetrone monohydrate.It is provided in formulations suitable for systemic or topical administration. For systemic administration, the Prograf® formulation provides an oral capsule or a sterile solution for injection. Prograf® is indicated for prevention of organ rejection in liver, kidney or heart transplants. For topical administration, the Protopic® formulation is indicated for the treatment of moderate-to-severe atopic dermatitis.

[0065] Pimecrolimus is a semi-synthetic analog of tacrolimus and lias the chemical name (lR,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(lE)-2-{(lR,3R,4S)-4-chloro-3- methoxycyclohexyl}-l-methylvinyl]-17-ethyl-l,14-dihydroxy-23,25-dirnethoxy-13,19,,21,27- tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone. It is provided in a formulation suitable for topical application and is indicated for the treatment of mild-to-moderate atopic dermatitis.

[0066] Studies have shown that tacrolimus and pimecrolimus do not suppress Langerhans’ cells or dermal connective tissue and therefore do not cause atrophy of the skin, unlike corticosteroids (Stuetz et al, Tut. Arch. Allergy Immunol. (2006), 141 : 199-212; Queille-Roussel et al, Br. J. Dermatol.(2001), 144:507-13). Because of the importance of calcineurin, systemic administration of calcineurin inhibitors leads to significant side effects. Systemic side effects are related to dose, exposure levels and duration of therapy. Prolonged elevated blood levels result in hypertension, nephrotoxicity, psychiatric disorders, hyperlipidemia, and profound immunosuppression. Topical application of tacrolimus or pimecrolimus has shown to afford very little, if any, systemic exposure, with tacrolimus having demonstrated less than 0.5 % bioavailability after topical application.

[0067] Other pharmaceutical agents that are optionally used in combination with immunomodulatmg-a agents for the treatment of autoimmune and / or inflammatory disorders include other agents that have been used to treat autoimmune and inflammatory’ disorders, including corticosteroids, local anesthetic agents, chemotherapeutic agents, including cytoxan, azathiaprine or methotrexate; treatment with collagen, gamma globulin, interferons, copaxone. or combinations thereof. Accordingly, also contemplated within the scope of the embodiments herein is the use of other plrarmaceutical agents in combination with the immunomodulating compositions and formulations disclosed in the treatment of autoimmune skin disorders.IKK Inhibitors

[0068] The transcription of TNF-D is dependent on the transcription factor NF-DB. In unstimulated ceils, NF-DB is in the cytoplasm as part of a protein complex with the protein inhibitor of NF-DB, also known as IDB. Activation of NF-DB depends on phosphorylation-induced ubiquitination of the IDB. Once poly-ubiquitinated, the IDB undergoes a rapid degradation through the 26S proteasome and the free NF-DB migrates to the nucleus to activate pro-inflammatory gene transcription. The phosphorylation event which releases NF-DB is mediated by the IDB kinase (IKK) complex, composed of IKK kinases. Two IKK enzymes generally referred to as IKK-D Dand IKK-D(Woronicz et al. Science (1997), 278:866; Zandi et al. Cell (1997), 91:243) or IKK-1 and IKK-2 (Mercurio et al. Science (1997), 278:860) have been discovered. Both forms of IKK can exist as homodimers and as IKK-D / IKK-D heterodimers. Another component of the 1DB kinase complex is a regulatoiy protein, known as :KK- or NEMO (NF- DB -Essential Modulator) (Rothwarf et al. Nature (1998). 395:297). NEMO does not contain a catalytic domain, and thus it appears to have no direct kinase activity and it probably serves a regulatory function. Existing data suggests that the predominant form of IKK in cells is an IKK-D / IKK-D heterodimer associated with either a dimer or a trirner of NEMO (Rothwarf et al. Nature (1998) 395:297). Biochemical and molecular biology experiments have identified IKK-D and IKK-D as the most likely mediators of TNF-D -induced IDB phosphory lation and degradation, which results in NF-DB activation and upregulation of families of genes involved in inflammatory processes (Woronicz et al. Science (1997); Karin, Oncogene (1999) 18:6867; Karin, J. Biol. Chem. (1999) 274:27339).

[0069] Many IKK-D inhibitors have been identified. SPC-839 lias been extensively studied. It inhibits IKK-D with an ICso of 62 nM and reduces paw edema in a rat arthritis model at 30 mg / kg. Carboline PS-1145 inhibits the IKK complex with an IC50 of 150 nM and reduces the production of TNF-n in LPS-challenged mice. BMS-345541 , an allosteric inhibitor, inhibits IKK-D with an IC50 of 0.3 DM. In the mouse collagen-induced arthritis model it significantly reduced the severity of disease at a 30mg / kg dose. A scientific review of IKK inhibitors lias been published (Karin et al., Nature Reviews Drug Discovery (2004), 3. 17-2.6), incorporated herein by reference for such disclosure.Interleukin Inhibitors

[0070] Interleukins are a class of cytokines. In certain instances, they are signtiling molecules secreted by leukocytes having encountered a pathogen. In certain instances, the secretion of interleukins activates and recruits additional leukocy tes to the site of infection. In certain instances, the recruitment of additional leukocytes to the site of infection results in inflammatton (due to the increase in leukocyte containing lymph).

[0071] 11-1 is a class of interleukins comprised of IL-la, and IL-ip. IL-1 is made by macrophages. B ceils, monocytes, and dendritic cells (DC). It binds to receptors ILIRI / CD121a and lLlR2 / CD121b. The binding of IL-1 to its receptors results in an increase in cell-surface adhesion factors. This enables the migration of leukocytes to the site of infection.

[0072] IL-2 is made by TH-1 cells and binds to the receptors CD25 / lL2Ra, CD122IL2Rb, and CD132 / lL2Rg. 11-2 secretion is stimulated by the binding of an antigen to a TH-1 cell. The binding of IL-2 to a receptor stimulates the growth, and differentiation of memory T cells.

[0073] IL-8 is made by macrophages, lymphocytes, epithelial cells, and endothelial cells. It binds to CXCRl / IL8Ra and CXCR2 / IL8Ra / CD128. Secretion of IL-8 initiates neutrophil chemotaxis to the site of infection,

[0074] In some embodiments, a subject in need thereof is administered an inhibitor of a pro- inflammatory interleukin. In some embodiments, the pro-inflammatory interleukin is IL- la, IL-ip, IL-2, or IL-8. In some embodiments, tire inhibitor of a pro-inflammatory interleukin is a WS-4 (an antibody against IL-8); [Ser IL-8]72; or [Ala IL-8]77(See U.S. Patent No. 5,451,399 which is hereby incorporated by reference for disclosures relating to these peptides); IL- IRA; SB 265610 (N-(2- Bromophenyl)-N'-(7~cyano-lH-benzotriazol~4-yl)urea); SB 225002 (N-(2-Brornophenyl)-N‘-(2- hydroxy -4-nitrophenyl)urea); SB203580 (4-(4-Fluorophenyl)-2-(4-rnethylsuIfinyl phenyl)-5-(4- pyridyl) IH-imidazole); SB272844 (GlaxoSmithKline); SB517785 (GlaxoSmithKline); SB656933 (GlaxoSmithKline); Scb527123 (2-hydroxy-N,N-dimetiiyl-3-{2-[[(R)-l-(5-methy4-furan-2-yl)- propyl]amino]-3,4-dioxo-cyclobut-l-enylamino}-benzamide); PD98059(2-(2-amino-3- methoxyphenyl)-4H-l-Benzopyran-4-one); reparixin; N-[4-chloro-2-hydroxy-3-(piperazine-l- sulfony l)phenyl]-N'-(2-chloro-3-fluorophenyl)urea p-toluenesulfonate (See WO / 2007 / 150016 which is hereby incorporated by reference for disclosures relating to this compound); sivelestat; bG3 IP (CXCL8((3-74))K11R / G31P); basiliximab; cyclosporin A; SDZ RAD (40-0-(2-hydroxyethyl)- rapamycin); FR235222 (Astellas Pharma); daclizumab; anakinra; AF12198 (Ac-Phe-Glu-Trp-Thr- Pro-Gly-Trp-Tyr-Gln-L-azetidine-2-carbonyl-Tyr-Ala-Leu~Pro-Leu~NH2); or combinations thereof.Platelet A ctivating Factor Antagonists

[0075] Platelet activating factor antagonists are contemplated for use in combination with the immunomodulating formulations disclosed herein. Platelet activating factor antagonists include, by way of example only, kadsurenone, phomactin G, ginsenosides, apafant (4-(2-chlorophenyl)-9- methyl-2[3(4-morpholinyl)-3-propanol-l-yl[6H-thieno[3.2-f[[1.2.4]triazolo]4,3-l]]1.4]diazepme), A-85783, BN-52063, BN-52021, BN-50730 (tetrahedra-4,7,8,10 methyl-1 (chloro-1 phenyl)-6 (methoxy-4 phenyl-carbamoyl)~9 pyrido [4’,3 '-4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine- 1,4), BN 50739, SM- 12502, RP-55778, Ro 24-4736, SR27417A, CV-6209, WEB 2086, WEB 2170, 14- deoxyandrographolide, CL 184005, CV-3988, TCV-309, PMS-601, TCV-309 and combinations thereof.TNF- Converting Enzyme (TACE) Inhibitors

[0076] TNF-D is initially expressed on the cell surface as a 26 kDa, 233-amino acid, membranebound precursor protein. Proteolytic cleavage of the membrane-bound TNF-D by the matrix metalloproteinase TNF-D converting enzyme occurs between Ala-76 and Val-77 and results in a 17kDa mature TNF-D which exists as a soluble trimer. Inhibition of the proteolytic cleavage could provide an alternative to the use of protein-based therapeutics in anti-inflammatory therapy. One potential complication, however, is that TACE is thought to be involved in the processing of other proteins in addition to TNF-D. For example, in a phase II clinical trial, indications of toxic effects in the liver occurred as a result of TACE inhibition. (Car el al, Society of Toxicology, 46®* Annual Meeting, Charlotte, North Carolina, March 25-29, 2007). The hypothesis for this meclianism-based toxicity is that TACE also acts on other membrane bound proteins, such as TNFRI and TNFRII.

[0077] While toxicides following oral administration are problematic for a drug administered systemically, local delivety to the site of action overcomes lliis problem. Inhibitor GW3333 has a TACE ICso of 40 nM and an ICso of 0.97 DM for inhibiting TNF-D production in the LPS-induced human PBMC cells (Conway et al, J. Pharmacol. Exp. Ther. (2001), 298:900). Nitroarginine analog A has an ICso TACE ICso of 4 nM and an IC5o of 0.034 DM for inhibiting TNF-D production in the LPS-induced MonoMac-6 cells (Musso et al, Bioorg. Med. Chem. Lett. (2001), 11:2147), but lacks oral activity. A scientific review of TNF-D converting enzymic inhibitors has been published (Skotnicki et al., Annual Reports in Medicinal Chemistry (2003), 38, 153-162), incorporated by reference herein for such disclosure.Toll-like Receptor Inhibitors

[0078] Toll-like receptors (TLR) are a family of at least 12 patern recognition cell-surface and intracellular receptors. The family is defined by the presence of two domains: a ligand-binding domain with multiple leucine-rich repeats, and a short Toll / Il-1 receptor domain: the latter controlling the initiation of downstream-signaling cascades. In certain instances, the receptors are activated by the binding of structurally conserved molecules (i.e. the “patterns”) found on pathogens. Each receptor recognizes and binds to specific conserved molecules found on pathogens (e.g. TLR 2 - lipopeptides; TLR3- viral dsRNA; TLR4 - LPS; TLR5 - flagellin; TLR9 - CpG DNA). In certain instances, the binding of a TLR to a pathogen, initiates the TLR signaling cascade which ultimately leads to the activation of various cytokines, chemokines, and antigen-specific and non-specific immune responses. In certain instances, the expression of TLR2 and / or TLR4 is up-regulated upon exposure to nontypeable Hemophilus influenzae (NTHi). Infection by NTHi is a common cause of otitis media.

[0079] Toll-like receptors belong to a class of single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from breached microbes are believed to play a key role in the innate immune system. Toll-like receptors thus recognize molecules that are broadly shared by pathogens, but are distinguishable from the host molecules. These receptors form a superfamily with Interleukin-1 receptors, and have in common a Toll-like receptor domain. Toll-like receptor agonists, such as CQ-07001, can stimulate Toll-like receptor 3 function, triggering anti-inflammatoEy and tissue regeneration activity. In some embodiments, toll-like receptor modulators include toll-like receptor antagonist, partial agonist, inverse agonist, neutral or competitive antagonist, allosteric antagonist, and / or orthosteric antagonist. Other toll-like receptor modulators include but are not limited to polyinosinic-polycytidylic acid [poly(l:C)J, polyAU, other nucleic acid molecules, including dsRNA agonists (such as AMPLIGEN®, Hemisphere, Inc., Rockville MD; and POLYADENUR®, Ipsen), and are also contemplated wi thin the scope of the embodiments disclosed herein.

[0080] In some embodiments, the TLR inhibitor is an ST2 antibody; sST2-Fc (functional murine soluble ST2-human IgGI Fc fusion protein; see Biochemical and Biophysical Research Communications, 29 December 2006, vol. 351, no. 4, 940-946 which is herein incorporated by reference for disclosures related to sST2.-Fc); CRX-52.6 (Corixa); lipid IVA; RSLA (Rhodobacter sphaeroides lipid A); E5531 ((6-0-{2-deoxy-6-0-methyl-4-0-phosphono-3-0-[(R)-3-Z-dodec-5- endoy]oxydecl]-2-[3-oxo-tetradecanoylamino]-P-O-pliosphono-a-D-giucopyranose tetrasodium salt); E5564 (a-D-Ghicopyranose,3-0-decyl-2-deoxy -6-O-[2 -deoxy -3-O-[(3R)-3-methoxydecyl]-6-O- methyl-2-[[(llZ)-l-oxo-ll-octadecenyI]amino]-4-O-phosphono-p-D-glucopynmosyl]-2-[(l,3- dioxotetradecyl)amino]-l-(dihydrogen phosphate), tetrasodium salt); compound 4a (hydrocirmamoyl- L-valyl pyrrolidine; see PNAS, June 24, 2003, vol. 100, no. 13, 7971-7976 which is herein incorporated by reference for disclosures related to compound 4a); CFG 52364 (Coley Pharmaceutical Group); LY294002 (2-(4-Morpholinyl)-8-phenyl-4H-l-benzopyran-4-one); PD98059 (2-(2-amino-3- methoxyphenyl)-4H-l-Benzopyran-4-one); chloroquine; and an immune regulatory oligonucleotide (for disclosures relating to IROs see U.S. Patent Applicationpublication No. 2008 / 0089883). Auto-Immune Agents

[0081] Also contemplated for use with the forniEilations disclosed herenr are agents which reduce or ameliorate symptoms or effects as a result of autoimmune disease). Accordingly, some embodiments may incorporate the use of agents which block the effects of TNF-a. including but not limited to anti- TNF agents. By way of example only, some anti-TNF agents include etanercept (ENBREL®), mfliximab (REMICADE®) and adalimumab (HUMIRA®), or combinations thereof. Other pharmaceutical agents to treat autoimmune disorders include chemotherapeutic agents, including cytoxan, azathiaprine or methotrexate; treatment with collagen, gamma globulin, interferons, copaxone, or combinations thereof.1L~1 Mo du lators

[0082] Interleukin- 1 (IL-1) is a pleiotropic cytokine tliat plays a role in the modulation of local as well as systemic inflammation, immune regulation and hemopoiesis. IL-1 p, a member of the IL-1 family, lias been implicated in angiogenesis processes, including tumor angiogenesis. In addition, IL- 1 has been shown to stimulate the synthesis of inflammatory eicosanoids in macrophages, fibroblasts, synovial cells and chondrocytes, and is believed to contribute to leukocyte activation and tissue destruction in arthritic models. Interfering with IL-1 activity, therefore, is an approach for developing a disease modifying therapy for chronic inflammatory disesaes. In some embodiments, IL-1 modulators include an IL-1 antagonist, partial agonist, inverse agonist, neutral or competitive antagonist, allosteric antagonist, and / or orthosteric antagonist. In some embodiments, IL-1 modulators include but are not limited to antibodies that specifically recognize IL-1 subunits or its receptors, proteins, peptides, nucleic acids, and small molecule therapeutics. In some embodiments, ILL-1 modulators are IL-1 antagonists, including, for example, AF12198, IL-1 natural antagonists, inactive receptor fragments that bind to IL- 1 molecule, and antisense molecules or factors that block expression of IL-1 cytokine proteins. In some embodiments, IL-1 antagonists are IL-1 antibodies including, by way of example, anakinra (Kinaret®) and ACZ885 (Canakinumab®). In some embdodiments, modulators of IL- 1 are antibodies that modulate cytokines and / or growth factors that affect the release and / or expression of IL- 1, including, by way of example, ranibizumab, tefibazumab, and bevacizumab. In some embodiments, IL-1 modulators are IL-1 traps tliat attach to IL-1 and neutralize IL-1 before it can bind to cell surface receptors and include, but are not limited to, rilonocept (Arcalyst®).Cytotoxic Agents

[0083] In some instances, the additional therapeutic agents are usefid in treatment of inflammatory skin disorders.

[0084] Any cytotoxic agent usefid for the treatment of skin disorders, e.g., inflammatory diseases of the skin, is suitable for use in the formulations and methods disclosed herein. In certain embodiments, the cytotoxic agent is an antimetabolite, an antifolate, an alkylating agent, a DNA intercalator, an anti- TNF agent, an anti-angiogenic agent, an anti-inflammatory agent, and / or an immunomodulatory agent. In some embodiments, the cytotoxic agent is a protein, a peptide, an antibody, DNA, a carbohydrate, an inorganic molecule, or an organic molecule. In certain embodiments, the cytotoxic agents are cytotoxic small molecules. Typically, cytotoxic small molecules are of relatively low molecular weight, e.g., less than 1.000, or less than 600-700, or between 300-700 molecular weight. In some embodiments, the cytotoxic small molecules will also have anti-inflammatory properties.

[0085] In certain embodiments, the cytotoxic agents are methotrexate (RHEUMATREX®, Amethopterin) cyclophosphamide (CYTOXAN®), and thalidomide (THALIDOMID®). All of the compounds can be used to treat cancer, including cancer of the ear. Further, all of the compoundshave anti-inflammatory properties and can be used in the formulations and compositions disclosed herein for the treatment of inflammatory' skin conditions.

[0086] Although systemic administration of methotrexate, cyclophosphamide, and thalidomide is currently used io treat or is being investigated for the treatment of certain disorders, such as inflammatoiy disorders, the cytotoxic agents are not without the potential for serious adverse side effects. Moreover, cytotoxic agents which demonstrate efficacy but are otherwise not approvable because of safety considerations is also contemplated within the embodiments disclosed herein. It is contemplated that localized application of the cytotoxic agents to the target structures for treatment of autoimmune and / or inflammatory disorders, as weli as cancer of the ear, will result in the reduction or elimination of adverse side effects experienced with systemic treatment. Moreover, localized treatment with the cytotoxic agents contemplated herein will also reduce the amount of agent needed for effective treatment of the targeted disorder.

[0087] In some embodiments, cytotoxic agents used in the compositions, formulations, and methods disclosed herein are metabolites, salts, polymorphs, prodrugs, analogues, and derivatives of cytotoxic agents, including methotrexate, cyclophosphamide, and thalidomide. Particularly preferred are metabolites, salts, polymorphs, prodrugs, analogues, and derivatives of cytotoxic agents, e.g., methotrexate, cyclophosphamide, and thalidomide, that retain at least partially the cytotoxicity and anti-inflammatory properties of the parent compounds. In certain embodiments, analogues of thalidomide used in the formulations and compositions disclosed herein are lenalidomide (REVLIMID®) and CC-4047 (ACTIMID®).

[0088] Cyclophosphamide is a prodrug that undergoes in vivo metabolism when administered systemically. The oxidized metabolite 4-hydroxy cyclophosphamide exists in equilibrium with aldophosphamide, and the two compounds serve as the transport forms of the active agent phosphoramide mustard and the degradation byproduct acrolein. Thus, in some embodiments, preferred cyclophosphamide metabolites for incorporation into the formulations and compositions disclosed herein are 4-hydroxy cyclophosphamide, aldophosphamide, pbosphoramide mustard, and combinations thereof.

[0089] Other cytotoxic agents used in the compositions, formulations, and methods disclosed herein, particularly for the treatment of cancer of the ear, are any conventional chemotherpeutic agents, including acridine carboxamide, actinomycin, 17-N-allylamino-r7-demetboxygeldanamycin, aminopterin, amsacrine, anthracycline. antineoplastic, antineoplaston, 5-azacytidine, azathioprine, BL22. bendamustine, biricodar, bleomycin, bortezomib, bryostatin, busulfan, calyculin, camptothecin, capecitabine, carboplatin, chlorambucil, cisplatin, cladribine, clofarabine, cytarabine, dacarbazine. dasalinib. daunorubicin, decitabine, dichloroacetic acid, discodermohde, docetaxel, doxorubicin, epirubicin, epothilone, eribulin, estramustine, etoposide, exatecan, exisulind, feiruginol, floxuridme, fludarabine, fluorouracil, fosfestrol, fotemustine, gemcitabine, hydroxyurea, IT-101, idarubicin,ifosfamide, imiquimod, irinotecan, irofulven, ixabepilone, laniquidar, lapatinib, lenalidomide, lomustine, lurtotecan, mafosfamide, masoprocol, mechloretbamine, melphalan, mercaptopurine, mitomycin, mitotane, mitoxantrone, nelarabine, nilotinib, oblimersen, oxaliplatin, PAC-1, paclitaxel, pemetrexed, pentostatin, pipobroman, pixantrone, plicamycin, procarbazine, proteasome inhibitors (e.g., bortezomib), raltitrexed, rebeccamycin, rubitecan, SN-38, salinosporamide A, satrapiatin, streptozotocin, swainsonine, tariquidar, taxane, tegafur-uracil, temozolomide, testolactone, tbioTEPA, tioguanine, topotecan, trabectedin, tretinoin, triplatin tetranitrate, tris(2-chloroetliyl)amine, troxacitabine, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zosuquidar.Sensory Cel! Modulators

[0090] In some instances, the additional therapeutic agent modulate the function of neurons and / or sensorj' cells. Contemplated for use with the formulations disclosed herein are agents that modulate the degeneration of neurons and / or sensory cells, promote the growth of neurons and / or sensor}' cells. Accordingly, some embodiments incorporate the use of agents which promote the survival of neurons and sensoiy cells, and / or the growth of neurons and sensory cells. In some embodiments, the agent which promotes the survival of sensory cells is a growth factor. In some embodiments, the growth factor modulator is a growth factor modulator antagonist, partial agonist, inverse agonist, neutral or competitive antagonist, allosteric antagonist, and / or orthosteric antagonist.Amifostine

[0091] Contemplated for use with the formulations disclosed herein are agents that modulate the degeneration of neurons and / or sensory cells. Accordingly, some embodiments incorporate the use of agents which rescue neurons and sensory cells from cisplatin-induced toxicity.

[0092] Amifostine (also known as WR-2721, orETHYOL®) is a cytoprotective agent. In certain instances, it prevents or ameliorates the damage to neuron and sensory cells caused by cisplatin. In certain instances, doses at or above 40 mg / kg are needed to protect against or ameliorate the toxic effects of cisplatin.Anti-intercellular adhesion molecule -1 antibody

[0093] Contemplated for use with the formulations disclosed herein are antibodies to anti- intercellular adhesion molecule (IC / kM). In some instances, ICAM blocks the cascade of reactive oxygen species associated with exposure to noise. In some instances modulation of the cascade of reactive oxygen species associated with exposure to noise ameliorates or reduces the degeneration of neurons and / or sensory ceils. Accordingly, some embodiments incorporate the use of agents that are antibodies to ICAMs (e.g., anti-ICAM-1 Ab, anti-ICAM-2 Ab or the like).Modulation ofAtoh / Math 1

[0094] Contemplated for use with the formulations disclosed herein are agents that promote the growth and / or regeneration of neurons and / or sensory cells. Atohl is a transcription factor which binds to an E-box. Accordingly, some embodiments incorporate modulation of the Atohl gene.

[0095] In some embodiments, a subject is administered a vector engineered to cany the human Atoh l gene (the “Atohl vector”). For disclosures of techniques for creating the Atohl vector see U.S. Pub. No. 2004 / 02475750, which is hereby incorporated by reference for those disclosures. In some embodiments, the Atohl vector is a retrovirus. In some embodiments, tire Atohl vector is not a retrovirus (e.g. it is an adenovirus; a lentivirus; or a polymeric delivery system such as METAFECTENE, SUPERFECT®, EFFECTENE®, or MIRUS TRANSIT).

[0096] In certain instances, after administration of the Atohl vector, the Atohl vector infects the cells at the site of administration. In certain instances the Atohl sequence is incorporated into the subject’s genome (e.g. when the Atohl vector is a retrovirus). In certain instances the therapy will need to be periodically re-administered (e.g. when the Atohl vector is not a retrovirus). In some embodiments, the therapy is re-administered annually. In some embodiments, the therapy is readministered semi -annually .

[0097] In some embodiments, a subject is administered a pharmaceutically acceptable agent which modulates the expression of the Atohl gene or activity of the Atohl polypeptide. In some embodiments, the expression of the Atohl gene or activity of the Atohl polypeptide is up-regulated. In some embodiments, the expression of the Atohl gene or activity of the Atoh l polypeptide is down- regulated.

[0098] In certain instances, a compound which agonizes or antagonizes Atohl is identified (e.g. by use of a high throughput screen). In some embodiments, a construct is designed such that a reporter gene is placed downstream of an E-box sequence. In some embodiments, the reporter gene is luciferase, CAT, GFP, 0-lactamase or ^-galactosidase. In certain instances, the Atohl polypeptide binds to the E-box sequence and initiates transcription and expression of the reporter gene. In certain instances, an agonist of Atohl aids or facilitates the binding of Atohl to the E-box sequence, thus increasing transcription and expression of the reporter gene relative to a pre-determined baseline expression level. In certain instances, an antagonist of Atohl blocks the binding of Atohl to the E- box, thus decreasing transcription and expression of the reporter gene relative io a pre-determined baseline expression level.BRN- 3 Modulators

[0099] Contemplated for use with the formulations disclosed herein are agents that promote the growth and / or regeneration of neurons and / or sensory cells. BRN-3 is a group of transcription factors that include, but are not limited to, BRN-3a, BRN-3b, and BRN-3c. / Accordingly, some embodiments incorporate modulation of the BRN3 genes, and / or polypeptides.

[0100] In some embodiments, a subject is administered a vector engineered to cany a human BRN-3 gene (the “BRN3 vector”). In some embodiments, the BRN3 vector is a retrovirus. In some embodiments, the BRN3 vector is not a retrovirus (e.g. it is an adenovirus; a lentivirus; or a polymeric delivery system such as METAFECTENE®, SUPERFECT®, EFFECTENE®, or MIRUS’ TRANSIT®).

[0101] In certain instances, after administration of the BRN3 vector, the BRN3 vector infects the cells al the site of administration. In certain instances the BRN3 sequence is incorporated into the subject’s genome (e.g. when the BRN3 vector is a retrovirus). In certain instances the therapy will need to be periodically re-administered (e.g. when the BRN3 vector is not a retrovirus).

[0102] In some embodiments, a subject is administered a pharmaceutically acceptable agent which modulates the expression of the BRN3 gene or activity of the BRN3 polypeptide. In some embodiments, the expression of the BRN3 gene or activity of the BRN3 polypeptide is up-regulated. In some embodiments, the expression of the BRN3 gene or activity of the BRN3 polypeptide is down- regulated.

[0103] In some embodiments, a compound which agonizes or antagonizes BRN3 is identified (e.g. by use of a high throughput screen). In some embodiments, a construct is designed such that a reporter gene is placed downstream of a BRN3 binding site. In some embodiments, the BRN3 binding site has the sequence ATGAATTAAT (SBNR3). In some embodiments, the reporter gene is luciferase, CAT, GFP. p-lactamase or p-galactosidase. In certain instances, the BRN3 polypeptide binds to the SBNR3 sequence and initiates transcription and expression of the reporter gene. In certain instances, an agonist of BRN3 aids or facilitates the binding of BRN3 to the SBNR3 sequence, thus increasing transcription and expression of the reporter gene relative to a pre-determined baseline expression level. In certain instances, an antagonist of BRN3 blocks the binding of BRN3 to the SBNR3, thus decreasing transcription and expression of the reporter gene relative to a pre-determined baseline expression level.Carbamates

[0104] Contemplated for use with the formulations disclosed herein are agents that modulate the degeneration of neurons and / or sensory’ cells. In certain instances, carbamate compounds protect neurons and sensory cells from glutamate-induced excitotoxicity. Accordingly, some embodiments incorporate the use of carbamate compounds. In some embodiments, the carbamate compounds are 2- phenyl-l,2-ethanediol monocarbomates and dicarbamates, derivatives thereof, and / or combinations thereof.Estrogen Receptors

[0105] In some embodiments, the agent that promotes the survival of sensory cells is an Estrogen Receptor agonist. In some embodiments, the estrogen receptor agonist is a partial agonist or inverse agonist.

[0106] In certain embodiments, agonism of ERa and / or ERp increases and / or up-regulates the expression of a neurotroph gene and / or the activity of a neurotroph polypeptide (e.g. BDNF). In certain embodiments, antagonism of ERa and / or ERp down-regulates the expression of a neurotroph gene and / or the activity of a neurotroph polypeptide (e.g. BDNF).

[0107] In some embodiments, the ERa agonist is PPT (4,4',4"-(4-Propyl-[lH]-pyrazole-l,3,5- triyl)trisphenol); SKF-82958 (6-chloro-7,8-dihydroxy-3-allyl-l-phenyl-2,3,4,5-tetrahydro-!H-3- benzazepine); estrogen; estradiol; estradiol derivatives, including but not limited to 17-D estradiol, estrone, estriol, synthetic estrogen compositions or combinations thereof. In some embodiments, the ERp agonist is ERp-131. phytoestrogen, MK 101 (bioNovo); VG-1010 (bioNovo); DPN (diaiylpropiolitrile); ERB-041; WAY -202196; WAY-214156; genistein; estrogen; estradiol; estradiol derivatives, including but not limited to 17-D estradiol, estrone, estriol, synthetic estrogen compositions or combinations thereof. Other ERp agonists include select benzopyrans and triazolo- tetrahydrofluorenones, disclosed in U.S. Patent No. 7,279,499, and Parker et al., Bioorg. & Med. Chem. Ltrs. 16: 4652-4656 (2006), each of which is incorporated herein by reference for such disclosure. In some embodiments, a neurotroph is administered before, after, or simultaneously with an Estrogen Receptor p (ER[3) agonist. In some embodiments, the neurotroph is BDNF, CNTF, GDNF, neurotrophin-3, neurotrophin-4, and / or combinations thereof.Fatty Acids

[0108] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells. Accordingly, some embodiments incorporate the use of fatty acids. In some embodiments, the fatty acid includes but is not limited to an omega-3 fatty acid, an omega-6 fatty acid, or combinations thereof. In some embodiments, the omega-3 fatty acid is a-LinoIenic acid, Stearidcmic acid, Eicosatrienoic acid, Eicosatetraenoic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Clupanodonic acid, Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid (Nisinic acid), or combinations thereof. In some embodiments, the omega-3 fatty acid is a-Linolenic acid, docosahexaenoic acid, eicosapentaenoic acid, or combinations thereof. In some embodiments, the omega-6 fatty acid is Linoleic acid, Gamma-linolenic acid, Eicosadienoic acid, Dihomo-gamma- linolenic acid, Arachidonic acid, Docosadienoic acid, Adrenic acid, Docosapentaenoic acid, Calendic acid, or combinations thereof.GammaSecretase Inhibitors

[0109] Contemplated for use with the formulations disclosed herein are agents that modulate the degeneration of neurons and / or sensory cell. Accordingly, some embodiments incorporate the use of agents which inhibit Notch! signaling. Notchl is a transmembrane polypeptide which participates in cell development. In some embodiments, the agents which inhibit Notchl signaling are y-secretase inhibitors. In certain instances, the inhibition of Notch! by a y-secretase inhibitor, following treatment2.5with an toxic agent, results in the production of neuron or sensory cells. In some embodiments, the y- secretase inhibitor is LY450139 (hydroxylvaleryl monobenzocaprolactam), L685458 (IS-benzyl- 4R[l-[l-S-carbamoyl-2-phenethylcarbamoyI)-l S-3-metbylbutylcarbamoylj-2R-bydroxyr-5- phenylpentyljcarbamic acid tert-butyl ester); LY411575 (N2-[(2S)-2-(3,5-difluorophenyl)-2- bydroxyetlranoylJ-N1[(7S)-5-methyl-6 -oxo-6, 7-dibydro-5H-dibenzo[bid]azepin-7yl]-L-alaninaroide), MK-0752 (Merck), tarenflurbil, and / or BMS-299897 (2-[(lR)-l-[[(4-cblorophenyl) sulfony](2,5- drfluoropheny l)amino] e thy 1] -5 -fluorobenzenepropanoic acid) .Glutamate-Recepior Modulators

[0110] Contemplated for use with the formulations disclosed herein are agents that modulate the degeneration of neurons and / or sensory cell. Accordingly, some embodiments incorporate the use of agents which modulate glutamate receptors. In some embodiments, the glutamate receptor is the AMP A receptor, the NMD A receptor, and / or a group II or III mGlu receptor.

[0111] In some embodiments, the agent that modulates the AMPA receptor is an AMPA receptor antagonist. In some embodiments, the agent which antagonizes the AMPA receptors is CNQX (6- cyano-7-nitroquinoxaline-2, 3-dione); NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl- benzo[f]quinoxaline-2, 3-dione); DNQX (6,7-dinitroquinoxaline-2, 3-dione); kynurenic acid; 2,3- dihydroxy-6-nitro-7-sulfamoyibenzo-[f]qumoxaline; or combinations thereof.

[0112] In some embodiments, the agent that modulates the NMD A receptor is an NMDA receptor antagonist. In some embodiments, the agent which antagonizes the NMDA receptor is 1 - aminoadamantane, dextromethorphan, dextrorpbau, ibogaine, ketamine, nitrous oxide, phencyclidine, riluzole, tiletamine, memantine, dizocilpine, aptiganel, remacimide, 7-chlorokynurenate, DCKA (5,7- dicblorokynurenic acid), kynurenic acid, 1 -aminocyclopropanecarboxylic acid (ACPC), AP7 (2- amino-7 -phospho noheplanoic acid). APV (R-2-amino-5-phosphonopentanoate), CPPene (3-[(R)-2- carboxypiperazin-4-yl]-prop-2-enyl-l-phosphonic acid); (-t-)-(lS, 2S)-l-(4-hydroxy-phenyl)-2-(4- hydroxy-4-phenylpiperidino)-I-pro-panol; (IS, 2S)-l-(4-hydroxy-3-metIioxyphenyI)-2-(4-hydroxy-4- phenylpiperi-dino)- 1 -propanol; (3R, 4S)-3 -(4-(4-fluorophenyl)-4-hydroxypiperidin- 1 -yl-)-chroman- 4,7-diol; (1R*, 2R*)-l-(4-hydroxy-3-methyiphenyl)-2-(4~(4-Iluoro-phenyl)-4-hydroxypiperidin-l-yl)- propan-l-ol-mesylate; and / or combinations thereof.

[0113] In certain instances, the over-activation of the AMPA and NMDA glutamate receptors by the binding of excessive amounts of glutamate, results in the excessive opening of the ion channels under their control. In certain instances, this results in abnormally high levels of Ca2+and Na entering the neuron. In certain instances, the influx of Ca2’ and Na+into the neuron activates multiple enzymes including, but not limited to, phospholipases, endonucleases, and proteases. In certain instances, the over-activation of these enzymes results in damage to the cytoskeleton, plasma membrane, mitochondria, and DNA of the neuron. Further, in certain instances, the transcription of multiple pro- apoptolic genes and anti-apoptotic genes are controlled by ( a levels.

[0114] The mGlu receptors, unlike the AMPA and NMD A receptors, do not directly control an ion channel. However, in certain instances, they indirectly control the opening of ion channels by the activation of biochemical cascades. The mGlu receptors are divided into three groups. In certain instances, the members of groups II and III reduce or inhibit post-synaptic potentials by preventing or decreasing the formation of cAMP. In certain instances, this causes a reduction in the release of neurotransmitters, especially glutamate. GRM7 is the gene which encodes the mGlu7 receptor, a group III receptor. In certain instances, the agonism of mGlu7 results in a decrease in synaptic concentrations of glutamate. This ameliorates glutamate excitotoxicity.

[0115] In some embodiments, the glutamate receptor is a group II mGlu receptor. In some embodiments, the agent which modulates the group II mGlu receptor is a group II mGlu receptor agonist. In some embodiments, the group II mGlu receptor agonist is LY389795 ((-)-2-thia-4- aminobicyclo-hexane~4,6-dicarboxylate); LY379268 ((-)~2-oxa-4-aminobicyclo-hexane-4,6- dicarboxylate); LY354740 ((+)-2-aminobicyclo-hexane-2,6dicarboxylate); DCG-TV ((2S.2'R,3’R)-2- (2',3'-dicarboxycyclopropyl)glycine); 2R.4R-APDC (2R,4R-4-aminopyrroIidine-2,4-dicarboxylate), (SI-3C4HPG ((S)-3-carboxy-4-hydroxyphenylglycine); (S)-4C3HPG ((S)-4-carboxy-3- hydroxyphenylglycine); L-CCG-1 ((2S,l'S,2’S)-2-(carboxycyclopropyl)glycine); and / or combinations thereof.

[0116] In some embodiments, the mGlu receptor is a group III mGlu receptor. In some embodiments, the group III mGlu receptor is mGlu 7. In some embodiments, the agent which modulates the group III mGlu receptor is a group III mGlu receptor agonist. In some embodiments, the group III mGlu receptor agonist is ACPT-I ((lS,3R.4S)-l-aminocyclopentene-I,3,4-tricarboxylic acid); L-AP4 (L- (+)-2-Amino-4-phosphonobutyric acid); (S)-3,4-DCPG ((S)-3,4~dicarboxyphenylglycine); (RS)-3,4- DCPG ((RS)-3,4-dicarboxyphenylglycine); (RS)-4-phosphonophenylglycine ((RS)PPG); AMN082 (,N'-bis(diphenylmethyl)-l,2-ethanediamine dihydrochloride); DCG-IV ((2S,2'R,3'R)-2-(2',3‘- dicarboxycyclopropyl)glycine); and / or combinations thereof. In some embodiments, the mGlu receptor is mGlu7. In some embodiments, the agonist of mGlu7 is AMN082. In some embodiments, the mGlu receptor modulator is 3,5-Dimethyl pyrrole-2,4-dicarboxyhc acid 2 -propyl ester 4-(l,2,2- trimethyl-propyl) ester (3,5-dimethyl PPP); 3,3'-difluorobenzaldazine (DFB), 3,3'- dimlethoxybenzaldazine (DMeOB), 3,3'-dichlorobenzaldazine (DCB) and other allosteric modulators of mGluRs disclosed in Mol. Pharmacol. 2003, 64, 731-740; (E)-6-methyl-2-(phenyldiazenyl)pyridin- 3-ol (SIB 1757); (E)-2-methyl-6-styrylpyridine (SIB 1893); 2-methyl-6-(phenylethynyl)pyridine (MPEP), 2-methyl-4-((6-methylpyridin-2-yl)ethynyl)thiazole (MTEP); 7-( Hydroxyimino)cyclopropa[b]clrramen-I O -carboxylate ethyl ester (CPCCOEt), N-cycIohexyl-3- metliyibenzo[d]thiazoio[3,2-a]iniidazole-2 -carboxamide (YM-298198), tricyclo[3.3.3.1]nonanyl quinoxaline-2 -carboxamide (NPS 2390); 6-methoxy-N~(4-methoxyphenyl)quinazolin-4-amine (LY 456239); mGluRl antagonists disclosed in W02004 / 058754 and W02005 / 009987; 2~(4~(2,3~dihydro~lH-inden-2-ylamino)-5,6,7,8-tetraltydroquinazolin-2-ylthio)ethanol; 3-(5-(pyridin-2-yl)-2H-tetrazol- 2-yl)benzonitrile, 2-(2 -methoxy -4-(4-(pyridin-2-yI)oxazol-2-yI)phenyI)acetonitriIe; 2-(4- (benzo[d]oxazol-2-yl)-2-methoxyphenyl)acetonitrile; 6-(3 -methoxy -4-(pyridin-2- yl)phenyl)imidazo[2.,l-b]thiazoie; (S)-(4-fluorophenyl)(3-(3-(4-fluorophe!iyl)-1.2.4-oxadiazol-5- yl)piperidin- 1 -ylimethanone (ADX47273) and / or combinations thereof.

[0117] In some embodiments, a glutamate receptor modulator is a nootropic agent. Contemplated for use with the formulations disclosed herein are nootropic agents that modulate neuronal signalling by activating glutamate receptors. Accordingly, some embodiments incorporate the use of nootropic agents including, and not limited to, piracetam, Oxiracetam, Amracetam, Pramiracetam, Phenylpiracetam (Carphedon), Etiracetam, Levetiracetam, Nefiracetam, Nicoracetam, Rolziracetam, Nebracetam, Fasoracetam, Coluracetam, Dimiracetam, Brivaracetam, Seletracetam, and / or Rolipram.Growth Factors

[0118] Contemplated for use with the formulations disclosed herein are agents that modulate the degeneration of neurons and / or sensory cells. Accordingly, some embodiments incorporate the use of agents which promote the survival of neurons and sensory cells, and / or the growth of neurons and sensorj' cells. In some embodiments, the agent which promotes the survival of sensory cells is a growth factor. In some embodiments, the growth factor is a neurotroph. In certain instances, neurotrophs are growth factors which prevent cells from initiating apoptosis, repair damaged neurons and sensory cells, and / or induce differentiation in progenitor cells. In some embodiments, the neurotroph is brain-derived neurotrophic factor (BDNF), ciliaiy neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF), neurotrophin-3, neurotrophin-4, and / or combinations thereof. In some embodiments, the growth factor is a fibroblast growth factor (FGF), an insulin-like growth factor (IGF), an epidermal growth factor (EGF), a platlel-derived growth factor (FGF) and / or agonists thereof. In some embodiments, the growth factor is an agonist of the fibroblast growth factor (FGF) receptor, the insulin-like growth factor (IGF) receptor, the epidermal growth factor (EGF) receptor, and / or the platlel-derived growth factor. In some embodiments, the growth factor is hepatocyte growth factor.

[0119] In some embodiments, the growth factor is an epidermal growth factor (EGF). In some embodiments, tire EGF is heregulin (HRG). In certain instances, HRG stimula tes the prolifera tion of utricular sensory epithelium.

[0120] In some embodiments, the growth factor is an insulin-like growth factor (IGF). In some embodiments, the IGF is IGF-1 . In some embodiments, the IGF-1 is mecasermin. In certain instances, IGF-1 attenuates the damage induced by exposure to an aminoglycoside. In certain instances, IGF-1 stimulates the differentiation and / or maturation of neurons or sensory cells.

[0121] In some embodiments, the FGF receptor agonist is FGF-2. In some embodiments, the IGF receptor agonist is IGF-1. Both the FGF and IGF receptors are found in the cells comprising the utricle epithelium.

[0122] In some embodiments, the growth factor is hepatocyte growth factor (HGF), Also contemplated for use in the formulations described herein are growth factors including Erythropoietin (EPO), Granulocyte-colony stimulating factor (G-CSF), Granulocyte-macrophage colony stimulating factor (GM-CSF), Growth differentiation factor-9 (GDF9), Insulin-like growth factor (IGF).Myostatin (GDF-8), Platelet-derived growth factor (PDGF), Thiombopoietin (TPO), Transforming growth factor alpha (TGF-a), Transforming growth factor beta (TGF-P), Vascular endothelial growth factor (VEGF) or combinations thereof.Neurotrophs

[0123] In some embodiments, the growth factor is a neurotroph. In certain instances, neurotrophs are growth factors which prevent cells from initiating apoptosis, repair damaged neurons and sensoiy cells, and / or induce differentiation in progenitor cells. In some embodiments, the neurotroph is brain- derived neuro trophic factor (BDNF), ciliary neurotrophic fac tor (CNTF), glial cell-line derived neurotrophic factor (GDNF), neurotrophin-3, neurotrophin-4, and / or combinations thereof.

[0124] In some embodiments, the neurotroph is BDNF. In certain instances, BDNF is a neurotroph which promotes the survival of existing neurons, and sensory cells by repairing damaged cells, inhibiting the production of ROS, and inhibiting the induction of apoptosis. In certain embodiments, it also promotes the differentiation of neural and sensory cell progenitors. Further, in certain embodiments, it protects the Cranial Nerve VII from degeneration. In some embodiments, BDNF is administered in conjunction with fibroblast growth factor.

[0125] In some embodiments, the neurotroph is neurotrophin-3. In certain embodiments. neurotrophin-3 promotes the survival of existing neurons and sensory cells, and promotes the differentiation of neural and sensory cell progenitors. Further, in certain embodiments, it protects the VII nerve from degeneration.

[0126] In some embodiments, the neurotroph is CNTF. In certain embodiments, CNTF promotes the synthesis of neurotransmitters and the growth of neuritis. In some embodiments, CNTF is administered in conjunction with BDNF.

[0127] In some embodiments, the neurotroph is GDNF. In certain embodiments, GDNF expression is increased by treatment with toxic agents. Further, in certain embodiments, cells treated with exogenous GDNF have higher survival rates after trauma then untreated cells.Toxic Agents

[0128] Contemplated for use with the formulations disclosed herein are agents that destroy neurons and / or sensoiy ceils. Accordingly, some embodiments incorporate the use of agents which fatally damage and / or induce apoptosis in the neurons and / or sensory cells. In some embodiments, the agentswhich fatally damage and / or induce apoptosis in the neurons and / or sensory cells are the aminoglycoside antibiotics (e.g. gentamicin, and amikacin), the macrolide antibiotics (e.g erythromycin), the glycopeptide antibiotics (e.g. vancomycin), the loop diuretics (e.g. furosemide) salicylic acid, and nicotine.Retinoblastoma Protein Modulation

[0129] Contemplated for use with the formulations disclosed herein are agents that modulate the degeneration of neurons and / or sensory cells. Further contemplated herein are agents that destroy neurons and / or sensory cells. Accordingly, some embodiments incorporate the use of agents that modulate retinoblastoma protein (pRB). pRB is a member of the pocket protein family. It is encoded by the RBI gene. In certain instances, it inhibits transition from G1 to S phase by binding to and inactivating the E2f family of transcription factors. In certain instances, it also regulates differentiation, and survival of sensory cells. In certain instances, pRB knock-out mice demonstrate increased prioliferation of sensory cells.

[0130] In some embodiments, the agent tliat modulates one or more of the pRB is an agonist of pRB. In some embodiments, the agent that modulates one or more of the pRB is an antagonist of pRB. In certain instances, a compound which agonizes or antagonizes pRB is identified (e.g. by use of a high throughput screen). In some embodiments, a construct is designed such that a reporter gene is placed downstream of an E2F binding sequence. In some embodiments, the binding sequence is TTTCGCGC. In some embodiments, the reporter gene is luciferase, CAT, GFP. p-lactamase or p- galactosidase. In certain instances, E2f binds to the binding sequence causing the transcription and expression of the reporter gene. In certain instances, an agonist of pRB causes an increase in the binding of pRB to E2f. In certain instances, the increase in binding of pRB and E2f results in a decrease in the transcription and expression of the reporter gene. In certain instances, an antagonist of pRB causes a decrease in tire binding of pRB to E2f. In certain instances, the decrease in binding of pRB and E2.f results in a increase in the transcription and expression of the reporter gene.

[0131] In some embodiments, the agent that modulates pRB is an siRNA molecule. In certain instances, the siRN A molecule is as described herein.Salicylic acid

[0132] Contemplated for use with the formulations disclosed herein are agents tliat modulate the degeneration of neurons and / or sensory ceils. Accordingly, some embodiments incorporate the use of salicylic acid. In certain instances, when administered before treatment with an aminoglycoside, it protects sensory' cells and neurons from aminoglycoside toxicity.Sodium Channel Blockers

[0133] Contemplated for use with the formulations disclosed herein are agents that modulate the degeneration of neurons and sensory cells. In certain instances, excitotoxicity causes the excessiveopening of Na’ channels. In certain instances, this results in excess Na ions entering the neuron. In certain instances, the excess influx of Na+ions into the neuron causes the neuron to fire more often. In certain instances, this increased firing y ields a rapid buildup of free radicals and inflammatory compounds. In certain instances, the free radicals damage the mitochondria, depleting the cell’s energy stores. Further, in certain instances, excess levels of Na ions activate excess le vels of enzymes including, but not limited to, phospholipases, endonucleases, and proteases. In certain instances, the over-activation of these enzymes results in damage to the cytoskeleton, plasma membrane, mitochondria, and DNA of the neuron. Accordingly, some embodiments incorporate the use of agents which antagonize the opening of Na’ channels. In some embodiments, sodium channel blockers are as described herein.Thyroid Hormone Receptor Modulation

[0134] Contemplated for use with the formulations disclosed herein are agents that modulate the degeneration of neurons and / or sensory cells, promote the growth of neurons and / or sensory cells. Accordingly, some embodiments incorporate the use of agents that modulate Thyroid Hormone (TH) receptors. The TH receptors are a family of nuclear hormone receptors. The family includes, but is not limited to TRal and TRp. In certain instances, TRp knock-out mice demonstrate a decreased responsiveness to stimuli, and a decrease in K+current in sensoiy cells.

[0135] In some embodiments, the agent that, modulates one or more of the TH receptors is an agonist of the one or more TH receptors. In some embodiments, the agonist of one or more of the TH receptors is Tj (3,5,3 ’-triiodo-L -thyronine); KB-141 (3,5-dichloro-4-(4-hydroxy-3- isopropylphenoxy)phenylacetic acid); GC-1 (3,5-dimetbyl-4-(4'-hydroxy-3'-isopropylbenzyl)- phenoxy acetic acid); GC-24 (3,5-dimethyl-4-(4Miydroxy-3'-beBzyl)benzylphenoxyacetic acid); sobetirome (QRX-431); 4-OII-PCB106 (4-OH-2’,3,3’,4’,5’-pentachlorobiphenyl); MB07811 ((2R,4S)-4-(3-chIorophenyi)-2-[(3,5-dimethyl-4-(4-hydroxy-3-isopropyIbenzyI)phenoxy)methyi]-2- oxido-[l,3,2]-dioxaphosphonane); MB07344 (3,5-dimethyl-4-(4-hydroxy-3- isopropylbenzyd)phenoxy)methylphosphonic acid); and combinations thereof. In certain instances, KB-141; GC-1; sobetirome; and GC-24 are selective for TRp.TRP V Modulation

[0136] Contemplated for use with the formulations disclosed herein are agents that modulate the degeneration of neurons and sensoiy cells. Accordingly, some embodiments incorporate the use of agents that modulate TRPV receptors. The TRPV (Transient Receptor Potential Channel Vanilloid) receptors are a family of non-selective ion channels permeable to calcium, amongst other ions. There are six members of the family: TRPV1-6. In certain instances, following treatment with kanamycin, TRPV I is upregulated. Additionally, in certain instances, antagonism of the TRPV 4 receptor makes mice vulnerable to acoustic trauma. Further, in certain instances, capsaicin, an agonist of TRPV 1, prevents hyperloco motion following an ischemic event.

[0137] In some embodiments, the agent that modulates one or more of the TRPV receptors is an agonist of the one or more TRPV receptors. In some embodiments, the agonist of one or more of the TRPV receptors is capsaicin, resiniferatoxin, or combinations thereof. In some embodiments, TRPV modulating include the TRPV modulators disclosed in US application publications 2005 / 0277643, 2005 / 0215572, 2006 / 0194801, 2006 / 0205773, 2006 / 0194801, 2008 / 0175794, 2008 / 0153857, 2008 / 0085901, 20080015183, 2006 / 0030618, 2005 / 0277646, 2005 / 02.77631, 2005 / 02.72931, 2005 / 0227986, 2005 / 0153984, 2006 / 0270682, 2006 / 0211741, 2006 / 0205980. and 2006 / 0100490, and / or combinations thereof.CNS modulating agents

[0138] In some instances, the additional therapeutic agent modulates central nervous system activity. Anticholinergics

[0139] Contemplated for use with the formulations disclosed herein are agents which ameliorate skin disorders through local modulation of central nervous system (CNS) activity. Accordingly, some embodiments incorporate the use of agents which inhibit the release of the neurotransmitter acetylcholine in the CNS. Anticholinergic agents are substances which block acetylcholine in the central and the peripheral nervous system. They treat balance disorders by suppressing conduction in vestibular cerebellar pathways, thus increasing motion tolerance.

[0140] In some embodiments, the anticholinergic is glycopyrrolate, homatropine, scopolamine or atropine. In some embodiments, the anticholinergic is glycopyrrolate. In some embodiments, the anticholinergic is homatropine. In some embodiments, the anticholinergic is scopolamine. In some embodiments, the anticholinergic is atropine.Antihistamines

[0141] Contemplated for use with the formulations disclosed herein are agents which ameliorate skin disorders through local modulation of central nervous system (CNS) activity. Accordingly, some embodiments incorporate the use of agents which block the action of neurotransmitters in the CNS. Histamine is a neurotransmitter in the CNS. Accordingly, some embodiments incorporate the use of agents winch modulate histamine receptors (e.g. the Hi receptor, II2receptor, and / or the II3 receptor). In some embodiments, anithistamines are as described herein.Calcium Channel Blockers

[0142] Contemplated for use with the formulations disclosed herein are agents which ameliorate skin disorders through local modulation of central nervous system (CNS) activity. Accordingly, some embodiments incorporate tire use of agents which block or antagonize Ca t channels. Calcium channels are channels formed in tire plasma membrane of neurons (amongst oilier cells) by integral membrane proteins. These channels conduct Ca+through a cell's plasma membrane. In neurons, theflow of Ca2+is partly responsible for creating and propagating action potentials in neurons. It can also be responsible for the release of certain neurotransmitters.

[0143] In some embodiments, the calcium channel antagonist is cinnarizine, flunarizine, or uimodipine, In some embodiments, the calcium channel antagonist is cinnarizine. In some embodiments, the calcium channel antagonist is flunarizine. In some embodiments, the calcium channel antagonist is nimodipine. Other calcium channel blockers include verapamil, diltiazem, ornega-conotoxm, GVIA, amlodipine, felodipine, lacidipine, mibefradil, NPPB (5-Nitro-2-(3- phenylpropylaminoibenzoic Acid), flunarizine, and / or combinations thereofGABA Receptor Modulators

[0144] Contemplated for use with the formulations disclosed herein are agents which ameliorate skin disorders through local modulation of central nervous system (CNS) activity. Accordingly, some embodiments incorporate the use of agents which modulate the action of GABA receptors in the CNS. GABA, or y-aminobutyric acid, is an inhibitory neurotransmitter in the CNS. It acts at inhibitory synapses of both pre- and postsynaptic neuronal processes. The binding of GABA to its receptors (the GAB AAreceptor, the GAB ABreceptor, and the GAB Acreceptor) results in the opening of ion channels, and the flow of CT into the cell and / or K+out of the neuron. The result is hyperpolarization of the neuron. Accordingly, some embodiments incorporate the use of agents which increase or decrease the sensitivity of the GABA receptors, or activate the GABA receptors by mimicking GABA.

[0145] The benzodiazepine class of therapeutic agents are agonists of the GABAA receptor. When a benzodiazepine binds to the GABAA receptor it induces a conformational change winch increases the affinity of GABA for its receptor. The result of the increase in the binding of GABA is an increase in the frequency with which the C1‘ channels in the neurons open. This causes hyperpolarization of the neural membrane. In some embodiments, the benzodiazepine is selected from the group consisting of: alprazolam, bromazepam, brotizolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, loprazolam, lorazepam, lormetazepam, idazolam, nimetazepam, nitrazepam, oxazepam, prazepam, temazepam, triazolam or combinations thereof. In some embodiments, the benzodiazepine is clonazepam, diazepam, lorazepam, or combinations thereof. In some embodiments, the benzodiazepine is diazepam.

[0146] In some embodiments, the GABA receptor modulator is a loop diuretic. In some embodiments, the loop diuretic is furosemide, bumetanide, or ethacrynic acid. In some embodiments, the loop diuretic is furosemide. In some embodiments, the loop diuretic is bumetanide. In some embodiments, the loop diuretic is ethacrynic acid. Furosemide, for example, binds to the GABAA receptor and reversibly antagonizes GABA-evoked currents of the a6, p2, and y2 receptors. By way of example only, useful loop diuretics include, but are not limited to, furosemide, bumetanide, and ethaciynic acid.

[0147] In some embodiments, the modulator of a GABA receptor is a GABA analogue. GABA analogues mimic GABA. Thus, when they bind to a GABA receptor, the receptor acts as though GABA is binding to it and the receptor is activated. In some embodiments, the GABA analog is gabapentin, pregabalin, muscimol, or baclofen. In some embodiments, the GABA analog is gabapentin. In some embodiments, the GABA analog is pregabalin. In some embodiments, the GABA analog is muscimol. In some embodiments, the GABA analogue is baclofen. Baclofen is an analogue of GABA which binds to and activates the GABAB receptor. Muscimol is also an analogue of GABA. It agonizes the GABAA receptor.Neurotransmitter Reuptake Inhibitors

[0148] Contemplated for use with the formulations disclosed herein are agents which ameliorate skin disorders through local modulation of central nervous system (CNS) activity. Accordingly, some embodiments incorporate the use of agents which inhibit the reuptake of neurotransmitters in the CNS. In some embodiments, the neurotransmitter reuptake modulator is an antagonist of a neurotransmitter reuptake target, partial agonist, inverse agonist, neutral or competitive antagonist, allosteric antagonist, and / or orthosteric antagonist. Neurotransmitter reuptake inhibitors inhibit the reuptake of neurotransmitters into presy naptic cells of the CNS. This increases the concentration of neurotransmitter available to stimulate post-synaptic cells of the CNS.

[0149] In some embodiments, the neurotransmitter reuptake inhibitors are tricyclic antidepressants. Tricyclic antidepressants work by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by pre-synaptic cells. This increases the level of serotonin and / or norepinephrine available to bind to the postsynaptic receptor. In some embodiments, the tricyclic antidepressant is amitriptyline, nortriptyline, ortrimipramine. In some embodiments, the tricyclic antidepressant is amitriptyline. In some embodiments, the tricyclic antidepressant is nortriptyline. In some embodiments, tlie tricyclic antidepressant is trimipramme.

[0150] In some embodiments, tlie neurotransmitter reuptake inhibitor is a selective serotonin reuptake inhibitor. By inhibiting the reuptake of serotonin into the presynaptic cells, SSRIs increase tlie extracellular level of serotonin. This increases the level of serotonin available to bind to tlie postsynaptic receptor. SSRIs are hypothesized to stimulate new neural growth within the inner ear. In some embodiments, the selective serotonin reuptake inhibitor is fluoxetine, paroxetine, or sertraline. In some embodiments, the selective serotonin reuptake inhibitor is fluoxetine. In some embodiments, the selective serotonin reuptake inhibitor is paroxetine. In some embodiments, the selective serotonin reuptake inhibitor is sertraline.

[0151] Contemplated for use with the formulations disclosed herein are agents that ameliorate skin disorders through local modulation of central nervous system (CNS) activity. Accordingly, some embodiments incorporate tire use of agents that antagonize neurokinin receptors. There are at least three neurokinin receptors: NK1. NK2 and NK3. In certain embodiments, the binding of a ligand (e.g.a tachykinin peptide, substance P, neurokinin A, and neurokinin B) to a neurokinin receptor induces the activation of phospholipase C. The activation of phospholipase C produces inositol triphosphate. In some embodiments, the neurokinin receptor is the NK1 receptor, the NK2 receptor, the NK3 receptor, or combinations thereof. In some embodiments, the neurokinin receptor is the NK 1 receptor. In some embodiments, the antagonist of the NK1 receptor is vestipitant.

[0152] In some embodiments, the SSRI inhibitor is administered in combination with a neurokinin receptor antagonist. In some embodiments, the SSRI is paroxetine and tire neurokinin receptor is NIC1. In some embodiments, the NKI receptor antagonist is vestipitant. In certain embodiments, the co-adrmnistration of paroxetine and vestipitant treats, and / or the symptoms of the skin condition.Local Anesthetics

[0153] Contemplated for use with the formulations disclosed herein are agents which ameliorate skin disorders through local modulation of central nervous system (CNS) activity. Accordingly, some embodiments incorporate tire use of agents which decrease the rate of the depolarization and repolarization of neurons by, for example, blocking the Na+channels in ceil membranes.

[0154] In some embodiments, the CNS modulator is a local anesthetic. In some embodiments, the local anesthetic is selected from the group consisting of: benzocaine, carticaine, cinchocaine, cyclomethycaine, lidocaine, prilocaine, propxycaine. proparacaine, tetracaine, tocainide, and trimecaine. In some embodiments, the local anesthetic is lidocaine. In some embodiments, the local anesthetic is tocainide.Sodium Channel Blockers

[0155] Contemplated for use with the formulations disclosed herein are agents which ameliorate skin disorders through local modulation of central nervous system (CNS) activity. Accordingly, some embodiments incorporate the use of agents which block or antagonize Na+ channels. Sodium channels are channels formed in the plasma membrane of neurons (amongst other cells) by integral membrane proteins. These channels conduct Na* through a cell's plasma membrane. In neurons, the flow of Na' is partly responsible for creating and propagating action potentials in the neurons.

[0156] In some embodiments, the sodium channel blocker is carbamazepine, oxcarbazepine, phenytein, valproic acid, or sodium valproate. In some embodiments, the sodium channel blocker is carbamazepine. In some embodiments, the sodium channel blocker is oxcarbazepine. In some embodiments, the sodium channel blocker is phenytein. In some embodiments, the sodium channel blocker is valproic acid. In some embodiments, the sodium channel blocker is sodium valproate.

[0157] In some embodiments, the Na+channel blocker is vinpocetine ((3a,16a)-Ebuniainenine~14~ carboxylic acid ethyl ester); sipatrigine (2-(4-Methylpiperazin-l-yi)-5-(2,3,5-trichiorophenyl)- pyrimidin-4-amine); amiloride (3,5-diamino-N-(aminoiminomethyl)-6-chloropyrazinecarbox amide hydrochloride); carbamazepine (5H-dibenzo[b,f]azepine-5-carboxamide); TTX (octahydro-12-(hydroxymetbyl)"2-imino-5,9:7,10a-dimethan o-10aH-[l,3]dioxociBo[6,5-d]pyrimidine-4,7,10,ll,12-pen tot); RS100642 (l-(2,6-dimethyi-phenoxy)-2 -ethylaminopropane hydrochloride); mexiletine ((1 - (2,6-dimethylphenoxy)-2-aminopropane hydrochloride)); QX-314 (N-(2,6- Dimethylphenykrarbamoyimethyl)triethylammonmm bromide); phenytoin (5,5- diphenylimidazolidine-2, 4-dione); lamotrigine (6-(2,3-dichloropbenyl)-l,2,4-triazine-3,5-diamine); 4030W92 (2,4-diamino-5-(2,3-dichlorophenyl)-6-fhioromethylpyriniidine); BW1003C87 (5-(2,3,5- trichlorophenyl) pyrimidine-2,4- 1.1 ethanesulphonate); QX-222 (2-[(2,6-dimethylphenyl)amino]- N,N,N-trimethyl-2-oxoetha niminium chloride); ambroxol (trans-4-[[(2-Amino-3,5- dibromophenyl)methyl]amino]cyclo hexanol hydrochloride); R56865 (N-[l-(4-(4- fluorophenoxy )butyl]-4-piperidinyl-N-methyl-2-benzo-thiazolamine); lubeluzole; ajmaline ((17R,21alpha)-ajmalan-17,21-diol); procainamide (4-amno-N-(2-diethylaminoethyl)beiizamide hydrochloride); flecainide; riluzoleor; or combinations thereof.

[0158] In some embodiments, agents which decrease the rate of the depolarization and repolarization of neurons by, for example, blocking the Na+channels in cell membranes include local anesthetics. In some embodiments, the local anesthetic is selected from the group consisting of: benzocaine, carticaine, cinchocaine, cyclomethycaine, lidocaine, prilocaine, propxycaine, proparacaine, tetracaine, tocainide, and trimecaine. In some embodiments, the local anesthetic is lidocaine. In some embodiments, the local anesthetic is tocainide,Thyrotropin-Releasing Hormone

[0159] Contemplated for use with the formulations disclosed herein are agents which ameliorate skin disorders through local modulation of central nervous system (CNS) activity. Accordingly, some embodiments incorporate the use of agents which modulate neurotransmitters. Thyrotropin-releasing hormone is a neurotransmitter which inhibits glutamate-induced excitation of neurons. In some embodiments, the CNS modulator is thyrotropin-releasing hormone.Antimicrobial Agents

[0160] Any antimicrobial agent useful for the treatment of skin disorders, e.g., inflammatoty skin diseases, is suitable for use in the formulations and methods disclosed herein. In some embodiments, tire antimicrobial agent is an antibacterial agent, an antifungal agent, or an antiviral agent. Antimicrobial agents include agents that act to inhibit or eradicate microbes, including bacteria, fungi, and viruses. Specific antimicrobial agents are used to combat specific microbes. Accordingly, a skilled practitioner would know which antimicrobial agent would be relevant or usefid depending on tlie microbe identified, or the symptoms displayed.

[0161] In some embodiments, the antimicrobial agent is a protein, a peptide, an antibody, DNA, a carbohydrate, an inorganic molecule, or an organic molecule. In certain embodiments, the antimicrobial agents are antimicrobial small molecules. Typically, antimicrobial small molecules are of relatively low molecular weight, e.g., less than 1,000, or less than 600-700. or between 300-700 molecular weight.

[0162] Antiviral agents include acyclovir, famciclovir and valacyclovir. Other antiviral agents include abacavir, aciclovir, adfovir, amantadine, amprenavir, arbidol., atazanavir, artipla, brivudine, cidofovir, combivir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, fomvirsen, fosamprenavir, foscamet, fosfonet, ganciclovir, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitors, interferons, including interferon type III, interferon type II, interferon type I, lamivudine, lopinavir, loviride, MK-0518, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir. penciclovir, peramivir, pleconaril. podophyllo toxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine. tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, and combinations thereof.

[0163] Antifungal agents include amrolfine, utenafine, naftifine, terbinafine, flucytosine, fluconazole, itraconazole, ketoconazole, posaconazole, ravuconazole, voriconazole, clotrimazole, econazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazole, nikkomycinZ, caspofungin, micafungin, anidulafungin, amphotericin B, liposomal nystastin, pimaricin, griseofulvin, ciclopirox olamine. haloprogin, tolnaftate, undecylenate, clioquinol, and combinations thereof. Free radical modulators

[0164] In some instances, the additional therapeutic agent relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory due to free radicals or the dysfunction of the mitochondria.Antioxidants

[0165] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensoiy cells due to free radicals or the dysfunction of the mitochondria. Accordingly, some embodiments incorporate the use of agents which prevent and / or ameliorate the damage caused by free radicals. In some embodiments, the agents which prevent and / or ameliorate the damage caused by free radicals is an antioxidant.

[0166] Antioxidants, as disclosed herein, are also useful as protectants against toxic agents through the prevention of reactive oxygen species, neutralization of toxic products or blockage of the apoptosis pathway. Resveratrol (3,5,4’-Trihydroxystilbene). a representative example of an antioxidant, exerts its effects through a variety of pathways, including the inhiition of MnSOD, which reduces superoxide to I-I2O2, which inhibits free radical chain reactions, reducing superoxide levels in the cell. Moreover, resveratrol has been implicated in preventing neuronal cell dysfunction and cell death. Oilier antioxidants include but are not limited to vitamin E (tocopherol), vitamin C (ascorbic acid), glutathione, lipoic acid, alpha iipoic acid, uric acid, carotenes, ubiquinol, melatonin, tocotrienols, selenium, flavonoids, polyphenols, lycopene, lutein, lignan, butyl hydroxytoluene, coenzyme Q10, salicylate, or combinations thereof.

[0167] In certain embodiments, nitrones act synergistically with antioxidants. In certain embodiments, nitrones trap free radicals. In some embodiments, a nitrone (e.g. alpha-phenyl-tert- butylnitrone (PEN), allpurinol) is co-administered with an antioxidant. In certain embodiments, a nitrone co-administered with an antioxidant treats a skin condition.

[0168] In some embodiments, the antioxidant is N-acetyicysteine; vitamin E (tocopherols and tocotrienols); vitamin C; vitamin A; lutein; selenium glutathione; melatonin; a polyphenol; a carotenoid (e.g. lycopene, carotenes); coenzyme Q-10; Ebselen (2-phenyl-l, 2-benzisoseIenazol- 3(2H)"One (also called PZ 51 orDR3305); L-metlhonine; azulenyl nitrones (e.g. stilbazulenyl nitrone); L-(+)-Ergothioneine ((S)-a-Carboxy-2,3-dihydro-N,N,N-lrimethyl-2-thioxo-lH-imidazole4- ethanaminium inner salt); Caffeic Acid Phenyl Ester (CAPE); dimethylthiourea; dimethylsulfoxide; disufenton sodium (NXY-059; disodium 4~[(Z)-(tert-butyl-oxidoazanmmylidene)methyl]benzene-l,3- disulfonate); pentoxifylline; MCI-186 (3-Methyl-l-phenyl-2-pyrazohn-5-one); Ambroxol (trans-4-(2- Amino-3,5-dibromobenzylamino)cyclohexane-HCl; U-83836E ((-)-2-((4-(2,6-di-l-Pyrrolidinyd-4- pyrimidinyl)-l-piperzainyl)methyI)-3,4-dihydro-2,5,7,8-tetramethyl-2H-l-benzopyran-6-ol®2HCl); MITOQ (mitoquinone mesylate, Antipodean Pharmaceuticals); Idebenone (2-(i0-hydroxydecyl)-5,6- dimethoxy-3-methyl-cycIohexa-2.5-diene-l, 4-dione); (+)-cyanidanol-3; or combinations thereof.Glutamate-Receptor Modulators

[0169] Contemplated for use with the formulations disclosed herein are agents that modulate the production of free-radicals and / or inhibit damage to the mitochondria. Accordingly, some embodiments incorporate the use of agents which modulate glutamate receptors. In some embodiments, the glutamate receptor is the AMPA receptor, the NMD A receptor, and / or a group II or III mGIu receptor. In some embodiments, a glutamate reptor modulator is as described herein.Iron Chelators

[0170] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells due to free radicals or the dysfunction of the mitochondria. Accordingly, some embodiments incorporate the use of agents which prevent and / or ameliorate the damage caused by free radicals. In some embodiments, the agents which prevent and / or ameliorate the damage caused by free radicals is an iron chelator.

[0171] In some embodiments, the iron chelator is desferrioxamine (DFO); hydroxybenzyl ethylene diamine; fullerenol-l, pyrrolidine dithiocarbamate; desferal; Vk-28 (5-[4-(2-hydroxyethvl) piperazine- l -yimetbyl]-quinoline-8-ol); clioquinol; echinochrome; PIH (pyridoxal isonicotinoyl hydrazone); deferasirox; HEED (N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid); SIH (salicylaldehyde isonicotinoyl hydrazone); deferiprone; LI (I,2-dimethyl-3-hydroxy- 4- pyridone); Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyrone); deferoxamine; 2,3-dibydroxybenzoate; or combinations thereof.Mitochondrial Modulators

[0172] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells due to free radicals or the dysfunction of the mitochondria. Accordingly, some embodiments incorporate the use of one or more agents that modulate the activity of the mitochondria. In some embodiments, the agent which modulates the activity of the mitochondria is acetylcarnitine; lipoic acid; or combinations thereof.Nitric Oxide Synthase modulators

[0173] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells due to free radicals or the dysfunction of the mitochondria. Nitric oxide (NO) is a neurotransmitter. It is synthesized by multiple nitric oxide synthases (NOS) from arginine and oxygen. It is also derived from the reduction of inorganic nitrate. In certain instances, it induces vasodilation; thus, increasing blood flow. In certain instances, NO damages blood vessel walls. In certain instances, NO ameliorates vascular protein leakage in the cochlea. In certain instances, NO increases the sensitivity of sensory cells. In certain instances, NO reacts with super-oxide to form the free radical peroxy nitrite. Accordingly, some embodiments incorporate the use of agents that modulate nitric oxide and / or nitric oxide synthase (NOS).

[0174] In some embodiments, the agent that modulates NO and / or NOS is an antagonist of NO or NOS. In some embodiments, the antagonist of NO and / or NOS is aminoguanidine; 1 -Amino-2- hydroxy guanidine p-toluensulfate; GED (guanidinoethyldisulfide); bromocriptine mesylate; dexamethasone; SDMA (symmetric NG,NG-Dimethyl-L-arginine); ADMA (asymmetric N°,NG- Dimethvl-L -arginine); L-NMMA (NG-monomethyI-L-arginine); L-NMEA (NG-monoethyl-L- arginine); D-MMA (NG-monomethyl-D-arginine); L-NIL (Nb-(1-Iminoethyl)-L4ysine hydrochloride); L-NNA (NG-nitro-L -arginine); L-NPA (N°-propyl-L-arginine); L-NAME (NG-nitro-L -arginine methyl ester dihydrochloride); L-VNTO (N'-(l-imino-3-butenyl)-l-ornithine); diphenyleneiodonium chloride; 2-ethyl-2-thiopseudourea; haloperidol; L-NIO (I.,-N>-(l-iminoethyl)ornithine); MEG (methylecgonidine); SMT (S-methylisothiourea sulfate); SMTC (S-methyl-L-thiocitiulline); 7-Ni (7- nitroindazole); nNOS inhibitor I ((4S)-N-(4-Amino-5[armnoetliyl]aminopentyl)-N’-nitroguanidine); 1,3-PBITU (S.S’-l,3-PhenyIene-bis(1.2-ethanediyI)-bis-isothiourea); L-thiocitmlline; TRIM (l-(2- trifluoromethylphenyl) imidazole); MTR-105 (S-ethylisothiuromurn diethylphosphate); BBS-1; BBS- 2; ONO-1714 ((lS,5S,6R,7R)~7chloro-3~anrino~5methyl~2-azabicyclo[4.1.0]heptane hydrochloride); GW273629 (3-[[2-[(l-iminoethyl)amino]ethyl]sulphonyl]-L -alanine); GW 274150 ((S)-2-amino-(l- iminoethy lamino)-5-thioheptanoic acid); PPA250 (3 -(2,4-difluoropheny l)-6-{ 2- [4-( I H-imidazol- 1 - ylmetbyl) phenoxy]ethoxy}-2-phenylpyridine); AR-R17477 ([N-(4-(2-((3-cbIorophenylmethyl) amino) ethyl) phenyI)-2-thiophecarboxamidine dihydrochloride); AR-R18512 (N(2-methyI-l, 2,3,4- tetrahy droisoquinoIine-7 -y l)-2-tbiophenecarboximidamide) ; spiroquinazolone; 1400 W (N- [ [3 - (aminomethyl)phenyl]metby]]-etbauimidamide dihydrochloride); or combinations thereof.

[0175] In some embodiments, the agent that modulates NO and / or NOS is an agonist of NO and / or NOS, or a donor of NO. In some embodiments, the agonist of NO and / or NOS, or donor of NO, is S- NC (S-nitrosocysteine); NTG (nitroglycerine); SNP (sodium nitroprusside); thapsigargin; vascular endothelial growth factor (VEGF); bradykinin; ATP; sphingosine-l-phosphate; estrogen; angiopoietin; acetylcholine; SIN-1 (3-morpholinosydnonimine); GEA 3162 (1 ,2,3,4-oxatriazolium, 5- ammo-3-(3,4-dichlorophenyl)-, chloride); GEA 3175 (3-(3-chloro-2.-methylphenyl)-5-[[4- methylphenyl)sulphonyl]amino]-)hydroxide); GEA 5024 ( 1,2,3, 4-oxatnazolium,5-amino-3-(30cliloro- 2-methyl-phenyl)chloride); GEA 5538 (,2.3.4-Oxatriazolium,3-(3-chIoro-2-methylphenyl)-5- [[[cyanomethylarmno]carbonyl]ammo]-hydroxide inner salt); SNAP (S-nitroso-N- acety {penicillamine); molsidomine; CNO-4 (l-[(4',5'-Bis(carboxymethoxy)-2'~nitrophenyl)methoxy]- 2-oxo~3,3,diethyl-l-triazene dipotassium salt); CNO-5 ([l-(4',5'-Bis(caiboymethoxy)-2!- nitrophenyl)methoxy]-2-oxo-3,3-diethyl-l-triazine diacetoxymethyl ester); DEA / NO, 1PA / NO, SPER / NO, SULF1 / NO, OXI / NO, DET AW; or combinations thereof.Sirtuin Modulators

[0176] The sirtuins (or Sii2 proteins) comprise class III of the histone deacetylases (HDACs). While they are classified as protein deacetylases some also function as mono-ADP-ribosyltransferases. Each sirtuin protein has a homologous core sequence of 250 amino acids. This sequence is highly conserved over multiple species. Further, in order to catalyze the deacetylation of a protein, each sirtuin requires NAD' as a cofactor. There are seven members of the family: Sirtl, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6, and Sirt7. Sirtl and Sirt3 are protein deacetylases. Sirt2 is involved in mitosis.

[0177] Agonism of Sirtl yields multiple benefits which have previously been identified in subjects undergoing caloric restriction. These benefits include, but are not limited to, decreased glucose levels and unproved insulin sensitivity, increased mitochondrial activity, and decreased adiposity (due to the Sirtl mediated repression of PPAR-y). Decreases in glucose levels and adiposity can contribute to the amelioration of presbycusis as diabetes and atherosclerosis are both factors which contribute to the development and progression of presbycusis.

[0178] Sirtl can prevent apoptosis by deacetylating the pro-apoptotic genes p.53 and Ku-70.Additional substrates for Sirtl include, but are not limited to, the transcription factors NFKB, FOXO 1 , Fox03a, Fox04, Fox05; the transcription repressor Hid; and Pgc-la, which regulates, among other cellular functions, adaptive thermogenesis, glucose metabolism, and triglyceride metabolism.Agonism of S irt3 results in increased cellular respiration and a decrease in the production of reactive oxygen species (ROS).

[0179] The catalysis of deacetylation by sirtuins is NAD+(nicotinamide adenine dinucleotide) dependent. Upon binding to an acetylated protein, the sirtuin hydrolyzes NAD4by breaking the glycosidic bond between nicotinamide and ADP -ribose. The acetyl group of the acetylated protein isthen transferred to ADP-ribose. At the completion of the reaction nicotinamide, the deacetylated protein, and 2’-O-acetyl-ADP-ribose are released.

[0180] Multiple compounds modulate the sirtuin catalyzed deacetylation of proteins. Administration of certain polyphenols such as, but not limited io, stilbenes, chaicones, flavones, isoflavones, flavanones, anthocyanidins, catechins, results in the decrease of the Kmof the deacetylation reaction. Further, as free nicotinamide antagonizes the deacetylation reaction, compounds which inhibit the binding of nicotinamide to sirtuins will also agonize the activity of sirtuins.

[0181] Administration of the sirtuin agonizing agent resveratrol (tran. s-3, 5, 4 ’-trihydroxy stilbene) decreases apoptosis. It also increases glutamate uptake and thus ameliorates excitotoxicity. Further, administration of resveratrol results in lower levels of reactive oxygen species (ROS) and thus ameliorates damage caused by ischemia, and excitotoxicity, e.g. caused by cisplatin and aminoglycosides.

[0182] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells due to free radicals or the dysfunction of the mitochondria. Accordingly, some embodiments incorporate the use of one or more agents the modulate sirtuin catalyzed deacetylation reactions. In some embodiments, the agent which modulates sirtuin catalyzed deacetylation reactions is a stilbene. In some embodiments, the stilbene is traras-stilbene, cis-stilbene, resveratrol, piceatannol, rhapontin, deoxy rhapontin, butein, or combinations thereof,

[0183] In some embodiments, tiie stilbene is resveratrol. In some embodiments, the stilbene is an analog of resveratrol. In some embodiments, the analog of resveratrol is SRT-501 (RM-1821). For additional analogs of resveratrol see U.S. Patent App. Pub. No. 2006 / 0276393, which is hereby incorporated by reference for this disclosure.

[0184] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells of due to free radicals or the dysfunction of the mitochondria. Accordingly, some embodiments incorporate the use of one or more agents the modulate sirtuin catalyzed deacetylation reactions. In some embodiments, the agent which modulates sirtuin catalyzed deacetylation reactions is a cbalcone. In some embodiments, the chaicone is chalcon; isoliquirtigen; butein; 4.2’,4’-trihydroxychalcone; 3,4,2’,4’,6’-pentahydroxychalcone; or combinations thereof.

[0185] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells due to free radicals or the dysfunction of tire mitochondria. Accordingly, some embodiments incorporate the use of one or more agents the modulate sirtuin catalyzed deacety lation reactions. In some embodiments, the agent which modulates sirtuin catalyzed deacetylation reactions is a flavone. In some embodiments, the flavone is flavone, morin, fisetin; luteolin; quercetin; kaempferol; apigenin; gossypetin; myricetin; 6-hydroxyapigenin; 5-hydroxyflavone; 5,7,3’.4’,5’-pentahydroxyflavone; 3.7,3 ’,4’, 5’- pentahydroxyflavone; 3.6.3 ’ ,4 ’ -tetrahydroxyflavone; 7,3 ’ ,4 ’ ,5 ’ -tetrabydroxyflavone; 3,6,2 ’ ,4’- tetrahydroxyflavone; 7,4’-dihydroxyflavone; 7,8.3 ’,4’-tetrahydroxyflavone; 3.6, 2’, 3 tetrahydroxyflavone; 4 ’-hydroxy flavone; 5-hydroxyflavone; 5,4’-dihydroxyflavone; 5,7- dihydroxyflavone; or combinations thereof.

[0186] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / sensoiy cells due to free radicals or the dysfunction of tire mitochondria. Accordingly, some embodiments incorporate the use of one or more agents the modulate sirtuin catalyzed deacetylation reactions. In some embodiments, the agent which modulates sirtuin catalyzed deacetylation reactions is an isoflavone. In some embodiments, the isoflavone is daidzein, genistein, or combinations thereof.

[0187] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells due to free radicals or the dysfunction of the mitochondria. Accordingly, some embodiments incorporate the use of one or more agents the modulate sirtuin catalyzed deacetylation reactions. In some embodiments, the agent which modulates sirtuin catalyzed deacetylation reactions is a flavanone. In some embodiments, the flavanone is naringenin; flavanone; 3,5,7,3’,4’-pentahydroxyrflavanone; or combinations thereof.

[0188] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells due to free radicals or the dysfunction of the mitochondria. Accordingly, some embodiments incorporate the use of one or more agents the modulate sirtuin catalyzed deacetylation reactions. In some embodiments, the agent which modulates sirtuin catalyzed deacetylation reactions is an anthocyanidin. In some embodiments, the anthocyanidin is pelargonidin chloride, cyanidin chloride, delphinidin chloride, or combinations thereof.

[0189] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells due to free radicals or the dysfunction of the mitochondria. Accordingly, some embodiments incorporate the use of one or more agents the modulate sirtuin catalyzed deacetylation reactions. In some embodiments, the agent which modulates sirtuin catalyzed deacetylation reactions is a catechin. In some embodiments, the catechin is (-)-epicatechin (Hydroxy Sites: 3, 5, 7, 3', 4'); (-)-catechin (Hydroxy Sites: 3, 5.7.3'.4');gallocatechin (Hydroxy Sites: 3, 5, 7, 3', 4', S') (4)-catechin (Hydroxy Sites: 3,5,7,3'',4r); (+)-epicatechin (Hydroxy Sites: 3, 5, 7, 3', 4'); or combinations thereof.

[0190] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells due to free radicals or the dysfunction of the mitochondria. Accordingly, some embodiments incorporate the use of one or more agents that modulate the cataly tic rate of sirtuin catalyzed deacetylation reactions. In someembodiments, the agent which modulates the catalytic rate of sirtuin catalyzed deacetylation reactions is dipyridamole, ZM 336372 (3-(dimethyIamino)-N-[3-[(4-hydroxybenzoyl)-amino]-4-met hylphenyljbenzamide), camptothecin, coumestrol. nordihydroguaiaretic acid, esculetin, SRT-1720 (Sirtris), SRT-1460 (Sirtris), SRT-2183 (Sirtris), or combinations thereof.

[0191] Contemplated for use with the formulations disclosed herein are agents that relieve, prevent, reverse or ameliorate the degeneration of neurons and / or sensory cells due to free radicals or the dysfunction of tire mitochondria. Accordingly, some embodiments incorporate the use of one or more agents the modulate sirtuin catalyzed deacetylation reactions. In some embodiments, the agent that modulates sirtuin catalyzed deacetylation reactions is a nicotinamide binding antagonist. In some embodiments, the nicotinamide binding antagonist is isonicotinamide or an analog of isonicotmamide. In some embodiments, the analog of isonicotinamide is p-lr-5-methyl-nicotinamide~2'-deoxyribose; p-D~r-5-methyl-nico~tinamide~2'-deoxyribofuranoside; P-l'-4,5~diinethyi-nicotinamide-2'-de- oxyribose; or p-D-l'-4,5-diinethyl-nicotinamide-2'-deoxyribofuranoside. For additional analogs of isonicotinamide see U.S. Pat. Nos. 5,985,848; 6,066,722; 6,228,847; 6,492,347; 6,803,455; and U.S. Patent Publication Nos. 2001 / 0019823; 2002 / 0061898; 2002 / 0132783; 2003 / 0149261; 2003 / 0229033; 2003 / 0096830; 2004 / 0053944; 2004 / 0110772; and 2004 / 0181063, which are hereby incorporated by reference for that disclosure.Ion channel modulatorsPotassium Ion Channel Modulators

[0192] Some embodiments incorporate tire use of agents that modulate potassium ion concentrations. In some embodiments, the agents that modulate potassium ion concentrations are agonists or antagonists of potassium ion channels. Potassium ion channels are channels that regulate the flow of potassium ions into and out of cells.

[0193] In some embodiments, the agent that modulates a potassium channel is an agoinst of a potassium channel (e.g. a potassium channel opener). In some embodiments, the agonist of a potassium channel is nicorandil; minoxidil, levcromakalim; lemakalim; cromakalim; L-735,334 (14- hydroxy CAF-603 oleate); retigabine; flupirtine; BMS-204352 (3S)-(+)-(5-Chloro-2-methoxyphenyl)- l,3-dlhydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); DMP-543 (10,10-bis((2-fluoro-4- pyridinyl)methyl)-9(10H)-anthracenone); or combinations thereof.

[0194] In some embodiments, the agent that modulates a potassium channel is an antagonist of a potassium channel (e.g. a potassium channel blocker). In some embodiments, the antagonist of a potassium channel is linopirdme; XE991 (10,10-bis(4-pyridinylmetbyl)-9(10H)-anihracenone); 4-AP (4-aminopyridine); 3,4-DAP (3,4-Diarninopyndine); E-4031 (4’-[[l-[2-(6-methyl-2-pyridyl)ethyl]-4- piperidinyl]carbonyl]-methanesulfonanilide); DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid);Way 123,398 (N-methyl-N-(2-(methyl(l-methyl-lH-benzimidazol-2-yl)amino)ethyl)-4- ((methylsulfonyl)amino) benzenesulfonamide HC1); CGS-12066A (7-Trifluoromethyl-4-(4-metliyI-l-piperazinyl)pyrrolo-[l,2-a]quinoxaline); dofetilide; sotalol; apamin; amiodarone; azimilide; bretylium; clofilium; tedisamil; ibutilide; sematihde; nifekalant; tamulustoxin and combinations thereof.Purigenic Receptor Modulators

[0195] Contemplated for use with the formulations disclosed herein are agents for modulating ion channels. Accordingly, some embodiments incorporate the use of agents that modulate the concentration of ions. In some embodiments, the agents that modulate the concentration of ions are agonists or antagonits of purigenic receptors.

[0196] Purigenic receptors are a family of plasma membrane-bound receptors. The family includes the P2X, P2Y, and Pl receptors. The P2X receptors comprise ion channels. When ATP binds to the receptor the channel opens. The P2Y receptors comprise G-coupled protein receptors. The ligands for these receptors are ATP, ADP, UTP, UDP, UDP -glucose. The Pl receptors comprise G-coupled protein receptors. The ligand for these receptors is adenosine.

[0197] In some embodiments, the agonist of a purigenic receptor is ATP; ADP; UTP; UDP; UDP- glucose; adenosine; 2-MeSATP; 2-MeSADP; apmeATP; dATPaS; ATPyS; Bz-ATP; MRS2703 (2- MeSADP with the beta-phosphate group blocked by a l-(3,4-dimethyloxyphenyl)eth-l-yl phosphoester)); denufosol tetrasodium; MRS2365 ([[(lR,2R,3S,4R,5S)-4-[6-amino-2-(methylthio)- 9H-purin-9 -yl]-2,3-dihydroxybicyclo[3.1.0]hex-l-yl]methyl] diphosphoric acid mono ester trisodium salt); MRS 2690 (diphosphoric acid 1-a-D-glucopyranosyl ester 2-[(4'-methylthio)uridin-5"-yl] ester disodium salt); PSB 0474 (3-(2-Oxo-2-phenylethyl)-uridme-5'-diphosphate disodium salt); or combinations thereof.

[0198] In some embodiments, the antagonist of a purigenic receptor is A-317491 ((5-([(3 - Phenoxybenzyl)[(lS)-l,2,3,4-tetrahydro-l~naphthalenyl]amino]carbonyl)-l,2,4-bem:enetricarboxylic acid)); RO-3 (Roche); suramin; PPADS (pyridoxalphosphate-6-azophenyl~2\4’-disulfonic acid);PPNDS (Pyridoxal-5'-phospliate-6-(2'-naphthylazo-6'-nitro-4',8' -disulfonate) tetrasodium salt); DIDS; pyridoxal-5-phosphate; 5-(3-bromophenyl)-l,3-dihydro-2 / 7-benzofuro- [3,2-e]-l,4-diazepin-2-one; cibacron blue; basilen blue; ivermectin; A-438079 (3-[[5-(2,3-Dichlorophenyl)-lH-tetrazoi-l- yljmethvljpyri dine hydrochloride); A-740003 ((N-(i-{[(cyanoimino)(5-qninolinylamino) methyl]aniino}’2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide); NF449 (4,4’,4”,4”’- (carbonylbis(imino-5,l,3-beBzenet:riylbis(carbonylimino)))tetrakis-benzene-l,3-disulfonic acid);NF 110 (nara-4,4’,4”,4” ’-(carbonylbis(imino-5, 1,3-beuzenetriylbis carbouylimino)))tetrakis- benzenesulfonic acid); MRS 2179 (2'-Deoxy-N6-methyladenosine 3',5'-bisphosphate tetrasodium salt); MRS 2211 (2-[(2-chloro-5-nitrophenyl)azo]-5-hydroxy-6-methyl-3-[( phosphonooxy)methyl]-4- pyridinecarboxaldehyde disodium salt); MRS 2279 ((lR,2S,4S,5S)-4-[2-chloro-6-(methylamino)-9H- purin-9-yl ]-2-(phosphonooxy)bicyclo[3.1.0]hexane-l-metIianol drhydrogen phosphate ester diammoniurn salt); MRS 2500 tetrasodium salt ((lR,2S,4S,5S)-4-[2-lodo-6-(methylamiuo)-9H-purin-9-3'1]- 2-(phospbonooxj')bicyclo[3.1.0]hexane-l-metlianol dihydrogen phosphate ester tetraammonium salt); NF157 (8,8'-[caibonyIbis[imino-3,l-pbenylenecarbonylimino(4-fl uoro-3,1- phenylene)carbonylimino]]bis-l,3,5-naphthalene trisulfonic acid hexasodium salt); TNP-ATP; tetramethylpyrazine; IpsI; Py-carboxymethylene ATP; py-chlorophosphomethylene ATP; KN-62 (4- [(2.S)-2-[(5-isoquinolinylsuifonyl)methylaminoj-3-oxo- 3-(4-phenyl-l-piperazinyl)propyl] phenyl isoquinolinesulfonic acid ester); NF023 (8,8'-[carbonylbis(imino-3,l-phenylenecarbonylimino)]bis - 1,3,5-naphthalene-trisulphonic acid, hexasodium salt); NF279 (8,8'-[Carbonyibis(imino-4,l- pheny leneciubonylimino-4, 1 - phenylenecarbony limino)] bis- 1 ,3 ,5 -naphlhalenetrisulfonic acid hexasodium salt); spinorphin; or combinations thereof.Other Therapeutic AgentsRNAi

[0199] In some embodiments, where inhibition or down-regulation of a target is desired (e.g. genes encoding a component of a potassium channel, genes encoding a purigenic receptor), RNA interference is optionally utilized. In some embodiments, the agent that inhibits or down-regulates the target is an siRNA molecule. In certain instances, the siRNA molecule is as described herein.A nti-Emetic Agents / Central Nervous System Agents

[0200] Anti-Emetic agents are optionally used in combination with any formulations disclosed herein. Anti-emetic agents include antihistamines and central nervous agents, including anti-psychotic agents, barbiturates, benzodiazepines and phenothiazines. Other anti-emetic agents include the serotonin receptor antagonists, which include dolasetron, granisetron, ondansetron, tropisetron, palonosetron, and combinations thereof; dopamine antagonists, including domperidone, properidol, haloperidol, chlorpromazine, promethazine, prochlorperazine and combinations thereof; cannabinoids, including dronabinol, nabilone, sativex, and combinations thereof; anticholinergics, including scopolamine; and steroids, including dexamethasone; trimethobenzarmne, emetrol, propofol, muscimol, and combinations thereof.

[0201] Optionally, Central Nervous System agents and barbiturates are useful in the treatment of nausea and vomiting symptoms that accompany an autoimmune disorder. When used, an appropriate barbiturate and / or central nervous system agent is selected to relieve or ameliorate specific symptoms without common side effects. Barbiturates, which act as a central nervous system depressant, include allobarbital, alphenal, amobarbital, aprobarbital, bamexaclone, barbital, brallobarbital, butabarbital, butalbital, butallylonal, butobarbital, corvalol, crotylbarbital, cyclobarbital, cyclopal, ethallobarbital, febarbamate, heptabarbital, hexethal, hexobarbital, metharbital, methohexital, methylphenobarbital, narcobarbital, nealbarbital, pentobarbital, phenobarbital, primidone, probarbital, propallylonal, proxibarbital, reposal, secobarbital, sigmodal, sodium thiopental, talbutal, thialbarbital, thiamylal, thiobarbital, thiobutabarbital, tuinal, valofane, vinbarbital, vinylbital, and combinations thereof.

[0202] Other central nervous system agents which are optionally used in conjunction with the formulations disclosed herein include benzodiazepines or phenotbiazines. Useful benzodiazepines include, but are not limited to diazepam, lorazepam, oxazepam, prazepam, alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, brotizolam, estazolam, flunitrazepam, flurazepam, loprazolam, lormetazepam, midazolam, nimetazepam, nitrazepam, temazepam, triazolam, and combinations thereof. Examples of phenotbiazines include prochlorperazine, chlorpromazine, promazine, trifiupromazine, levopromazine, meihotrimepramazine, mesoridazine, thiroridazine, fluphenazine, perphenazine, flupentixol, trifluoperazine, and combinations thereof.

[0203] Antihistamines, or histamine antagonists, act to inhibit the release or action of histamine. Antihistamines that target the Hl receptor are useful in the alleviation or reduction of symptoms that are associated with autoimmune disorders, as well as anti-inflammatory disorders. Accordingly, some embodiments incorporate the use of agents which modulate histamine receptors (e.g. the Hi receptor, H2receptor, and / or the H3receptor).

[0204] Such antihistamines include, but are not limited to, meclizine, diphenhydramine, loratadine and quetiapine. Other antihistamines include mepyramine, piperoxan, antazoline, carbinoxamine, doxylamine, clemastine, dimenhydrinate, pheniramine, chlorphenamine, chlorpheniramine, dexchlotpheniramine, brompheniramine, triprolidine, cyclizine, chlorcyclizine, hydroxyzine, promethazine, alimemazine, trimeprazine, cyproheptadine, azatadine, ketotifen, oxatomide and combinations thereof,

[0205] In some embodiments, the Hi receptor antagonist is meclizine hydrochloride. In some embodiments, die Hi receptor antagonist is promethazine hydrochloride. In some embodiments, the Hi receptor antagonist is dimenhydrinate. In some embodiments, the Hi receptor antagonist is diphenhydramine. In some embodiments, the Hi receptor antagonist is cinnarizine. In some embodiments, the Hi receptor antagonist is hydroxyzine pamoate.

[0206] Antihistamines which target the H3receptor include, but are not limited to betahistine dihydrochloride.Corticosteroids

[0207] Contemplated for use in combination with any formulation described herein (e.g, immunomodulator formulations described herein) are corticosteroid agents which reduce or ameliorate symptoms or effects as a result of an autoimmune disease and / or inflammatory disorder. In some embodiments, corticosteroids modulate the degeneration of neurons and / or sensory’ cells.Accordingly, some embodiments incorporate the use of agents which protect neurons or sensory cells. In some embodiments, the agent which protects sensory’ cells from toxins is a corticosteroid. Such steroids include prednisolone, dexamethasone, dexamethasone phosphate, beclomethasone, 21- acetoxypregnenolone, alclometasone, algestone, amcinonide. beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, eiocortolone, cloprednol, corticosterone,cortisone, cortivazol, deflazacort, desonide. desoximetasone, diflorasone, diflucortolone, difhiprednate. enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl. fluocortolone, fluoromethoIone, fluperolone acetate, fluprednidene acetate, fluprednisoione, flurandrenolide. fluticasone propionate, fonnocortal, lialcinonide, halobetasol propionate, halometasone, halopredone acetate, bydrocortamate, hydrocortisone, ioteprednol elaborate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylammo-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol. triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide and combinations thereof. In certain instances, triamicinolone actenoide and dexamethasone protect sensory cells from damage caused by the na turally occurring toxin 4-hydroxy-2,3-nonenal (HNE), which is produced in response to oxidative stress.Chemotherapeutic Agents

[0208] Chemotherapeuctic agents are also contemplated for use with the formulations disclosed herein. Chemotherapeutic agents act by killing cancer cells or microorganisms, and may include antineoplastic agents that target cancer or malignant cells. However, use of cisplatin in combination with antioxidants are protective and lessen the toxic effects of the chemotherapeutic agent. Moreover, the localized application of the cytotoxic drug may lessen the toxic effects that might otherwise occur through systemic application through the use of lower amounts with maintained efficacy, or the use of targeted amounts for a shorter period of time. Accordingly, a skilled practitioner choosing a course of therapy for tumor growth will have the knowledge to avoid or combine a toxic compound, or to vary die amount or course of treatment to avoid or lessen toxic effec ts.

[0209] Chemotherapeutic agents that are used in combination with the formulations disclosed herein include, for example, but are not limited to adriamycin, imidazole carboxamide, cyclophosphamide, mechlorethamine, chlorambucil, inelphalan, daunorubicin, doxorubicin, epirubicm, idarubicin, mitoxanthrone, valmbicin, paclitaxel, docetaxel, etoposide, teniposide, tafluposide. azacitidine, azathioprine. capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, tioguanine, bleomycin, carboplatin, cisplatin, oxaliplatin, all-trans retinoic acid, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof.Homeostasis modulators

[0210] Homeostatis modulators are contemplated as useful with the formulations described herein. Homeostasis modulators include ion and fluid (e.g. water) homeostasis modulators. In some instances, homeostasis modulators include Na / K-ATPase modulators, ENaC modulators, vasopressin receptor modulators, diuretics or the like as described herein.Antiseptics

[0211] Antiseptics such as peroxides are contemplated as useful with the formulations described herein. In some embodiments, the antiseptic peroxide is benzoyl peroxide. In some embodiments, the antiseptic peroxide is hydrogen peroxide.Na / K. .4 TPase Modulators

[0212] Na / K-ATPase modulators are contemplated for use with the formulations disclosed herein. Examples of Na / K-A TPase modulators include, and are not limited to, nimodipine (a sodiumpotassium adenosine triphosphatase stimulator), ouabain, and furosemide.

[0213] In some embodiments, the composition optionally comprises one or more further beneficial components. In some embodiments, the one or more further components are beneficial for the treatment of a skin condition. In some embodiments, the one or more further components, provide some beneficial effect not related to the trea tment of skin conditions, such as inflammatory skin conditions, but beneficial to skin generally. In some embodiments, the one or more further components are selected from a further substituted or unsubstituted retinoid compound, an antibiotic compound, a substituted or unsubstituted azelaic acid compound, an oral contraceptive compound, sulphur, a sulphur-containing compound, a substituted or unsubstituted salicylic acid compound, a substituted or unsubstituted resorcinol compound, a plant product, a mineral, a vitamin (typically not vitamin A which instead in some embodiments is present as a retinoid compound), and a neutraceutical prodnet. Thus, additional further components in some embodiments include one or more of: omega 3, omega 6, B vitamins including folic acid and vitamin B 12, vitamin C, vitamin D, vitamin E, betaine hydrochloride, pepsin, zinc, kelp, one or more minerals, one or more herbal supplements, one or more polyphenolic compounds from the bergamot fruit (Citrus bergamid) preferably when extracted and concentrated, and bergamot.

[0214] In some embodiments, the further component comprises either one or more of the further components described above, depending upon the requirements of the formulation.

[0215] In some embodiments, the antibiotic compound is any such compound known in the art that is suitable for use with the skin. In some embodiments, the antibiotic compound is suitable for oral and / or topical application and is selected from tetracycline, oxytetracycline, minocycline, doxycycline, erythromycin and trimethoprim.

[0216] In some embodiments, the azelaic acid compound is any such compound known in the art that is suitable for use with the skin. In some embodiments, the azelaic acid compound suitable for use with the skin comprises an antibacterial and / or an anti-inflammatory property.

[0217] In some embodiments, the oral contraceptive compound is any such compound known in die art ttyd is suitable for use with the skin. In some embodiments, tire oral contraceptive comprises a female hormone and / or a compound with female hormone activity, capable of counteracting the effect of a male hormone, in some embodiments, the female hormone is estrogen and the male hormone is testosterone.

[0218] In some embodiments, the sulphur or sulphur-containing compound is any such compound known in the art that is suitable for use with the skin. In some embodiments, the sulphur or sulphur-containing compound comprises sulphur either alone or in combination with other substances such as alcohol, salicylic acid and / or resorcinol.

[0219] In some embodiments, the resorcinol compound is any such compound known in the art that is suitable for use with the skin. In some embodiments, the resorcinol compound comprises a compound with an antibacterial and / or an anti-inflammatory property .

[0220] In some embodiments, the plant product is an extract from one or more of the following:* Urtica dioica (stinging nettle) - lias significant anti-inflammatory effects helping to reduce the redness and swelling in acne* Ribes nigrum (blackcurrant) - lias significant anti -inflammatory' and antioxidant properties* Echinacea purpurea and / or Echinacea angustifoha - contain active substances that enhance the activity of the immune system, reduce inflammation and antioxidant effects® Cnidium monnieri - acts through its antibacterial, antifungal, and astringent properties* Berberis aquafolium (Oregon grape) - in some embodiments decrease sebum production, and reduce infection and inflammation* Chamomile Matricaria (German chamomile) - lias antibacterial properties and inactivates bacterial toxins. In some embodiments reduce inflammation, and speed wound healing* Phytolacca decandra (poke root)* Cruciferous vegetables - synergistic effects in some embodiments are achieved by the addition of extracts, concentrates and processed extracts of cruciferous vegetables such as broccoli, sprouts etc. These in some embodiments provide active products with significant added antioxidant and anti-inflammatory effects.

[0221] In some embodiments, the mineral comprises one or more of:* Zinc - in some embodiments promote reduction of inflammation and healing of damaged skin* Chromium - in some embodiments help boost the body's ability to break down glucose* Selenium - in some embodiments help to balance decreased levels of antioxidant enzymes and / or in some embodiments reduce persistent acne and help lessen the appearance of scars

[0222] In some embodiments, the vitamin comprises one or more of:* Vitamin B complex - combinations of B vitamins Bl, B2, B3, B4, B5, B6, B7, B9 and B12 - in some embodiments balance the metabolism of hormones, which have a significant role in skin conditions, such as inflammatory skin conditions.* Vitamin C - a highly effective antioxidant, which stimulates tissue growth and repair. In some embodiments contribute to the healing process in skin conditions, such as inflammatory skin conditions.• Vitamin E - a potent antioxidant

[0223] In some embodiments, the neutraceutical product lias some further nutritional or pharmaceutical property that is complementary or supplementary to the effect of the first and / or second component. In some embodiments, one or more neutraceutical products are selected from:• Evening primrose oil - contains fatty acids, which in some embodiments help decrease inflammation related to skin conditions, such as inflammatory skin conditions.• Plant isoflavones - from foods including soy bean and red clover - have significant natural antioxidant properties and a balancing effect on estrogenic hormones• Turmeric - has anti-inflammatory properties from the primary active component curcumin• Essential and non-essential fatty acids, such as omega fatty acids (omega-3, omega-6, etc. - long-chain n~3 fatty acids in some embodiments have anti-inflammatory activity

[0224] In some embodiment, the additional therapeutic agent is a vitamin D and D-like actives (calcipotriol, tacalcitol, calcitriol, etc.). In some embodiment, the additional therapeutic agent is Dithranol (anthracen derivative). In some embodiment, the additional therapeutic agent is Brimonidine (alpha adrenergic agonist). In some embodiment, the additional therapeutic agent is Apremilast, a phosphodiesterase type 4 (PDE4) inhibitor. Excluded Therapeutic Agents

[0225] In some embodiments, the compositions described herein is essentially free of any substituted or unsubstituted retinoid compound. In some embodiments, the excluded retinoid compound is any such compound known in the art that is suitable for use with the skin. For example, in some embodiments, it is selected from a substituted or unsubstituted first generation retinoid, a substituted or unsubstituted second generation retinoid, and a substituted or unsubstituted third generation retinoid. In some embodiments, the retinoid is a substituted or unsubstituted first generation retinoid. In some embodiments, the substituted or unsubstituted first generation retinoid is selected from a substituted or unsubstituted retinol, a substituted or unsubstituted retinal, a substituted or unsubstituted tretinoin (e.g., retinoic acid or Retin A), a substituted or unsubstituted isotretinoin (e.g,. AccutaneTM), and a substituted or unsubstituted alitretinoin. In some embodiments, the retinoid is vitamin A. In some embodiments, the retinoid is a substituted or unsubstituted second generation retinoid selected from a substituted or unsubstituted etretinate, and a substituted or unsubstituted acitretin. In some embodiments, the retinoid is a substituted or unsubstituted third generate on retinoid selected from a substituted or unsubstituted tazarotene, a substituted or unsubstituted bexarotene, and a substituted or unsubstituted adapalene. In some embodiments, the excluded retinoid compound is a vitamin A compound (e.g, vitamin A palmitate).

[0226] In some embodiments, the compositions described herein is essentially free of CYP450 enzyme modulators. In some embodiments, the excluded CYP450 enzyme modulator is any suchcompound known in the art that is suitable for use with the skin. For example, in some embodiments, it is selected from CYP1A1. CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP3A4, CYP2C19, and CYP19A1.

[0227] In some embodiments, the compositions described herein is essentially free of antibiotic agents. The excluded antibiotic agents include, but are not limited to, lincosamides (such as clindamycin), sulfones (such as dapsone), tetracyclines (such as tetracycline, doxycycline, minocycline, lymecy cline), macrolides (such as erythromycin, azithromycin), sulphonamides (such as sulfamethoxazole, co-trimoxazole), diaminopyrimidines (trimethoprim), penicillin and its derivatives, and cephalosporins and its derivatives,

[0228] In some embodiments, the compositions described herein is essentially free of probiotic agents. The probiotic agents can be pre-biotic agents or post-biotic agents. The probiotic agents include, but are not limited to, Lactobacillus rhamnosus, Lactobacillus paracasei, Lactobacillus acidophilis, Lactobacillus salivarius, Lactobacillus sakei, Lactobacillus johnsonii, Lactobacillus reuteri, Lactobacillus bulgaricus, Lactobacillus plantarum, Lactobacillus sporogenes, Bifidobacterium lactis, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium infantis, Roseomonas mucosa. Proprionibacterium, VitreosciUa filifoimis, Streptococcus tbermophilus, and Enterococcus faecalis.

[0229] In some embodiments, the compositions described herein is essentially free of anti-protozoal agents. In some embodiments, the excluded anti-protozoal agent is any such compound known in the art that is suitable for use with the skin. For example, in some embodiments, it is selected from atovaquone, amodiaquine, amphotericin, butoconazole, clindamycin, eflornithine, fumagillin, lodoquinol (diiodohydroxyquin), clioquinol (iodochlorhydroxyquin), Etanidazole, Benznidazole, fluoroquinolones, enoxacin, ciprofloxacin, doxy cycline, melarsoprol, metronidazole, miltefosine, nifurtimox, nitazoxanide, paromomycin, pentamindine, sodium stibogluconate, suramin, tinidozole, pyrimethamine, proguanil (chloroguanide), spiramycin, and sulfadoxine. Natural product derived antiprotozoal drugs useful for combined use include sesquiterpene lactones related to artemisinin from Artemisia annua, particularly artemisinin, dihydroartemisinin, artemether, artesunate, and further derivatives of artemisinin, quinolines like quinine derived from the bark of the South American chinchona tree, including quinine and quinine-related quinolines, halofantrine, mefloquine, lumefantrine, amodiaquine, pyronaridine, piperaquine, chloroquine, hydroxychloroquine, napthoquine, primaquine, and tafenoquine, curcuminoids derived from curcumin, an extract from Curcuma domestica, including 6-gingerol and 6-paradol, corouaridine, 18-methoxycoronaridine, selected flavonoids, including luteolin, extracts the fruit pericarp of Sapindus mukorossi, arid extracts of Yucca schidigera. Excluded antiprotozoal agent also include artemisinin derivatives, atovaquone, chloroquine, iodoquinol (diiodohydroxyquin), clioquinol (iodochlorhydroxyquin), sodium stibogluconate, and curcumin.. Excluded antiprotozoal agent also include antiprotozoal naturalproducts such as teas and extracts made from Artemisia annua, teas and extracts made from Curcuma domestica, extracts from garlic which include allicin and other thiosulfinates, root extracts of Uvaria chamae (Annonaceae) and Hippocratea Africana (Hippocrateaceae), and root extracts of Homalium letestui.Bioavasiabihty of substituted or imsubstituted DIM

[0230] Diindolylmethane (DIM) is a natural compound formed during the autolytic breakdown of glucobrassicin present in food plants of the Brassica genus, including broccoli, cabbage, Brussels sprouts, cauliflower and kale. The autolytic breakdown of glucobrassicin requires the catalytic reaction of the enzyme myrosinase, which is endogenous to these plants and released upon rupture of the cell wall. The compound is normally manufactured by chemical synthesis but in some embodiments is also prepared by natural means from the extracts of Brassica vegetables, as listed above, particularly from sprouting broccoli or from broccoli seeds. Thus, the substituted or unsubstituted DIM in some embodiments is synthetic, or in some embodiments is a natural product obtained from a Brassica plant, as discussed above. In some embodiments, the composition described herein, includes as a first component, any substituted or unsubstituted DIM, or a combination of the substituted or unsubstituted DIMs described above.

[0231] In some embodiments, the substituted or unsubstituted DIM is adapted for increased bioavailability, in order to reduce the required dosage. In some embodiments, the DIM with increased bioavailability is an unsubstituted DIM. In some embodiments, the DIM with increased bioavailability is BR-DIM (from BioResponse LLC).Dosage of administration

[0232] In some embodiments, the composition comprising a first component comprising a substituted or unsubstituted DIM, is administered at a dosage that is sufficiently low to avoid toxicity7, whilst still maintaining the required pharmaceutical effect. In some embodiments, the dosage depends on the bioavailability of the substituted or unsubstituted DIM. In some embodiments, tire dosage varies depending upon whether it is a natural or synthetic product. In some embodiments, the dosage of the first component comprising the substituted or unsubstituted DIM is determined by whether or not the DIM lias been adapted to improve bioavailability’.

[0233] In some embodiments, the first component comprising a substituted or unsubstituted DIM is in a form suitable for providing a daily DIM dosage of 1500 mg or less, 1000 mg or less, 900 mg or less, 800 mg or less, 700 mg or less, 600 mg or less, 500 mg or less, from 10-750 mg, from 150-650 mg, from 250-550 mg, and from 300-500 mg. In some embodiments, the first component comprising a substituted or unsubstituted DIM is in a form suitable for providing a daily DIM dosage of about 300 mg or about 350 mg, or about 400 mg or about 450 mg, or about 500 mg. In some embodiments, the first component comprising a BR-DIM is in a form suitable for providing a daily BR-DIM dosage of 1500 mg or less, 1000 mg or less, 900 mg or less, 800 mg or less, 700 mg or less,600 mg or less, 500 mg or less, from 10-750 mg, from 150-650 mg, from 250-550 mg, and from 300-500 mg. In some embodiments, the first component comprising a BR-DIM Is in a form suitable for providing a daily BR-DIM dosage of about 300 mg or about 350 mg, or about 400 mg or about 450 mg, or about 500 mg. In some embodiments, the first component comprising a BR-DIM that has not been adapted to improve bioavailability, is administered in higher dosages.

[0234] In some embodiments, the first component comprising a substituted or unsubstituted DIM is in a form suitable for providing an intermediate daily DIM dosage, such as from 50-350 mg, 100- 200 mg. 140-160 mg. or about 150 mg, or alternatively 250-350 mg, 290-310 mg or about 300 mg. In some embodiments, the first component comprising a substituted or unsubstituted DIM is in a form suitable for providing a low daily DIM dosage, such as from 15-100 mg, 50-100 mg, 18-80 mg, 18- 75 mg, 70-80 mg, or about 75 mg. In some embodiments, tire first component comprising a BR-DIM is in a form suitable for providing an intermediate daily BR-DIM dosage, such as from 50-350 mg, 100-200 mg, 140-160 mg, or about 150 mg, or alternatively 250-350 mg, 290-310 mg or about 300 mg. In some embodiments, the first component comprising a BR-DIM is in a form suitable for providing a low daily BR-DIM dosage, such as from 15-100 mg, 50-100 mg, 18-80 mg, 18-75 mg, 70-80 mg, or about 75 mg.

[0235] In some embodiments, the first component comprising a substituted or unsubstituted DIM that has been adapted to improve bioavailability is administered in intermediate and lower dosages. In some embodiments, the first component comprising a substituted or unsubstituted DIM that has been adapted to improve bioavailability is administered in any of the above dosages, including the higher dosages, if desired. In some embodiments, the DIM that has been adapted to improve bioavailability is BR-DIM.

[0236] In some other embodiments, the first component comprising a substituted or unsubstituted DIM is present in a dose which is a fraction of the daily dose, such as a lialf of the daily dose, or a quarter of the daily dose, and thus is present in a half or a quarter of any of the dosages recited above. In these embodiments, each dose fraction is taken separately over time to spread the dose across the day. In some other embodiments, the first component comprising a BR-DIM is present in a dose which is a fraction of the daily dose, such as a half of the daily dose, or a quarter of the daily dose, and thus is present in a half or a quarter of any of the dosages recited above. In these embodiments, each dose fraction is taken separately over time to spread the dose across the day.

[0237] In some embodiments, the second component comprising an additional therapeutic agent is administered at a dosage that it is sufficiently low to avoid toxicity, whilst still maintaining the required pharmaceutical effect. In some embodiments, the dosage of the second component depends on the bioavailability of the retinoid compound. In some embodiments, the bioavailability of the additional therapeutic agent, vanes depending upon whether it is a natural or synthetic product. In some embodiments, the bioavailability of the additional therapeutic agent, may vary depending onwhether it lias been adapted to improve its bioavailability. In some embodiments, the second component comprising an additional therapeutic agent is in a form suitable for providing a daily dosage of 250 mg or less, 200 mg or less, 150 mg or less, 100 mg or less, 50 mg or less, or 15 mg or less. In some embodiments, the second component comprising an additional therapeutic agent is in a form suitable for providing a daily dosage of 10,000 pg or less, 5,000 pg or less, or 3,000 pg or less. In some embodiments, the second component comprising an additional therapeutic agent is in a form suitable for providing a daily dosage of 50 pg or more, 100 pg or more, or 200 pg or more. In some embodiments, the second component comprising an additional therapeutic agent is in a form suitable for providing a daily dosage from 200-15,000 pg, from 200-5000 pg, or from 200-3000 pg.

[0238] In some embodiments, daily dosage of the composition comprising a first component and a second component is provided in the form of one or more capsules or tablets. In some embodiments, daily dosage of foe composition comprising a first component and a second component is provided in the form of 2 or 4 capsules or tablets. In these embodiments the capsules or tablets are taken during the course of a single day, such as one in the morning and one in the evening, or four spread evenly across the day, or two capsules or tablets simultaneously twice a day.Dosage Form

[0239] In some embodiments, the compositions described herein are used to prepare a formulation suitable for administration to a human or other subject. In some embodiments, the composition components are formulated for oral or topical administration. In some embodiments, the composition components, are provided in the form of a tablet, capsule, liquid (such as in the form of a drink, e.g., a yoghurt drink), gel. cream, or ointment. In some embodiment, the composition components comprise tlie first component present in a first formulation, and the optional second component present in a second formulation, wherein the first and second formulations are co-administered to a patient, either concurrently or in a sequential manner. In some embodiment, the composition and / or the kit components comprises the first component and second component present in one formulation that is administered to a patient.Methods of Preparation

[0240] In some embodiments, are provided, methods for preparing the compositions described herein, suitable for use in treatment of skin conditions, such as inflammatory skin conditions. In some embodiments, any methods known in the art forblending or mixing various components of the composition are employed. In some embodiments, the methods employ ed are methods for blending and / or mixing powders. In some embodiments, foe method comprises mixing a first component with one or more excipients and / or additives, optionally with a second component, and optionally a further component to form the composition. In some embodiments, the first, second and / or further components are each, separately from each other, mixed with one or more excipients and / or additives before being mixed together to form the composition. In some additional embodiments, thecomponents, additives, and / or excipients are added sequentially to the mixture during the mixing process.

[0241] In some embodiments, the selection of the excipients and the method of blending are adapted in order to overcome any mixing, flow and fill issues or punch issues with the composition. In some embodiments, the composition comprising a first component comprising a substituted or unsubstituted DIM or a BR-DIM, is provided in micro-encapsulated form, such that the powder particles have a tendency to clump together. In some embodiments, the composition comprising a first component, comprising a substituted or unsubstituted DIM or a BR-DIM is blended using a method tiiat is adapted to avoid creating hot spots of increased concentrations of the active ingredients. In some embodiments, the composition comprising a first component, optionally a second component, and optionally a further component, is blended using a method that involves short processing / blending times, to protect the composition from light and air, wherein the composition is hygroscopic and light sensitive. In some embodiments, the composition comprising a first component, optionally a second component, and optionally a further component, is prepared in the form of a powder, and the powder is protected from both light and air, during storage.

[0242] In some embodiment, one or more of microcrystalline cellulose, magnesium silicate, tricalcium phosphate, and magnesium stearate (a traditional lubricant) are employ ed as additives and excipients, in preparing the compositions described herein, to help with flow characteristics and / or lubrication. In some embodiments, other additives and excipients known in the art are employed if desired. In some embodiments, the composition comprises 50.0-65.0% by weight of tri-calcium phosphate. In some embodiments, the composition comprises, 55.0-60.0% by weight, or 57.0-59.0% by weight of tri-calcium phosphate. In some embodiments, the composition comprises about 58% by weight of tri-calcium phosphate. In some embodiments, the composition comprises about 58.3% by weight of tri-calcium phosphate.

[0243] In some embodiments, the correct blending of all ingredients is desirable in achieving uniform capsule fills of the compositions as described herein. In some embodiments, the correct blending of ail ingredients is desirable in achieving uniform capsule fills of the compositions as described herein. In some embodiments, a V-blender is highly effective for successful mixing. In some embodiments, a minimum 316 grade stainless steel vessel is used for the mixing process. In some embodiments, sieving is performed at one or more of the start, the middle, and the end of the mixing process. In some embodiments, blend studies to confirm blend uniformity are completed to validate the method and formulation, using methods and techniques known in the field.NON-LIMITING EXAMPLES

[0244] The following specific, non-limiting examples are to be construed as merely illustrative, and do not limit the present disclosure of the scope of the disclosure. Without further elabora tion, it isbelieved that one skilled in the art can, based on the description herein, utilize the present disclosure to its fullest extent.Example 1: Oral DIM Compositions Containing Additional Therapeutic AgentsManufacture of composition

[0245] A batch of DIM formulation containing an additional therapeutic agent was manufactured.The details of manufacture and formulation are set out below.Formulation1 capsule contains:* 75 mg BR-DIM (BioResponse LLC)* 0.01-500mg of an additional therapeutic agent (e.g, antibiotic agent)* 175 mg tri-calcium phosphate® 20 mg microciystalline cellulose* 10 mg fumed silicon dioxide (or a fine particle precipitated silica)® 6 mg magnesium stearateBlending method for formulation

[0246] Mixing was carried out in a sequential process according to the following protocol:1. The BR-DIM was sieved through a fine sieve and then mixed with the magnesium stearate, lialf of the tricalcium phosphate and the silicon dioxide for 15 mins in a V mixer. The mixed powder was transferred into a food grade bag.2. Separately, the additional therapeutic agent were mixed with the second half of the tricalcium phosphate and the microcrystalline cellulose for 15 mins in a V mixer.3. The mixed powders obtained from 1 and 2 were blended together for 20 mins in a V mixer, then sieved, and mixed further for 1 hour and 45 minutes in a V mixer.4. The blended powder was transferred to a suitable opaque and air-tight container to ensure minimal contact with light and oxygen.5. A sample was taken from the top and bottom of the batch to test for uniformity of mixing.Encapsulation

[0247] The DIM referred to above in some embodiments is encapsulated. The BR-DIM is spray dried into particles of approximately 8 to 12 microns in diameter. BR-DIM is known to be light sensitive. Therefore, opaque capsules are preferred, typically, size “0” capsules. Light resistant containers are preferred.Example 2 - Topical Gel DIM Compositions Containing Additional Therapeutic Agents

[0248] In this non-limiting example, the topical DIM composition is formulated as an emulsion gel, in which the oil phase contains the DIM compounds and the aquesous phase comprises a hydrogel. Below is a list of the ingredients for the emulsion gel formulation.

[0249] Water - aquesous earner

[0250] Glycerin - carrier

[0251] DIM - active agent (0.1-10 wt%)

[0252] Additional therapeutic agent, e.g. antibiotic agent (0. 1-10 wt%)

[0253] Dicaprylyl carbonate ester - emollient

[0254] Ammonium acryloyldimethyltaurate / VP copolymer - rheology modifier

[0255] Carbomer - rheology modifier

[0256] Poly glycetyl-10 laurate - emulsifier

[0257] Levulinic acid - skin conditioner and preservative

[0258] Sodium anisate - preservative

[0259] Sodium levulinate - skin conditioner and preservative

[0260] Sodium hydroxide - pH adjusting agent

[0261] Tocopherol - moistorizer / antioxidant

[0262] To make the formulation, various ingredients were mixed together until a uniform emulsion gel is obtained.Example 3 - Topical Cream DIM Compositions Containing Additional Therapeutic Agents

[0263] In this non-limiting example, the topical DIM composition is formulated as an emulsion cream, in which the oil phase contains the DIM compounds and the aqueous phase comprises a base cream. Below is a list of the ingredients for the emulsion cream formulation,

[0264] Water - aquesous carrier

[0265] Prunus amygdaius dulcis (sweet almond) oil

[0266] DIM - active agent (0.1-10 wt%)

[0267] Additional therapeutic agent, e.g. antibiotic agent (0.1-10 wt%)

[0268] Dicapiylyl carbonate ester - emollient

[0269] Glycerin - carrier

[0270] Steaayl alcohol fatty alcohol

[0271] Poly gly eery 1-3 stearate - emulsifier

[0272] Potassium cetyl phosphate - emulsifier

[0273] Glyceryl stearate citrate - emulsifier

[0274] Xanthan gum - rheology modifier / gum

[0275] Levulinic acid - skin conditioner and preservative

[0276] Ammonium acryloyldimethyltauiate / VP copolymer rheology modifier - rheology modifier

[0277] Sodium anisate - preservative

[0278] Sodium levulinate - skin conditioner and preservative

[0279] Helianthus annuus (sunflower) seed oil

[0280] Sodium hydroxide - pH adjusting agent

[0281] Rosmarinus officinalis (rosemary) leaf extract

[0282] Tocopherol - moisturizer / antioxidant

[0283] To make the formulation, various ingredients were mixed together until a uniform emulsion cream is obtained,

[0284] While specific embodiments described herein have been shown and described in detail to illustrate the application of the principles of the disclosure, it will be understood that the disclosure may be embodied otherwise without departing from such principles. Numerous variations, changes, and substitutions will be understood by those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the specific embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the claims define the scope of the disclosure, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWhat is claimed is:1 . A composition for use in treating a skin disease or condition, the composition comprising: a first component comprising a substituted or unsubstituted diindolylmethane; and a second component comprising at least one supplemental therapeutic agent, wherein the composition is essentially free of substituted or unsubstituted retinoid compounds, wherein the composition is essentially free of CYP450 enzyme modulators, wherein the composition is essentially free of probiotic agents, and wherein the composition is essentially free of anti-protozoal agents.

2. The composition of claim 1, wherein the composition further comprises a further component selected from one or more of, a substituted or unsubstituted azelaic acid compound, an oral contraceptive compound, sulphur, a sulphur-containing compound, a substituted or unsubstituted salicylic acid compound, a substituted or unsubstituted resorcinol compound, a peroxide (optionally benzoyl peroxide), a plant product, a mineral, a vitamin, and a neutraceutical product.

3. The composition of claim 1 -2 , wherein the substituted or unsubstituted retinoid compounds comprise substituted or unsubstituted first-generation retinoids, substituted or unsubstituted second-generation retinoids, and substituted or unsubstituted third -generation retinoids.

4. The composition according to claim 3, wherein the substituted or unsubstituted first-generation retinoids comprise substituted or unsubstituted retinols, substituted or unsubstituted retinals, substituted or unsubstituted tretinoins, substituted or unsubstituted isoretinoins, and substituted or unsubstituted ali tretinoins.

5. The composition according to claim 3 , wherein the second-generation retinoids comprise substituted or unsubstituted etretinates and substituted or unsubstituted acitretins.

6. The composition according to claim 3, wherein the third-generation retinoids comprise substituted or unsubstituted tazarotenes, substituted or unsubstituted bexarotenes, and substituted or unsubstituted adapalenes.

7. The composition of claim 1-6, wherein the first component comprises a diindoly Imetliane of Formula 1 :Formula 1wherein the R groups are independently selected from hydrogen atoms and Ci-Ce hydrocarbon substituents; and wherein the indolyl groups are independently selected from indole-3 -yl and indole- 2-yl groups; and wherein the indolyl groups are unsubstituted, or are substituted with one or more Ci-Cf, hydrocarbon substituents.

8. The composition of claim 1-6, wherein the first component comprises a substituted or unsubstituted 3,3’diindolylmethane, of Formula 2, or a substituted or unsubstituted 2,2’diindolylmethane, of Formula 3:wherein the R groups are independently selected from hydrogen atoms, and Ci-Ce hydrocarbon substituents.

9. The composition of claim 1-6, wherein the first component comprises a 3,3 ’diindolylmethane, of Formula 4 or a 2,2’diindolylmethane, of Formula 5:

10. The composition of claim 1-6, wherein the first component comprises 3,3 ’diindolylmethane.

11. The composition of claim 1-10, wherein the first component is in a form suitable for providing a daily substituted or unsubstituted diindolylmethane dosage of up to 1500 mg or less.

12. The composition of claim 1-10, wherein the first component is in a form suitable for providing a daily substituted or unsubstituted diindolylmethane dosage of about 10 mg to about 750 mg.

13. The composition of claim 1-12, wherein the substituted or unsubstituted diindolylmetliane is adapted for increased bioavailability.

14. The composition of claim 13, wherein the substituted or unsubstituted diindolylmetliane is microencapsulated.

15. The composition of claim 14, wherein the first component comprises one or more lipophilic compounds selected from vitamin E mid phosphatidylcholine.

16. The composition of claim 13, wherein the substituted or unsubstituted diindolylmethane is BR-DIM.

17. The composition of claim 1-16, wherein the composition is formulated for oral administration.

18. The composition according to claim 17, wherein the composition is in the form of a tablet or capsule.

19. The composition of claim 1-16, wherein the composition is formulated for topical administration.

20. The composition of claim 19, wherein the composition is in the form of a gel, cream, ointment, or a liquid.

21. The composition of claim 1-20, wherein the first and second components are combined into one dosage form.

22. The composition of claim 1-20, wherein the first and second components are in separate dosage forms.

23. The composition of claim 1-22, wherein the first component is in a form suitable for providing a daily substituted or unsubstituted diindolylmetliane dosage of about 10 mg to about 750 mg.

24. The composition of claim 1-23, wherein the first component is in a form suitable for providing a daily substituted or unsubstituted diindolylmetliane dosage of about 150 mg to about 650 mg, about 250 mg to about 550 mg, about300 mg to about 500 mg, about 400 mg to about 450 mg, or about 500 mg.2.

5. The composition of claim 1-2.4, wherein the first component is present in a dose which is a fraction of the daily dose, preferably a half of the daily dose, or a quarter of the daily dose.

26. Use of the composition of claims 1-25, for treating a skin condition.

27. The use of claim 26, wherein the skin condition is an inflammatory skin condition.

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