US 2011 0195096A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0195096 A1 Kindler et al. (43) Pub. Date: Aug. 11, 2011

(54) COMPOSITIONS AND METHODS FOR Related U.S. Application Data TREATING INFLAMMATORY DISORDERS (60) Provisional application No. 61/085,008, filed on Jul. (75) Inventors: Seth Kindler, Tel Aviv (IL); 31, 2008, provisional application No. 61/098,802, Ascher Shmulewitz, Tel Aviv (IL) filed on Sep. 22, 2008. Publication Classification Assignee: DEKEL PHARMACEUTICALS (73) (51) Int. Cl. LTD., Bnei-Brak (IL) A 6LX 3/573 (2006.01) A6IR 9/00 (2006.01) (21) Appl. No.: 13/056,872 A6IP 29/00 (2006.01) (22) PCT Fled: Jul. 29, 2009 (52) U.S. Cl...... 424/400: 514/171 (57) ABSTRACT (86) PCT NO.: PCT/IL09/00739 Compositions which include a corticosteroid in combination S371 (c)(1), with an additional compound active in treatment of an inflam (2), (4) Date: Apr. 28, 2011 matory disorder are provided.

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COMPOSITIONS AND METHODS FOR 0007 Tri-cyclic antidepressants, described inter alia in TREATING INFLAMMATORY DSORDERS U.S. Pat. Nos. 2,554,736, 3,438,981, 3,420,851, 3,534,041, 3,505,321, 4,013,639, 4,105,785, 6,368.814, have been used FIELD AND BACKGROUND OF THE for years as anti-depression agents. Topical 5% doxepin INVENTION hydrochloride (ZonalonTM) cream is also used for treatment of moderate pruritus in adult patients with atopic dermatitis or 0001. The present invention relates to compositions suit lichen simplex chronicus. U.S. Pat. No. 7,335,371, assigned able for treatment of inflammatory disorders and to methods to CombinatoRX, discloses compositions formulated for topi utilizing same in treatment of inflammatory disorders such as cal administration, comprising as the sole active ingredients a cutaneous inflammatory diseases. tricyclic antidepressant and a corticosteroid, and their use in 0002 Inflammation occurs when tissues are injured by treating inflammatory disorders. This patent neither discloses viruses, bacteria, trauma, chemicals, heat, cold or any other nor Suggests in any way the ability of compositions of the harmful stimulus. Chemicals including bradykinin, hista present invention to utilize a low-potency steroid in therapeu mine, serotonin and others are released, attracting tissue mac tic situations wherein a mid-potency or high-potency steroid rophages and white blood cells to localize in an area to engulf would otherwise be required; or to utilize a mid-potency and destroy foreign Substances. During this process, chemical steroid wherein a high-potency steroid would otherwise be mediators such as TNFC. are released, giving rise to inflam required. mation. Inflammatory disorders are those in which the inflammation is Sustained or chronic. One example of an 0008 Sulfonamide-class carbonic anhydrase inhibitors inflammatory disorder is osteoarthritis. Such as Sulfamate-substituted monosaccharides, of which 0003 Local inflammatory diseases include, for example, topiramate is an example, have been long used as anti-con asthma, oral mucosal, gastrointestinal inflammation, ocular, Vulsive compounds. Topical formulations containing Such nasal and aural inflammation and other steroid responsive compounds are proposed for use in treatment of glaucoma inflammatory disorders and conditions. Cutaneous inflam and in the assessment of corneal function, as described in U.S. matory diseases include for example, psoriasis, atopic der Pat. Nos. 5,059,613 and 5,242,937, and for eczema, as matitis, Scleroderma and other steroid responsive cutaneous described in WO2007/067036. None of the above references inflammatory disorders conditions such as uremic pruritus discloses or Suggests use of Such compounds in combination and skin conditions associated with exposure to radiation and with corticosteroids and their use in treating cutaneous chemotherapy as well as exposure to environmental radiation inflammatory diseases and disorders. and irritants. 0009 Monoamine oxidase inhibitors (MAOI) and used as 0004 Topical steroids have been used in the treatment of anti-depressive treatments and are described interalia in U.S. inflammatory disorders, as described in U.S. Pat. No. 3,934, Pat. Nos. 5,508,311, 5,792,799, 6,472,423, and 6,569,470. 013 to Poulsen and references cited therein. Typically, mod None of the above references discloses or Suggests use of erate to severe cases of psoriasis require use of a mid-potency Such compounds in combination with corticosteroids and steroid such as mometasone furoate (EloconTM) or even a their use in treating cutaneous inflammatory diseases or dis high-potency steroid such as halobetasol (UltravateTM). Topi orders. cal application of glucocorticoids may suppress the body's 0010 Cannabinoids are described inter alia in U.S. Pat. own production of cortisol by the adrenal glands, however, Nos. 5,747,524, 5,596,106, 6,017,919, 6,432,984, 6,509,367, especially in the case of relatively high potent products. 6,645,985, and 7,169,942. Use of such compounds for treat Accordingly, compositions for treating inflammatory disor ing psoriasis has been suggested (Namazi MR. J. Eur Acad ders without utilizing mid-potency or high-potency steroids Dermatol Venereol. 2005 May: 19(3):319-22). None of the or with use of substantially reduced steroid concentrations above references discloses or suggests use of Such com would be very useful. pounds in combination with corticosteroids and the use 0005 Palmitoylethanolamine (PEA), a member of the thereof in treating cutaneous inflammatory diseases or disor class of compounds known as N-acylethanolamines (NAEs), ders. was discovered in 1957 by Kuehl et al (The Identification of 0011 While reducing the present invention to practice, the N-(2-hydrooxytheyl)-palmitamide as a naturally occurring present inventors have uncovered that combined use of cor anti-inflammatory agent, JAm ChemSoc. 1957, 79:5577). ticosteroids and PEA, as well as other compounds produces 0006 PEA, or N-(2-hydroxyethyl)hexadecanamide (also unexpected results in treatment of inflammatory disorders known as palmitoylethanolamide or palmidrol), is a naturally and that PEA has the potential to augment the therapeutic occurring C16:0 fatty acid derivative wherein the carboxylate properties of steroids—including increasing therapeutic function is amidated by the primary amine of ethanolamine. activity as well as reducing steroid associated adverse effects. N-acylethanolamine compounds are known to have anti-in flammatory and anti-nociceptive effects, as described in Lambert et al (Lambert D. M. Vandevoorde S. Jonsson KO. SUMMARY OF THE INVENTION Fowler C.J. Curr Med Chem. 2002: 9:663-74); Lambert DM etal (Lambert DM, DiPaolo FG, Sonveaux P, Kanyonyo M, 0012. According to one aspect of the present invention Govaerts SJ, Hermans E, Bueb J, Delzenne NM, Tschirhart there is provided a composition-of-matter comprising an E.J. Biochim Biophys Acta. 1999: 1440:266-74); Brown AJ N-acylethanolamine compound and a corticosteroid. (Br J Pharmacol. 2007: 152(5):567-75); and U.S. Pat. No. 0013. According to further features in preferred embodi 5,506,224 and United States patent application 2005/ ments of the invention described below, the N-acylethanola 0054730. None of the above references discloses or suggests mine compound is N-palmitoylethanolamine. use of Such compounds in combination with corticosteroids 0014. According to still further features in the described and the use thereof in treating inflammatory diseases or dis preferred embodiments the corticosteroid is a low potency orders. corticosteroid. US 2011/O 195096 A1 Aug. 11, 2011

0015. According to still further features in the described 0034. According to yet another aspect of the present preferred embodiments the composition-of-matter of claim 1 invention there is provided a composition-of-matter compris and a pharmaceutically acceptable carrier. ing a GABA agonist and a corticosteroid. 0016. According to still further features in the described 0035. According to still further features in the described preferred embodiments the pharmaceutically acceptable car preferred embodiments the GABA agonist is selected from rier is suitable for topical administration. the group consisting of topiramate, muscimol, progabide, 0017. According to still further features in the described riluzole, baclofen, gabapentin, vigabatrin, valproic acid, preferred embodiments the pharmaceutically acceptable car tiagabine, lamotrigine, pregabalin, phenyloin, and carbam rier is Suitable for mucosal administration. aZepine. 0018. According to still further features in the described preferred embodiments the pharmaceutically acceptable car 0036. According to yet another aspect of the present rier is suitable for oral administration. invention there is provided a composition-of-matter compris 0019. According to still further features in the described ing a monoamine oxidase inhibitor (MAOI), and a corticos preferred embodiments the N-acylethanolamine compound teroid. is N-palmitoylethanolamine. 0037 According to still further features in the described 0020. According to still further features in the described preferred embodiments the monoamine oxidase inhibitor is preferred embodiments the corticosteroid is hydrocortisone. selected from the group consisting of moclobemide, clor 0021. According to another aspect of the present invention giline, iproclozide, iproniazid, isocarboxazid, minaprine, there is provided a medical device comprising the composi nialamide, pargyline, phenelZine, rasagiline, selegiline, tion-of-matter described herein. toloxatone, tranylcypromine, furazolidone, and procarba 0022. According to still further features in the described Z10. preferred embodiments the composition-of-matter forms a 0038 According to still another aspect of the present coating of the medical device. invention there is provided a composition-of-matter compris 0023. According to still another aspect of the present ing a cannabinoid receptor agonist and a corticosteroid. invention there is provided a method for treating an inflam 0039. According to still further features in the described matory disorder comprising administering to a Subject in preferred embodiments the cannabinoid receptor agonist is need thereof a composition comprising an N-acylethanola selected from the group consisting of cannabidiol (CBD), mine compound and a corticosteroid, thereby treating the cannabidivarol (CBDV), cannabinol (CBN), cannabigerol inflammatory disorder. (CBG), cannabivarol (CBV), cannabicyclol (CBL), tetrahy 0024. According to still further features in the described drocannabinol (THC), tetrahydrocannabinol-C4. (THC-C4), preferred embodiments the N-acylethanolamine compound tetrahydrocannabivarin, 11-Hydroxy-A-tetrahydrocannab is N-palmitoylethanolamine. inol, (11-OH-THC), and 11-nor-9-Carboxy-A9-tetrahydro 0025. According to still further features in the described cannabinol. preferred embodiments the corticosteroid is a low-potency 0040. According to still another aspect of the present corticosteroid. invention there is provided a composition-of-matter compris 0026. According to still further features in the described ing an inhibitor of an immunophilin and a low-potency cor preferred embodiments the corticosteroid is hydrocortisone. ticosteroid. 0027. According to still further features in the described preferred embodiments the inflammatory disorder is caused 0041 According to still further features in the described by a cutaneous inflammatory disease or disorder and the preferred embodiments the inhibitor of an immunophilin is administering is effected via topical delivery. selected from the group consisting of FK 1706, GPI 1046, 0028. According to still further features in the described GPI 1485, GM-284, (3R)-4-(p-Toluenesulfonyl)-1,4-thiaz preferred embodiments the cutaneous inflammatory disease ane-3-carboxylic acid-L-Leucine ethyl ester and (3R)-4-(p- is selected from the group consisting of psoriasis, atopic Toluenesulfonyl)-1,4-(thiazane-3-carboxylic acid-L-pheny dermatitis and Scleroderma. lalanine benzyl ester. 0029. According to still further features in the described 0042. According to yet another aspect of the present preferred embodiments the inflammatory disorder is caused invention there is provided a pharmaceutical composition by asthma and the administering is effected via inhalation. comprising any of the composition-of-matters described 0030. According to still further features in the described hereinabove and a pharmaceutically acceptable carrier preferred embodiments the inflammatory disorder is caused selected for topical delivery. by gastrointestinal inflammation. 0043. The present invention successfully addresses the 0031. According to still further features in the described shortcomings of the presently known configurations by pro preferred embodiments the inflammatory disorder is caused viding a composition for treating inflammatory disorder by ocular inflammation. which employs Substantially reduced doses of a corticoster 0032. According to still another aspect of the present oid. invention there is provided a composition-of-matter compris 0044) Unless otherwise defined, all technical and scien ing a corticosteroid and a tricyclic antidepressant. tific terms used herein have the same meaning as commonly 0033 According to still further features in the described understood by one of ordinary skill in the art to which this preferred embodiments the tricyclic antidepressant is invention belongs. Although methods and materials similar or selected from the group consisting of amitriptyline, mapro equivalent to those described herein can be used in the prac tiline, clomipramine, desipramine, imipramine, trimi tice or testing of the present invention, Suitable methods and pramine, nortriptyline, and protriptyline materials are described below. In case of conflict, the patent US 2011/O 195096 A1 Aug. 11, 2011 specification, including definitions, will control. In addition, of inflammatory disorders. As a result of this synergism, the the materials, methods, and examples are illustrative only and present compositions can be used to treat inflammatory dis not intended to be limiting. orders with substantially lower concentrations of corticoster oids or with low potency corticosteroids, thereby augmenting BRIEF DESCRIPTION OF THE DRAWINGS the therapeutic properties of steroids by increasing its thera 0045. The invention is herein described, by way of peutic activity and/or reducing steroid associated adverse example only, with reference to the accompanying drawings. effects. As a result the present compositions provide a Sub With specific reference now to the drawings in detail, it is stantial corticosteroid sparing effect. stressed that the particulars shown are by way of example and 0056. Thus according to one aspect of the present inven for purposes of illustrative discussion of the preferred tion there is provided a composition which includes a corti embodiments of the present invention only, and are presented costeroid and an additional compound selected for comple in the cause of providing what is believed to be the most menting the anti-inflammatory effect of the corticosteroid. useful and readily understood description of the principles 0057 According to a presently preferred embodiment of and conceptual aspects of the invention. In this regard, no the present invention, the composition of the present inven attempt is made to show structural details of the invention in tion includes a corticosteroid and an N-acylethanolamine more detail than is necessary for a fundamental understand compound Such as palmitoylethanolamide (PEA). ing of the invention, the description taken with the drawings 0.058 N-acylethanolamine compounds are well known in making apparent to those skilled in the art how the several the art, and are described, interalia, in Lambert etal (Lambert forms of the invention may be embodied in practice. DM, Vandevoorde S, Jonsson KO, Fowler C. J. Curr Med 0046. In the drawings: Chem. 2002: 9:663-74) and in U.S. Pat. No. 5,506,224 and 0047 FIG. 1 is a graph representing mean group earswell United States patent application 2005/0054730, which are ing (in mm). Earthickness was measured prior to (baseline), incorporated by reference herein. and 3 hours following, croton oil induced ear sensitization. 0048 FIG.2a is a graph representing left Earthickness (in 0059 Preferably, the N-acylethanolamine compound of mm) 6 hours post sensitization. Thickness of sensitized ears methods and compositions of the present invention is palmi was measured 24 hours prior to (baseline), and 6 hours fol toylethanolamine (PEA) lowing, croton oil induced ear sensitization 0060. The N-acylethanolamine compound can also be 0049 FIG.2b is a graph representing mean left Earthick OEA, Me-PEA or PIA (Jonsson et al. Vandevoorde S. Lam ness (in mm) 6 hours post sensitization. Thickness of sensi bert DM, Tiger G, Fowler C.J. Br J Pharmacol. 2001; 133: tized ears was measured 24 hours prior to (baseline), and 6 1263-75): hours following, croton oil induced ear sensitization 0050 FIG. 3 is a graph representing left ear thickness (in mm) 6 hours and 9 hours post sensitization. DESCRIPTION OF THE PREFERRED EMBODIMENTS 0051. The present invention is of compositions which can be used to treat inflammatory disorders. Palmitoylethanolamide (PEA) 0052. The principles and operation of the present inven O tion may be better understood with reference to the drawings and accompanying descriptions. o 1N1OH 0053 Before explaining at least one embodiment of the H invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The Oleoylethanolamide (OEA) invention is capable of other embodiments or of being prac ticed or carried out in various ways. Also, it is to be under stood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. cr 0054) Inflammatory disorders are typically treated with Palmitoylisopropylamide (PIA) corticosteroids which can lead to serious side effects which mimic Cushing's disease, a malfunction of the adrenal glands resulting in an overproduction ofcortisol. Other potential side effects associated with use of corticosteroids include increased appetite and weight gain, deposits of fat in chest, face, upper back, and stomach and water and salt retention cirr leading to Swelling and edema. Thus, there is a great need to decrease the use of corticosteroids in treatment of inflamma R-palmitoyl-(2-methyl)ethanolamide tory disorders. (Me-PEA) 0055. The present inventors have devised compositions which include a corticosteroid and a second compound which 0061 The N-acylethanolamine compound can have a side synergistically complements the corticosteroid in treatment chain length of 16 carbon units. Alternatively, the N-acyle US 2011/O 195096 A1 Aug. 11, 2011

thanolamine compound can be decanoylethanolamide (C10: cream under the name Eumovate(R). Flucinonide (available O) lauroylethanolamide (C12:0), or myristoylethanolamide as 0.05% and 0.01% cream under the names 15 Lidex(R) and (C14:0). Lidemol(R), fluocinolone acetonide (available as 0.025% and 0062. The N-acylethanolamine compound can be an N-15 0.01% cream under the names Synalar R, Synamol(R), and acylethanolamine derivative. The ethanolamide group of the Derma-SmoothR), and triamcinolone acetonide (available as N-acylethanolamine compound can be replaced with a moi 0.025% and 0.1% cream under the names Aristocort DR, ety such as, butylamide, isopro-pylamide, cyclohexamide Aristocort R(R), Kenalog(R), and Vicoderm-KC(R). and (2-methyl)ethanolamide. Each possibility represents a 0071 Non-limiting examples of high-25 potency topical separate embodiment of the present invention. corticosteroids include betamethasone-17-benzoate (avail 0063. The N-acylethanolamine compound can be a palmi able as a 0.025% cream under the name Beben(R), betametha toylethanolamine derivative. The ethanolamide group of sone dipropionate (available as a 0.025% cream under the palmitoylethanolamine can be replaced with a moiety such as name Propaderm R) and as a 0.05% cream under the names butylamide, isopropylamide, cyclohexamide and (2-methyl) Diprosone(R) and Diprolene GlycolR), halcinonide (available ethanolamide. The N-acylethanolamine compound can be, as a 0.1% cream under the name Halog(R), and triamcinolone for example, palmitoylcyclohexamide, palmitoylbutylamide, acetonide (available as a 0.5% cream under the name 30 palmitoylisopropylamide, palmitoylethanolamide, or Aristocort C(R). Me-palmitoylethanolamide. Each possibility represents a 5 0072 A non-limiting example of a very-high-potency separate embodiment of the present invention. topical corticosteroid is clobetasol-17-propionate (available 0064. The N-acylethanolamine compound of the compo as a 5 0.05% cream under the name Dermovate(R). The cor sition of the present invention can be, for example, oleoyle ticosteroid of the compositions of the present invention can thanolamide (OEA) or a derivative thereof. The ethanolamide exhibit glucocorticoid activity and/or mineralocorticoid group of OEA can be replaced with a moiety Such as, buty activity. The corticosteroid can be, for example, mometaSone lamide, isopro-pylamide, cyclohexamide or (2-methyl)etha and a salt thereof, hydrocortisone, hydrocortisone acetate, nolamide. hydrocortisone butyrate, hydrocortisone sodium phosphate, 0065 OEA, its derivatives, and methods for synthesizing hydrocortisone sodium Succinate, hydrocortisone cypionate, same are well known in the art, and are described, interalia, hydrocortisone probutate, and hydrocortisone Valerate. in U.S. Pat. Nos. 6,656,972 and 7,348,338 and United States 0073. The corticosteroid can also be, for example, dexam patent application 2002/0173550, which are incorporated ethasone, betamethasone, triamcinolone, triamcinolone herein by reference. acetonide, triamcinolone diacetate, triamcinolone hexac 0066 Methods for synthesizing N-acylethanolamine etonide, beclomethasone, dipropionate, beclomethasone compounds are well known in the art. As described in Lam dipropionate monohydrate, flumethasone pivalate, diflo bert et al., PEA was initially synthesized by refluxing ethano rasone diacetate, fluocinolone acetonide, fluorometholone, lamine with palmitic acid (Roe et al. JAm Chem Soc 1952, fluorometholone acetate, clobetasol propionate, des 74:3442), yielding white crystals melting at 98-99 C. Due to Oximethasone, fluoxymesterone, fluprednisolone, cortisone the simplicity of structure, various syntheses of PEA have acetate, paramethasone 25 acetate, methylprednisolone, been described: the acyl chloride is the most common, but methylprednisolone acetate, methylprednisolone sodium activating agents such as dicyclohexylcarbodiimide and car Succinate, prednisolone, prednisolone acetate, prednisolone bonyldiimidazole allow the condensation between the acid Sodium phosphate, prednisolone tebutate, clocortolone piv and the ethanolamine in very good yields (>80%). alate, flucinolone, dexamethasone 21-acetate, betamethasone 0067. As is described in the Examples section which fol 17-valerate, isoflupredone, 9-fluorocortisone, 6-hydroxydex lows, the present inventors have shown, for the first time, that amethasone, dichlorisone, meclorisone, flupredidene, doxi N-acylethanolamine compounds exhibit a steroid-sparing betasol, halopredone, halometasone, 30 clobetasone, diflu effect. Such effects enable use of a low-potency steroid in cortolone, isoflupredone acetate, instances wherein a mid-potency or high-potency steroid is fluorohydroxyandrostenedione, beclomethasone, flumetha typically required or use of lower doses of a high potency Sone, diflorasone, fluocinolone, clobetasol, cortisone, steroid, in addition to mitigating steroid associated cutaneous paramethasone, clocortolone, prednisolone 21-hemisucci adverse effects. Each possibility represents a separate nate free acid, prednisolone metasulphobenzoate, predniso embodiment of the present invention. Corticosteroid and lone terbutate, and triamcinolone acetonide 21-palmitate. N-acylethanolamine compounds useful in the invention 0074 The corticosteroid can be any naturally occurring or include those described herein in any of their pharmaceuti synthetic steroid hormone that can be chemically derived cally acceptable forms, including isomers such as diastere from cholesterol and is characterized by a hydrogenated omers and enantiomers, salts, Solvates, and polymorphs cyclopentanoperhydrophenanthrene ring system. Naturally thereof, as well as racemic mixtures of the compounds occurring corticosteriods are typically generally produced by described herein. the adrenal cortex. Synthetic corticosteriods may be haloge 0068 Corticosteroids that form a part of the present com nated. Functional groups required for activity include a position include low to very high potency corticosteroids. double bond at a C3 ketone, and a C20 ketone. 0069. Non-limiting examples of low-potency topical cor 0075. The compositions of the present invention can be ticosteroids include hydrocortisone (available as 0.5% and formulated into a pharmaceutical composition. 1% cream under the names Cortate(R), Unicort(R), and Cor 0076. As used herein, a “pharmaceutical composition' tisporinR). refers to a preparation of the active ingredients described 0070. Nonlimiting examples of mid-potency topical cor herein with other chemical components such as physiologi ticosteroids include betamethasone Valerate, (available as cally Suitable carriers and excipients. The purpose of a phar 0.05% and 0.1% cream under the names Betnovate(R) and maceutical composition is to facilitate administration of a CelestodermR), clobetasone-17-butyrate (available as 0.05% compound to an organism. US 2011/O 195096 A1 Aug. 11, 2011

0077. Hereinafter, the phrases “physiologically accept starch, wheat starch, rice starch, potato starch, gelatin, gum able carrier and “pharmaceutically acceptable carrier.” tragacanth, methyl cellulose, hydroxypropylmethyl-cellu which may be used interchangeably, refer to a carrier or a lose, and Sodium carbomethylcellulose; and/or physiologi diluent that does not cause significant irritation to an organ cally acceptable polymers such as polyvinylpyrrolidone ism and does not abrogate the biological activity and proper (PVP). If desired, disintegrating agents. Such as cross-linked ties of the administered composition. An adjuvant is included polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, under these phrases. Such as sodium alginate, may be added. 0078 Herein, the term “excipient” refers to an inert sub stance added to a pharmaceutical composition to further I0087 Dragee cores are provided with suitable coatings. facilitate administration of an active ingredient. Examples, For this purpose, concentrated Sugar Solutions may be used without limitation, of excipients include calcium carbonate, which may optionally contain gum arabic, talc, polyvinyl calcium phosphate, various Sugars and types of starch, cellu pyrrolidone, carbopol gel, polyethylene glycol, titanium lose derivatives, gelatin, vegetable oils, and polyethylene gly dioxide, lacquer Solutions, and Suitable organic solvents or cols. solvent mixtures. Dyestuffs or pigments may be added to the 007.9 Techniques for formulation and administration of tablets or dragee coatings for identification or to characterize drugs may be found in the latest edition of “Remington's different combinations of active compound doses. Pharmaceutical Sciences.” Mack Publishing Co., Easton, Pa., I0088 Pharmaceutical compositions that can be used which is herein fully incorporated by reference. orally include push-fit capsules made of gelatin, as well as 0080 Suitable routes of administration may, for example, soft, sealed capsules made of gelatin and a plasticizer, Such as include topical, oral, rectal, transmucosal, especially transna glycerol or Sorbitol. The push-fit capsules may contain the sal, intestinal, or parenteral delivery, including intramuscular, active ingredients in admixture with filler Such as lactose, Subcutaneous, and intramedullary injections, as well as binders such as starches, lubricants such as talc or magnesium intrathecal, direct intraventricular, intravenous, intraperito Stearate, and, optionally, stabilizers. In soft capsules, the neal, intranasal, or intraocular injections. active ingredients may be dissolved or Suspended in Suitable 0081 Alternately, one may administer the pharmaceutical liquids, such as fatty oils, liquid paraffin, or liquid polyethyl composition in a local rather than systemic manner, for example, via injection of the pharmaceutical composition ene glycols. In addition, stabilizers may be added. All formu directly into a tissue region of a patient. lations for oral administration should be in dosages Suitable 0082 Pharmaceutical compositions of the present inven for the chosen route of administration. tion may be manufactured by processes well known in the art, I0089 For buccal administration, the compositions may e.g., by means of conventional mixing, dissolving, granulat take the form of tablets or lozenges formulated in conven ing, dragee-making, levigating, emulsifying, encapsulating, tional manner or in adhesive carriers. entrapping, or lyophilizing processes. 0090. For administration by inhalation, the active ingredi 0083) Pharmaceutical compositions for use in accordance ents for use according to the present invention are conve with the present invention thus may beformulated in conven niently delivered in the form of an aerosol spray presentation tional manner using one or more physiologically acceptable from a pressurized pack or a nebulizer with the use of a carriers comprising excipients and auxiliaries, which facili Suitable propellant, e.g., dichlorodifluoromethane, trichlorof tate processing of the active ingredients into preparations that luoromethane, dichloro-tetrafluoroethane, or carbon dioxide. can be used pharmaceutically. Proper formulation is depen In the case of a pressurized aerosol, the dosage may be deter dent upon the route of administration chosen. mined by providing a valve to deliver a metered amount. 0084. For topical, the active ingredients of the pharmaceu Capsules and cartridges of for example, gelatin for use in a tical composition may be formulated in cremes, ointments, dispenser may be formulated containing a powder mix of the Solutions, patches, sprays, lotions, liniments, varnishes, Solid compound and a suitable powder base. Such as lactose or preparations such as silicone sheets, and the like. starch. 0085 For injection, the active ingredients of the pharma 0091. The pharmaceutical composition described herein ceutical composition may be formulated in aqueous solu may be formulated for parenteral administration, e.g., by tions, preferably in physiologically compatible buffers such bolus injection or continuous infusion. Formulations for as Hank's Solution, Ringer's solution, or physiological salt injection may be presented in unit dosage form, e.g., in buffer. For transmucosal administration, penetrants appropri ampoules or in multidose containers with, optionally, an ate to the barrier to be permeated are used in the formulation. added preservative. The compositions may be suspensions, Such penetrants are generally known in the art. Solutions, or emulsions in oily or aqueous vehicles, and may I0086 For oral administration, the pharmaceutical compo contain formulatory agents such as Suspending, stabilizing, sition can be formulated readily by combining the active and/or dispersing agents. compounds with pharmaceutically acceptable carriers well 0092 Pharmaceutical compositions for parenteral admin known in the art. Such carriers enable the pharmaceutical istration include aqueous solutions of the active preparation composition to be formulated as tablets, pills, dragees, cap in water-soluble form. Additionally, suspensions of the active Sules, liquids, gels, syrups, slurries, Suspensions, and the like, ingredients may be prepared as appropriate oily or water for oral ingestion by a patient. Pharmacological preparations based injection Suspensions. Suitable lipophilic solvents or for oral use can be made using a solid excipient, optionally vehicles include fatty oils such as Sesame oil, or synthetic grinding the resulting mixture, and processing the mixture of fatty acid esters such as ethyl oleate, triglycerides, or lipo granules, after adding Suitable auxiliaries as desired, to obtain Somes. Aqueous injection Suspensions may contain Sub tablets or dragee cores. Suitable excipients are, in particular, stances that increase the Viscosity of the Suspension, such as fillers such as Sugars, including lactose, Sucrose, mannitol, or sodium carboxymethyl cellulose, sorbitol, or dextran. Sorbitol; cellulose preparations such as, for example, maize Optionally, the Suspension may also contain Suitable stabiliz US 2011/O 195096 A1 Aug. 11, 2011 ers or agents that increase the solubility of the active ingre 0100. The compositions of the present invention can also dients, to allow for the preparation of highly concentrated be delivered from medical devices, such as orthopedic Solutions. implants, contact lenses, micro needle arrays, patches and the like. 0093. Alternatively, the active ingredient may be in pow 0101 Sustained-release (SR), extended-release (ER, XR, der form for constitution with a suitable vehicle, e.g., a sterile, or XL), time-release or timed-release, controlled-release pyrogen-free, water-based solution, before use. (CR), or continuous-release (CR or Contin) pills are tablets or 0094. The pharmaceutical composition of the present capsules formulated to dissolve slowly and release a drug invention may also be formulated in rectal compositions such overtime. Sustained-release tablets are formulated so that the as Suppositories or retention enemas, using, for example, active ingredient is embedded in a matrix of insoluble sub conventional Suppository bases such as cocoa butter or other stance (e.g. acrylics, polysaccharides etc) Such that the dis glycerides. Solving drug diffuses out through the holes in the matrix. In some SR formulations the matrix physically swells up to form 0095. The present compositions can also be delivered a gel, so that the drug has first to dissolve in matrix, then exit using an in-situ formed depot (ISFD). Examples of in-situ through the outer surface. Difference between controlled formed depots include semi-solid polymers which can be release and Sustained release is that controlled release is per injected as a melt and form a depot upon cooling to body fectly Zero order release that is, the drug releases with time temperature. The requirements for such ISFD include low irrespective of concentration. On the other hand, Sustained melting or glass transition temperatures in the range of release implies slow release of the drug over a time period. It 25-658 C and an intrinsic viscosity in the range of 0.05-0.8 may or may not be controlled release. dI/g 12-14. Below the viscosity threshold of 0.05 dl/g no 0102 Pharmaceutical compositions suitable for use in the delayed diffusion could be observed, whereas above 0.8dl/g context of the present invention include compositions the ISFD was no longer injectable using a needle. At injection wherein the active ingredients are contained in an amount temperatures above 378 C but below 658 C these polymers effective to achieve the intended purpose. More specifically, a behave like viscous fluids which solidify to highly viscous “therapeutically effective amount’ means an amount of active depots. Drugs are incorporated into the molten polymer by ingredients (e.g., a nucleic acid construct) effective to pre mixing without the application of Solvents. Thermoplastic vent, alleviate, or ameliorate symptoms of a disorder (e.g., pastes (TP) can be used to generate a Subcutaneous drug ischemia) or prolong the Survival of the Subject being treated. reservoir from which diffusion occurs into the systemic cir 0103) Determination of a therapeutically effective amount culation. is well within the capability of those skilled in the art, espe cially in light of the detailed disclosure provided herein. 0096. In situ cross-linked polymer systems utilize a cross 0104 For any preparation used in the methods of the linked polymer network to control the diffusion of macromol invention, the dosage or the therapeutically effective amount ecules over a prolonged period of time. Use of in situ cross can be estimated initially from in vitro and cell culture assays. linking implants necessitate protection of the bioactive agents For example, a dose can be formulated in animal models to during the cross-linking reaction. This could be achieved by achieve a desired concentration or titer. Such information can encapsulation into fast degrading gelatin microparticles. be used to more accurately determine useful doses inhumans. 0097. An ISFD can also be based on polymer precipita 0105. The dosage of each compound of the claimed com tion. A water-insoluble and biodegradable polymer is dis binations depends on several factors, including: the adminis Solved in a biocompatible organic solvent to which a drug is tration method, the disease to be treated, the severity of the added forming a solution or Suspension after mixing. When disease, whether the disease is to be treated or prevented, and this formulation is injected into the body the water miscible the age, weight, and health of the person to be treated. Addi organic solvent dissipates and water penetrates into the tionally, pharmacogenomic (the effect of genotype on the organic phase. This leads to phase separation and precipita pharmacokinetic, pharmacodynamic or efficacy profile of a tion of the polymer forming a depot at the site of injection. therapeutic) information about a particular patient may affect One example of such a system is AtrigeleTM (ARTIX Labo dosage used. ratories). 0106 Continuous daily dosing may not be required; a 0098. Thermally inducedgelling systems can also be used therapeutic regimen may require cycles, during which time a as ISFDs. Numerous polymers show abrupt changes in solu drug is not administered, ortherapy may be provided on an as bility as a function of environmental temperature. The proto needed basis during periods of acute inflammation. type of a thermosensitive polymer is poly(N-isopropyl acryl 0107 Dosages for PEA and various steroids for topical amide), poly-NIPAAM, which exhibits a rather sharp lower application are exemplified below. critical solution temperature. Topical Steroid Group I 0099. Thermoplastic pastes such as the new generation of poly(ortho esters) developed by AP Pharma can also be used (0.108 PEA (0.3-5%)+Clobetasol diproprionate (0.01-0. for depot drug delivery. Such pastes include polymers that are 05%) semi-solidat room temperature, hence heating for drug incor PEA (0.3-5%)--Betamethasone diproprionate 0.05-0.25% poration and injection is no longer necessary. Injection is PEA (0.3-5%)--Halbetasol proprionate 0.01-0.05% possible through needles no larger than 22 gauge. The drug PEA (0.3-5%)--Diflorasone diacetate 0.01-0.05% can be mixed into the systems in a dry and, therefore, stabi Topical Steroid Group II lized state. Shrinkage or Swelling upon injection is thought to PEA (0.3-5%)--Fluocinonide (0.01 0.05%) be marginal and, therefore, the initial drug burst is expected to be lower than in the other types of ISFD. An additional advan PEA (0.3-5%)--Halcinonide (0.01-0.05%) tage is afforded by the self-catalyzed degradation by surface PEA (0.3-5%)--Amcinonide (0.01 0.05%) erosion. PEA (0.3-5%)--Desoximetasone (0.05-0.25%) US 2011/O 195096 A1 Aug. 11, 2011

Topical Steroid Group III I0120 Ciclesonide (CIC): 80-320 mcg twice daily. I0121 Fluticasone propionate (FP) 100-500 mcg twice 0109 PEA (0.3-5%)--Triamcinalone acetonide daily. (0.01-0.5%) I0122) Mometasone furoate (MF) 220-440 mcg once daily. PEA (0.3-5%)--Mometasone furoate (0.02-0.1%) I0123. A nasal spray formulation of the present composi PEA (0.3-5%)--Fluticasone proprionate (0.001-0.005%) tion can include, for example, a dose of PEA of about 1 PEA (0.3-5%)--Betamethasone diproprionate (0.01-0.05%) microgram to about 500 milligrams per kilogram of the Sub ject, about 100 micrograms to about 200 milligrams per kilo Topical Steroid Group IV gram of the subject, about 100 micrograms to about 5 milli grams per kilogram of the Subject, or about 200 micrograms 0110 PEA (0.3-5%)--Fluocinolone acetonide to about 2 milligrams per kilogram of the Subject. (0.05-0.2%) 0.124. As a nasal formulation, PEA can be delivered in PEA (0.3-5%)--Hydrocortisone valerate (0.05-0.2%) combination with the following steroids: PEA (0.3-5%)--Hydrocortisone butyrate (0.02-0.1%) 0.125 Beclomethasone dipropionate, monohydrate, Nasal spay, (84-336 mcg/day). PEA (0.3-5%)--Flurandrenolide (0.01-0.05%) 0.126 fluticasone propionate Nasal Spray, (50-200 mcg/ day). 0111 PEA (0.3-5%)--Triamcinalone acetonide I0127 Triamcinolone Acetonide (110-220 mcg per day (0.02-0.1%) I0128. The present composition can also be formulated for PEA (0.3-5%)--Mometasone furoate (0.02-0.1%) ophthalmic delivery (e.g. as drops) for treatment of oph thalmic diseases. Topical Steroid Group V I0129. An ophthalmic formulation of the present composi O112 PEA (0.3-5%)--Triamcinalone acetonide tion can include: (0.02-0.1%) I0130 PEA (0.3-5%)+loteprednol etabonate ophthalmic PEA (0.3-5%)--Fluticasone propionate (0.01-0.05%) Suspension, 0.2%); I0131 PEA (0.3-5%)--Betamethasone sodium phosphate PEA (0.3-5%)--Desonide (0.01-0.05%) (0.05-0.1%); or I0132 PEA (0.3-5%)--Dexamethasone sodium phosphate 0113 PEA (0.3-5%)--Fluocinolone acetonide (0.005-0. O.05-0.1% 025%) 0.133 Aural preparations of the present invention can PEA (0.3-5%)--Hydrocortisone valerate (0.04-0.2%) include: 0.134 PEA (0.3-5%)--Betamethasone sodium phosphate Topical Steroid Group VI (0.05-0.1%); or 0.135 PEA (0.3-5%)--Dexamethasone sodium phosphate PEA (0.3-5%)--Prednicarbate (0.01-0.05%) O.05-0.1% 0114 PEA (0.3-5%)--Triamcinalone acetonide (0.005-0. 0.136. One skilled in the art will be able to ascertain suit 025%) able dosages for other steroid compounds for any of the above PEA (0.3-5%)--Fluocinolone acetonide (0.002-0.01%) described formulations. 0.137 Toxicity and therapeutic efficacy of the active ingre PEA (0.3-5%)--Desonide (0.01-0.05%) dients described herein can be determined by standard phar maceutical procedures in vitro, in cell cultures or experimen Topical Steroid Group VII tal animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating PEA (0.3-5%)--Hydrocortisone (0.5-2.5%) a range of dosage for use in human. The dosage may vary PEA (0.3-5%)--Hydrocortisone (0.2-1%) depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of 0115. An Inhalation formulation of a corticosteroid (ICS) administration, and dosage can be chosen by the individual and PEA for treatment of, for example, Asthma, COPD and physician in view of the patient's condition. (See, e.g., Fingl, other Steroid responsive respiratory diseases and conditions E. et al. (1975), “The Pharmacological Basis of Therapeu can include a dose of PEA of about 1 microgram to about 500 tics.' Ch. 1, p. 1.) milligrams per kilogram of the Subject, about 100 micro 0.138. Dosage amount and administration intervals may be grams to about 200 milligrams per kilogram of the Subject, adjusted individually to provide sufficient plasma or brain about 100 micrograms to about 5 milligrams per kilogram of levels of the active ingredient to suppress inflammation (i.e., the Subject, or about 200 micrograms to about 2 milligrams minimally effective concentration, MEC). The MEC will per kilogram of the Subject. vary for each preparation, but can be estimated from in vitro 0116. The composition can be delivered by dispenser, data. Dosages necessary to achieve the MEC will depend on wherein the dispenser delivers a dose for inhalation of PEA of individual characteristics and route of administration. Detec 1 microgram to about 500 milligrams per kilogram of a Sub tion assays can be used to determine plasma concentrations. ject in need of asthma treatment. 0.139. Depending on the severity and responsiveness of the 0117. As an inhalant, PEA can be delivered in combina condition to be treated, dosing can be of a single or a plurality tion with any of the following steroids: of administrations, with course of treatment lasting from 0118 Beclometasone dipropionate (BDP) 40 to 320 mcg several days to several weeks, or until cure is effected or twice daily diminution of the disease state is achieved. 0119 Budesonide (BUD) Budesonide 180 to 720 mcg 0140. The amount of a composition to be administered twice daily will, of course, be dependent on the subject being treated, the US 2011/O 195096 A1 Aug. 11, 2011

severity of the affliction, the manner of administration, the A corticosteroid suitable for use with this aspect of the present judgment of the prescribing physician, etc. invention is described hereinabove. 0141 Compositions of the present invention may, if 0147 Compositions including any of the combinations desired, be presented in a pack or dispenser device, such as an described above can be formulated as for topical administra FDA approved kit, which may contain one or more unit dos tion for treatment of a cutaneous inflammatory disorder that age forms containing the active ingredient. The pack may, for otherwise (in the absence of the tricyclic antidepressant) example, comprise metal or plastic foil. Such as ablisterpack. requires a mid-potency steroid or high-potency steroid). In The pack or dispenser device may be accompanied by instruc another embodiment, the tricyclic antidepressant and corti tions for administration. The pack or dispenser device may costeroid are the Sole active ingredients in the composition. In also be accompanied by a notice in a form prescribed by a another embodiment, one or more additional active ingredi governmental agency regulating the manufacture, use, or sale ents are present. In another embodiment, the tricyclic antide of pharmaceuticals, which notice is reflective of approval by pressant and corticosteroid are present in amounts that, when the agency of the form of the compositions for human or administered together to a patient having cutaneous inflam Veterinary administration. Such notice, for example, may matory disease or disorder, inhibit or reduce inflammation include labeling approved by the U.S. Food and Drug Admin istration for prescription drugs or of an approved product caused therefrom. In another embodiment, the active ingre insert. Compositions comprising a preparation of the inven dients are present in amounts that treat the disorder. Each tion formulated in a pharmaceutically acceptable carrier may possibility represents a separate embodiment of the present also be prepared, placed in an appropriate container, and invention. labeled for treatment of an indicated inflammatory disorder, 0.148. In another embodiment, the present invention pro as further detailed above. vides a method for treating a cutaneous inflammatory disease 0142. According to another aspect of the present invention or disorder in a subject in need thereof, the method compris there is provided a method of treating an inflammatory dis ing the step of topically administering to the Subject a com order. The method is effected by administering to a subject in position comprising a tricyclic antidepressant and a low-po need a therapeutically effective amount of the present com tency corticosteroid, thereby treating a cutaneous position. As used herein, the phrase “subject in need” refers to inflammatory disease or disorder. In another embodiment, the a mammal, preferably a human that is Suffering from or is cutaneous inflammatory disease or disorder is a disease or predisposed to an inflammatory disorder. disorder that otherwise (in the absence of the tricyclic anti 0143 Local and systemic inflammatory disorders can be depressant) requires a mid-potency steroid or high-potency treated with the pharmaceutical composition of the present steroid). In another embodiment, a method of the present invention. Examples of local inflammatory disorders include, invention enables use of a mid-potency Steroid in situations but are not limited to, asthma, gastrointestinal inflammation, wherein a high-potency steroid would otherwise be required. ocular inflammation and cutaneous inflammatory disorder. In another embodiment, the method is used to alleviate a Gastrointestinal inflammation can be caused by gastritis, cutaneous inflammatory disease or disorder in a Subject in enteritis, proctitis, inflammatory bowel disease, Crohn dis need thereof. In another embodiment, the topical administra ease (CD) or ulcerative colitis (UC). Ocular inflammation can tion is performed at a site afflicted by the inflammatory dis becaused by uvetis or iritis. Cutaneous inflammatory disor order. In another embodiment, the tricyclic antidepressant der can be caused by psoriasis, atopic dermatitis, and Sclero and corticosteroid are the sole active ingredients in the com derma. position. In another embodiment, one or more additional 0144. The present invention also envisages use of a corti active ingredients are present. In another embodiment, the costeroid along with a second active agent Such as a tricyclic tricyclic antidepressant and corticosteroid are present in the antidepressant, a GABA agonist, a monoamine oxidase composition in amounts that, when administered together to a inhibitor, a cannabinoid receptoragonist, and an immunophi patient having cutaneous inflammatory disease or disorder, lin inhibitor. The beneficial effects of such second active inhibit or reduce inflammation caused therefrom. In another agent enable use of a low-potency Steroid in instances embodiment, the active ingredients are present in amounts wherein a mid-potency or high-potency steroid is typically that treat the disorder. Each possibility represents a separate required, use of a mid-potency steroid in instances wherein a embodiment of the present invention. high-potency steroid is typically required or use of lower 014.9 The tricyclic antidepressant of methods and compo doses of a high-potency steroid. sitions of the present invention is, in some preferred embodi 0145 Thus, according to another aspect of the present ments, amitriptyline (available as (ElavilR). Non-limiting invention there is provided a composition-of-matter which examples of tricyclic antidepressants useful in methods and includes a corticosteroid and at least one additional active compositions of the present invention are amoxapine, 8-hy ingredient selected form the group consisting of a tricyclic droxyamoxapine, 7-hydroxyamoxapine, loxapine, loxapine antidepressant, a GABA agonist, a monoamine oxidase Succinate, loxapine hydrochloride, 8-hydroxyloxapine, dox inhibitor, a cannabinoid receptoragonist, and an immunophi epin, maprotiline, clomipramine, desipramine, imipramine, lin inhibitor. trimipramine, nortriptyline, and protriptyline. In another 0146 The tricyclic antidepressant, GABA agonist, embodiment, the tricyclic antidepressant is any other tricyclic monoamine oxidase inhibitor, and cannabinoid receptorago antidepressant known in the art. Tricyclic antidepressants are nist compounds useful in the invention include those well known in the art, and are described in, for example, U.S. described hereinunder in any of their pharmaceutically Pat. Nos. 2,554,736,3,438,981, 3,420,851, 3,534,041, 3,505, acceptable forms, including isomers such as diastereomers 321, 4,013,639, 4,105,785, 6,368.814, which are incorpo and enantiomers, salts, Solvates, and polymorphs thereof, as rated herein by reference in their entirety. Each possibility well as racemic mixtures of the compounds described herein. represents a separate embodiment of the present invention. US 2011/O 195096 A1 Aug. 11, 2011

0150. In another embodiment, “tricyclic antidepressant' ticosteroid. In another embodiment, the composition is indi refers to a compound having one of the formulas: having one cated for a cutaneous inflammatory disease or disorder that the formulas (I), (II), or (III): otherwise (in the absence of the GABA agonist) requires a mid-potency steroid or high-potency steroid). In another embodiment, the GABA agonist and corticosteroid are the (I) X sole active ingredients in the composition. In another embodi ment, one or more additional active ingredients are present. In another embodiment, the GABA agonist and corticosteroid are present in amounts that, when administered together to a patient having cutaneous inflammatory disease or disorder, inhibit or reduce inflammation caused therefrom. In another

A X embodiment, the active ingredients are present in amounts n N(B) that treat the disorder. Each possibility represents a separate (II) embodiment of the present invention. X X 0157. In another embodiment, the present invention pro X Y X vides a method for treating a cutaneous inflammatory disease or disorder in a subject in need thereof, the method compris ing the step of topically administering to the Subject a com X X position comprising a GABA agonist and a corticosteroid, thereby treating a cutaneous inflammatory disease or disor X A X der. In another embodiment, the method is used to alleviate a SN(B), cutaneous inflammatory disease or disorder in a Subject in (III) X X need thereof. In another embodiment, the topical administra tion is in situ topical administration. In another embodiment, the corticosteroid is a low-potency corticosteroid. In another embodiment, the cutaneous inflammatory disease or disorder is a disease or disorder that otherwise (in the absence of the GABA agonist) requires a mid-potency steroid or high-po tency steroid). In another embodiment, the topical adminis tration is performed at a site afflicted by the inflammatory disorder. In another embodiment, the GABA agonist and corticosteroid are the sole active ingredients in the composi tion. In another embodiment, one or more additional active ingredients are present. In another embodiment, the GABA agonist and corticosteroid are present in the composition in amounts that, when administered together to a patient having 0151 wherein each X is, independently, H, Cl, F, Br, I, cutaneous inflammatory disease or disorder, inhibit or reduce CH, CF, OH, OCH, CHCH, or OCHCH;Y is CH, O, inflammation caused therefrom. In another embodiment, the NH, S(O) (CH), (CH), CHO, CHNH, CHN, or active ingredients are present in amounts that treat the disor 0152 CHS; Z is C or S: A is a branched or unbranched, der. Each possibility represents a separate embodiment of the saturated or monounsaturated hydrocarbon chain having present invention. between 3 and 6 carbons, inclusive; each Bis, independently, 0158. In another embodiment of methods and composi H, C1, F, Br, I, CX, CHCH, OCX, or OCX2CX; and D tions of the present invention, a topical composition com 0153) is CH, O, NH, S(O). prises an additional active ingredient besides the GABA ago 0154) In another embodiment, each X is, independently, nist and corticosteroid. In another embodiment, more than H, Cl, or F: Y is (CH), Z is C; A is (CH); and each B is, one additional active ingredients are present. In another independently, H, Cl, or F. embodiment, two additional active ingredients are present. In 0155. In another embodiment of methods and composi another embodiment, more than two additional active ingre tions of the present invention, a topical composition com dients are present. Each possibility represents a separate prises an additional active ingredient besides the tricyclic embodiment of the present invention. antidepressant and corticosteroid. In another embodiment, 0159) “GABA agonist” refers, in another embodiment, to more than one additional active ingredients are present. In an activator of a GABA-gated chloride channel. In another another embodiment, two additional active ingredients are embodiment, the GABA agonist of methods and composi present. In another embodiment, more than two additional tions of the present invention is, in some preferred embodi active ingredients are present. Each possibility represents a ments, topiramate. Non-limiting examples of GABA agonists separate embodiment of the present invention. useful in methods and compositions of the present invention 0156. In another embodiment, the present invention pro are topiramate, muscimol, progabide, riluzole, baclofen, vides a composition formulated for topical administration, gabapentin, vigabatrin, valproic acid, tiagabine, lamotrigine, the composition comprising a GABA agonist and a corticos pregabalin, phenyloin, and carbamazepine. In another teroid. In another embodiment, the topical administration is embodiment, the GABA agonist is any other GABA agonist in situ topical administration. In another embodiment, the known in the art. GABA agonists are well known in the art, topical administration is in situ topical administration. In and are described, for example, in U.S. Pat. Nos. 5,006,560, another embodiment, the corticosteroid is a low-potency cor 5,248,678, 6,077,839, 6,720,348, and 6,821,985, which are US 2011/O 195096 A1 Aug. 11, 2011

incorporated herein by reference in their entirety. Each pos embodiment, the carbonic anhydrase inhibitor is any other sibility represents a separate embodiment of the present carbonic anhydrase inhibitor known in the art. Carbonic invention. anhydrase inhibitors are well known in the art, and are 0160. In another embodiment, the present invention pro described, for example, in the above patents. Each possibility vides a composition formulated for topical administration, represents a separate embodiment of the present invention. the composition comprising a carbonic anhydrase inhibitor 0163. In another embodiment of methods and composi and a corticosteroid. In another embodiment, the corticoster tions of the present invention, a topical composition com oid is a low-potency corticosteroid. In another embodiment, prises an additional active ingredient besides the carbonic the cutaneous inflammatory disease or disorder is a disease or anhydrase inhibitor and corticosteroid. In another embodi disorder that otherwise (in the absence of the carbonic anhy ment, more than one additional active ingredients are present. drase inhibitor) requires a mid-potency steroid or high-po In another embodiment, two additional active ingredients are tency steroid). In another embodiment, a method of the present. In another embodiment, more than two additional present invention enables use of a mid-potency steroid in active ingredients are present. Each possibility represents a situations wherein a high-potency steroid would otherwise be separate embodiment of the present invention. required. In another embodiment, the topical administration 0164. In another embodiment, the present invention pro is in situ topical administration. In another embodiment, the vides a composition formulated for topical administration, carbonic anhydrase inhibitor and corticosteroid are the sole the composition comprising a sulfamate-substituted active ingredients in the composition. In another embodi monosaccharide and a corticosteroid. In another embodi ment, one or more additional active ingredients are present. In ment, the topical administration is in situ topical administra another embodiment, the carbonic anhydrase inhibitor and tion. In another embodiment, the corticosteroid is a low corticosteroid are present in amounts that, when administered potency corticosteroid. In another embodiment, the together to a patient having cutaneous inflammatory disease composition is indicated for a cutaneous inflammatory dis or disorder, inhibit or reduce inflammation caused therefrom. ease or disorder that otherwise (in the absence of the sulfa In another embodiment, the active ingredients are present in mate-substituted monosaccharide) requires a mid-potency amounts that treat the disorder. Each possibility represents a steroid or high-potency steroid). In another embodiment, a separate embodiment of the present invention. method of the present invention enables use of a mid-potency 0161 In another embodiment, the present invention pro steroid in situations wherein a high-potency steroid would vides a method for treating a cutaneous inflammatory disease otherwise be required. In another embodiment, the sulfamate or disorder in a subject in need thereof, the method compris Substituted monosaccharide and corticosteroid are the sole ing the step of topically administering to the Subject a com active ingredients in the composition. In another embodi position comprising a carbonic anhydrase inhibitor and a ment, one or more additional active ingredients are present. In corticosteroid, thereby treating a cutaneous inflammatory another embodiment, the Sulfamate-substituted monosaccha disease or disorder. In another embodiment, the method is ride and corticosteroid are present in amounts that, when used to alleviate a cutaneous inflammatory disease or disorder administered together to a patient having cutaneous inflam in a subject in need thereof. In another embodiment, the matory disease or disorder, inhibit or reduce inflammation topical administration is in situ topical administration. In caused therefrom. In another embodiment, the active ingre another embodiment, the corticosteroid is a low-potency cor dients are present in amounts that treat the disorder. Each ticosteroid. In another embodiment, the cutaneous inflamma possibility represents a separate embodiment of the present tory disease or disorder is a disease or disorder that otherwise invention. (in the absence of the carbonic anhydrase inhibitor) requires 0.165. In another embodiment, the present invention pro a mid-potency steroid or high-potency steroid). In another vides a method for treating a cutaneous inflammatory disease embodiment, the topical administration is performed at a site or disorder in a subject in need thereof, the method compris afflicted by the inflammatory disorder. In another embodi ing the step of topically administering to the Subject a com ment, the carbonic anhydrase inhibitor and corticosteroid are position comprising a Sulfamate-substituted monosaccharide the Sole active ingredients in the composition. In another and a corticosteroid, thereby treating a cutaneous inflamma embodiment, one or more additional active ingredients are tory disease or disorder. In another embodiment, the method present. In another embodiment, the carbonic anhydrase is used to alleviate a cutaneous inflammatory disease or dis inhibitor and corticosteroid are present in the composition in order in a subject in need thereof. In another embodiment, the amounts that, when administered together to a patient having topical administration is in situ topical administration. In cutaneous inflammatory disease or disorder, inhibit or reduce another embodiment, the corticosteroid is a low-potency cor inflammation caused therefrom. In another embodiment, the ticosteroid. In another embodiment, the cutaneous inflamma active ingredients are present in amounts that treat the disor tory disease or disorder is a disease or disorder that otherwise der. Each possibility represents a separate embodiment of the (in the absence of the sulfamate-substituted monosaccharide) present invention. requires a mid-potency steroid or high-potency steroid). In 0162 The carbonic anhydrase inhibitor of methods and another embodiment, the topical administration is performed compositions of the present invention is, in some preferred at a site afflicted by the inflammatory disorder. In another embodiments, topiramate. In another embodiment, the car embodiment, the Sulfamate-substituted monosaccharide and bonic anhydrase inhibitor is a Sulfonamide-class carbonic corticosteroid are the sole active ingredients in the composi anhydrase inhibitor. Non-limiting examples of carbonic tion. In another embodiment, one or more additional active anhydrase inhibitors useful in methods and compositions of ingredients are present. In another embodiment, the Sulfa the present invention are topiramate and those compounds mate-substituted monosaccharide and corticosteroid are described in U.S. Pat. Nos. 4,929,637, 5,276,025, 5,464,831, present in the composition in amounts that, when adminis 5,473,067, 5,646,142, 7,030,250, 7,109,353, which are incor tered together to a patient having cutaneous inflammatory porated herein by reference in their entirety. In another disease or disorder, inhibit or reduce inflammation caused US 2011/0195096 A1 Aug. 11, 2011 therefrom. In another embodiment, the active ingredients are embodiments, moclobemide. In another embodiment, the present in amounts that treat the disorder. Each possibility monoamine oxidase inhibitor is a monoamine oxidase A represents a separate embodiment of the present invention. inhibitor. Non-limiting examples of monoamine oxidase (0166 In another embodiment of methods and composi inhibitors useful in methods and compositions of the present tions of the present invention, a topical composition com invention are clorgiline, iproclozide, iproniazid, isocarbox prises an additional active ingredient besides the sulfamate azid (Marplan), minaprine, nialamide, pargyline, phenelzine Substituted monosaccharide and corticosteroid. In another (Nardil), rasagiline, selegiline (Eldepryl), toloxatone, tranyl embodiment, more than one additional active ingredients are cypromine (Parnate), furazolidone (Furoxone), and procar present. In another embodiment, two additional active ingre bazine (Matulane). In another embodiment, the monoamine dients are present. In another embodiment, more than two oxidase inhibitor is any other monoamine oxidase inhibitor additional active ingredients are present. Each possibility that increases endogenous concentrations of epinephrine represents a separate embodiment of the present invention. (adrenaline). In another embodiment, the monoamine oxi (0167. In another embodiment, the present invention pro dase inhibitor is any other monoamine oxidase inhibitor that vides a composition formulated for topical administration, increases endogenous concentrations of norepinephrine (no the composition comprising a monoamine oxidase inhibitor radrenaline). In another embodiment, the monoamine oxi (MAOI), and a corticosteroid. In another embodiment, the dase inhibitor is any other monoamine oxidase inhibitor that topical administration is in situ topical administration. In increases endogenous concentrations of dopamine. In another embodiment, the topical administration is in situ another embodiment, the monoamine oxidase inhibitor is any topical administration. In another embodiment, the corticos other monoamine oxidase inhibitor that increases endog teroid is a low-potency corticosteroid. In another embodi enous concentrations of serotonin. In another embodiment, ment, the composition is indicated for a cutaneous inflamma the monoamine oxidase inhibitor is any other monoamine tory disease or disorder that otherwise (in the absence of the oxidase inhibitor known in the art to exhibit monoamine monoamine oxidase inhibitor) requires a mid-potency steroid oxidase A inhibitory activity. Monoamine oxidase inhibitors or high-potency steroid). In another embodiment, the are well known in the art, and are described in, for example, monoamine oxidase inhibitor and corticosteroid are the sole U.S. Pat. Nos. 5,508,311, 5,792,799, 6,472,423, and 6,569, active ingredients in the composition. In another embodi 470, which are incorporated herein by reference in their ment, one or more additional active ingredients are present. In entirety. Each possibility represents a separate embodiment another embodiment, the monoamine oxidase inhibitor and of the present invention. Each possibility represents a sepa corticosteroid are present in amounts that, when administered rate embodiment of the present invention. together to a patient having cutaneous inflammatory disease (0170. In another embodiment of methods and composi or disorder, inhibit or reduce inflammation caused therefrom. tions of the present invention, a topical composition com In another embodiment, the active ingredients are present in prises an additional active ingredient besides the monoamine amounts that treat the disorder. Each possibility represents a oxidase inhibitor and corticosteroid. In another embodiment, separate embodiment of the present invention. more than one additional active ingredients are present. In (0168 In another embodiment, the present invention pro another embodiment, two additional active ingredients are vides a method for treating a cutaneous inflammatory disease present. In another embodiment, more than two additional or disorder in a subject in need thereof, the method compris active ingredients are present. Each possibility represents a ing the step of topically administering to the subject a com separate embodiment of the present invention. position comprising a monoamine oxidase inhibitor and a (0171 In another embodiment, the present invention pro corticosteroid, thereby treating a cutaneous inflammatory Vides a composition formulated for topical administration, disease or disorder. In another embodiment, the method is the composition comprising a reversible inhibitor of used to alleviate a cutaneous inflammatory disease or disorder monoamine oxidase A (RIMA compound) and a corticoster in a subject in need thereof. In another embodiment, the oid. In another embodiment, the topical administration is in topical administration is in situ topical administration. In situ topical administration. In another embodiment, the topi another embodiment, the corticosteroid is a low-potency cor cal administration is in situ topical administration. In another ticosteroid. In another embodiment, the cutaneous inflamma embodiment, the corticosteroid is a low-potency corticoster tory disease or disorder is a disease or disorder that otherwise oid. In another embodiment, the composition is indicated for (in the absence of the monoamine oxidase inhibitor) requires a cutaneous inflammatory disease or disorder that otherwise a mid-potency steroid or high-potency steroid). In another (in the absence of the RIMA compound) requires a mid embodiment, the topical administration is performed at a site potency steroid or high-potency steroid). In another embodi afflicted by the inflammatory disorder. In another embodi ment, the monoamine oxidase inhibitor and corticosteroid are ment, the monoamine oxidase inhibitor and corticosteroid are the sole active ingredients in the composition. In another the sole active ingredients in the composition. In another embodiment, one or more additional active ingredients are embodiment, one or more additional active ingredients are present. In another embodiment, the monoamine oxidase present. In another embodiment, the monoamine oxidase inhibitor and corticosteroid are present in amounts that, when inhibitor and corticosteroid are present in the composition in administered together to a patient having cutaneous inflam amounts that, when administered together to a patient having matory disease or disorder, inhibit or reduce inflammation cutaneous inflammatory disease or disorder, inhibit or reduce caused therefrom. In another embodiment, the active ingre inflammation caused therefrom. In another embodiment, the dients are present in amounts that treat the disorder. Each active ingredients are present in amounts that treat the disor possibility represents a separate embodiment of the present der. Each possibility represents a separate embodiment of the invention. present invention. (0172. In another embodiment, the present invention pro 0169. The monoamine oxidase inhibitor of methods and vides a method for treating a cutaneous inflammatory disease compositions of the present invention is, in some preferred or disorder in a subject in need thereof, the method compris US 2011/O 195096 A1 Aug. 11, 2011

ing the step of topically administering to the Subject a com caused therefrom. In another embodiment, the active ingre position comprising a reversible inhibitor of monoamine oxi dients are present in amounts that treat the disorder. Each dase A (RIMA compound) and a corticosteroid, thereby possibility represents a separate embodiment of the present treating a cutaneous inflammatory disease or disorder. In invention. another embodiment, the method is used to alleviate a cuta 0176). In another embodiment, the present invention pro neous inflammatory disease or disorder in a subject in need vides a method for treating a cutaneous inflammatory disease thereof. In another embodiment, the topical administration is or disorder in a subject in need thereof, the method compris in situ topical administration. In another embodiment, the ing the step of topically administering to the Subject a com corticosteroid is a low-potency corticosteroid. In another position comprising a cannabinoid receptor agonist and a embodiment, the cutaneous inflammatory disease or disorder corticosteroid, thereby treating a cutaneous inflammatory is a disease or disorder that otherwise (in the absence of the disease or disorder. In another embodiment, the method is RIMA compound) requires a mid-potency steroid or high used to alleviate a cutaneous inflammatory disease or disorder potency Steroid). In another embodiment, the topical admin in a subject in need thereof. In another embodiment, the istration is performed at a site afflicted by the inflammatory topical administration is in situ topical administration. In disorder. In another embodiment, the RIMA compound and another embodiment, the corticosteroid is a low-potency cor corticosteroid are the sole active ingredients in the composi ticosteroid. In another embodiment, the cutaneous inflamma tion. In another embodiment, one or more additional active tory disease or disorder is a disease or disorder that otherwise ingredients are present. In another embodiment, the RIMA (in the absence of the cannabinoid receptor agonist) requires compound and corticosteroid are present in the composition a mid-potency steroid or high-potency steroid). In another in amounts that, when administered together to a patient embodiment, the topical administration is performed at a site having cutaneous inflammatory disease or disorder, inhibit or afflicted by the inflammatory disorder. In another embodi reduce inflammation caused therefrom. In another embodi ment, the cannabinoid receptoragonist and corticosteroid are ment, the active ingredients are present in amounts that treat the sole active ingredients in the composition. In another the disorder. Each possibility represents a separate embodi embodiment, one or more additional active ingredients are ment of the present invention. present. In another embodiment, the cannabinoid receptor 0173 The RIMA compound of methods and compositions agonist and corticosteroid are present in the composition in of the present invention is, in another embodiment, selected amounts that, when administered together to a patient having from the group consisting of befloxatone, brofaromine, and cutaneous inflammatory disease or disorder, inhibit or reduce cimoxatone. In another embodiment, the RIMA compound is inflammation caused therefrom. In another embodiment, the a beta-carboline RIMA compound. In another embodiment, active ingredients are present in amounts that treat the disor the RIMA compound is harmaline). In another embodiment, der. Each possibility represents a separate embodiment of the the RIMA compound is any other RIMA compound known in present invention. the art to exhibit monoamine oxidase A inhibitory activity. 0177. The cannabinoid receptor agonist of methods and Each possibility represents a separate embodiment of the compositions of the present invention is, in some preferred present invention. embodiments, cannabidiol (CBD). In another preferred 0.174. In another embodiment of methods and composi embodiment, the cannabinoid receptoragonist is an endocan tions of the present invention, a topical composition com naboid compound. Non-limiting examples of cannabinoid prises an additional active ingredient besides the RIMA com receptor agonists useful in methods and compositions of the pound and corticosteroid. In another embodiment, more than present invention are cannabidivarol (CBDV), cannabinol one additional active ingredients are present. In another (CBN), cannabigerol (CBG), cannabivarol (CBV), cannabi embodiment, two additional active ingredients are present. In cyclol (CBL), tetrahydrocannabinol (THC), tetrahydrocan another embodiment, more than two additional active ingre nabinol-C4. (THC-C4), tetrahydrocannabivarin (also known dients are present. Each possibility represents a separate as tetrahydrocannabivarol, THCV, and THV), 11-Hydroxy embodiment of the present invention. A-tetrahydrocannabinol, (11-OH-THC), 11-nor-9-Carboxy 0.175. In another embodiment, the present invention pro A9-tetrahydrocannabinol (11-COOH-THC, THC-COOH, vides a composition formulated for topical administration, THC-1 1-oic acid), arachidonoyl ethanolamide (Ananda the composition comprising a cannabinoid receptor agonist mide, AEA), 2-arachidonoylglycerol (2-AG), 2-Arachidonyl and a corticosteroid. In another embodiment, the topical glyceryl ether (noladin ether), Virodhamine, N-arachidonoyl administration is in situ topical administration. In another dopamine (NADA), oleamide, A-41988, ajulemic acid, embodiment, the topical administration is in situ topical AM-087, AM-411, AM-855, AM-905, AM-906, AM-919, administration. In another embodiment, the topical adminis AM-938, AM-4030, AMG-1, AMG-3, AMG-36, AMG-41, tration is in situ topical administration. In another embodi dexanabinol (HU-211), DMHP dronabinol, HU-210, JWH ment, the corticosteroid is a low-potency corticosteroid. In 051, JWH-133, JWH-139, L-759,633, L-759,656, levonant another embodiment, the composition is indicated for a cuta radol, nabilone, Nabitan, O-806, O-823, O-1057, O-1125, neous inflammatory disease or disorder that otherwise (in the O-1238, O-2545, O-2694, parahexyl, THC-O-acetate, THC absence of the cannabinoid receptor agonist) requires a mid O-phosphate, CP 47,497, CP 55,244, CP 55,940, HU-308, potency steroid or high-potency Steroid). In another embodi 2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cy ment, the cannabinoid receptoragonist and corticosteroid are clohex-1-ene, AM-630, AM-1241, JWH-015, JWH-018, the Sole active ingredients in the composition. In another JWH-073, JWH-081, JWH-200, L-768,242, pravadoline, embodiment, one or more additional active ingredients are WIN 55, 212-2, JWH-030, JWH-147, JWH-307, AM-883, present. In another embodiment, the cannabinoid receptor Arachidonyl-2'-chloroethylamide, arachidonylcyclopropyla agonist and corticosteroid are present in amounts that, when mide, methanandamide, O-585, O-689, O-1812, O-1860, administered together to a patient having cutaneous inflam O-1861, BAY 38-7271, BAY 59-3074, JWH-171, and matory disease or disorder, inhibit or reduce inflammation O-2220. Cannabinoid receptoragonists are well known in the US 2011/O 195096 A1 Aug. 11, 2011

art, and are described in, for example, U.S. Pat. Nos. 5,747, embodiment, the corticosteroid is a low-potency corticoster 524, 5,596,106, 6,017,919, 6,432,984, 6,509,367, 6,645,985, oid. In another embodiment, the cutaneous inflammatory dis and 7,169,942, which are incorporated herein by reference in ease or disorder is a disease or disorder that otherwise (in the their entirety. In another embodiment, the cannabinoid recep absence of the immunophilin inhibitor) requires a mid-po tor agonist is any other agonist of a cannabinoid receptor tency steroid or high-potency Steroid). In another embodi known in the art. Each possibility represents a separate ment, the topical administration is performed at a site afflicted embodiment of the present invention. by the inflammatory disorder. In another embodiment, the 0178. In another embodiment, the cannabinoid receptor immunophilin inhibitor and corticosteroid are the sole active agonist of methods and compositions of the present invention ingredients in the composition. In another embodiment, one targets a type 1 (CB1) receptor. In another embodiment, the or more additional active ingredients are present. In another cannabinoid receptoragonist targets a type 2 (CB2) receptor. embodiment, the immunophilin inhibitor and corticosteroid In another embodiment, the cannabinoid receptor agonist are present in the composition in amounts that, when admin targets a WIN receptor. In another embodiment, the cannab istered together to a patient having cutaneous inflammatory inoid receptoragonist targets an abnormal-cannabidiol (abn disease or disorder, inhibit or reduce inflammation caused CBD) receptor. In another embodiment, the cannabinoid therefrom. In another embodiment, the active ingredients are receptor agonist targets an anandamide receptor. Each possi present in amounts that treat the disorder. Each possibility bility represents a separate embodiment of the present inven represents a separate embodiment of the present invention. tion. 0182. In another embodiment of methods and composi 0179. In another embodiment of methods and composi tions of the present invention, a topical composition com tions of the present invention, a topical composition com prises an additional active ingredient besides the immunophi prises an additional active ingredient besides the cannabinoid lin inhibitor and corticosteroid. In another embodiment, more receptor agonist and corticosteroid. In another embodiment, than one additional active ingredients are present. In another more than one additional active ingredients are present. In embodiment, two additional active ingredients are present. In another embodiment, two additional active ingredients are another embodiment, more than two additional active ingre present. In another embodiment, more than two additional dients are present. Each possibility represents a separate active ingredients are present. Each possibility represents a embodiment of the present invention. separate embodiment of the present invention. 0183 The immunophilin inhibitor of methods and com 0180. In another embodiment, the present invention pro positions of the present invention is, in another embodiment, vides a composition formulated for topical administration, a non-immunosuppressive immunophilin inhibitor. Non-im the composition comprising an immunophilin inhibitor and a munosuppressive immunophilin inhibitors are well known in corticosteroid. In another embodiment, the topical adminis the art, and include Astellas Pharmaceuticals FK 1706; tration is in situ topical administration. In another embodi Guildford (now MGI) Pharmaceuticals' GPI 1046 and GPI ment, the topical administration is in situ topical administra 1485; 2,2'-(1,3,4-oxadiazole-2,5-diyl)bis 1-(3,3-dimethyl-1, tion. In another embodiment, the topical administration is in situ topical administration. In another embodiment, the cor 2-dioxopentyl)-pyrrolidine (GM-284); (3R)-4-(p-Toluene ticosteroid is a low-potency corticosteroid. In another Sulfonyl)-1,4-thiazane-3-carboxylic acid-L-Leucine ethyl embodiment, the composition is indicated for a cutaneous ester; and (3R)-4-(p-Toluenesulfonyl)-(-14thiazane-3-car inflammatory disease or disorder that otherwise (in the boxylic acid-L-phenylalanine benzyl ester. Additional non absence of the immunophilin inhibitor) requires a mid-po immuno-Suppressive immunophilin inhibitors are described tency steroid or high-potency Steroid). In another embodi in Adalsteinsson, H., and T. C. Bruice. 2000. Bioorg. Med. ment, the immunophilin inhibitor and corticosteroid are the Chem. 8:625-635: Gold B. G. Expert Opin Investig Drugs. sole active ingredients in the composition. In another embodi 2000 October 9(10):2331-42. PMID: 11060810; Gold, B. ment, one or more additional active ingredients are present. In G. M. Zeleny-Pooley, M. S. Wang, P. Chaturvedi, and D. M. another embodiment, the immunophilin inhibitor and corti Armistead. 1997. Exp. Neurol. 147:269-278; Guo, X. V. L. costeroid are present in amounts that, when administered Dawson, and T. M. Dawson. 2001. Eur. J. Neurosci. 13:1683 together to a patient having cutaneous inflammatory disease 1693; Sabatini, D. M., M. M. Lai, and S. H. Snyder. 1997. or disorder, inhibit or reduce inflammation caused therefrom. Mol. Neurobiol. 15:223-239; Sauer, H., J. M. Francis, H. In another embodiment, the active ingredients are present in Jiang, G. S. Hamilton, and J. P. Steiner. 1999. Brain Res. amounts that treat the disorder. Each possibility represents a 842:109-118; Sich, C. S. Improta, D.J. Cowley, C. Guenet, J. separate embodiment of the present invention. P. Merly, M. Teufel, and V. Saudek. 2000. Eur. J. Biochem. 0181. In another embodiment, the present invention pro 267:5342-5355; Steiner, J. P., M. A. Connolly, H. L. Valen vides a method for treating a cutaneous inflammatory disease tine, G. S Hamilton, T. M. Dawson, L. Hester, and S. H. or disorder in a subject in need thereof, the method compris Snyder. 1997. Nat. Med. 4:412–428. Additional non-immu ing the step of topically administering to the Subject a com nosuppressive immunophilin inhibitors are described in U.S. position comprising an immunophilin inhibitor and a corti Pat. Nos. 7,153,883, 6,486,151, 6,331,537, 6,054,452, and costeroid, thereby treating a cutaneous inflammatory disease 5,846,979 and U.S. Patent application numbers 2003/ or disorder. In another embodiment, the method is used to 0186961, 2002/0198250, and 2001/0034362, which are alleviate a cutaneous inflammatory disease or disorder in a incorporated herein by reference. subject in need thereof. In another embodiment, the topical 0184. In another embodiment, the immunophilin inhibitor administration is in situ topical administration. In another is any other immunophilin inhibitor known in the art. Non-- US 2011/O 195096 A1 Aug. 11, 2011

limiting examples of immunophilin inhibitors are cyclophi 0190. Materials and Methods lin, FK506 binding protein (FKBP), rapamycin, and ana Test System logues thereof. Each immunophilin inhibitor represents a Species/Strain: Mice/Balb/c separate embodiment of the present invention. Source: Harlan Israel, Ltd. 0185. It is expected that during the life of this patent many 0191 Age: Young adults, 6-7 weeks of age at study initia relevant corticosteroids will be developed and the scope of the tion. term corticosteroid is intended to include all such new tech Body Weight: Weight variation of animals at the time of nologies a priori. treatment initiation did not exceed-t15% of the mean weight. Animals Health: The health status of the animals used in this 0186. As used herein the term “about” refers to +10%. study was examined on arrival. Only animals in good health 0187. Additional objects, advantages, and novel features were acclimatized to laboratory conditions and were used in of the present invention will become apparent to one ordi the study. narily skilled in the art upon examination of the following Acclimation: 5 days. examples, which are not intended to be limiting. Additionally, Housing: During acclimation and following dosing, animals were housed within a limited access rodent facility in con each of the various embodiments and aspects of the present ventional cages and kept in groups of maximum 10 mice, in invention as delineated hereinabove and as claimed in the polypropylene cages, fitted with solid bottoms and filled with claims section below finds experimental Support in the fol sterile wood shavings as bedding material. lowing examples. EXAMPLES Reference is now made to the Food and Water: Animals were provided with ad libitum—a following examples, which together with the above descrip commercial sterile rodent diet and free access to sterile drink tions, illustrate the invention in a non limiting fashion. ing water, Supplied to each cage via polyethylene bottles with stainless steel sipper tubes. Feed lot analysis of the diet batch used in the study was included in the archives with the study EXAMPLES data. Environment: Automatically controlled environmental con 0188 Reference is now made to the following examples, ditions were set to maintain temperature at 20-24°C. with a which together with the above descriptions, illustrate the relative humidity (RH) of 30-70%, a 12:12 hour light: dark invention in a non limiting fashion. cycle and 10-30 air changes/hr in the study room. Tempera ture and RH were monitored daily. Identification: Animals were given a unique animal identifi Example 1 cation ear number. This number also appeared on a cage card, visible on the front of each cage. The cage card also contained 0189 A study was undertaken in order to evaluate the the study number, and all other relevant details as to treatment effect of topical preparations of various test items (TI) and TI group and dose level. combined with Croton oil on earswelling. Earthickness was Randomization: Animals were randomly assigned to experi measured before croton oil induced ear swelling and 3 hours mental groups. post ear edema induction. The various TIS were applied topi Termination: At the end of the study surviving animals were cally 1 hour prior to ear edema sensitization and 2 hours post euthanized by Isoflurane. earedema sensitization. The difference in earthickness of the Test Groups and Dosages intact ear was subtracted from the ear thickness of the 0.192 The Experimental groups used in this study are inflamed ear. This value is defined as “ear swelling. listed in Table 1 below.

TABLE 1. the 12 experimental groups comprising the study

Ear Group Group Test Volume Thickness & Gender Size Item Route Concentration (ml) Regime Measurement

1F 4 Vehicle Topical O 0.1 1 hour 24 hours 2F 4 Amitriptyline 2 mg/m prior to prior to 3F 4 Topiramate 2 mg/m sensitization sensitization 4F 4 Moclobimide 2 mg/m and 2 hours and 3 SF 4 PEA 5 mg/m post hours post 6F 4 CBD 5 mg/m sensitization sensitization 7F 4 Hydrocortisone 600 nmolear 8F 4 Hydrocortisone + 600 nmolear + Amitriptyline 2 mg/m 9F 4 Hydrocortisone + 600 nmolear + Topiramate 2 mg/m 1OF 5 Hydrocortisone + 600 nmolear + Moclobimide 2 mg/m 11F 5 Hydrocortisone + 600 nmolear + PEA 5 mg/m 12F 5 Hydrocortisone + 600 nmolear + CBD 5 mg/m US 2011/O 195096 A1 Aug. 11, 2011

Test Procedure In view of the findings obtained herein it can be concluded (0193 100 mL (50 mL each side) of freshly prepared Cro that the CBD test preparation resulted in a significant (72%) ton oil in acetone (2.5% V/v) solution was applied on Left ear inhibition in ear edema compared to the vehicle. The PEA test on Study Day 0 to induce sensitization. Prior to sensitization preparation showed increased (52%) but not significant inhi animals were anesthetized. Earthickness was measured 24 bition of ear Swelling in comparison to the hydrocortisone hours prior to croton oil sensitization; this measurement group (40%). However, a combination of the PEA test prepa served as a baseline. On sensitization day, the animals were ration and the Hydrocortisone test preparation demonstrated anesthetized using Ketamine and Xylazine formulation. a significant reduction in ear edema in comparison to the Then, the animals were administered with TI topically. One vehicle group and the hydrocortisone group. hour later the animals were introduced to croton oil sensiti zation (50 uL). Two hours post croton oil sensitization the TABLE 2 animals were administered with TI again. Three hours post croton oil sensitization the earthickness of the animals were Mean Group Body weight (g measured again. Treatment TIs were administered twice, the first dose was 1 hour prior to Groupii & Gender MEAN SEM croton oil sensitization and the second time was 2 hours post Vehicle 8.48 O.22 croton oil sensitization. All TIs were dissolved in 10% Etha Group 1F nol and were applied topically on the surface of the sensitized Amitriptyline 8. OS O41 ea. Group 2F Topiramate 8.78 O.25 Group 3F Observations and Examinations Moclobimide 8.78 O.86 Group 4F 0194 Determination of individual body weights of ani PEA 8.45 O.S8 mals was made one day before sensitization phase. A single Group SF person was responsible for ear thickness measurement CBD 8.68 0.44 Group 6F throughout the entire study. The earthickness of both left and Hydrocortisone 8.35 O.26 right ears was measured using analogue calipers (Instrumen Group 7F tation 0.01 mm L-01) on 2 occasions: 24 hours prior to croton Hydrocortisone + 8.25 O.22 oil sensitization, and 3 hours post croton oil sensitization. Amitriptyline Group 8F Hydrocortisone + 8.2O O.45 All data are presented in MEAN-SEM. T-test, two tailed, Topiramate Group 9F unpaired was applied to all data. P value was considered Hydrocortisone + 8.34 O.49 significant if p<0.05. Moclobimide Group 1 OF Hydrocortisone + PEA 8.70 O.61 No abnormalities were observed following the treatment with Group 11 F all test items. Animal #2 from Group 3F died post anesthesia. Hydrocortisone + CBD 8.70 O.76 The death of this animal was not related to the treatment. Group 12F Animal #4 (Group 7F) was excluded from the study as red ness on ear appeared prior to sensitization with Croton oil. The mean body weight of the animals on the day of study initiation was 18.48+0.15 g. Ear thickness was measured TABLE 3 before Croton oil induced ear sensitization (baseline) and 3 Mean Group Ear Swelling (mm) and hours post ear edema induction. Treatment with various TI % of Ear Thickness Inhibition (% was applied topically 1 hour prior to sensitization and 2 hours 3 Hours Post % of Ear post induction. The difference in earthickness of the intact ear Treatment Baseline Croton Oil Thickness was subtracted from the ear thickness measured of the inflamed ear. This value was referred to as ear swelling. Groupii & Gender MEAN SEM MEAN SEM Inhibition (0195 Results Vehicle O.231 O.OO8 O.283 O.O12 O 0196. As is shown in Table 3 below and in FIG. 1, the ears Group 1F of the Vehicle treated animals (Group 1F) swelled signifi Amitriptyline O.223 O.OO6 O.248 O.OOS 62 Group 2F cantly over baseline. The difference between the inflamed and Topiramate O.223 O.OO9 O.243 O.OO7 63 intact earthickness was 0.073+0.012 mm. Treatment with the Group 3F topical preparation containing CBD (Group 6F) resulted in a Moclobimide O.219 O.OO3 O.26S O.O15 52 significant (72%) inhibition in ear edema compared to the Group 4F PEA O.21O O.OO4 O.268 O.OO9 52 Vehicle group (0.020+0.010 p<0.05). Treatment with the Group SF topical preparation containing PEA (Group 5F) resulted in a CBD O.225 O.OO3 O.240 O.O11 72 52% inhibition of ear swelling, which was not statistically Group 6F significant. Treatment with the Hydrocortisone preparation Hydrocortisone O.230 O.OO7 O.243 O.OO9 40 Group 7F (Group 7F) inhibited earswelling by 40% (0.043+0.003 mm) Hydrocortisone + O.230 O.OO8 O.258 O.O10 55 which was not statistically significant compared to the vehicle Amitriptyline Group 8F group. Hydrocortisone + O.230 O.OO7 O.26S O.O10 62 Topiramate Group 9F Treatment with a combination of the topical preparation con Hydrocortisone + O.218 O.OO3 O.240 O.OO7 64 taining PEA and the preparation containing Hydrocortisone Moclobimide Group 1 OF (Group 11F) resulted in 78% inhibition of ear edema Hydrocortisone + PEA O.216 O.OO2 O.23O*# O.OO6 78 (0.016+0.004 p<0.01 vs. Vehicle and p<0.01 vs. Hydrocorti Group 11 F sone). US 2011/O 195096 A1 Aug. 11, 2011 16

0201 Treatment with PEA 0.5% resulted in a 52% inhi TABLE 3-continued bition of ear Swelling, which was not statistically sig nificant versus Hydrocortisone or Vehicle (0.035+0.012 Mean Group Ear Swelling (mm) and mm). % of Ear Thickness Inhibition (% 0202 Treatment with a combination of Hydrocortisone 3 Hours Post % of Ear and the topical preparation containing PEA (Group 11F) Treatment Baseline Croton Oil Thickness resulted in 78% inhibition of ear edema (0.016+0.004 Group# & Gender MEAN SEM MEAN SEM Inhibition p<0.01 vs. Vehicle and p-0.01 vs. Hydrocortisone). Hydrocortisone + CBD O.212 O.OO2 O.2SO. O.OO4 59 Group 12F Example 2 *p < 0.05 vs. Vehicle: 0203) A study was undertaken in order to evaluate the **p < 0.01 vs. Vehicle; effect of topical preparations of Hydrocortisone, Betametha #p < 0.01 vs. Hydrocortisone Sone and PEA at various concentrations (as single agents and 0.197 Conclusions in various combinations) on ear edema in mice. Earthickness 0198 The ears of the Vehicle treated animals swelled was measured before croton oil induced ear Swelling and 6 significantly over baseline and the difference between hours post ear edema induction. The preparations were the inflamed and intact ear thickness was 0.073+0.012 applied topically 1 hour prior to ear edema sensitization. . 0204. The difference in earthickness of the intact ear was 0199 Treatment with the topical preparation containing subtracted from the ear thickness of the inflamed ear. This CBD resulted in a significant (72%) inhibition in ear edema compared to the Vehicle group (0.020+0.010 value is defined as “ear swelling. p<0.05) 0205 Materials and Methods 0200 Hydrocortisone preparation inhibited ear swell 0206 Test systems and procedures are as described above ing by 40% (0.043+0.003 mm). Not statistically signifi in Example 1, the experimental groups are listed in Table 4 Cant below.

TABLE 4 the 14 experimental groups comprising the study

Ear Group Volume Thickness Group Size Test Item Route Concentration (ml) Regime Measurement

1F O O.S90 PEA Topica O.S9/o 25 0.5 hour 24 hours per ear prior to prior to 2F O 196 PEA Topica 190 25 sensitization sensitization be ear and 6 3F O 5% PEA Topica 59% 25 hours be ear post 4F O O.S90 Topica O.S9/o 25 sensitization PEA+ Hydrocortisone be ear EDso 5F O 190 Topica 190 25 PEA+ Hydrocortisone be ear EDso 6F O 59% Topica 59% 25 PEA+ Hydrocortisone be ear EDso 7F O O.S90 Topica O.S9/o 25 PEA+ Betamethasone be ear EDso 8F O 190 Topica 190 25 PEA+ Betamethasone be ear EDso 9F O 59% Topica 59% 25 PEA+ Betamethasone be ear EDso 1OF O Hydrocortisone EDso Topica 55 g/25 Jul 25 per ear be ear 11F O Hydrocortisone Topica 200 g/25 Jul 25 EDnax per ear be ear 12F O Betamethasone ED50 Topica 1 g/25 Jul 25 per ear be ear 13F O Betamethasone Topica 4 g/25 Jul 25 EDnax per ear be ear 14F O Vehicle (100% Topica O 25 Ethanol) be ear US 2011/O 195096 A1 Aug. 11, 2011 17

0207 Results 0212. In view of these results it can be concluded that 0208 Ear Thickness results are listed in Table 6 and illus topical treatment with PEA (1%) results in a significant trated in FIGS. 2a-b); Ear Delta results are listed in Table 7. reduction in ear edema compared to the Vehicle. In addition, 0209 Significant ear swelling was measured 6 hours post this study also demonstrated that treatment with topical sensitization in Vehicle treated groups (Group 14F: 0.32+0.01 preparations of Betamethasone (1 lug/25ul per ear calculated post sensitization vs. 0.26+0.003 baseline; p<0.01). Treat (EDs) and 4 g/25 ul per ear calculated (ED) lead to ment with topical preparations of Hydrocortisone at concen significant reduction in ear edema in a dose related manner trations of 55 lug/25ul per ear—calculated (EDs) and 200 when compared to vehicle. ug/25ul per ear calculated (ED) was not active compared to vehicle in reducing ear thickness in the current model. TABLE 5 Betamethasone at concentrations of 1 g/25ul per ear calcu lated (EDs) and 4 ug/25ul per ear calculated (ED) dem Mean Group Body Weight (g onstrated significant reduction in ear edema compared to Treatment and Group # Mean SEM vehicle in a dose related manner (Betamethasone at EDso 0.30+0.008, p<0.1: Betamethasone at ED, 0.29+0.005 0.5% PEA(1F) 18.9 O.38 <0.05 vs. Vehicle) f % PEA(2F) 18.4 O3S p

TABLE 6

Mean Left Ear Thickness

Left Ear Thickness (mm SEM Study Day -1 Study Day O Study Day -1 Study Day O (24 H pre (6 H post (24 H pre (6 H post Treatment and Group # sensitization) sensitization) sensitization) sensitization) 0.5% PEA(1F) O.25 O.38 O.OO O.O2 % PEA(2F) O.26 0.29 * * O.OO O.OO 5% PEA(3F) O.26 O.32 O.OO O.OO 0.5% PEA+ Hydro. EDs (4F) O.26 O.33 O.OO O.O1 % PEA+ Hydro. EDs (5F) O.25 O.34 O.OO O.O1 5% PEA + Hydro. EDs 6F) O.26 O.31 O.OO O.O1 0.5% PEA+ Beta. EDso (7F) O.25 O.32 O.OO O.O1 % PEA + Beta. EDso (8F) O.25 O.36 O.OO O.O1 5% PEA+ Beta. (9F) O.25 O.34 O.OO O.O1 Hydr. EDso (10F) O.26 O.32 O.OO O.O1 Hydro. ED (11F) O.25 O.31 O.OO O.O1 Beta. EDso (12F) O.25 O.30 * O.OO O.O1 Beta ED (13F) O.26 0.29 * * O.OO O.OO 00% Ethanol (Veh.) (14F) O.26 O.32 O.OO O.O1 * p < 0.1 vs. relevant Vehicle; ** p < 0.01 vs. relevant Vehicle

TABLE 7

Mean Left Ear Delta thickness Hydrocortisone Bethametasone Treatment Group # Delta + 6 h vs baseline SEM Treatment/Group it Delta + 6 h vs baseline SEM 0.5% PEA(1F) O.13S 0.017 0.5% PEA(1F) O.13S O.O17 1% PEA(2F) 0.031: 0.004 1% PEA(2F) 0.031: O.OO)4 5% PEA(3F) O.062 0.0035% PEA(3F) O.062 O.OO3 0.5% PEA + Hydro. ED50(4F) O.O68 0.012 0.5% PEA+ Betha. ED50(7F) O.O70 O.OO8 1% PEA+ Hydro. ED50(5F) O.O90 0.010 1% PEA + Betha. ED50(8F) O. 106 O.OO9 5% PEA+ Hydro. ED50(6F) O.OS1 0.013 5% PEA+ Betha. ED50(9F) O.O81 O.O13 US 2011/O 195096 A1 Aug. 11, 2011 18

TABLE 7-continued

Mean Left Ear Delta thickness

Hydrocortisone Bethametasone Treatment Group # Delta + 6 h vs baseline SEM Treatment Group # Delta + 6 h vs baseline SEM Hydro. ED50(10F) O.O60 0.008 Betha. ED50(12F) O.043 O.OO7 Hydro. EDmax(11F) O.OS4 0.008 Betha. EDmax(13F) 0.031: O.OO)4 100% Ethanol (veh.)(14F) O.062 0.010 100% Ethanol (veh.)(14F) O.062 O.O10 *p < 0.05 vs. relevant Vehicle

0213 Conclusions 0221 Materials and Methods 0214. Significant ear swelling was measured 6 hours post sensitization in Vehicle treated groups (Group 14F: 0222 Test systems and procedures are as described above 0.32+0.01 post sensitization vs. 0.26+0.003 baseline: in Example 1, the experimental groups are listed in Table 8 p<0.01). below.

TABLE 8 the 4 experimental groups comprising the study

Volume Ear Group (ml) Thickness Group Size Test Item Route Concentration Per ear Regime Measurement 1F 10 Vehicle Topical O 25 Jul 0.5 hour 24 hours (100% Ethanol) prior to prior to 2F 10 196 PEA Topical 1% 25 Jul sensitization sensitization 3F 10 19 PEA- Topical 1% + 25 ul and 6 hours Betamethasone 41g25 ul post EDna. per ear sensitization 4F 10 Betamethasone Topical 4 g/25 ul 25 ul EDnax per ear

0215 Treatment with topical preparations of Hydrocor- 0223 Results tisone at concentrations of 55 ug/25ul per ear—calcu- 0224 Ear Thickness results are listed in Table 10 and lated (ED50) and 200 ug/25ul per ear calculated (ED illustrated in FIG. 3: Delta Thickness results are listed in max) were not active compared to vehicle in reducing Table 11. earthickness in the current model. 0225. A significantearswelling was measured 6 hours and 0216 Betamethasone at concentrations of 1 g/25 ul 9 hours post sensitization in Vehicle treated group (Group per ear calculated (ED50) and 4 ug/25ul per ear calcu 1F). Earthickness increased by 0.9 mm 6 hours post sensiti lated (EDmax) demonstrated significant reduction in ear zation and increased by 0.13 mm 9 hours post sensitization. edema compared to vehicle in a dose related manner 0226 PEA 1% preparation (Group 2F) demonstrated sig (Betamethasone at ED50 0.30+0.008, p<0.1; nificant activity in inhibiting ear Swelling 6 hours post sensi Betamethasone at EDmax 0.29+0.005 p-0.05 vs. tization. (p<0.01 vs. Vehicle) but was not active in inhibiting Vehicle). ear Swelling 9 hours post sensitization. 0217 Topical PEA at a concentration of 1% was sig 0227. A single mixture preparation of PEA (1%)+Be nificantly active in reducing ear thickness by approxi tamethasone 4 g/25 Jul per ear calculated (ED) (Group mately 50% (0.29+0.004, p<0.05 vs. Vehicle). 3F) demonstrated significant activity in inhibiting ear swell 0218 No significant activity was detected for the other ing 6 hours post sensitization (p<0.001 vs. Vehicle) and main preparation groups in this current model. tained significant activity at 9 hours post sensitization (p<0. 05 vs. Vehicle). Example 3 Betamethasone 4 g/25ul per ear calculated (ED) (Group 0219. A study was undertaken in order to determine the 4F) was active in inhibiting ear Swelling 6 hours post sensi effect of topical application of a combined preparation of tization (p<0.001 vs. Vehicle) but was not active at 9 hours Betamethasone and PEA on earedema in mice. Earthickness post sensitization. was measured before croton oil induced ear Swelling and 6 0228. The single mixture preparation of PEA (1%)+Be and 9 hours post ear edema induction. The preparations were tamethasone 4 g/25 Jul per ear calculated (ED) (Group applied topically 1 hour prior to ear edema sensitization. 3F) was the only preparation that demonstrated significant 0220. The difference in earthickness of the intact ear was activity at 9 hours post sensitization (p<0.05 vs. Vehicle subtracted from the ear thickness of the inflamed ear. This In view of the above results it can be concluded that a prepa value is defined as “ear swelling. ration of PEA (1%)+Betamethasone 4 ug/25ul per ear (Group US 2011/O 195096 A1 Aug. 11, 2011

3F) demonstrated significant activity in inhibiting ear swell tion. (p<0.01 vs. Vehicle) but was not active in inhibiting ing 6 hours post sensitization and continued to demonstrate ear Swelling 9 hours post sensitization. significant activity 9 hours post sensitization 0233. Betamethasone 4 g/25ul per ear calculated was 0229 Topical PEA (1%) preparation (Group 2F) demon active in inhibiting ear Swelling 6 hours post sensitiza strated significant activity in inhibiting ear Swelling 6 hours tion (p<0.001 vs. Vehicle) but was not active at 9 hours post sensitization (p<0.01 vs. Vehicle) but was not active at 9 post sensitization. hours post sensitization. Betamethasone 4 g/25 Jul per ear 0234. A single mixture preparation of PEA (1%)+Be calculated (ED) (Group 4F) demonstrated significant tamethasone 4 ug/25ul per ear demonstrated significant activity in inhibiting ear Swelling 6 hours post sensitization activity in inhibiting ear Swelling 6 hours post sensitiza but was not active at 9 hours post sensitization. tion (p<0.001 vs. Vehicle) and maintained significant activity at 9 hours post sensitization (p<0.05 vs. TABLE 9 Vehicle). 0235 Combination of PEA and Betamethasone pro Mean Group Body Weight (g longed anti-inflammatory activity Treatment and Group # Mean SEM 0236. It is appreciated that certain features of the inven tion, which are, for clarity, described in the context of separate 100% Ethanol (Veh.) (1 F) 18.16 O.42 embodiments, may also be provided in combination in a 1% PEA (2F) 19.08 0.44 1% PEA + Beta. EDmax (3F) 18.62 O.33 single embodiment. Conversely, various features of the Beta. EDmax(4F) 18.45 O.32 invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

TABLE 10

Mean Left Ear Thickness

Mean Left Ear Thickness (mm Day 0 SEM Day -1 Day 0 (9 h Day -1 Day 0 Day 0 Treatment and (24h pre (6 h post post (24h pre (6 h post (9h post Group # sensitization) sensitization) sensitization) sensitization) sensitization) sensitization) 100% Ethanol O.25 O.34 O.38 O.OO3 O.O13 O.O17 (veh.) (1F) 1% PEA (2F) O.25 O.30** O.39 O.OO3 O.OO8 O.O24 196 O.24 0.27* * * 0.31% O.OO3 O.004 O.OO7 PEA+ Beta.EDmax (3F) Beta.EDmax (4F) O.24 0.27* * * O.33 O.OO3 O.OO6 O.O12 *p < 0.05 vs. relevant Vehicle; **p < 0.01 vs. relevant Vehicle; ***p < 0.001 vs. relevant Vehicle

0237 Although the invention has been described in con TABLE 11 junction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be appar Mean Left Ear Delta Thickness ent to those skilled in the art. Accordingly, it is intended to Delta + Delta + embrace all Such alternatives, modifications and variations 6h vs 9hvS 6h 9h that fall within the spirit and broad scope of the appended Treatment Group # baseline baseline SEM SEM claims. All publications, patents and patent applications men 100% Ethanol (veh.)(1F) O.098 O.133 O.O13 OO16 tioned in this specification a herein incorporated in their 1% PEA(2F) 0.056* O.147 O.OO9 O.O24 entirety by reference into the specification, to the same extent 1% PEA+ Beta. EDmax(3F) 0.032** 0.066** O.005 O.OO6 as if each individual publication, patent or patent application Beta. EDmax(4F) O.O36** O.O92ii O.OOS O.O11 was specifically and individually indicated to be incorporated #p < 0.1, herein by reference. In addition, citation or identification of *p < 0.05 vs. Vehicle, any reference in this application shall not be construed as an **p < 0.01 vs Vehicle admission that such reference is available as prior art to the 0230 Conclusions present invention. 0231 Significant ear swelling was measured 6 hours and 9 hours post sensitization in Vehicle treated group. 1. A composition-of-matter comprising an N-acylethano Earthickness increased by 0.9 mm 6 hours post sensiti lamine compound and a corticosteroid. zation and increased by 0.13 mm 9 hours post sensitiza 2. The composition-of-matter of claim 1, wherein said tion. N-acylethanolamine compound is N-palmitoylethanolamine. 0232 PEA 1% preparation demonstrated significant 3. The composition-of-matter of claim 1, wherein said activity in inhibiting ear Swelling 6 hours post sensitiza corticosteroid is a low potency corticosteroid. US 2011/O 195096 A1 Aug. 11, 2011 20

4. A pharmaceutical composition comprising the compo 23. A composition-of-matter comprising a GABA agonist sition-of-matter of claim 1 and a pharmaceutically acceptable and a corticosteroid. carrier. 24. The composition-of-matter of claim 23, wherein said 5. The pharmaceutical composition of claim 4, wherein GABA agonist is selected from the group consisting of topi said pharmaceutically acceptable carrier is Suitable for topi ramate, muscimol, progabide, riluzole, baclofen, gabapentin, cal administration. vigabatrin, Valproic acid, tiagabine, lamotrigine, pregabalin, 6. The pharmaceutical composition of claim 4, wherein phenyloin, and carbamazepine. said pharmaceutically acceptable carrier is suitable for 25. A composition-of-matter comprising a monoamine mucosal administration. oxidase inhibitor (MAOI), and a corticosteroid. 7. The pharmaceutical composition of claim 4, wherein 26. The composition-of-matter of claim 25, wherein said said pharmaceutically acceptable carrier is Suitable for oral monoamine oxidase inhibitor is selected from the group con administration. sisting of moclobemide, clorgiline, iproclozide, iproniazid, 8. The pharmaceutical composition of claim 4, wherein isocarboxazid, minaprine, nialamide, pargyline, phenelzine, said N-acylethanolamine compound is N-palmitoylethanola rasagiline, selegiline, toloxatone, tranylcypromine, furazoli mine. done, and procarbazine. 9. The pharmaceutical composition of claim 4, wherein 27. A composition-of-matter comprising a cannabinoid said corticosteroid is hydrocortisone. receptor agonist and a corticosteroid. 10. A medical device comprising the composition-of-mat 28. The composition-of-matter of claim 27, wherein said ter of claim 1. cannabinoid receptor agonist is selected from the group con 11. The medical device of claim 10, wherein said compo sisting of cannabidiol (CBD), cannabidivarol (CBDV), can sition-of-matter forms a coating of the medical device. nabinol (CBN), cannabigerol (CBG), cannabivarol (CBV), 12. A method for treating an inflammatory disorder com cannabicyclol (CBL), tetrahydrocannabinol (THC), tetrahy prising administering to a subject in need thereof a composi drocannabinol-C4. (THC-C4), tetrahydrocannabivarin, tion comprising an N-acylethanolamine compound and a cor 11-Hydroxy-A-tetrahydrocannabinol, (11-OH-THC), and ticosteroid, thereby treating the inflammatory disorder. 11-nor-9-Carboxy-A9-tetrahydrocannabinol. 13. The method of claim 12, wherein said N-acylethanola mine compound is N-palmitoylethanolamine. 29. A composition-of-matter comprising an inhibitor of an 14. The method of claim 12, wherein said corticosteroid is immunophilin and a low-potency corticosteroid. a low-potency corticosteroid. 30. The composition-of-matter of claim 29, wherein said 15. The method of claim 12, wherein said corticosteroid is inhibitor of an immunophilin is selected from the group con hydrocortisone. sisting of FK 1706, GPI 1046, GPI 1485, GM-284, (3R)-4- 16. The method of claim 12, wherein said inflammatory (p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-Leu disorder is caused by a cutaneous inflammatory disease or cine ethyl ester and (3R)-4-(p-Toluenesulfonyl)-1,4- disorder and said administering is effected via topical deliv (thiazane-3-carboxylic acid-L-phenylalanine benzyl ester. ery. 31. A pharmaceutical composition comprising the compo 17. The method of claim 16, wherein said cutaneous sition-of-matter of claim 21 and a pharmaceutically accept inflammatory disease is selected from the group consisting of able carrier selected for topical delivery. psoriasis, atopic dermatitis and Scleroderma. 32. A pharmaceutical composition comprising the compo 18. The method of claim 12, wherein said inflammatory sition-of-matter of claim 23 and a pharmaceutically accept disorder is caused by asthma and said administering is able carrier selected for topical delivery. effected via inhalation. 33. A pharmaceutical composition comprising the compo 19. The method of claim 12, wherein said inflammatory sition-of-matter of claim 25 and a pharmaceutically accept disorder is caused by gastrointestinal inflammation. able carrier selected for topical delivery. 20. The method of claim 12, wherein said inflammatory 34. A pharmaceutical composition comprising the compo disorder is caused by ocular inflammation. sition-of-matter of claim 27 and a pharmaceutically accept 21. A composition-of-matter comprising a corticosteroid able carrier selected for topical delivery. and a tricyclic antidepressant. 35. A pharmaceutical composition comprising the compo 22. The composition-of-matter of claim 21, wherein said sition-of-matter of claim 29 and a pharmaceutically accept tricyclic antidepressant is selected from the group consisting able carrier selected for topical delivery. of amitriptyline, maprotiline, clomipramine, desipramine, imipramine, trimipramine, nortriptyline, and protriptyline c c c c c