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(11) EP 1 765 376 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/198 (2006.01) A61K 8/44 (2006.01) 10.04.2013 Bulletin 2013/15 A61K 8/46 (2006.01) A61K 8/49 (2006.01) A61K 9/00 (2006.01) A61Q 19/00 (2006.01) (21) Application number: 05757465.9 (86) International application number: (22) Date of filing: 13.06.2005 PCT/US2005/020555

(87) International publication number: WO 2005/123103 (29.12.2005 Gazette 2005/52)

(54) Topical compositions and use thereof for the treatment of epithelial-related conditions Topische Zusammensetzungen und Verwendung davon zur Behandlung von epithelialbedingte Leiden Compositions topiques et utilisation de celles-ci pour lutter contre des maladies epitheliales

(84) Designated Contracting States: (74) Representative: ABG Patentes, S.L. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Avenida de Burgos, 16D HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR Edificio Euromor 28036 Madrid (ES) (30) Priority: 12.06.2004 US 579093 P 14.02.2005 US 652921 P (56) References cited: WO-A-2004/087064 US-A- 5 043 268 (43) Date of publication of application: US-A- 5 202 456 US-A- 5 202 456 28.03.2007 Bulletin 2007/13 US-A- 5 705 528

(73) Proprietor: SIGNUM BIOSCIENCES, INC. • CLARKE ET AL: "Ras antagonist Monmouth Junction, NJ 08852 (US) farnesylthiosalicylic acid (FTS) reduces glomerularcellular proliferation and macrophage (72) Inventors: number in rat Thy- 1 nephritis" JOURNAL OF THE • STOCK, Jeffry B. AMERICAN SOCIETY OF NEPHROLOGY, vol. 14, Rocky Hill, NJ 08553 (US) 2003, pages 848-854, XP002518799 • GORDON, Joel • DING J ET AL: "FARNESYL-L-CYSTEINE Princeton Junction, NJ 08550 (US) ANALOGS CAN INHIBIT OR INITIATE • STOCK, Maxwell SUPEROXIDE RELEASE BY HUMAN Rocky Hill, NJ 08553 (US) NEUTROPHILS" JOURNAL OF BIOLOGICAL • STOCK, Gregory CHEMISTRY, AMERICAN SOCIETY OF Princeton, NJ 08542 (US) BIOLOCHEMICAL BIOLOGISTS, BIRMINGHAM,; US, vol. 269, no. 24, 17 June 1994 (1994-06-17), pages 16837-16844, XP001151963 ISSN: 0021-9258

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 765 376 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 1 765 376 B1 2

Description they interact, or other intracellular signaling proteins, can be used to mitigate leukocyte responses and, theoreti- CROSS REFERENCE TO RELATED APPLICATIONS cally, to treat inflammatory-related conditions. (see e. g. Volker et al., Methods Enzymol., 1995,250, 216-225). [0001] This application claims the benefit of priority of 5 WO 2004/087064 describes a method for the treatment U.S. Provisional Application No. 60/579,093 filed on June of neoplasia, including cancer and other diseases and 12, 2004. This application also claims the benefit of pri- conditions in humans and mammals. More particularly, ority of U.S. Provisional Patent Application No.it provides a method for the use of prenylcysteine analogs 60/652,921 filed on February 14, 2005. The entire dis- for the treatment of neoplasia, hyperproliferative cell closures of U.S. Provisional Patent Application No.10 growth including psoriasis, restenosis following cardio- 60/597,093 and U.S. Provisional Patent Application No. vascular surgery, hyperplasia, including renal hyperpla- 60/652,921 are herein incorporated by reference. sia, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others. US5043268 describes FIELD OF THE INVENTION a specific class of compounds as substrates and/or in- 15 hibitors specifically for prenyl cysteine methyltransferase [0002] The present invention relates to pharmaceuti- enzymes which catalyze the methyl transfer from S-ad- cal, cosmetic and cosmeceutical topical compositions enosylmethionine to the C-termini of proteins and pep- containing polyisoprenyl-protein inhibitor compounds tides with prenylated cysteine residus at their C-termini. and methods useful in the promotion of healthy epitheli- The compounds, as substrates, are described as being um and the treatment of epithelial-related conditions. 20 particularly suitable for use in assays for qualitatively or quantitatively detecting the farnesyl cysteine methyl- BACKGROUND OF THE INVENTION transferase enzymes. [0006] One such compound is N-acetylfar- [0003] Many skin or mucosal membrane conditions or nesyl-cysteine (AFC). AFC has been shown to inhibit disorders result from inflammation caused by, inter alia 25 membrane-associated polyisoprenoid methyl trans- bacteria, fungi, viruses, parasites, autoimmune disor- ferase and to block some neutrophil, macrophage, and ders, allergens, environmental conditions, such as ex- platelet responses in vitro. Unfortunately, AFC requires treme temperatures, wounds, hormones and/or malig- high concentrations for efficacy and is expected to result nant agents. Thus, inflammation can be associated with in generalized systemic effects and multiple side effects numerous underlying conditions ranging from dry skin to 30 since it interferes with a central cell regulation mecha- infections to cancer, as well as being symptomatic of in- nism, characteristics which would seem to preclude its flammatory disorders such as dermatitis. use in vivo. However, because such inhibitory com- [0004] Inflammation is often characterized by a strong pounds have the potential to be highly efficacious, there infiltration of leukocytes at the site of inflammation, par- is a need in the art for compositions containing these ticularly neutrophils (polymorphonuclear cells). These 35 compounds that can act as a safe and effective antidote cells promote tissue damage by releasing toxic substanc- for skin and mucosal membrane conditions. es at the vascular wall or in uninjured tissue. [0007] The invention provides a topical composition [0005] Neutrophil infiltration results from amplifying comprising: cascades of cell-cell communication involving signal transduction proteins such as G-proteins that can facili- 40 at least one polyisoprenyl-protein inhibitor com- tate intracellular regulation and intercellular communica- pound, wherein the at least one polyisoprenyl-pro- tion by interactingwith a widerange of different regulatory tein inhibitor compound comprises a compound of receptor-transducer proteins such as membrane-bound Formula 1; receptors. For these interactions to occur, many of the signal transduction proteins, including virtually all G- pro- 45 teins, must first be modified by the post- translational ad- dition of a C 15 farnesyl or C20 geranylgeranyl polyiso- prenoid moiety in thioether linkage to a cysteine residue located at or near the carboxy terminus within a so- called or its pharmaceutically acceptable salts and esters CAAX box or related cysteine- containing sequence. Car- 50 thereof, wherein boxy terminal polyisoprenoid cysteines that ultimately re- R1 is alkyl of 1 to 3 carbon atoms; 2 sult from these modifications are subject to methylester- R is --COX; wherein X is --OH, --OCH3, --NH2, 4 4 ification by a specific membrane-associated S- adenosyl- --NHR , --N(R )2 or halogen; methionine-dependent polyisoprenyl-S-cysteinyl meth- R3 is a straight or branched chain alkyl of 10 to 25 yltransferase. Compounds that can inhibit these enzy- 55 carbon atoms or a straight or branched chain alkenyl matic reactions or otherwise alter the interactions among of 10 to 25 carbon atoms; and polyisoprenylated signal transduction proteins, such as R4 is an alkyl of 1 to 25 carbon atoms; and a carrier; G-proteins and the protein regulatory targets with which

2 3 EP 1 765 376 B1 4 wherein said topical composition is in the form of a pow- 10 to 25 carbon atoms; and R 4 is an alkyl of 1 to 25 carbon der, an oil, a cream, a gel, or a bandage, and wherein atoms; and the topicalcomposition is formulatedto deliveran amount wherein the topical composition is formulated to deliver of at least one polyisoprenyl-protein inhibitor compound an amount of the at least one polyisoprenyl-protein in- that is effective to inhibit inflammation when applied top- 5 hibitor compound that is effective to inhibit inflammation ically. when applied topically. [0008] In another embodiment, provided herein is a topical composition comprising at least one polyisopre- BRIEF DESCRIPTION OF THE FIGURES nyl-protein inhibitor compound selected from the group consisting of S-farnesylcysteine, N-acetyl-S-geranyl- 10 [0012] FIG 1. Induction of edema by TPA cysteine, N-acetyl-S-farnesylcysteine ("AFC"), also re- [0013] FIG 2. AFC, alone, does not cause mouse ear ferred to as N-acetyl-S-trans, trans-famesyl-L-cysteine, edema. N-acetyl-S-geranylgeranylcysteine ("AGGC"), far- S- [0014] FIG 3. AFC inhibits TPA-induced edema nesyl-2-mercaptoethanesulfonic acid, farnesylthio- S- [0015] FIG 4. AFC treatment produces a dose depend- , S-farnesylmercaptosuccinic acid, S-far- 15 ent inhibition of TPA-induced MPO nesylthiotriazole, S-farnesylthiosalicylic acid ("FTS"), S- [0016] FIG 5. Histology of AFC inhibition of neutrophil farnesylthiosuccinic acid, 2-chloro-5-farnesylaminoben- infiltration zoic acid, 2-famesyl-thionicotinic acid ("FTN"), 5-fluoro- [0017] FIG 6. AFC inhibits TPA-induced neutrophil in- FTS, 5-chloro-FTS, 4-chloro-FTS, S-farnesyl-methylthi- filtration osalicylic acid and combinations thereof; and a carrier; 20 [0018] FIG 7. AFC inhibition of TPA-induced MPO ac- wherein said topical composition is in the form of a pow- tivity at different application times der, an oil, a cream, a gel, or a bandage, and wherein [0019] FIG 8A. AFC does not effect TPA-induced MPO the topicalcomposition is formulatedto deliveran amount activity in the contralateral vehicle treated ear. of at least one polyisoprenyl-protein inhibitor compound [0020] FIG 8B. Dexamethasone acts to increase inhi- that is effective to inhibit inflammation when applied top- 25 bition of TPA-induced MPO activity in the contralateral ically. vehicle treated ear [0009] In a further embodiment, the invention provides [0021] FIG 8C. Indomethacin acts to increase inhibi- a topical composition comprising N-acetyl-S-far-tion of TPA-induced MPO activity in the contralateral ve- nesyl-cysteine; and hicle treated ear. a carrier; 30 [0022] FIG 9. AFC inhibits AA-induced induced MPO. wherein said topical composition is in the form of a pow- [0023] FIG 10. AFC reduces TPA-induced erythema der, an oil, a cream, a gel, or a bandage, and wherein [0024] FIG 11. Inhibition of contact dermatitis in a vol- the topicalcomposition is formulatedto deliveran amount unteer of at least one polyisoprenyl-protein inhibitor compound that is effective to inhibit inflammation when applied top- 35 DETAILED DESCRIPTION OF THE INVENTION ically [0010] In another embodiment, provided herein, is a [0025] Surprisingly, the inventors have recognized that composition for use as a medicament for topical applica- inventive compositions containing polyisoprenyl-protein tion to a mammal, including a human, for the treatment inhibitor compounds such as AFC can be used effectively or prevention of a condition associated with inflammation 40 in topical applications to promote healthy epithelia or to in the mammal. treat epithelial-related disorders. These inventive com- [0011] In a further embodiment, the invention provides positions do not exhibit systemic effects when topically a method of preparing a topical composition, the method applied. Such inventive compositions are useful for, inter comprising admixing at least one polyisoprenyl-protein alia, their soothing, moisturizing and detergent proper- inhibitor compound and a carrier to form a powder, an 45 ties, for treating cosmetic conditions and/or for generally oil, a cream, a gel, or a bandage, promoting healthy skin. The compositions of the present wherein the at least one polyisoprenyl-protein inhibitor invention may be usefully employed in cosmetic, cos- compound comprises a compound of Formula 1 meceutical and general skincare compositions as well as in pharmaceutical compositions. 50 [0026] The phrase "epithelia" or "epithelial" or "epithe- lial tissues" as used throughout the specification and claims is meant to include skin and mucosal membranes. Thus, the present invention offers compositions useful or its pharmaceutically acceptable salts and esters there- for treating a condition of the skin or a mucosal mem- of wherein R 1 is alkyl of 1 to 3 carbon atoms; R 2 is -- COX; 55 brane, such as, but not limited to, that of a nose, a mouth, 4 4 wherein X is -- OH, --OCH3, --NH2, NHR ,-N(R )2 or hal- an eye, an ear, a vagina and a rectum. ogen; R3 is a straight or branched chain alkyl of 10 to 25 [0027] The term "topical" refers to administration of an carbon atoms or a straight or branched chain alkenyl of inventive composition at, or immediately beneath, the

3 5 EP 1 765 376 B1 6 point of application. action inhibit G-protein-mediated inflammatory respons- [0028] The phrase "topically applying" describes appli- es. Consequently, it is believed that polyisoprenyl-S- cation onto one or more surfaces(s) including epithelial cysteine carboxyl methyltransferase inhibitors may serve surfaces. "Topically applying" refers to direct application as anti-inflammatory agents (Volker et al., Methods En- to the area of the surface to be affected. The composition 5 zymol., 1995,250,216-225). may be applied by pouring, dropping, or spraying, if a [0036] Other preferred mechanisms for G-protein inhi- liquid; rubbing on, if an ointment, lotion, cream, gel, or bition are discussed in Volker, C., Miller, R.A., McCleary, thelike; dusting, if a powder;spraying, if a liquid or aerosol W.R., Rao, A., Poenie, M., Backer, J.M., and Stock, J.B. composition; or by any other appropriate means. (1991), Effects of farnesylcysteine analogs on protein [0029] In one embodiment, the composition of the in- 10 carboxyl methylation and signal transduction. J. Biol. vention is a pharmaceutical composition. As used herein, Chem. 266, 21515-21522. a "pharmaceutical composition" refers to a composition [0037] Non-limiting examples ofpolyisoprenyl-protein that is employed to prevent, reduce in intensity, cure or inhibitor compounds for use in the composition of the otherwise treat a target condition or disease. present invention are described in US Patent 5,043,268 [0030] As used herein a "cosmetic composition’ refers 15 issued August 27, 1992 to Jeffry B. Stock; U.S. Patent to a composition that is intended to be rubbed, poured, 5,202,456, issued April 13, 1993 to Robert R. Rando; sprinkled, or sprayed on, introduced into, or otherwise U.S. Patent 5,705,528 issued January 6, 1998 to Yoel applied to a subject or any part thereof for cleansing, Kloog; U.S. Patent 6,096,740 issued August 1, 2000 to beautifying, promoting attractiveness, or altering the ap- Mechoulam, et al.; U.S. Patent 5,521,215 issued May pearance, or an article intended for use as a component 20 28, 1996 to Mechoulam; U.S. Patent 5,284,867 issued of any sucharticle, except that such termdoes not include February 8, 1994 to Mechoulam; U. S. Patent 6,482,086 soap. to Kloog issued Oct. 8, 2002; U.S. Patent Application [0031] As used herein the term "cosmeceutical com- 2003/0203942A1 published Oct. 30, 2003; U.S. Patent position" refers to a composition that is employed as both No. 6,372, 793 issued April 6, 2002 to Nazarius S. La- a cosmetic composition and as a pharmaceutical com- 25 mango and J. Invest. Dermatol. 2003 Jan; 120(1): 109-15 position. by Halaschek-Wiener, et al. [0032] In another embodiment, the composition in- Other compounds include cannabinoids such asΔ -tet- cludes one or more polyisoprenyl-protein inhibitor com- rahydrocannabinol (THC) and cannabidiol; certain un- pounds and a carrier. saturated fatty acids such as linoleic acids and omega- [0033] As used herein "polyisoprenyl-protein inhibitor 30 3 fatty acids. Additional useful polyisoprenyl- protein s can compound" refers to a compound that can inhibit or re- be found in Volker, C.R.. 1995. Carboxyl Methylation at duce the activity of a polyisoprenylated protein such as C-terminal S-prenylcysteine residues. Ph.D. thesis, Prin- a G-protein. As used herein a "G-protein" refers to het- ceton University, Princeton, NJ. It should be understood erotrimeric G-proteins that associate with receptors of that analogs of these compounds that show this inhibitor the seven transmembrane domain superfamily and are 35 activity are also useful, as are compounds having differ- involved in signal transduction and the small GTP-bind- ent structural characteristics than those described. ing signal transduction proteins that act to regulate cel- [0038] In one embodiment, preferred compounds in- lular processes, including but not limited to cytoskeletal clude pharmaceutically-acceptable salts and esters of organization, secretion and any other protein that is sub- those set forth in U.S. Patent 5,043,268 represented by ject to polyiso- prenylation, such as, but not limited to, 40 Formula (I) above. arrestin and nuclear laminar proteins. [0039] As used herein the term a "pharmaceutical- [0034] Without being limited by theory, compounds ly-acceptable salt" refers to salts generally that are pre- known in the art to inhibit or reduce G-protein signal trans- pared by reacting a free base with a suitable organic or ducing activity act by, inter alia, effecting the ability of a inorganic acid or by reacting an acid with a suitable or- G-protein to bind to an interacting regulatory target pro- 45 ganic or inorganic base, wherein a basic group or an tein that is frequently, although not always, located in a acidic group is present in the compound of the inventive cellular membrane. In order to interact with these regu- composition. latory target proteins, G proteins and related polyisopre- [0040] As used herein, the term "alkyl" refers to a nylated proteins undergo several post- translational mod- straight or branched chain hydrocarbon, optionally sub- ifications including covalent attachment of a farnesyl or 50 stituted with lower alkyl or cycloalkyl substituents, with geranylgeranyl moiety in thioether linkage to cysteine multiple degrees of substitution being allowed. As used residues located at or in close proximity to their carboxy herein, "cycloalkyl" refers to an alicyclic hydrocarbon termini and methylesterification of exposed terminal far- group optionally possessing one or more degrees of un- nesyl- or geranylgeranyl-S-cysteinyl residues. saturation, having from three to twelve carbon atoms, [0035] Inflammatory agonists stimulate the methyles- 55 optionally substituted with nitrogen, oxygen, or sulfur. terification of polyisoprenyl-S-cysteinyl residues of some "Cycloalkyl" includes by way of example cyclopropyl, cy- G-proteins (Volker et al., Methods Enzymol., 1995, 250, clobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooc- 216-225). Agents that inhibit this methylesterification re- tyl, and the like

4 7 EP 1 765 376 B1 8

[0041] The term "straight or branched chain alkyl" as farnesylmercaptosuccinic acid, famesylthiotriazole, used for R 3 denotes groups including decyl, undecyl, do- famesylthiosuccinic acid, farnesyl-thiosalicylic acid dedecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, de- ("FTS"), 2-chloro-5-farnesylaminobenzoic acid, 2-far- cosyl, tricosyl, tetracosyl, pentacosyl, and the branched nesyl-thionicotinic acid("FTN"), 5-fluoro-FTS, 5-chloro- isomers thereof. 5 FTS, 4-chloro-FTS, and S-farnesyl-methylthiosalicylic [0042] The term "straight or branched chain alkenyl" acid. refers to a hydrocarbon moiety having at least one car- [0050] In another preferred embodiment, AGGC and bon-carbon double bond , which can be optionally sub- AFC are used in combination. stituted with a nitrogen-carbon double bond (including [0051] In a more preferred embodiment, AFC is used polyunsaturated alkenyl). Alkenyl as used herein for R3 10 in the inventive composition. denotes groups including decenyl, undecenyl, dodece- [0052] In another embodiment, two or more polyiso- nyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, prenyl-protein inhibitor compounds are used in the inven- heneicosenyl, docosenyl, tricosenyl, tetracosenyl, pen- tive composition to obtain a specific pharmaceutical or tacosenyl, the branched chain isomers thereof, and pol- cosmetic effect. yunsaturated alkenes including octadec- 9,12-dienyl, oc- 15 [0053] In one embodiment, polyisoprenyl-protein in- tadec-9,12,15-trienyl, and eicos-5,8,11,14-tetraenyl. hibitor compounds prevent post-translational carboxyl [0043] In a preferred embodiment, R 2 is -COOH. When methylation. R2 is -COOH, the alkali metal, alkaline earth metal, am- [0054] Inanother embodimentof thepresent invention, monium, and substituted ammonium salts thereof are de- polyisoprenyl-protein inhibitor compounds act by inhibit- sired. 20 ing polyisoprenyl cysteine methyltransferase. [0044] In another preferred embodiment, R 1 is methyl. [0055] In another embodiment, the polyisoprenyl-pro- In yet another preferred embodiment, R3 is farnesyl. tein inhibitor compound is contained within a botanical [0045] Even more preferably, 1 R is methyl, 2 R is extract. Botanical extracts may be assayed for polyiso- COOH, and R3 is farnesyl. prenyl-protein inhibitor activity by using the methods de- [0046] In yet another preferred embodiment, R 1 is me- 25 scribed in the example section below. As used herein a 3 thyl, X is -OCH3, and R is farnesyl. "botanical extract" refers to a fresh or processed (e.g. [0047] Regarding the farnesyl and geranylgeranyl moi- cleaned, frozen, dried, sliced, liquified) part of a single eties, hydrogen generally may be replaced by fluorine, species of plant or a fresh or processed alga or macro- and a methyl group may generally be replaced by a bro- scopic fungus. mine. Accordingly, "substituted farnesyl group" means a 30 [0056] In another embodiment, the polyisoprenyl-pro- farnesyl moiety in which one or more hydrogens have tein inhibitor compound is contained within a bacterial been replaced by fluorine or one or more methyl groups extract. Bacterial extracts likewise can be assayed for have been replaced by a bromine, and "substituted ger- polyisoprenyl-protein inhibitor activity according to the anylgeranyl group" means a geranylgeranyl moiety in methods described in herein. which one or more hydrogens have been replaced by 35 [0057] In another aspect of the present invention, the fluorine or one or more methyl groups have been re- composition of the present invention includes a carrier. placed by bromine. In addition, the C=C double bonds in As used herein "carrier" describes a material that does the farnesyl or geranylgeranyl groups may be replaced not abrogate the biological activity and properties of the bysingle bonds with theconcurrent addition of hydrogens polyisoprenyl-protein inhibitor compound of the compo- and/or halogens to the participating carbons. 40 sition of the present invention. Carriers must be of suffi- [0048] In a preferred embodiment, the compounds for ciently high purity and of sufficiently low toxicity to render use in the composition of the invention are S-farnesyl- them suitable for administration to the mammal being cysteine, N-acetyl-S-geranylcysteine, N-acetyl-S-far- treated. The carrier can be inert, or it can possess phar- nesylcysteine ("AFC"), also referred to as N-acetyl-S- maceutical benefits, cosmetic benefits or both. trans, trans-famesyl-L-cysteine, N-acetyl-S-geranylger- 45 [0058] Some non-limiting representative examples of anylcysteine ("AGGC"), S-farnesyl-2-mercaptoethane- carriers include moisturizing agents or humectants, pH sulfonic acid, S-farnesylthioacetic acid, S-farnesylmer- adjusting agents, a deodorant agent, fragrances, hair captosuccinic acid, S-farnesylthiotriazole, S-farnesylthi- conditioning agents, chelating agents, preservatives, osalicylic acid ("FTS"), S-farnesylthiosuccinic acid, 2- emulsifiers, thickeners, solubilizing agents, penetration chloro-5-farnesylaminobenzoic acid, 2-farnesyl-thionic- 50 enhancers, anti-irritants, colorants and surfactants. otinic acid("FTN"), 5-fluoro-FTS, 5-chloro-FTS, 4-chloro- [0059] As used herein a "moisturizing agent" is a sub- FTS, S-farnesyl-methylthiosalicylic acid or combinations stance that adds or restores moisture to the skin. Rep- thereof. resentative examples of moisturizing or humectant [0049] In a more preferred embodiment, the inventive agents that are usable in the present invention include, compositions contain one or more of farnesylcysteine, 55 without limitation, guanidine, glycolic acid and glycolate N-acetylgeranylcysteine, N-acetylfamesylcysteine ("AF- salts (e.g. ammonium salt and quaternary alkyl ammo- C"), N-acetylgeranylgeranylcysteine("AGGC"), farnesyl- nium salt), aloe vera in any of its variety of forms (e.g., 2-mercaptoethanesulfonic acid, farnesylthioacetic acid, aloe vera gel), allantoin, urazole, polyhydroxy alcohols

5 9 EP 1 765 376 B1 10 such as sorbitol, glycerol, hexanetriol, propylene glycol, ols, quaternary ammonium compounds, halogenated butylene glycol, hexylene glycol and the like, polyethyl- quaternary ammonium compounds, alkoxylated carbox- ene glycols, sugars and starches, sugar and starch de- ylic acids, alkoxylated alcohols, alkoxylated amides, rivatives (e.g., alkoxylated glucose), hyaluronic acid, sorbitan derivatives, esters, polymeric ethers, glyceryl lactamide monoethanolamine, acetamide monoeth-5 esters, or any combinations thereof. anolamine and any combination thereof. [0065] Chelating agents are optionally added to the [0060] As is widely recognized in the art, since the pH compositions of the present invention so as to enhance of the skin is 5.5, compositions for topical skin application the preservative or preservative system. Preferred (to avoid irritation) should preferably have a pH value of chelating agents are mild agents, such as, for example, between 4.0 and 7.0, preferably between 5.0 and 6.0, 10 ethylenediaminetetraacetic acid (EDTA), EDTA deriva- most preferably about 5.5 or substantially 5.5. Hence, a tives, or any combination thereof. pH adjusting composition is typically added to bring the [0066] Suitable preservatives for use in the composi- pH of the composition to the desired value. The compo- tions of the present composition include, without limita- sitions of the present invention therefore preferably are tion, one or more alkanols, disodium EDTA (ethylenedi- formulated to have a pH value that ranges between about 15 amine tetraacetate), EDTA salts, EDTA fatty acid conju- 4.0 and about 7.0, more preferably between about 5.0 gates, isothiazolinone, parabens such as methylparaben and about 6.0. and propylparaben, propylene glycols, sorbates, urea [0061] Suitable pH adjusting agents include, for exam- derivatives such as diazolindinyl urea, or any combina- ple, but are not limited to, one or more adipic acids, gly- tions thereof. cines, citric acids, calcium hydroxides, magnesium alu- 20 [0067] "Emulsifiers" as used herein promote the for- minometasilicates, buffers or any combinations thereof. mation and stabilization of an emulsion. Suitable emul- [0062] As used herein "deodorant agent" refers to a sifiers may be natural materials, finely divided solids, or substance for inhibiting or masking perspiration or other synthetic materials. Natural emulsifying agents may be bodily odors. Representative examples of deodorant derived from either animal or vegetable sources. Those agents that are usable in the context of the present in- 25 from animal sources include gelatin, egg yolk, casein, vention include, without limitation, quaternary ammoni- wool fat, or cholesterol. Those from vegetable sources um compounds such as cetyl-trimethylammonium bro- include acacia, tragacanth, chondrus, or pectin. Vegeta- mide, cetyl pyridinium chloride, benzethonium chloride, ble sources specifically from cellulose derivatives include diisobutyl phenoxy ethoxy ethyl dimethyl benzyl ammo- methyl cellulose and carboxymethyl cellulose to increase nium chloride, sodium N-lauryl sarcosine, sodium N- 30 the viscosity. Finely divided emulsifiers include ben- palmIthyl sarcosine, lauroyl sarcosine, N-myristoyl gly- tonite, magnesium hydroxide, aluminum hydroxide, or cine, potassium N- lauryl sarcosine, stearyl, trimethyl am- magnesium trisylicate. Synthetic agents include anionic, monium chloride, sodium aluminum chlorohydroxy lac- cationic or nonionic agents. Particularly useful are sodi- tate, tricetylmethyl ammonium chloride, 2,4,4’-trichloro- um lauryl sulfate, benzalkonium chloride or polyethylene 2’-hydroxy diphenyl ether, diaminoalkyl amides such as 35 glycol 400 monostearate, or any combinations thereof. L-lysine hexadecyl amide, heavy metal salts of citrate, [0068] "Thickeners" as used herein refer to agents that salicylate, and piroctose, especially zinc salts, and acids make the composition of the present invention dense or thereof, heavy metal salts of pyrithione, especially zinc viscous in consistency. Suitable thickeners that can be pyrithione and zinc phenolsulfate. Other deodorant used in the context of the present invention include, for agents include, without limitation, odor absorbing mate- 40 example, non-ionic water-soluble polymers such as hy- rials such as carbonate and bicarbonate salts, e.g. as droxyethylcellulose (commercially available under the the alkali metal carbonates and bicarbonates, ammoni- Trademark NatrosolRTM 250 or 350), cationic water-sol- um and tetraalkylammonium carbonates and bicarbo- uble polymers such as Polyquat 37 (commercially avail- nates, especially the sodium and potassium salts, or any able under the Trademark Synthalen RTM CN), fatty alco- combination of the above. Antiperspirant agents can be 45 hols, fatty acids, anionic polymers, and their alkali salts incorporated in the compositions of the present invention and mixtures thereof. either in a solubilized or a particulate form and include, [0069] As used herein "solubilizing agents" are those for example, aluminum or zirconium astringent salts or substances that enable solutes to dissolve. Represent- complexes. ative examples of solubilizing agents that are usable in [0063] As used herein "fragrance" refers to a sub-50 the context of the present invention include, without lim- stance having a pleasant aroma. Suitable fragrances in- itation, complex-forming solubilizers such as citric acid, clude, but are not limited to, eucalyptus oil, camphor syn- ethylenediamine-tetraacetate, sodium meta-phosphate, thetic, peppermint oil, clove oil, lavender, chamomile and succinicacid, urea, cyclodextrin, polyvinylpyrrolidone, di- the like. ethylammonium-ortho-benzoate, and micdle-forming [0064] Suitable hair conditioning agents that can be 55 solubilizers such as TWEEN® and spans, e.g., TWEEN used in the context of the present invention include, for 80®. Other solubilizers that are usable for the composi- example, one or more collagens, cationic surfactants, tions of the present invention are, for example, polyox- modified silicones, proteins, keratins, dimethicone poly- yethylene sorbitan fatty acid ester, polyoxyethylene n-

6 11 EP 1 765 376 B1 12 alkylethers, n- alkylamine n- oxides,polyoxamers, organ- fates, ammonium alkyl sulfates, sodium alkyleth sulfates, ic solvents, such as acetone, phospholipids and cyclo- ammonium alkyleth sulfates, and combinations thereof. dextrins. [0076] In another embodiment, the inventive composi- [0070] A "penetration enhancer" is an agent known to tions are incorporated into a carrier which may be in the accelerate the delivery of a substance through the skin. 5 form of a mouthwash, rinse, oral spray, suspension, den- Suitable penetration enhancers usable in the present in- tal gel, and the like. Typical oral carriers known in the art vention include, but are not limited to, dimethylsulfoxide may be used in the present invention. The preferred phar- (DMSO), dimethyl formamide (DMF), allantoin, urazole, maceutical and/or cosmetic carriers are water, ethanol, N,N-dimethylacetamide (DMA), decylmethylsulfoxide and water-ethanol mixtures. The water- ethanol mixtures 10 (C10MSO), polyethylene glycol monolaurate (PEGML), are generally employed in a weight ratio from about 1:1 propylene glycol (PG), propylene glycol monolaurate to about 20:1, preferably from about 3:1 to about 20:1, (PGML), glycerol monolaurate (GML), lecithin, the 1- sub- and most preferably from about 3:1 to about 10:1, re- stituted azacycloheptan-2-ones, particularly n-do- 1- spectively. The pH value of the oral vehicle is generally decylcyclazacycloheptan-2-one (available under the from about 4 to about 7, and preferably from about 5 to trademark AzoneRTM from Whitby Research Incorporat- 15 about 6.5. An oral topical vehicle having a pH value below ed, Richmond, Va.), alcohols, and the like. The perme- about 4 is generally irritating to the oral cavity and an oral ation enhancer may also be a vegetable oil. Such oils vehicle having a pH value greater than about 7 generally include, for example, safflower oil, cottonseed oil and results in an unpleasant mouth feel. corn oil. [0077] The oral topical inventive compositions may al- [0071] Additional thickeners, penetration enhancers 20 so contain conventional additives normally employed in and other adjuvants may generally be found in Reming- those products. Conventional additives include a fluorine ton’s Pharmaceutical Sciences, 18th or 19th editions, providing compound, a sweetening agent, a coloring published by the Mack Publishing Company of Easton, agent, a humectant, a pH adjusting agent, and an emul- Pennsylvania. sifier, providing the additives do not interfere with the [0072] As used herein, an "anti-irritant" is an agent that 25 therapeutic or cosmetically beneficial properties of the prevents or reduces soreness, roughness, or inflamma- inventive compositions. tion of a bodily part. Suitable anti-irritants that can be [0078] The coloring agents, humectants, pH adjusting used in the context of the present invention include, for agents and emulsifiers set out above as useful in the example, steroidal and non steroidal anti-inflammatory non-oral topical inventive compositions may be used in agents or other materials such as aloe vera, chamomile, 30 the oral inventive composition. alpha-bisabolol, cola nitida extract, green tea extract, tea [0079] Fluorine providing compounds may be fully or tree oil, licoric extract, allantoin, caffeine or other xan- slightly water soluble and are characterized by their abil- thines, glycyrrhizic acid and its derivatives. ity to release fluoride ions or fluoride containing ions in [0073] The presently known anti-irritants can be divid- water and by their lack of reaction with other components ed into water-soluble anti-irritants and water-insoluble 35 in the composition. Typical fluorine providing compounds anti-irritants. Representative examples of such compo- are inorganic fluoride salts such as water-soluble alkali sitions are described, for example, in U.S. Pat. No. metal, alkaline earth metal, and heavy metal salts, for 5,482,710. example, sodium fluoride, potassium fluoride, ammoni- [0074] Colorants may also be used in the compositions um fluoride, cuprous fluoride, zinc fluoride, stannic fluo- of the invention. Colorants include pigments or dyes or 40 ride, stannous fluoride, barium fluoride, sodium fluorosil- a combination thereof as the cosmetic benefit requires. icate, ammonium fluorosilicate, sodium fluorozirconate, Preferred pigments include, but are not limited to, iron sodium monofluorophosphate, aluminum mono- and di- oxides, and titanium oxides. Suitable dyes include FD&C fluorophosphates and fluorinated sodium calcium pyro- approved colorants, D&C approved colorants, and those phosphate. Alkali metal fluorides, tin fluoride and approved for use in Europe and Japan. See Marmion, D. 45 monofluorophosphates, such as sodium and stannous M., Handbook of US Colorants for Food, Drugs, Cosmet- fluoride, sodium monofluorophosphate and mixtures ics, and Medical Devices, 3rd ed, 1991. thereof, are preferred. [0075] "Surfactants" as used herein are surface-active [0080] The amount of fluorine providing compound substances, such as a detergent. Suitable surfactants present in the present oral topical inventive compositions for use with the inventive compositions include, but are 50 is dependent upon the type of fluorine providing com- not limited to, sarcosinates, glutamates, sodium alkyl sul- pound employed, the solubility of the fluorine compound, fates, ammonium alkyl sulfates, sodium alkyleth sulfates, and the nature of the final oral inventive composition. The ammonium alkyleth sulfates, ammonium laureth-n-sul- amount of fluorine providing compound used must be a fates, sodium laureth-n-sulfates, isothionates, glyceryl- nontoxic amount. In general, the fluorine providing com- ether sulfonates, sulfosuccinates and combinations55 pound when used will be present in an amount up to thereof. More preferably, the anionic surfactant is select- about 1%, preferably from about 0.001 % to about 0.1%, ed from the group consisting of sodium lauroyl sarcosi- and most preferably from about 0.001 % to about 0.05%, nate, monosodium lauroyl glutamate, sodium alkyl sul- by weight of the oral topical inventive composition.

7 13 EP 1 765 376 B1 14

[0081] When sweetening agents (sweeteners) are included are the carriers described hereinabove. used, those sweeteners well known in the art, including [0087] In another embodiment, the compositions of the both natural and artificial sweeteners, may be employed. present invention can further include one or more addi- The sweetening agent used may be selected from a wide tional compatible active ingredients which are aimed at range of materials including water-soluble sweetening 5 providing the composition with another pharmaceutical, agents,water- solubleartificial sweetening agents, water- cosmeceutical or cosmetic effect, in addition to that pro- soluble sweetening agents derived from naturally occur- vided by a polyisoprenyl-protein inhibitor compound of ring water-soluble sweetening agents, dipeptide based the inventive composition. "Compatible" as used herein sweetening agents, and protein based sweetening means that the components of such a composition are agents, including mixtures thereof. 10 capable of being combined with each other in a manner [0082] In a preferred embodiment, a pharmaceutically such that there is no interaction that would substantially acceptable carrier is included in the composition. As used reduce the efficacy of the composition under ordinary herein "a pharmaceutically acceptable carrier" is any use conditions. substantially non-toxic carrier conventionally useable for [0088] In one embodiment, the polyisoprenyl-protein topical administration of pharmaceuticals in which the 15 inhibitor compound of the inventive compositions is an polyisoprenyl-protein inhibitor compound will remain sta- active ingredient. ble and bioavailable when applied directly to skin or mu- [0089] As used herein, the phrase "additional active cosal surfaces ingredient" refers to an agent, other than a polyisopre- [0083] In another, preferred, embodiment, the compo- nyl-protein inhibitor compound of the inventive composi- sitions of the present invention include a cosmetically 20 tion, that exerts a pharmacological, dermatological or any acceptable carrier. As used herein the phrase "cosmet- other beneficial activity. It is to be understood that "other ically acceptable carrier" refers to a substantially non-tox- beneficial activity" may be one that is only perceived as ic carrier, conventionally useable for the topical admin- such by the subject using the inventive compositions. istration of cosmetics, with which polyisoprenyl-protein [0090] In another embodiment, the polyisoprenyl-pro- inhibitor compounds will remain stable and bioavailable. 25 tein inhibitor compound of the inventive composition is a It will be understood that cosmetically acceptable carriers new excipient. As used herein a "new excipient" means and pharmaceutically acceptable carriers are similar, if any inactive ingredient that is intentionally added to the not often identical, in nature. composition of the present invention and is not intended [0084] Suitable pharmaceutically acceptable carriers to exert therapeutic effects at the intended dosage, al- include water, petroleum jelly (Vaseline™), petroleum, 30 though it may act to improve product delivery. A new mineral oil, vegetable oil, animal oil, organic and inorgan- excipient is not fully qualified by existing safety data with ic waxes, such as microcrystalline, paraffin and ozocerite respect to the currently proposed level of exposure, du- wax, natural polymers, such as xanthanes, gelatin, cel- ration of exposure or route of administration. Additional lulose, collagen, starch, or gum arabic, alcohols, polyols, characteristics of new excipients can be found in the and the like. Also included are the carriers described35 Guidance for Industry Nonclinical Studies for the Safety hereinabove. Evaluation of Pharmaceutical Excipients issued by the [0085] In another embodiment, the pharmaceutically US Food and Drug Administration Center for Drug Eval- acceptable carrier of the composition of the present in- uation and Research, in May, 2005. vention includes a sustained release or delayed release [0091] Compositions according to the present inven- carrier. The carrier can be any material capable of sus- 40 tion, which further include one or more additional active tained or delayed release of the polyisoprenyl-protein in- ingredients, can therefore be further efficiently used, in hibitor compound to provide a more efficient administra- addition to their use as a treatment for an epithelial-re- tion resulting in less frequent and/or decreased dosage lated condition, in the treatment of any medical, cosmetic of the polyisoprenyl-protein inhibitor compound, ease of and/or cosmeceutical condition in which applying the ad- handling, and extended or delayed effects on epithelial- 45 ditional active ingredient is beneficial. related conditions. Non-limiting examples of such carri- [0092] Preferred additional active ingredients accord- ers include liposomes, microsponges, microspheres, or ing to the present invention include, without limitation, microcapsules of natural and synthetic polymers and the one or more, in any combination, of a protective agent, like. Liposomes which may enhance the localized deliv- an emollient, an astringent, an irritant, a keratolytic, a sun ery of the compounds of the inventive composition within 50 screening agent, a sun tanning agent, an antibiotic agent, skin layers, may be formed from a variety of phospholi- an antifungal agent, an antiviral agent, an antiprotozoal pids, such as cholesterol, stearylamines or phosphatidyl- agent, an anti-acne agent, an anesthetic agent, a steroi- cholines. dal anti-inflammatory agent, a non-steroidal anti-inflam- [0086] Suitable cosmetically acceptable carriers are matory agent,an antipruritic agent,an anti- oxidant agent, described in the CTFA International Cosmetic Ingredient 55 a chemotherapeutic agent, an anti-histamine agent, a Dictionary and Handbook, 8th edition, edited by Wennin- vitamin, a hormone, an anti-dandruff agent, an anti- wrin- ger and Canterbery, (The Cosmetic, Toiletry, and Fra- kle agent, an anti- skin atrophy agent, a sclerosing agent, grance Association, Inc., Washington, D.C., 2000). Also a cleansing agent, a caustic agent and a hypo- pigment-

8 15 EP 1 765 376 B1 16 ing agent. istate, myristyl alcohol, and oleyl alcohol. [0093] In the broadest pharmacological sense, a "pro- [0097] "Astringents" are locally applied, generally pro- tective" is any agent that isolates the exposed surface of tein precipitants, that have such a low cell penetrability the skin or other membrane from harmful or annoying that the action essentially is limited to the cell surface stimuli. Protectives as described herein may take the 5 and interstitial spaces. The astringent action is accom- form of dusting powders, adsorbents, mechanical pro- panied by contraction and wrinkling of the tissue and by tective agents, and plasters. Dusting powders are rela- blanching. Astringents are used therapeutically to arrest tively inert and insoluble materials that are used to cover hemorrhage by coagulating the blood, to promote heal- and protect epithelial surfaces, ulcers and wounds. Usu- ing, to toughen the skin or to decrease sweating. The ally, these substances are finely subdivided powders that 10 principal components of astringents are salts of alumi- absorb moisture and can act as a dessicant. The absorp- num, zinc, manganese, iron or bismuth. tion of skin moisture decreases friction and also discour- [0098] An "irritant" is a material that acts locally on the ages certainbacterial growth. Some ofthe materials used skin to induce, based on irritant concentration, hypere- as protective adsorbents include bentonite, insoluble mia, inflammation, and desiccation. Irritant agents in- salts of bismuth, boric acid, calcium carbonate, (precip- 15 clude, but are not limited to, alcohol, aromatic ammonia itated), cellulose, corn starch, magnesium stearate, talc, spirits, benzoin tincture, camphor capsicum, and coal tar titanium dioxide, zinc oxide, and zinc stearate. extracts. Preferably, the irritant is a rubefacient. As used [0094] Protectives also can be administered to the skin herein "rubefacients" are agents that induce hyperemia, to form an adherent, continuous film that may be flexible wherein hyperemia means an increased amount of blood or semi-rigid depending on the materials and the formu- 20 in a body part or organ. Rubefaction, which is induced lations as well as the manner in which they are applied. by rubefacients, results from increased circulation to an This material may serve several purposes including pro- injured area and is accompanied by a feeling of comfort, viding occlusion from the external environment, providing warmth, itching and hyperesthesia. chemical support, and serving as vehicles for other med- [0099] "Keratolytics" (desquamating agents) act to re- icaments. Mechanical protectives are generally either 25 move outer layers of the stratum corneum. This is par- collodions or plasters. Examples include aluminum hy- ticularly useful in hyperkeratotic areas. The keratolytics droxide gel, collodium, dimethicone, petrolatum gauze, include benzoyl peroxide, fluorouracil, resorcinol, salicyl- absorbable gelatin film, absorbable gelatin sponge, zinc ic acid, tretinoin, and the like. gelatin, kaolin, lanolin, anhydrous lanolin, mineral oil, [0100] Representative examples of sun screening mineral oil emulsion, mineral oil light, olive oil, peanut oil, 30 agents usable in context of the present invention include, petrolatum, silicones, hydrocolloids and the like. without limitation, p-aminobenzoic acid and its salts and [0095] Preferably, protectives included in the compo- derivatives thereof (ethyl, isobutyl, glyceryl esters; p- sition of the invention are demulcents. Demulcents are dimethylaminobenzoic acid); anthranilates (i.e., o-ami- protective agents employed primarily to alleviate irrita- no-benzoates; methyl, menthyl, phenyl, benzyl, phenyle- tion, particularly mucous membranes or abraded tissues. 35 thyl, linalyl, terpinyl, and cyclohexenyl esters); salicylates They often are applied to the surface in a viscid, sticky (amyl, phenyl, octyl, benzyl, menthyl, glyceryl, and dipro- preparation that covers the area readily and may be med- pylene glycol esters); cinnamic acid derivatives (menthyl icated. A number of chemical substances possess de- and benzyl esters, a-phenyl cinnamonitrile; butyl cin- mulcent properties. These substances include the algi- namoyl pyruvate); dihydroxycinnamic acid derivatives nates, mucilages, gums, dextrins, starches, certain sug- 40 (umbelliferone, methylumbelliferone, methylaceto-um- ars, and polymeric polyhydric glycols. Others include belliferone); trihydroxy-cinnamic acid derivatives (escu- acacia, agar, benzoin, carbomer, gelatin, glycerin, hy- letin, methylesculetin, daphnetin, and the glucosides, es- droxyethyl cellulose, hydroxypropyl cellulose, hydroxy- culin and daphnin); hydrocarbons (diphenylbutadiene, propyl methylcellulose, propylene glycol, sodium algi- stilbene); dibenzylacetone and benzylacetophenone; nate, tragacanth, hydrogels and the like. 45 naphtholsulfonates (sodium salts of 2-naphthol-3,6-di- [0096] "Emollients" are generally bland, fatty or oleag- sulfonic and of 2-naphthol-6,8-disulfonic acids); di-hy- inous materials which can be applied locally, particularly droxynaphthoic acid and its salts; o- and p-hydroxybi- to the skin. Emollients increase the tissue moisture con- phenyldisulfonates; coumarin derivatives (7-hydroxy, 7- tent, thereby rendering the skin softer and more pliable. methyl, 3-phenyl); diazoles (2-acetyl-3-bromoindazole, Increased moisture content in the skin can be achieved 50 phenyl benzoxazole, methyl naphthoxazole, various aryl by preventing water loss with an occlusive water-immis- benzothiazoles); quinine salts (bisulfate, sulfate, chlo- cible barrier, by increasing the water-holding capacity in ride, oleate, and tannate); quinoline derivatives (8-hy- the skin with humectants, or by altering the desquamation droxyquinoline salts, 2-phenylquinoline); hydroxy- or of the outermost skin layer, the stratum corneum. Useful methoxy-substituted benzophenones; uric and violuric emollients include lanolin, spermaceti, mineral oil, paraf- 55 acids; tannic acid and its derivatives (e.g., hexaethyl- fin, petrolatum, white ointment, white petroleum, yellow ether); (butyl carbotol) (6- propyl piperonyl) ether; hydro- ointment. Also included are vegetable oils, waxes, cetyl quinone; benzophenones (oxybenzene, sulisobenzone, alcohol, glycerin, hydrophilic petrolatum, isopropyl myr- dioxybenzone, benzoresorcinol, 2,2’,4,4’-tetrahydroxy-

9 17 EP 1 765 376 B1 18 benzophenone, 2,2’-dihydroxy-4,4’-dimethoxybenzo- Calcium Propionate, Chlorphenesin, Ciclopirox, Cloxy- phenone, octabenzone; 4-isopropyldibenzoylmethane; quin, Coparaffinate, Diamthazole, Exalamide, Flucyto- butylmethoxydibenzoylmethane; etocrylene; octocryle- sine,Halethazole, Hexetidine, Loflucarban, Nifuratel, Po- ne; [3-(4’-methylbenzylidene boman-2-one) and 4-iso- tassium Iodide, , Pyrithione, Salicylanilide, propyl-di-benzoylmethane, and any combination thereof. 5 Sodium Propionate, Sulbentine, Tenonitrozole, Triace- [0101] Representative examples of sunless tanning tin, Ujothion, Undecylenic Acid, and Zinc Propionate. agents usable in the present invention include, without [0104] The term "anti-viral agent" as used herein limitation, dihydroxyacetone, glyceraldehyde, indoles means any of a group of chemical substances having the and their derivatives. The sunless tanning agents can be capacity to inhibit the replication of or to destroy viruses used in combination with the sunscreen agents. 10 used chiefly in the treatment of viral diseases. Anti-viral [0102] The term "antibiotic agent" as used herein agents include, but are not limited to, Acyclovir, Cidofovir, means any of a group of chemical substances having the Cytarabine, Dideoxyadenosine, Didanosine, Edoxudine, capacity to inhibit the growth of, or to destroy bacteria, Famciclovir, Floxuridine, Ganciclovir, Idoxuridine, Inos- and other microorganisms, used chiefly in the treatment ine Pranobex, Lamivudine, MADU, Penciclovir, Sorivu- of infectious diseases. Examples of antibiotic agents in- 15 dine, Stavudine, Trifluridine, Valacyclovir, Vidarabine, clude, but are not limited to, Penicillin G; Methicillin; Naf- Zalcitabine, Zidovudine, Acemannan, Acetylieucine, cillin; Oxacillin; Cloxacillin; Dicloxacillin; Ampicillin; Amantadine, Amidinomycin, Delavirdine, Foscamet, Amoxicillin; Ticarcillin; Carbenicillin; Mezlocillin; Azlocil- Indinavir, Interferon-α, Interferon-β, Interferon-γ, lin; Piperacillin; Imipenem; Aztreonam; Cephalothin; Ce- Kethoxal, Lysozyme, Methisazone, Moroxydine, Nevi- faclor; Cefoxitin; Cefuroxime; Cefonicid; Cefmetazole; 20 rapine, Podophyllotoxin, Ribavirin, Rimantadine, Ri- Cefotetan; Cefprozil; Loracarbef; Cefetamet; Cefopera- tonavir2, Saquinavir, Stailimycin, Statolon, Tromanta- zone; Cefotaxime; Ceftizoxime; Ceftriaxone; Ceftazi- dine, Zidovudine (AZT) and Xenazoic Acid. dime; Cefepime; Cefixime; Cefpodoxime; Cefsulodin; [0105] The term "anti-protozoal agent" as used herein Fleroxacin; Nalidixic acid; Norfloxacin; Ciprofloxacin; means any of a group of chemical substances having the Ofloxacin; Enoxacin ; Lomefloxacin; Cinoxacin; Doxycy- 25 capacity to inhibit the growth of or to destroy protozoans cline; Minocycline; Tetracycline; Amikacin; Gentamicin; used chiefly in the treatment of protozoal diseases. Ex- Kanamycin; Netilmicin; Tobramycin; Streptomycin; Azi- amples of antiprotozoal agents, without limitation include thromycin; Clarithromycin; Erythromycin; Erythromycin pyrimethamine (Daraprim®) sulfadiazine, and Leucov- estolate ; Erythromycin ethyl succinate; Erythromycin orin. glucoheptonate; Erythromycin lactobionate; Erythromy- 30 [0106] Suitable anti-acne agents of the present inven- cin stearate; Vancomycin; Teicoplanin; Chlorampheni- tion include, without limitation, keratolytics, such as sal- col; Clindamycin; Trimethoprim; Sulfamethoxazole; Ni- icylic acid, sulfur, glycolic, pyruvic acid, resorcinol, and trofurantoin; Rifampin; Mupirocin; Metronidazole; Ce- N-acetylcysteine; and such as retinoic acid and phalexin; Roxithromycin; Co-amoxiclavuanate; combi- its derivatives (e.g., cis and trans, esters). nations of Piperacillin and Tazobactam; and their various 35 [0107] "Anesthetic agents" refers to agents that result- salts, acids, bases, and other derivatives. Anti-bacterial ing in a reduction or loss of sensation. Non-limiting ex- antibiotic agents include, but are not limited to, penici llins, amples of anesthetic drugs that are suitable for use in cephalosporins, carbacephems, cephamycins, carbap- the context of the present invention include pharmaceu- enems, monobactams, aminoglycosides, glycopeptides, tically acceptable salts of lidocaine, bupivacaine, chlo- quinolones, tetracyclines, macrolides, and fluoroquinolo- 40 rprocaine, dibucaine, etidocaine, mepivacaine, tetra- nes. caine, dyclonine, hexylcaine, procaine, cocaine, keta- [0103] The term "anti-fungal agent" as used herein mine, pramoxine and phenol. means any of a group of chemical substances having the [0108] "Steroidal anti-inflammatory agent", as used capacity to inhibit the growth of or to destroy fungi. An- herein, refer to any one of numerous compounds con- ti-fungal agents include but are not limited to Amphoter- 45 taining a 17-carbon 4- ring system and includes the ster- icin B, Candicidin, Dermostatin, Filipin, Fungichromin, ols, various hormones (as anabolic steroids), and glyco- Hachimycin, Hamycin, Lucensomycin, Mepartricin, Na- sides. Representative examples of steroidal anti-inflam- tamycin, Nystatin, Pecilocin, Perimycin, Azaserine, Gri- matory drugs include, without limitation, corticosteroids seofulvin, Oligomycins, Neomycin, Pyrrolnitrin, Siccanin, such as hydrocortisone, hydroxyltriamcinolone, alpha- Tubercidin, Viridin, Butenafine, Naftifine, Terbinafine, Bi- 50 methyl dexamethasone, dexamethasone-phosphate, fonazole, Butoconazole, Chlordantoin, Chlormidazole, beclomethasone dipropionates, clobetasol valerate, Cloconazole, Clotrimazole, Econazole, Enilconazole, desonide, desoxymethasone, desoxycorticosterone ac- Fenticonazole, Flutrimazole, Isoconazole, Ketocona- etate, dexamethasone, dichlorisone, diflorasone diace- zole, Lanoconazole, Miconazole, Omoconazole, Oxico- tate, diflucortolone valerate, fluadrenolone, fluclorolone nazole, Sertaconazole, Sulconazole, Tioconazole, Tol- 55 acetonide, fludrocortisone, flumethasone pivalate, fluosi- ciclate, Tolindate, Tolnaftate, Fluconawle, Itraconazole, nolone acetonide, fluocinonide, flucortine butylesters, Saperconazole, Terconazole, Acrisorcin, Amorolfine, Bi- fluocortolone, fluprednidene (fluprednylidene) acetate, phenamine, Bromosalicylchloranilide, Buclosamide, flurandrenolone, halcinonide, hydrocortisone acetate,

10 19 EP 1 765 376 B1 20 hydrocortisone butyrate, methylprednisolone, triamci- salts, lipoic acid, amines (e.g., N- N,diethylhydroxy- nolone acetonide, cortisone, cortodoxone, flucetonide, lamine, amino-guanidine), sulfhydryl compounds (e.g., fludrocortisone, difluorosone diacetate, fluradrenolone, glutathione), dihydroxy fumaric acid and its salts, glycine fludrocortisone, diflurosonediacetate, fluradrenolone ac- pidolate, arginine pilolate, nordihydroguaiaretic acid, bi- etonide, medrysone, amcinafel, amcinafide, betametha- 5 oflavonoids, , lysine, methionine, proline, su- sone and the balance of its esters, chloroprednisone, peroxide dismutase, silymarin, tea extracts, grape skin/ chlorprednisone acetate, clocortelone, clescinolone, seed extracts, melanin, and rosemary extracts. dichlorisone, diflurprednate, flucloronide, flunisolide, [0112] "Chemotherapetic agent" refers to chemicals fluoromethalone, fluperolone, fluprednisolone, hydrocor- useful in the treatment or control of a disease. Non-lim- tisone valerate, hydrocortisone cyclopentylpropionate, 10 iting examples of chemotherapeutic agents usable in hydrocortamate, meprednisone, paramethasone, pred- context of the present invention include daunorubicin, nisolone, prednisone, beclomethasone dipropionate, tri- doxorubicin, idarubicin, amrubicin, pirarubicin, epiru- amcinolone, and mixtures thereof. bicin, mitoxantrone, etoposide, teniposide, vinblastine, [0109] "Non-steroidal anti-inflammatory agents" refers vincristine, mitomycin C, 5- FU, paclitaxel, docetaxel, ac- to a large group of agents that are -like in their 15 tinomycin D, colchicine, topotecan, irinotecan, gemcitab- action, including (Advil)®, sodium ine cyclosporin, verapamil, valspodor, probenecid, (Aleve)®, and acetaminophen (Tylenol) ®. Additional ex- MK571, GF120918, LY335979, biricodar, terfenadine, amples of non-steroidal anti-inflammatory agents that quinidine, pervilleine A and XR9576. are usable in the context of the present invention include, [0113] "Antihistamine agent" as used herein refers to without limitation, , such as , , 20 any of various compounds that counteract histamine in , sudoxicam, and CP-14,304; disalcid, benor- the body and that are used for treating allergic reactions ylate, trilisate, safapryn, solprin, , and fendosal; (such as hay fever) and cold symptoms. Non-limiting ex- acetic acid derivatives, such as , , amples of antihistamines usable in context of the present indomethacin, , , isoxepac, furofenac, ti- invention include chlorpheniramine, brompheniramine, opinac, zidometacin, acematacin, , , 25 dexchlorpheniramine, tripolidine, clemastine, diphenhy- clindanac, oxepinac, , and ; fenamates, dramine, promethazine, piperazines, piperidines, astem- such as mefenamic, meclofenamic, flufenamic, niflumic, izole, loratadine and terfenadine. and tolfenamic acids; propionic acid derivatives, such as [0114] "Vitamin" as used herein, refers to any of vari- ibuprofen, naproxen, , , keto- ous organic substances essential in minute quantities to profen, , , indopropfen, ,30 the nutrition of most animals act especially as coenzymes , , , miroprofen, tioxapro- and precursors of coenzymes in the regulation of meta- fen, , , and tiaprofenic; pyrazoles, bolic processes. Non-limiting examples of vitamins usa- such as , , , ble in context of the present invention include vitamin A , and trimethazone. Mixtures of these non- and its analogs and derivatives: retinol, retinal, retinyl steroidal anti-inflammatory agents may also be em-35 palmitate, retinoic acid, tretinoin, iso- tretinoin (known col- ployed, as well as the dermatologically acceptable salts lectively as retinoids), vitamin E (tocopherol and its de- and esters of these agents. For example, , rivatives), vitamin C (L-ascorbic acid and its esters and a derivative, is particularly useful for top- other derivatives), vitamin B 3 (niacinamide and its deriv- ical application. atives), alpha hydroxy acids (such as glycolic acid, lactic [0110] "Antipruritic agents" as used herein refers to 40 acid, tartaric acid, malic acid, citric acid, etc.) and beta those substances that reduce, eliminate or prevent itch- hydroxy acids (such as and the like). ing. Suitable antipruritic agents include, without limita- [0115] "Hormone" as used herein refers to natural sub- tion, pharmaceutically acceptable salts of methdilazine stances produced by organs of the body that travel by and trimeprazine. blood to trigger activity in other locations or their synthetic [0111] "An anti-oxidant agent" as used herein refers to 45 analogs. Suitable hormones for use in the context of the a substance that inhibits oxidation or reactions promoted present invention include, but are not limited to, calciferol by oxygen or peroxides. Non-limiting examples of anti- (Vitamin D3) and its products, androgens, estrogens and oxidants that are usable in the context of the present progesterones. invention include ascorbic acid (vitamin C) and its salts, [0116] "Anti-dandruff agents" as used herein refer to ascorbyl esters of fatty acids, ascorbic acid derivatives 50 agents that reduce, eliminate or prevent a scurf from (e.g., magnesium ascorbyl phosphate, sodium ascorbyl forming on skin, especially of the scalp, that comes off phosphate, ascorbyl sorbate), tocopherol (vitamin E), to- in small white or grayish scales. Exemplary anti-dandruff copherol sorbate, tocopherol acetate, other esters of to- ingredients usable in context of the present invention in- copherol, butylated hydroxy benzoic acids and their salts, clude, without limitation, zinc pyrithione, shale oil and de- 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic ac- 55 rivatives thereof such as sulfonated shale oil, id (commerciallyavailable under the tradename Trolox R), sulfide, sulfur; salicylic acid, coal tar, povidone-iodine, gallic acid and its alkyl esters, especially propyl gallate, imidazoles such as ketoconazole, dichlorophenyl imida- uric acid and its salts and alkyl esters, sorbic acid and its zolodioxalan, clotrimazole, itraconazole, miconazole,

11 21 EP 1 765 376 B1 22 climbazole, tioconazole, sulconazole, butoconazole, flu- nol, acetone). conazole, miconazolenitrite and any possible stereo iso- [0124] In another preferred embodiment, an inventive mers and derivatives thereof such as anthralin, piroctone composition comprising a polyisoprenyl-protein inhibitor olamine (Octopirox), selenium sulfide, and ciclopirox- compound, a carrier and other, optional ingredients can olamine, and mixtures thereof. 5 be dispersed in an emulsion. An emulsion is a two-phase [0117] "Anti-skin atrophy actives" refers to substances system prepared by combining two immiscible liquid car- effective in replenishing or rejuvenating the epidermal riers, one of which is disbursed uniformly throughout the layer by promoting or maintaining the natural process of other and consists of globules that have diameters equal desquamation. Examples of antiwrinkle and antiskin at- to or greater than those of the largest colloidal particles. rophy actives which can be used in context of the present 10 The globule size is critical and must be such that the invention include retinoic acid its prodrugs and its deriv- system achieves maximum stability. Usually, separation atives (e.g., cis and trans) and analogues; salicylic acid of the two phases will not occur unless a third substance, and derivatives thereof, sulfur-containing D and L amino an emulsifying agent, is incorporated. Thus, a basic acids and their derivatives and salts, particularly the N- emulsion contains at least three components, the two acetyl derivatives, a preferred example of which is N- 15 immiscible liquid carriers and the emulsifying agent as acetyl L-cysteine; thiols, e.g. ethane thiol; alpha- hydroxy well as the polyisoprenyl-protein inhibitor compound. acids, e.g. glycolic acid, and lactic acid; phytic acid, lipoic Most emulsions incorporate an aqueous phase into a acid; lysophosphatidic acid, and skin peel agents (e.g., non-aqueous phase (or vice versa). However, it is pos- phenol and the like). Sclerosing agents or sclerosants sible to prepare emulsions that are basically non-aque- may be also employed. A "sclerosant" refers to an agent 20 ous, for example, anionic and cationic surfactants of the used as a chemical irritant injected into a vein in sclero- non-aqueous immiscible system glycerin and olive oil. therapy. The most common ones are morrhuate sodium, [0125] Emulsifying agent carriers useful in the present sodium tetradecyl sulfate, laureth 9 and ethanolamine invention are described hereinabove. oleate. [0126] When the composition of the invention is an [0118] Cleansing agents which may be use in the25 emulsion including AFC, non-lipid-based vehicles are present invention include surfactant based cleansing preferred due to the lipophilic nature of the compound. agents,examples ofwhich have beenlisted hereinabove: [0127] In yet, another embodiment, the inhibitors of the Other non-surfactant-based cleansing agents known to inventive compositions can be mixed with a gel suspen- those of skill in the art may also be employed. sion, (a semi-solid carrier) or solid carrier to form a paste, [0119] "Caustic agents" refer to substances capable 30 powder, ointment, cream, lotion, hydrogel or the like. of destroying or eating away epithelial tissue by chemical [0128] For example, ointments may be prepared which action. Caustic agents can be used to remove dead skin are in gel-suspension form. These are semi-solid prep- cells. For example, beta-hydroxy acids, naturally derived arations intended for external application to the epitheli- acids with a strong kerolytic effect, are useful for problem um. Generally, ointment bases are categorized into hy- skin, acne or peeling. 35 drocarbon bases (oleaginous), which may use white pe- [0120] "Hypopigmenting agents" refer to substances troleum as a base; adsorption bases (anhydrous), which capable of depigmenting the skin. Suitable hypopigment- might use hydrophilic petroleum or anhydrous lanolin; ingagents include hydroquinones, mequinol, and various emulsion bases (water and oil type); emulsion bases (oil protease inhibitors including serine protease inhibitors, and water type); and water soluble bases, which often active soy and retinoic acid. 40 use polyethylene glycol as an ointment base. [0121] The topical compositions of the present inven- [0129] Additional compositions of the present inven- tion can be applied locally to the skin or mucosa and may tion using polyisoprenyl-protein inhibitor compounds and be in any form including solutions, oils, creams, oint- carriers can be readily prepared using technology which ments, gels, lotions, shampoos, milks, cleansers, mois- is known in the art such as described in Remington’s turizers, sprays, skin patches and the like. 45 Pharmaceutical Sciences, 18th or 19th editions, pub- [0122] In another embodiment, a polyisoprenyl-protein lished by the Mack Publishing Company of Easton, Penn- inhibitor compound, carrier and, optionally, additional ac- sylvania. tive ingredients are formed into a composition comprising [0130] Preferably, the compositions of the present in- a solution, emulsion or gel suspension. vention include about 0.01% to about 50% w/w of a [0123] In some embodiments, a polyisoprenyl-protein 50 polyisoprenyl-protein inhibitor compound. In a more pre- inhibitor compound, a pharmaceutical or cosmetic carrier ferred embodiment, the amount of the polyisoprenyl- pro- and, optionally, one or more additional active ingredients tein inhibitor compound is about 0.1% to about 20% w/w. are in the form of a solution. A solution can be prepared In an even more preferred embodiment, the amount of by mixing a solute or dissolved substance (such as a the polyisoprenyl-protein inhibitor compound present in polyisoprenyl-protein inhibitor compound of the invention 55 the inventive composition is preferably no more than and,optionally, one or more active ingredient (s)) uniform- about 10% w/w. In a yet, even more preferred embodi- ly throughout a solvent carrier such as water or organic ment, the amount of the polyisoprenyl-protein inhibitor solvents, such as the alcohols (e.g. ethanol or isopropa- compound is less than about 5% w/w.

12 23 EP 1 765 376 B1 24

[0131] According to another aspect of the present in- four times a day, more preferably twice a day (e. g., once vention, there is provided a method of preparing the novel in the morning and once in the evening). The topical ap- compositions described hereinabove. The process gen- plication of the compositions of the present invention is erally includes admixing the at least one polyisopre- preferably carried out for a time period that ranges be- nyl-protein inhibitor compound, as described herein-5 tween 1 and 30 days, more preferably for a time period above, and the pharmaceutically, cosmetically or cos- of about fourteen days. Some conditions may require top- meceutically acceptable carrier. In cases where addition- ical application for an indeterminate length of time. al active ingredients, as detailed above, are present in [0136] The inventive compositions may be topically ad- the compositions, the process includes admixing these ministered to the epithelial surface of a subject. Non lim- ingredients together with the active ingredients and the 10 iting examples of epithelial surfaces onto which the com- carrier. The mixing technique utilized in the process of positions of the present invention can be applied topically the present invention can involve any one of the known include the lateral aspect of forearms, the lateral aspect techniques for formulating topical compositions. A variety of legs, elbows, feet, backhands, back, scalp, face, but- of exemplary formulation techniques that are usable in tocks, the ear canal and any other skin surfaces, and any the process of the present invention is described, for ex- 15 mucosal membrane described herein. Topical applica- ample, in Harry’s Cosmeticology, Seventh Edition, Edit- tion also includes applying the inventive compositions ed by J B Wilkinson and RJ Moore, Longmann Scientific orally to the gingiva. & Technical, 1982. [0137] The surface may be a wound surface. In chronic [0132] Compositions according to an aspect of the wounds, topical application may include applying the in- present invention can be used in a method of treating a 20 ventive compositions to a non-epithelial surface such as medical, cosmetic and/or cosmeceutical condition asso- the dermis. The wound surface may be an open wound ciated with epithelial tissues. The method is effected by surface. As used herein an "open wound" is a physical topically applying, a pharmaceutically, cosmetically or trauma where the skin is lacerated, cut or punctured. As cosmeceutically effective amount of the composition of used herein, "a cut" is an injury that results in a break or the present invention as described above onto a surface. 25 opening in the skin, "a laceration" is a jagged, irregular [0133] As used herein the terms "pharmaceutically ef- cut, and "a puncture" is a wound made by a pointed object fective amount" "cosmetically effective amount" or "cos- (like a nail, knife, or sharp tooth). meceutically effective amount" refer to the amount of any [0138] Alternatively, the compositions may be admin- of the compositions of the invention that result in a ther- istered to the epithelial condition as a component of, for apeutic or beneficial effect following its administration to 30 example, a bandage, adhesive, or transdermal patch. In a subject. The pharmaceutical, cosmeceutical or cosmet- these instances, the compositions may be an integral ic effect can be curing, minimizing, preventing or amel- component of the bandage, adhesive, or transdermal iorating a disease or disorder, improving the physical ap- patch and are thereby applied to the epithelial surface. pearance and aesthetics (e. g., skin hydration), or may [0139] The compositions of the invention may be ap- have any other pharmaceutical, cosmeceutical or cos- 35 plied to the inside of a latex glove. When the skin touches metic beneficial effect. The concentration of the sub- the inside of the latex glove, the composition of the in- stance is selected so as to exert its pharmaceutical, cos- vention is applied to the skin. The compositions of the meceutical or cosmetic effect, but low enough to avoid invention act to prevent inflammation of the skin caused, significant side effects within the scope and sound judg- at least in part, by being enclosed in the glove. ment of the skilled artisan. The effective amount of the 40 [0140] As used herein the term "treating" includes ab- composition may vary with the particular epithelial tissue rogating, substantially inhibiting, slowing or reversing the being treated, the age and physical condition of the bio- progression of a condition, substantially ameliorating logical subject being treated, the severity of the condition, clinical or aesthetical symptoms of a condition, substan- the duration of the treatment, the nature of concurrent tially preventing the appearance of clinical or aesthetical therapy, the specific compound, composition or other ac- 45 symptoms of a condition, protecting from harmful or an- tive ingredient employed, the particular carrier utilized, noying stimuli or generally promoting healthy epithelial and like factors. tissue. [0134] A skilled artisan can determine a pharmaceuti- [0141] The term "condition" includes a variety of con- cally effective amount of the inventive compositions by ditions related to skin or mucosal membranes. This term determining the unit dose. As used herein, a "unit dose" 50 is meant to include disorders or diseases, the promotion refers to the amount of inventive composition required to of healthy epithelium; dry skin; and inflammation caused produce a response of 50% of maximal effect (i.e. ED 50). by any underlying mechanism or disorder. The unit dose can be assessed by extrapolating from [0142] As used herein "promotion of healthy skin" or dose-response curves derived from in vitro or animal "promoting healthy skin", refers to providing cooling or model test systems. 55 soothing sensations, or reducing puffiness, or promoting [0135] The compositions of the present invention are the appearance of reduced wrinkling or puffiness. This preferably topically applied as needed. The inventive phrase also refers to the subject’s perception of his/her compositions may be topically applied between one and skin as appearing healthy or having the perception of

13 25 EP 1 765 376 B1 26 wellness or youth. derma gangrenosum, erythema multiforme, aphthous ul- [0143] The inventive compositions may be applied to cers, granulomatous cheilitis, dermitis herpetiformis, der- an epithelial tissue surface to protect the surface from matomyositis, including juvenile DM and amyopathic exposure to environmental factors. Such factors include, DM, eosinophilic fascitis; q) insect bites and animal bites but are not limited to, UV radiation, wind, hot climate ex- 5 and stings, including, but not limited to, sea bather’s erup- tremes or cold climate extremes. tion, seaweed dermatitis, swimmers itch, scombroid fish [0144] The inventive compositions may be applied to poisoning, scabies, popular urticaria, and cutaneous lar- prevent wrinkles. The inventive compositions may be ap- va migrans; r) fungal infections including, but not limited plied to prevent photo- aging. The inventive composition to, dermatophyte infections, tinea corporis, tinea pedis, may be administered to prevent redness or puffiness10 tinea unguium, tinea capitis, tinea cruris, tinea versicolor, such as occurs in diaper rash. tinea barbae, athlete’s foot, and jock itch; s) yeast infec- [0145] The compositions of the present invention may tions including, but not limited to, candidiasis, such as be used to prevent dry skin. The inventive compositions candida albicans, oral candida (thrush), candidal paro- can be administered to moisturize and protect the skin nychia, and; t) parasites including, but not limited to, sca- from the condition of dryness. 15 bies, pediculosis including pediculosis capitis, pediculo- [0146] The compositions of the invention also may be sis corporis, and pediculosis pubis; and v) viral infections administered to treat a skin disorder that is already including, but not limited to, herpes, including simplex present, such as dry cracked skin. The inventive compo- lesions and zoster, chicken pox (varicella) lesions, rube- sitions may be administered to treat irritated skin, such ola (measles) and rubella (German measles); w) vasodi- as occurs with diaper rash. 20 lation, including, but not limited to, reye’s syndrome and [0147] The inventive compositions may be applied to wound healing; x) trauma from breaks in skin; y) autoim- treat inflammation. As used herein "inflammation" refers mune conditions, including, but not limited to, cutaneous to a response to infection and injury in which cells in- lupus erythematosus; z) bullous disease, including, but volved in detoxification and repair are mobilized to the not limited to, phemphigus; aa) adverse drug reactions; compromised site by inflammatory mediators. Thus, the 25 bb)a immune hyper-reactivity conditions including, but body’s response may include edema, vasodilation, fever not limited to, polymorphic light eruption, photosensitiv- and pain. When inflammation is localized to the skin and ity, dermographism, and erythema multiforme; cc) can- mucosa, erythema (redness) occurs and can be treated cer; dd) bums; ee) wounds; ff) cysts, gg) hidradinitis sup- by the compositions of this invention. purativa hh) cellulitis. [0148] Inflammation can result from a wide variety of 30 [0149] While the compositions discussed hereinbefore non-limiting conditions. These conditions include, but are do not necessarily treat the underlying disease state that not limited to, a) dermatitis, including, but not limited to, may give rise to the inflamed conditions, the inventive atopic dermatitis, medicamentosa, contact dermatitis, compositions are useful for diminishing or alleviating the seborrheic, nummular dermatitis, chronic dermatitis of inflammation of the skin. hands and feet, generalized exfoliative stasis, and local- 35 [0150] Additionally, the compositions may be used in ized scratches; b) acne, including, but not limited to, acne anorectal creams and suppositories to treat conditions vulgaris, nodulocystic acne, acne fulminans, steroid ac- such as a pruritus, proctitis, anal fissures, and hemor- ne, acne keloidalis nuchae, chloracne, pyoderma faciale, rhoids. and cysts; c) folliculitis, including, but limited to, scalp [0151] The topical therapeutic compositions may fur- folliculitis, spa pool fo lliculitis, oil folliculitis, pityrosporum 40 ther be used in ophthalmological preparations to treat folliculitis, and gram negative folliculitis; d) pseudofollicu- inflammation such as that which results from corneal ul- litis barbae; e) chilblains; f) miliaria (prickly heat); g) ro- cers, radialkeratotomy, corneal transplants, epikerat- sacea including, but not limited to, tinea rosacea, steroid ophakia and other surgically induced wounds in the eye. rosacea andperioral dermatitis; h) eczema andpsoriasis; [0152] The inventive compositions also may be used i) bacterial infections including, but not limited to, staphy- 45 orally in the form of a mouth wash or spray to protect and lococcal diseases, staphylococcal scalded skin syn- accelerate the healing of injured oral tissue such as drome, erysipelas, folliculitis, furuncles, carbuncles, par- mouth sores, bums or gingivitis. onychial infections, and erythrasma; j) surgical interven- [0153] The present invention described hereinabove tions; k) crodermatitis enteropathica; 1) Sweet’s disease; has both human and veterinary utility. The term "subject" m) amyloidosis including, but not limited to, lichen amy- 50 as used herein includes animals of, avian, reptilian or loidosis and macular amyloidosis; n) hives, including, but mammalian origin. Preferably, subjects are mammals. not limited to, acute generalized and chronic generalized Even more preferably, subjects are human. hives and physical hives; o) erythema annulare cen- [0154] Where a range of values is provided, it is un- trifugum and annular erythema, including, but not limited derstood that each intervening value, to the tenth of the to, erythema perstans, erythema gyratum perstans, ery- 55 unit of the lower limit unless the context clearly dictates thema gyratum repens and erythema figuratum pertans; otherwise,between the upper andlower limit of that range p) bachet syndrome including, but not limited to, uveitis, and any other stated or intervening value in that stated erythema nodosum, biotin response, dermatoses, pyo- range is encompassed within the invention. The upper

14 27 EP 1 765 376 B1 28 and lower limits of these smaller ranges which may in- the dermis to the site of inflammation after they have dependently be included in the smaller ranges is also passed through the vascular endothelium. Alternatively, encompassed within the invention, subject to any spe- these mediators could act directly or indirectly on the vas- cifically excluded limit in the stated range. Where the stat- cular endothelium of the dermis to cause leakage leading ed range includes one or both of the limits, ranges ex- 5 toedema and/or theattraction andadhesion ofcirculating cluding either both of those included limits are also in- inflammatory cells. Thus, there are multiple G-protein cluded in the invention. and other polyisoprenyl-protein mediated signaling re- [0155] Unless defined otherwise, all technical and sci- sponses between keratinocytes and inflammatory re- entificterms used hereinhave the samemeaning as com- sponding cells, which may provide multiple potential tar- monly understood by one of ordinary skill in the art to 10 gets where AFC could act to reduce inflammation. The which this invention belongs. Although any methods and topical delivery route has the major advantage of giving materials similar or equivalent to those described herein AFC nearly direct access to the site of inflammation. This can also be used in the practice or testing of the present avoids pharmacokinetic problems, such as drug dilution, invention, the preferred methods and materials are now major organ drug catabolism, and binding to serum com- described. All publications mentioned herein are incor- 15 ponents. porated herein by reference to disclose and described [0160] Example 1. Polyisoprenyl-protein inhibitor the methods and/or materials in connection with which compound AFC in an acetone carrier suppresses the publications are cited. TPA-elicited edema in the murine ear acute contact [0156] It must be noted that as used herein and in the irritation model appended claims, the singular forms "a", "and", and "the" 20 [0161] In order to assess the effects of the AFC inven- include plural references unless the context clearly dic- tive composition for reducing edema in the mouse ear tates otherwise. All technical and scientific terms used model, an established model of dermal inflammation, herein have the same meaning. wasused. (See Carlson,R.P., et al., Modulationof mouse [0157] The publications discussed herein are provided ear edema by and lipoxygenase inhibi- solely for their disclosure prior to the filing date of the 25 tors and other pharmacologic agents. Agents Actions, present application. Nothing herein is to be construed as 1985. 17(2): p. 197-204; Kuehl, F.A., Jr., et al., Role of an admission that the present invention is not entitled to endoperoxide PGG2 in inflammatory proc- antedatesuch publication by virtueof prior invention. Fur- esses. Nature, 1977. 265(5590): p. 170-3; Trancik RJ, ther, the dates of publication provided may be different L.N., Evaluation of topical nonsteroidal anti- inflammatory from the actual publication dates which may need to be 30 agents, in Models in Dermatology, L. Maibach, Editor. independently confirmed. 1985, Karger. p. 35-42; and Tramposch, K.M., Skin In- flammation, in In Vivo Models of Inflammation, M.L. Mor- EXAMPLES gan DW, Editor. 1999, Birkhauser Verlag. p. 179-204.) [0162] The standard agents for initiating inflammation [0158] The following examples are put forth so as to 35 are the phorbol ester, tetradecanoylphorbol acetate, provide those of ordinary skill in the art with a complete (TPA) and (AA). TPA produces a greater disclosure and description of how to make and use the and more prolonged neutrophil infiltration response than present invention, and are not intended to limit the scope AA (See Rao, T.S., et al., Comparative evaluation of ara- of what the inventors regard as their invention nor are chidonic acid (AA)- and tetradecanoylphorbol acetate they intended to represent that the experiments below 40 (TPA)-induced dermal inflammation. Inflammation, are all or the only experiments performed. Efforts have 1993. 17(6): p. 723-41.) TPA- induced inflammation is the been made to ensure accuracy with respect to numbers preferred agent and was used for this example. used (e.g. amounts, temperature, etc.) but some exper- [0163] A. Dose response Curve for irritant. imental errors and deviations should be accounted for. [0164] A dose response range for TPA, a compound Unless indicated otherwise, parts are parts by weight, 45 known to induce edema, was determined. TPA produces molecular weight is weight average molecular weight, an increase in edema (ear swelling) that reaches a max- temperature is in degrees Centigrade, and pressure is imum at 6 hrs. at or near atmospheric. [0165] Increasing concentrations of TPA dissolved in [0159] Dermal inflammation results in edema, ery- acetone were applied with the aid of a micropipetter onto thema and tenderness. Dermal inflammation has the ad- 50 the right ear of each of the five 6-8 week old, male Swiss vantage of being rapidly induced, easily observed and Webster mice used in this analysis. Ten microliters were rapidly measured. In addition, there are a number of fac- spread evenly onto the inner and outer surfaces using tors involved in eliciting an inflammatory response. Epi- the pipette tip. The mice were then returned to their cag- dermal keratinocytes, which respond directly to a irritant es. The contralateral ear was treated only with acetone. because of their superficial location, also, release inflam- 55 After 5.5 hours, the mice were sacrificed and 6 mm matory mediators. These mediators can act directly (1) punches were taken from each ear and weighed. Edema to attract inflammatory cells to the endothelium of the response was expressed as a percent increase in the dermal venules or (2) to guide inflammatory cells through treated ear’s weight over the untreated ear. The dose

15 29 EP 1 765 376 B1 30 response curve, as well as an ED50 value, was deter- over the increase in ear punch weight induced by TPA. mined using the Lichtfield method (Lichtfield JT W.F., A [0172] When AFC is tested in this acute inflammation simplified method of evaluating dose- effect experiments, mouse-ear assay, AFC reduces acute chemically in- Journal of Pharmacology and Experimental Therapeu- duced inflammation significantly. The inventive compo- tics, 1948, 96: P. 99-113). 5 sition reduced the TPA-induced ear weight increase in a [0166] As seen in FIG 1, the increase in ear weight dose dependent manner (FIG 3). The inventive compo- depends on TPA dose from 0.25 to 1.75 mg / 20 ml, reach- sition resulted in a maximum 80% reduction in edema. ing a maximum increase of approximately 150% of the The ED50 of the inventive AFC composition was approx- acetone-treated ear. This experiment identified doses imately 0.44 mg/ 20 ml for TPA- induced edema inhibition. between 1.5 - 2.0 mg / 20 ml as suitable to use in eliciting 10 [0173] Example 2. AFC inhibits TPA-induced neu- edema in future tests of anti-inflammatory agents. trophil infiltration in mice. [0167] B. Polyisoprenyl-protein inhibitor com- [0174] A. TPA induces neutrophil infiltration in pound AFC in an acetone carrier, itself, is not an ir- mice. ritant. [0175] Acute contact irritants such as TPA can also [0168] A range of from 5 mg to 32 mg AFC, a polyiso- 15 induce dermal infiltration of neutrophils. This may or may prenyl-protein inhibitor compound, was mixed with 20 ml not be independent of the reduction of edema, as: 1) the acetone to produce an inventive AFC composition. Each maximum neutrophil response is delayed relative the concentration was applied with the aid of a micropipetter maximal edema response; 2) some irritants will induce onto the right ear of each of six mice so that 10 ml of each edema independent of neutrophil infiltration; and 3) some of the concentrations of the AFC inventive compositions 20 of the known anti-inflammatory agents reduce one, but were applied to an inner ear surface and 10 ml was ap- not the other. (See Rao, T.S., et al., Comparative eval- plied to an outer ear surface of the right ear. The AFC uation of arachidonic acid (AA)- and tetradecanoylphor- inventive compositions were spread evenly with a pipette bol acetate (TPA)-induced dermal inflammation. Inflam- tip. Each contralateral ear was treated with only acetone mation, 1993. 17 (6): p. 723-41.) We sought to determine in the same manner. The mice then were returned to their 25 if topically applied AFC would affect neutrophil infiltration cages. After 5.5 hours, mice were sacrificed and 6 mm in response to acute topical irritation produced by TPA. punches were taken from each ear and weighed. Edema [0176] Neutrophil-infiltration Assay: Swiss Webster response was expressed as the percent increase in the male mice (n = 6) were treated with 1 mg/20 ml of TPA treated ear’s weight over the untreated (acetone, vehicle as described above in order to assess whether or not only) ear. 30 TPA induced neutrophil infiltration. Acetone was used as [0169] As shown in FIG. 2, AFC in acetone alone had a control. TPA was administered as described above. no effect on the edema response. The AFC inventive The mice were returned to their cages for 24 hrs to allow compositions had no effect on the ear punch biopsy neutrophil infiltration, then sacrificed by cervical disloca- weight at a dose up to 32 mg/20 ml. AFC did not induce tion. The ears were immediately removed for punch bi- edema on its own at doses 60 fold greater than doses 35 opsy, and punches were fixed for subsequent histological having efficacy against chemically-induced edema. This analysis and MPO enzymatic assay. finding suggests an excellent safety profile for AFC. [0177] MPO Assay: This assay measures myeloper- [0170] C. Result of AFC inventive composition on oxidase, ("MPO") which is packaged in the primary gran- TPA-induced edema. ules of mature granulocytes including the neutrophil. [0171] In order to assess the effects of the inventive 40 Thus, the amount of MPO in the ear is proportional to the composition on TPA-induced edema, 2 mg of TPA in 20 number of infiltrating neutrophils. ml acetone was applied with the aid of a micropipetter [0178] MPO enzyme activity of the ears was assayed onto both ears of each of 6 mice. The mice were returned using the technique detailed by Griffiths and coworkers to their cages. Fifteen minutes later, increasing concen- (1988). To conduct the assay, each ear was homoge- trations of AFC in 10 ml of acetone were applied to the 45 nized in1.0 mlof cetyltrimethylammoniumbromide buffer inside and outside surfaces of the right ears as described for 5 sec using a Pro 200 tissue blender (Pro Scientific, above. 20 ml of an acetone vehicle was applied similarly Inc.,Oxford, CT) at setting 5. These samples were then to the left ear of each mouse as an internal negative con- centrifuged for 5 minutes at 15,000 rpm in a 5415 Ep- trol. After treatment, the mice were returned to their cages pendorf microcentrifuge. Triplicate 20 microliter aliquots for 5.5 hours. The mice were sacrificed by cervical dis- 50 of supernatant were added to 200 microliters of reaction location. The ears were immediately removed at their mixture (1.25 ml 1M Potassium Phosphate, 4.175 mg o- base and a 6 mm diameter punch biopsy was taken from dianisidine dihydrochloride and 5 ml of 1% peroxide in a the center of each ear. The ear punch was weighed on final volume of 25 ml). Absorbance at 450 nm was then an analytical balance for edema measurements as de- measured at room temperature at three 60 second inter- scribed above. The ability of the various concentrations 55 vals using Bio-Kinetics Reader EL 312E (Bio- Tek Instru- of AFC to inhibit TPA-induced edema was assessed by ments). Activity, which was determined by a Bradford determining the difference in weight between the AFC- assay ofthe homogenate(BioRad ProteinAssay, BioRad treated ear and the acetone (vehicle)-only treated ear Laboratories, Inc. Hercules, CA) was expressed as units

16 31 EP 1 765 376 B1 32

MPO per mg tissue +/-standard error. times before and after TPA application was assessed [0179] Neutrophil Counting Assay: Ear punches buff- using MPO as a measure of neutrophil infiltration. In this ered in 10% formalin in PBS at ambient temperature for example, both ears of six mice were treated with a 1 mg/ a minimum of 24 hrs. were sectioned and stained with 20ml dose of TPA in acetone. The right ear was then Hematoxilin & Eosin ("H&E"). The number of neutrophils, 5 treated with 1 mg/ 20ml AFC inventive composition at var- identified by their multilobular nuclei, in 6 randomly 100x ious times before and after TPA application, while simul- magnified fields distributed along the length of the ear taneously treating the contralateral ear with acetone. were manually counted. The results are expressed as [0190] The results show the efficacy of AFC treatment the average number per field for each ear. prior to, simultaneous with, or after exposure of skin to [0180] B. AFC inhibits TPA-induced neutrophil in- 10 TPA (Fig. 7). There was a gradual decrease in MPO ac- filtration. tivity with time at which AFC was applied after TPA ap- [0181] Inventive AFC compositions were used also to plication, the steroid dexamethasone showed a similar assess efficacy in the reduction of dermal neutrophil in- time dependence. Thus, it can be anticipated that AFC filtration. (See Rao, T.S., et al., Comparative evaluation will act like steroids in reducing established inflammatory of arachidonic acid (AA)- and tetradecanoylphorbol ac- 15 conditions. etate (TPA)-induced dermal inflammation. Inflammation, [0191] These results support a wide range of possible 1993. 17(6): p. 723-4 for a discussion regarding the re- cosmetic and pharmaceutical applications for AFC. lationship between edema and neutrophil infiltration and [0192] Example 3. The AFC inventive composition the effect of known anti-inflammatory agents on these does not exhibit systemic effects. variables.) 20 [0193] Theeffect of AFC on TPA induction ofneutrophil [0182] Two micrograms of TPA in 20 ml of acetone was MPO activity was compared with two other agents rep- applied onto both ears of each mouse to induce neu- resentingdifferent classesof commonlyused anti-inflam- trophil infiltration. After 15 minutes, varying concentra- matories that inhibit inflammation by mechanisms differ- tions of AFC in acetone were applied to the right ear of entfrom AFC. Theseincluded dexamethasone, asteroid, each mouse. After 24 hours, the mice were sacrificed. 25 and indomethasone, a non-steroid anti-inflammatory The ears were removed and the efficacy of AFC on neu- drug, which targets cycloxgenases. The action of AFC in trophil infiltration was assessed by an MPO assay and this model was, therefore, compared to that of dexame- histological analysis. thasone and indomethasone. Each of these agents were [0183] 1. MPO analysis tested using the same protocols used to test AFC. [0184] The results showed that AFC acts to reduce 30 [0194] As shown in FIGS. 8B and 8C, when the con- neutrophil infiltration in a dose dependent manner when centration of dexamethasone and indomethasone is in- neutrophil infiltration is measured by an MPO analysis. creased, the contralateral vehicle-treated ear shows in- When AFC was tested in the Neutrophil-Infiltration As- creasing inhibition of MPO activity, reflective of inhibition say, it was found to have no inflammation activity of its of neutrophil infiltration. This is evidence that topically own. The data indicate that AFC produced over an 80% 35 applied dexamethasome and indomethasone are enter- inhibition of TPA-induced increases in MPO activity and ing the circulation and exerting a systemic effect with had an ED50 of 0.065 mg/20ml (FIG 4). increasing effective local doses. With AFC, no effect was [0185] 2. Neutrophil Counts: seen on the vehicle-treated ear (FIG 8A). Topically ap- [0186] This histological analysis demonstrated the ef- plied AFC, even at its highest effective local doses is not ficacy of AFC in suppressing dermal neutrophil infiltration 40 entering the circulation and, therefore, has no systemic in response to acute contact irritation. As seen in FIG. 5, effect in the mouse model. the presence of neutrophils in the TPA alone treated ears [0195] Example 4. Effect of an AFC and acetone was clearly observed 24 hours after treatment. Essen- composition on arachadonic acid-induced edema tially no neutrophils were observed in the ears that were and arachadonic acid-induced neutrophil infiltration not exposed to TPA. In the ears pretreated with TPA and 45 [0196] Aracadonic acid ("AA"), another standard agent then treated with vehicle or AFC, the numbers of neu- that is routinely used as a contact irritant in the mouse trophils were comparable between vehicle plus TPA- ear model to assay the effectiveness of both steroidal treatedear and ears treated with TPA alone. A substantial and nonsteroidal anti-inflammatory agents, is the meta- reductionof neutrophils can be observed in theAFC treat- bolic precursor for a number of lipoxygenase and cy- ed ear. 50 clooxgenase products. Its mechanism of action and, [0187] Upon counting the neutrophils, (FIG. 6) 1.0 thus, the signaling pathways it activates, differ from those mg/20 ml of AFC produced a statistically significant 80% activated by topically applied TPA. AA produces a more reduction in dermal neutrophils produced in response to rapid edema than TPA that peaks at 1 hr after application. acute contact irritation by TPA. (Statistical significance There is minimal histologically observable neutrophil in- was calculated using a Student’s paired t-test). 55 filtration in response to AA, but an increase in MPO can [0188] C. The effect of AFC on neutrophils is time be detected. Experience has shown that effectiveness dependent against cyclooxygenase activated inflammation in this [0189] The effectiveness of AFC treatment at various model is less predictive of effectiveness against human

17 33 EP 1 765 376 B1 34 inflammatory diseases than effectiveness against TPA tration and microphage infiltration, is used as a positive activated inflammation. control. The results will show that AFC in acetone reduc- [0197] The effect of the inventive compositions on ara- es chronic edema and neutrophil number in mice. chidonic acid(AA)-induced inflammation was assayed [0205] Example 8. The effect of the AFC inventive using the same protocols as above, but with the following 5 composition on delayed-type hypersensitivity. modifications. AA was applied to both ears at 4 mg/40 ml [0206] The mouse ear model, described above, is acetone. The ears were harvested at 1 hr to measure modified to assay the effect of anti-inflammatory agents edema, the maximum response time, and at 5 hr for in- in an immune based inflammation model (See Trampo- flammatory neutrophil infiltration as measured by an sch, K.M., Skin Inflammation, in In Vivo Models of Inflam- MPO assay. 10 mation, M.L. Morgan DW, Editor. 1999, Birkhauser Ver- [0198] The AFC inventive composition, prepared as lag. p. 179-20 and Chapman, J.R., Z. Ruben, and G.M. described above, is less effective in reducing granulocyte Butchko, Histology of and quantitative assays for oxa- infiltration induced by AA than TPA. It has 50% of the zolone-induced allergic contact dermatitis in mice. Am J activity of TPA and a 10 fold higher ED50 (FIG 9). Dermatopathol, 1986. 8(2): p. 130-8). In this model, a [0199] Example 5. AFC inventive composition vis- 15 sensitizing dose of dinitrofluorobenzene ("DNFB") 1-3% ibly reduces TPA-induced erythema. in acetone is applied topically according to a modification [0200] For this example, both ears of a mouse were of the method by Back et al. (See Back, O. and T. Egelrud, treated with a 1 mg/20 ml dose of TPA in acetone. After Topical glucocorticoids and suppression of contact sen- 1 hour, the right ear was treated with 1 mg/20m l of in- sitivity. A mouse bioassay of anti-inflammatory effects. ventive AFC composition and the left ear was treated 20 Br J Dermatol, 1985. 112 (5): p. 539-45 and Bailey, S.C., with acetone alone. The photo was taken 23 hours later et al., A novel contact hypersensitivity model for rank- using a Nikon D70 digital camera. We have observed an ordering formulated corticosteroids. Inflamm Res, 1995. effect of the AFC inventive composition on TPA- induced 44 Suppl 2: p. S162-3) to the shaved bellies of mice to erythema (FIG 10). elicit an immune response. Mice are challenged on day [0201] Example 6. AFC inventive compositions re- 25 5 with 40 ml of 0.5-1% DNFB to each ear. The AFC in- duce inflammation in humans when pre-applied. ventive compound is applied either 0.5 hr before or 15 [0202] An irritant was applied to the middle of the upper min after the challenge to one ear and the vehicle is ap- back of a human subject using a 0.2 ml 20% SDS solution plied to the other ear. The ears are assayed for edema and a Hill-Top Chamber patch with Webril pad. AFC, at or neutrophil infiltration 5 hr later. Dexamethasone is a concentration of 140 mM in aqueous formulation, was 30 used as a positive control. Five days later, the ears are pre-applied to patch areas 1a and 1b (FIG 11). Patches challenged topically with a dose of DNFB insufficient to 1a and 2a were removed after 2 hours, while patches 1b produce contact irritation. Simultaneously, cell infiltration and 2b were removed after 2 hours and 30 minutes. High studies are initiated. Initially, there are more neutrophils levels of irritation were visible in patch sites 2a and 2b. than macrophages. By 48-72 hrs, macrophages become Site 1a showed normal skin while 1b showed a mild re- 35 the predominant population. No inflammatory response sponse. These results show that the inventive composi- is seen. The inventive AFC composition is, therefore, ef- tion can reduce or prevent inflammation when human fective in reducing both edema and neutrophil infiltration. skin is exposed to an irritant. [0203] Example 7. The effect of AFC on chronic ir- ritation in mice. 40 Claims [0204] The effectiveness of the inventive compositions against established chronic irritation is assayed using a 1. A topical composition comprising: modification of the technique of Stanley PL et al., Mouse skin inflammation induced by multiple topical application at least one polyisoprenyl- protein inhibitor com- 12-O-tetradeconoyphorbol-13-acetate. Skin Pharmacol. 45 pound, wherein the at least one polyisoprenyl- 1991, 4: p 262-271. (1991). Both ears of each mouse are protein inhibitor compound comprises a com- treated with TPA in acetone, as above, in a series of 5 pound of Formula 1; applications on the mornings of days 0, 2, 4, 7, and 9. The treated ear receives the inventive compositions con- taining AFC and acetone, in series of three paired appli- 50 cations, such that it is applied 6 hr apart on days 7, 8 and 9. Punches of the ears are taken the afternoon of the tenth day and prepared, as above, for the edema assay and the infiltration of neutrophils. Total granulocyte infil- tration is assayed by measuring MPO activity. Macro- 55 or its pharmaceutically acceptable salts and es- phage infiltration is determined immunocytologically us- ters thereof, wherein ing the MOMA-2 antibody. Hydrocortisone, which is R1 is alkyl of 1 to 3 carbon atoms; 2 known to reduce inflammatory edema granulation infil- R is --COX; wherein X is --OH, --OCH3, -NH2,

18 35 EP 1 765 376 B1 36

4 4 --NHR , --N(R )2 or halogen; nesyl-cysteine; and R3 is a straight or branched chain alkyl of 10 to a carrier; 25 carbon atoms or a straight or branched chain wherein said topical composition is in the form of a alkenyl of 10 to 25 carbon atoms; and powder, an oil, a cream, a gel, or a bandage, and R4 is an alkyl of 1 to 25 carbon atoms; and 5 wherein the topical composition is formulated to de- a carrier; liver an amount of at least one polyisoprenyl- protein wherein said topical composition is in the form inhibitor compound that is effective to inhibit inflam- of a powder, an oil, a cream, a gel, or a bandage, mation when applied topically arid wherein the topical composition is formulat- ed to deliver an amount of at least one polyiso- 10 10. The composition according to claim 1, wherein the prenyl-protein inhibitor compound that is effec- at least one polyisoprenyl-protein inhibitor com- tive to inhibit inflammation when applied topical- pound is at least one of N- acetyl-S-farnesyl-cysteine ly. and N-acetyl-S-geranyl-geranylcysteine.

2. The composition according to claim 1, wherein R 1 is 15 11. The composition according to claim 1 or claim 9, methyl. wherein the pharmaceutically acceptable carrier is a delayed release carrier. 3. The composition according to claim 1, wherein R 2 is COOH. 12. The composition according to claim 11, wherein the 20 delayed release carrier is a carrier selected from the 4. The composition according to claim 1, wherein R 3 is group consisting of a liposome, a microsponge, a farnesyl. microsphere and a microcapsule.

5. The composition according to claim 1, wherein R 1 is 13. The composition according to claim 1 or claim 9, fur- methyl, R2 is COOH, and R3 is farnesyl. 25 ther comprising a second active ingredient.

6. The composition according to claim 1, wherein R 1 is 14. The composition according to claim 13 wherein the methyl, X is --OCH3, and R3 is farnesyl. active ingredient is at least one ingredient selected from the group consisting of a protective agent, an 7. The composition according to claim 1, wherein R 2 is 30 emollient, an astringent, an irritant, a keratolytic COOH and the pharmaceutically acceptable salts agent, a sun screening agent, a sun tanning agent, are salts selected from the group consisting of an an antibiotic agent, an antifungal agent, an antiviral alkali metal salt, an alkaline earth metal salt, an am- agent, an antiprotozoal agent, an anti-acne agent, monium salt and a substituted ammonium salt. an anesthetic agent, a steroidal anti-inflammatory 35 agent, a non-steroidal anti-inflammatory agent, an 8. A topical composition comprising at least one antipruritic agent, an anti-oxidant agent, a chemo- polyisoprenyl-protein inhibitor compound selected therapeutic agent, an anti-histamine agent, a vita- from the group consisting of S-farnesylcysteine, N- min, a hormone, an anti-dandruff agent, an anti- wrin- acetyl-S-geranylcysteine, acetyl- N- S-farnesyl- kle agent, an anti-skin atrophy agent, a sclerosing cysteine ("AFC"), also referred to as acetyl- N- S- 40 agent, a cleansing agent, a caustic agent and a hypo- trans, trans-farnesyl-L-cysteine, N-acetyl-S-geran- pigmenting agent. ylgeranylcysteine ("AGGC"), S-famesyl-2-mercap- toethanesulfonic acid, S-farnesylthioacetic acid, S- 15. The composition according to claim 14, wherein the farnesylmercaptosuccinic acid, S-farnesylthiotria- protective is-a-protective-agent is selected from the zole, S-farnesylthiosalicylic acid ("FTS"), S-far-45 group consisting of an adsorbent, a demulcent and nesylthiosuccinic acid, chloro- 2- 5-farnesylami- a desiccant. nobenzoic acid, farnesyl- 2- thionicotinic acid ("FTN"), 5-fluoro-FTS, 5-chloro-FTS, 4-chloro-FTS, 16. The composition according to claim 14, wherein the S-farnesyl-methylthiosalicylic acid and combina- irritant is a rubefacient. tions thereof; and a carrier; wherein said topical com- 50 position is in the form of a powder, an oil, a cream, 17. A compositionaccording to claim 1or claim 8 or claim a gel, or a bandage, and wherein the topical compo- 9 for use as a medicament for topical application to sition is formulated to deliver an amount of at least a mammal, including a human, for the treatment or one polyisoprenyl-protein inhibitor compound that is prevention of a condition associated with inflamma- effective to inhibit inflammation when applied topi- 55 tion in the mammal. cally. 18. The composition for use according to claim 17, 9. A topical composition comprising acetyl- N- S-far- wherein the carrier is at least one agent selected

19 37 EP 1 765 376 B1 38

from the group consisting essentially of a moisturiz- membrane. ing agent, a pH adjusting agent, a deodorant agent, a thickener, a solubilizing agent, a penetration en- 26. A method of preparing a topical composition, the hancer, an anti-irritant, a colorant and a surfactant. method comprising admixing at least one polyiso- 5 prenyl-protein inhibitor compound and a carrier to 19. The composition for use according to claim 17, form a powder, an oil, a cream, a gel, or a bandage, wherein the carrier is a pharmaceutically acceptable wherein the at least one polyisoprenyl- protein inhib- carrier. itor compound comprises a compound of Formula 1

20. The composition for use according to claim 19,10 wherein the pharmaceutically acceptable carrier is a delayed release carrier selected from the group consisting of a liposome, a microsponge, a micro- sphere, and a microcapsule. 15 21. The composition for use according to claim 17, or its pharmaceutically acceptable salts and esters wherein the composition further comprises an addi- thereof wherein R1 is alkyl of 1 to 3 carbon atoms; 2 tional active ingredient selected from the group con- R is --COX; wherein X is OH, -- --OCH3, --NH2, 4 4 3 sisting of a protective agent, an emollient, an astrin- NHR , -N(R )2 or halogen; R is a straight or gent, an irritant, a keratolytic agent, a sun screening 20 branched chain alkyl of 10 to 25 carbon atoms or a agent, a sun tanning agent, an antibiotic agent, an straight or branched chain alkenyl of 10 to 25 carbon antifungal agent, an antiviral agent, an antiprotozoal atoms; and R4 is an alkyl of 1 to 25 carbon atoms; agent, an anti-acne agent, an anesthetic agent, a or wherein the polyisoprenyl-protein inhibitor is a steroidal anti-inflammatory agent, a non-steroidal compound of claim 8 anti-inflammatory agent, an antipruritic agent, an an- 25 and wherein the topical composition is formulated to ti-oxidant agent, a chemotherapeutic agent, an anti- deliver an amount of the at least one polyisoprenyl- histamine agent, a vitamin, a hormone, an anti- dan- protein inhibitor compound that is effective to inhibit druff agent, an anti-wrinkle agent, an anti-skin atro- inflammation when applied topically. phy agent, a sclerosing agent, a cleansing agent, a caustic agent and a hypo-pigmenting agent. 30 27. The method according to claim 26, wherein the at least one polyisoprenyl-protein inhibitor compound 22. The composition for use according to claim 17, is N-acetyl-S-farnesyl-cysteine. wherein the polyisoprenyl-protein inhibitor com- pound is at least one of N-acetylfarnesyl-cysteine 28. The method according to claim 26, wherein the at and acetyl-geranyl-geranylcysteine. 35 least one polyisoprenyl-protein inhibitor compound is a N-acetyl-S-geranyl-geranylcysteine. 23. The composition for use of claim 17, wherein the at least one polyisoprenyl-protein inhibitor compound 29. The method of claim 26, wherein the at least one is selected from the group consisting of S-farnesyl- polyisoprenyl-protein inhibitor compound is selected cysteine, N-acetyl-S-geranylcysteine, N-acetyl-S- 40 from the group consisting of S-farnesyl-2-mercap- farnesylcysteine ("AFC"), also referred to as N- toethanesulfonic acid, S-farnesylthioacetic acid, S- acetyl-S-trans, trans-famesyl-L-cysteine, N-acetyl- farnesylmercaptosuccinic acid, S-farnesylthiotria- S-geranylgeranylcysteine ("AGGC"), S-farnesyl-2- zole, S-farnesylthiosalicylic acid ("FTS"), S-far- mercaptoethane-sulfonic acid, S-farnesylthioacetic nesylthiosuccinic acid, 2-chloro-5-farnesylami- acid,S- farnesylmercaptosuccinic acid, S- farnesylth- 45 nobenzoic acid, farnesyl- 2- thionicotinic acid iotriazole, S-farnesylthiosalicylic acid ("FTS"), S- far- ("FTN"), 5-fluoro-FTS, 5-chloro-FTS, 4-chloro-FTS, nesylthiosuccinic acid, chloro- 2- 5-famesylami- S-farnesyl-methylthiosalicylic acid and combina- nobenzoic acid, farnesyl- 2- thionicotinic acid tions thereof. ("FTN"), 5-fluoro-FTS, 5-chloro-FTS, 4-chloro-FTS, S-farnesyl-methylthiosalicylic acid and combina-50 30. The composition of claim 1 or claim 9, further com- tions thereof. prising an agent selected from the group consisting of a , an alpha- hydroxy acid, a beta- hydroxy 24. The composition for use according to claim 17, acid, an antibiotic agent, an antifungal agent, a sun wherein the medicament is for applying to an epithe- screening agent, a steroidal inflammatory anti- lial surface. 55 agent, titanium oxide, zinc oxide, benzoyl peroxide, fluorouracil, resorcinol, salicylic acid, or mixtures 25. The composition for use according to claim 17, thereof. wherein the medicament is for applying to mucosal

20 39 EP 1 765 376 B1 40

31. The composition of claim 30, wherein said retinoid 42. The topical composition of claim 40, wherein the pol- is at least one of vitamin A, retinol, retinal, retinyl yhydroxy alcohol is selected from the group consist- palmitate, retinoic acid, tretinoin or iso- tretinoin or a ing of sorbitol, glycerol, and hexanetriol. mixture thereof. 5 43. The topical composition of claim 40, wherein the gly- 32. The composition of claim 30, wherein said alpha- colate salt is selected from the group consisting of hydroxy acid is at least one of glycolic acid, lactic ammonium salt and quarternary alkyl ammonium acid, tartaric acid, malic acid or citric acid or a mixture salt. thereof. 10 33. The topical composition of claims 1 or 9 or the use Patentansprüche according to claim 17 or the method of claim 26, wherein N-acetyl-S-farnesyl-cysteine or the polyiso- 1. Topische Zusammensetzung, umfassend: prenyl-protein inhibitor compound is present at a concentration of about 0.01% to about 50% by15 mindestens eine Polyisoprenylproteininhibitor- weight. Verbindung, wobei die mindestens eine Polyiso- prenylproteininhibitor-Verbindung eine Verbin- 34. The topical composition of claims 1 or 9 or the use dung der Formel 1 umfasst, according to claim 17 or the method of claim 26, wherein the polyisoprenyl-protein inhibitor com- 20 pound or N-acetyl-S-farnesyl-cysteine is present at a concentration of about 0.1% to about 20% by weight.

35. The topical composition of claims 1 or 9 or the use 25 according to claim 17 or the method of claim 26, oder ihre pharmazeutisch verträglichen Salze wherein the polyisoprenyl-protein inhibitor com- und Ester davon, wobei pound or N-acetyl-S-farnesyl-cysteine is present at R1 Alkyl mit 1 bis 3 Kohlenstoffatomen ist; 2 a concentration of less than 10% by weight. R --COX ist; wobei X --OH, --OCH3, --NH2, -- 30 4 4 NHR , --N(R )2 oder Halogen ist; 36. The topical composition of claims 1 or 9 or the use R3 ein gerad- oder verzweigtkettiges Alkyl mit according to claim 17 or the method of claim 26, 10 bis 25 Kohlenstoffatomen oder ein gerad- wherein the polyisoprenyl-protein inhibitor com- oder verzweigtkettiges Alkenyl mit 10 bis 25 pound or N-acetyl-S-farnesyl-cysteine is present at Kohlenstoffatomen ist; und a concentration of less than 5% by weight. 35 R4 ein Alkyl mit 1 bis 25 Kohlenstoffatomen ist; und 37. The topical composition of claim 1 or claim 9, wherein einen Träger; the topical composition comprises hyaluronic acid. wobei die topische Zusammensetzung in Form eines Pulvers, eines Öls, einer Creme, eines 38. The topical composition of claim 1 or claim 9, wherein 40 Gels oder eines Verbands vorliegt, und wobei the topical composition comprises glycerin. die topische Zusammensetzung so formuliert ist, dass sie eine Menge von mindestens einer 39. The topical composition of claim 1 or claim 9, wherein Polyisoprenylproteininhibitor-Verbindung be- the topical composition comprises at least one mois- reitstellt, die bei topischer Anwendung wirksam turizing agent. 45 zur Hemmung einer Entzündung ist.

40. The topical composition of claim 39, wherein the 2. Zusammensetzung gemäß Anspruch 1, wobei R1 moisturizing agent is selected from the group con- Methyl ist. sisting of guanidine, glycolic acid, glycolate salts, al- oe vera, allantoin, urazole, polyhydroxy alcohols, 50 3. Zusammensetzung gemäß Anspruch 1, wobei R2 propylene glycol, butylene glycol, hexylene glycol, COOH ist. polyethylene glycols, sugars, starchs, alkoxylated glucose, hyaluronic acid, lactamide monoeth- 4. Zusammensetzung gemäß Anspruch 1, wobei R3 anolamine, acetamide monoethanolamine, and Farnesyl ist. combinations thereof. 55 5. Zusammensetzung gemäß Anspruch 1, wobei R1 41. The topical composition of claim 1 or claim 9, wherein Methyl ist, R2 COOH ist und R3 Farnesyl ist. the topical composition has a pH between 4 and 7.

21 41 EP 1 765 376 B1 42

6. Zusammensetzung gemäß Anspruch 1, wobei R1 13. Zusammensetzung gemäß Anspruch 1 oder An- Methyl ist, X --OCH3 ist und R3 Farnesyl ist. spruch 9, ferner umfassend einen zweiten Wirkstoff.

7. Zusammensetzung gemäß Anspruch 1, wobei R2 14. Zusammensetzung gemäß Anspruch 13, wobei der COOH ist und die pharmazeutisch verträglichen Sal- 5 Wirkstoff mindestens ein Wirkstoff ist ausgewählt ze Salzesind ausgewählt aus der Gruppe bestehend aus der Gruppe bestehend aus einem Schutzmittel, aus einem Alkalimetallsalz, einem Erdalkalimetall- einem Linderungsmittel, einem Adstringens, einem salz, einem Ammoniumsalz und einem substituier- Reizmittel, einem keratolytischen Mittel, einem Son- ten Ammoniumsalz. nenschutzmittel, einem Sonnenbräunungsmittel, ei- 10 nem Antibiotikum, einem Antimykotikum, einem an- 8. Topische Zusammensetzung, umfassend minde- tiviralen Mittel, einem antiprotozoalen Mittel, einem stens eine Polyisoprenylproteininhibitor-Verbin- Mittel gegen Akne, einem anästhetischen Mittel, ei- dung, ausgewählt aus der Gruppe bestehend aus nem steroidalen Entzündungshemmer, einem nicht- S-Farnesylcystein, N-Acetyl-S-geranylcystein, N- steroidalen Entzündungshemmer, einem antipruriti- Acetyl-S-farnesylcystein ("AFC") auch bezeichnet 15 schen Mittel, einem Anti-oxidationsmittel, einem als N-Acetyl-S-trans, trans-Farnesyl-L-cystein, N- chemotherapeutischen Mittel, einem Antihistamini- Acetyl-S-geranylgeranylcystein ("AGGC"), S- Fame- kum, einem Vitamin, einem Hormon, einem Mittel syl-2-mercaptoethansulfonsäure, S- Farnesylthioes- gegen Schuppen, einem Anti-Falten-Mittel, einem sigsäure, S-Farnesylmercaptobemsteinsäure, S- Mittel gegen Hautatrophie, einem Verödungsmittel, Farnesylthiotriazol, S-Farnesylthiosalicylsäure ("F- 20 einem Reinigungsmittel, einem kaustischen Mittel TS"), S-Farnesylthiobernsteinsäure, 2-Chlor-5-Far- und einem Mittel gegen Hypopigmentierung. nesylaminobenzoesäure, Famesyl- 2- thionikotin- säure ("FTN"), 5-Fluor-FTS, 5-Chlor-FTS, 4-Chlor- 15. Zusammensetzung gemäß Anspruch 14, wobei das FTS, S-Farnesyl-methylthiosalicylsäure und Kombi- Schutzmittel ein Schutzmittel ist ausgewählt aus der nationen davon; und einen Träger; wobei die topi- 25 Gruppe bestehend aus einem Adsorbens, einem sche Zusammensetzung in Form eines Pulvers, ei- reizlindernden Mittel oder einem Trockenmittel. nes Öls, einer Creme, eines Gels oder eines Ver- bands vorliegt, und wobei die topische Zusammen- 16. Zusammensetzung gemäß Anspruch 14, wobei das setzung so formuliert ist, dass sie eine Menge von Reizmittel ein hautrötendes Mittel ist. mindestens einer Polyisoprenylproteininhibitor-Ver- 30 bindung bereitstellt, die bei topischer Anwendung 17. Zusammensetzung gemäß Anspruch 1 oder An- wirksam zur Hemmung einer Entzündung ist. spruch 8 oder Anspruch 9 zur Verwendung als Me- dikament zur topischen Anwendung bei einem Säu- 9. Topische Zusammensetzung, umfassend N- Acetyl- ger, einschließlich eines Menschen, zur Behandlung S-farnesyl-cystein; und einen Träger; 35 oder Vorbeugung eines Zustands, der mit Entzün- wobeidie topische Zusammensetzungin Form eines dung bei Säugern assoziiert ist. Pulvers, eines Öls, einer Creme, eines Gels oder eines Verbands vorliegt, und wobei die topische Zu- 18. Zusammensetzung zur Verwendung gemäß An- sammensetzung so formuliert ist, dass sie eine Men- spruch 17, wobei der Träger mindestens ein Mittel ge von mindestens einer Polyisoprenylproteininhibi- 40 ist, ausgewählt aus der Gruppe hauptsächlich be- tor-Verbindung bereitstellt, die bei topischer Anwen- stehend aus einem feuchtigkeitsspendenden Mittel, dung wirksam zur Hemmung einer Entzündung ist. einem Mittel zur pH-Einstellung, einem desodorie- renden Mittel, einem Verdickungsmittel, einem Lö- 10. Zusammensetzung gemäß Anspruch 1, wobei die sungshilfsmittel, einem Penetrationsförderer, einem mindestens eine Polyisoprenylproteininhibitor-Ver- 45 reizmildernden Mittel, einem Farbstoff und einem bindung mindestens eine von N-Acetyl-S-farnesyl- oberflächenaktiven Mittel. cystein und N-Acetyl-S-geranyl-geranylcystein ist. 19. Zusammensetzung zur Verwendung gemäß An- 11. Zusammensetzung gemäß Anspruch 1 oder An- spruch17, wobeider Träger ein pharmazeutischver- spruch 9, wobei der pharmazeutisch verträgliche 50 träglicher Träger ist. Träger ein Träger mit verzögerter Freisetzung ist. 20. Zusammensetzung zur Verwendung gemäß An- 12. Zusammensetzung gemäß Anspruch 11, wobei der spruch 19, wobei der pharmazeutisch verträgliche Träger mit verzögerter Freisetzung ein Träger aus- Träger ein Träger mit verzögerter Freisetzung ist, gewählt aus der Gruppe bestehend aus einem Lipo- 55 ausgewählt aus der Gruppe bestehend aus einem som, einem Mikroschwamm, einer Mikrosphäre und Liposom, einem Mikroschwamm, einer Mikrosphäre einer Mikrokapsel ist. und einer Mikrokapsel.

22 43 EP 1 765 376 B1 44

21. Zusammensetzung zur Verwendung gemäß An- spruch 17, wobei die Zusammensetzung ferner ei- nen zusätzlichen Wirkstoff umfasst, ausgewählt aus der Gruppe bestehend aus einem Schutzmittel, ei- nem Weichmacher, einem Adstringens, einem Reiz- 5 mittel, einem keratolytischen Mittel, einem Sonnen- schutzmittel, einem Sonnenbräunungsmittel, einem Antibiotikum, einem Antimykotikum, einem antivira- oder ihre pharmazeutisch verträglichen Salze und len Mittel, einem antiprotozoalen Mittel, einem Mittel Ester davon, wobei R 1 Alkyl mit 1 bis 3 Kohlenstoffa- 10 2 gegen Akne, einem anästhetischen Mittel, einem tomen ist; R --COX ist; wobei X --OH, --OCH3 -- 4 4 3 steroidalen Entzündungshemmer, einem nicht-ste- NH2, NHR , --N(R )2 oder Halogen ist; R ein gerad- roidalen Entzündungshemmer, einem antipruriti- oder verzweigtkettiges Alkyl mit 10 bis 25 Kohlen- schen Mittel, einem Antioxidationsmittel, einem che- stoffatomen oder ein gerad- oder verzweigtkettiges motherapeutischen Mittel, einem Antihistaminikum, Alkenyl mit 10 bis 25 Kohlenstoffatomen ist; und R 4 einem Vitamin, einem Hormon, einem Mittel gegen 15 ein Alkyl mit 1 bis 25 Kohlenstoffatomen ist; oder Schuppen, einem Anti-Falten-Mittel, einem Mittel wobei der Polyisoprenylprotein-Inhibitor eine Ver- gegen Hautatrophie, einem Verödungsmittel, einem bindung gemäß Anspruch 8 ist, und wobei die topi- Reinigungsmittel, einem kaustischen Mittel und ei- sche Zusammensetzung so formuliert ist, dass sie nem Mittel gegen Hypopigmentierung. eine Menge der mindestens einen Polyisoprenylpro- 20 teininhibitor-Verbindung bereitstellt, die bei topi- 22. Zusammensetzung zur Verwendung gemäß An- scher Anwendung zur Hemmung einer Entzündung spruch 17, wobei die Polyisoprenylproteininhibitor- wirksam ist. Verbindung mindestens eines von N- Acetylfarnesyl- cystein und Acetyl-geranyl-geranylcystein ist. 27. Verfahren gemäß Anspruch 26, wobei die minde- 25 stens eine Polyisoprenylproteininhibitor- Verbindung 23. Zusammensetzung zur Verwendung gemäß An- N-Acetyl-S-farnesyl-cystein ist. spruch 17, wobei die mindestens eine Polyisopre- nylproteininhibitor-Verbindung ausgewählt ist aus 28. Verfahren gemäß Anspruch 26, wobei die minde- der Gruppe bestehend aus S-Farnesylcystein, N- stens eine Polyisoprenylproteininhibitor- Verbindung Acetyl-S-geranylcystein,N- Acetyl-S-famesylcystein 30 N-Acetyl-S-geranyl-geranylcystein ist. ("AFC"), auch bezeichnet als Acetyl- N- S-trans, trans-Famesyl-L-cystein, N-Acetyl-S-geranylgera- 29. Verfahren gemäß Anspruch 26, wobei die minde- nylcystein ("AGGC"), S-Famesyl-2-mercaptoethan- stens eine Polyisoprenylproteininhibitor- Verbindung sulfonsäure, ausgewählt ist aus der Gruppe bestehend aus S- S-Farnesylthioessigsäure, Farnesylmercapto- S- 35 Farnesyl-2-mercaptoethansulfonsäure, Farne- S- bernsteinsäure, S-Famesylthiotriazol, sylthioessigsäure, S-Farnesylmercaptobernstein- S-Farnesylthiosalicylsäure ("FTS"), S-Farnesylthi- säure, S-Farnesylthiotriazol, S-Farnesylthiosalicyl- obernsteinsäure, 2-Chlor-5-farnesylaminobenzoe- säure ("FTS"), S-Farnesylthiobernsteinsäure, 2- säure, 2-Farnesyl-thionikotinsäure ("FTN"), 5- Fluor- Chlor-5-farnesylaminobenzoesäure, Farnesyl- 2- FTS, 5-Chlor-FTS, 4-Chlor-FTS, S-Farnesyl-me- 40 thionikotinsäure ("FTN"), 5- Fluor-FTS, 5-Chlor-FTS, thylthiosalicylsäure und Kombinationen davon. 4-Chlor-FTS, Farnesyl- S- methylthiosalicylsäure und Kombinationen davon. 24. Zusammensetzung zur Verwendung gemäß An- spruch 17, wobei das Medikament zur Anwendung 30. Zusammensetzung gemäß Anspruch 1 oder An- auf eine Epitheloberfläche bestimmt ist. 45 spruch 9, ferner umfassend ein Mittel ausgewählt aus der Gruppe bestehend aus einem Retinoid, einer 25. Zusammensetzung zur Verwendung gemäß An- alpha-Hydroxysäure, einer beta-Hydroxysäure, ei- spruch 17, wobei das Medikament zur Anwendung nem Antibiotikum, einem Antimykotikum, einem auf eine Mukosamembran bestimmt ist. Sonnenschutzmittel, einem steroidalen Entzün- 50 dungshemmer, Titanoxid, Zinkoxid, Benzoylperoxid, 26. Verfahren zur Herstellung einer topischen Zusam- Fluoruracil, Resorcin, Salicylsäure oder Gemischen mensetzung, wobei das Verfahren das Zugeben davon. mindestens einer Polyisoprenylproteininhibitor-Ver- bindung und eines Trägers umfasst, zur Bildung ei- 31. Zusammensetzung nach Anspruch 30, wobei das nes Pulvers, eines Öls, einer Creme, eines Gels oder 55 Retinoid mindestens eines von Vitamin A, Retinol, eines Verbands, wobei die mindestens eine Polyiso- Retinal, Retinylpalmitat, Retinolsäure, Tretinoin prenylproteininhibitor-Verbindung eine Verbindung oder Isotretinoin oder ein Gemisch davon ist. der Formel 1 umfasst,

23 45 EP 1 765 376 B1 46

32. Zusammensetzung gemäß Anspruch 30, wobei die zung einen pH-Wert zwischen 4 und 7 hat. alpha-Hydroxysäure mindestens eine von Glykol- säure, Milchsäure, Weinsäure, Apfelsäure oder Zi- 42. Topische Zusammensetzung gemäß Anspruch 40, tronensäure oder ein Gemisch davon ist. wobei der Polyhydroxyalkohol aus der Gruppe be- 5 stehend aus Sorbit, Glycerin und Hexantriol ausge- 33. Topische Zusammensetzung gemäß den Ansprü- wählt ist. chen 1 oder 9 oder Verwendung gemäß Anspruch 17 oder Verfahren gemäß Anspruch 26, wobei N- 43. Topische Zusammensetzung gemäß Anspruch 40, Acetyl-S-farnesyl-cystein oder die Polyisoprenylpro- wobei das Glykolatsalz aus der Gruppe bestehend teininhibitor-Verbindung in einer Konzentration von 10 aus Ammoniumsalz und quaternärem Alkylammoni- etwa 0,01 bis etwa 50 Gew.-% vorliegt. umsalz ausgewählt ist.

34. Topische Zusammensetzung gemäß den Ansprü- chen 1 oder 9 oder Verwendung gemäß Anspruch Revendications 17 oder Verfahren gemäß Anspruch 26, wobei die 15 Polyisoprenylproteininhibitor-Verbindung oder N- 1. Composition topique comprenant : Acetyl-S-farnesyl-cystein in einer Konzentration von etwa 0,1 bis etwa 20 Gew.-% vorliegt. au moins un composé inhibiteur de protéines agissant sur le polyisoprényle, où l’au moins un 35. Topische Zusammensetzung gemäß den Ansprü- 20 composé inhibiteur de protéines agissant sur le chen 1 oder 9 oder Verwendung gemäß Anspruch polyisoprényle comprend un composé de for- 17 oder Verfahren gemäß Anspruch 26, wobei die mule 1 ; Polyisoprenylproteininhibitor-Verbindung oder N- Acetyl-S-farnesyl-cystein in einer Konzentration von weniger als 10 Gew.-% vorliegt. 25

36. Topische Zusammensetzung gemäß den Ansprü- chen 1 oder 9 oder Verwendung gemäß Anspruch 17 oder Verfahren nach Anspruch 26, wobei die Po- lyisoprenylproteininhibitor-Verbindung oder N-Ace- 30 ou ses sels pharmaceutiquement acceptables tyl-S-farnesyl-cystein in einer Konzentration von we- et les esters de ceux-ci, dans laquelle niger als 5 Gew.-% vorliegt. R1 est un alkyle de 1 à 3 atomes de carbone ; 2 R est --COX ; dans lequel X est -OH, --OCH3, 4 4 37. Topische Zusammensetzung gemäß Anspruch 1 NH2, --NHR - -N(R )2 ou oder Anspruch 9, wobei die topische Zusammenset- 35 un halogène ; zung Hyaluronsäure umfasst. R3 est un alkyle à chaîne droite ou ramifiée de 10 à 25 atomes de carbone ou un alcényle à 38. Topische Zusammensetzung gemäß Anspruch 1 chaîne droite ou ramifiée de 10 à 25 atomes de oder Anspruch 9, wobei die topische Zusammenset- carbone ; et zung Glycerin umfasst. 40 R4 est un alkyle de 1 à 25 atomes de carbone ; et un véhicule ; 39. Topische Zusammensetzung gemäß Anspruch 1 dans laquelle ladite composition topique se pré- oder Anspruch 9, wobei die topische Zusammenset- sente sous la forme d’une poudre, d’une huile, zung mindestens ein feuchtigkeitsspendendes Mit- d’une crème, d’un gel ou d’un pansement, et tel umfasst. 45 dans laquelle la composition topique est formu- lée pour libérer une quantité d’au moins un com- 40. Topische Zusammensetzung gemäß Anspruch 39, posé inhibiteur de protéines agissant sur le po- wobei das feuchtigkeitsspendende Mittel ausge- lyisoprényle qui est efficace pour inhiber une in- wählt ist aus der Gruppe bestehend aus Guanidin, flammation lors de son application par voie to- Glykolsäure, Glykolatsalzen, Aloe Vera, Allantoin, 50 pique. Urazol, Polyhydroxyalkoholen, Propylenglykol, Bu- tylenglykol, Hexylenglykol, Polyethylenglykolen, 2. Composition selon la revendication 1, dans laquelle Zuckern, Stärken, alkoxylierter Glucose, Hyaluron- R1 est le méthyle. säure, Lactamidmonoethanolamin, Acetamidmo- noethanolamin und Kombinationen davon. 55 3. Composition selon la revendication 1, dans laquelle R2 est COOH. 41. Topische Zusammensetzung gemäß Anspruch 1 oder Anspruch 9, wobei die topische Zusammenset- 4. Composition selon la revendication 1, dans laquelle

24 47 EP 1 765 376 B1 48

R3 est le famésyle. 11. Composition selon la revendication 1 ou la revendi- cation 9, dans laquelle le véhicule pharmaceutique- 5. Composition selon la revendication 1, dans laquelle ment acceptable est un véhicule à libération différée. R1 est le méthyle, R2 est COOH, et R3 est le famé- syle. 5 12. Composition selon la revendication 11, dans laquelle le véhicule à libération différée est un véhicule sé- 6. Composition selon la revendication 1, dans laquelle lectionné dans le groupe constitué par un liposome, R’ est le méthyle, X est- OCH3, et R 3 est le famésyle. une microéponge, une microsphère et une micro- capsule. 7. Composition selon la revendication 1, dans laquelle 10 R2 est COOH et les sels pharmaceutiquement ac- 13. Composition selon la revendication 1 ou la revendi- ceptables sont des sels sélectionnés dans le groupe cation 9, comprenant en outre un deuxième principe constitué par un sel de métal alcalin, un sel de métal actif. alcalinoterreux, un sel d’ammonium et un sel d’am- monium substitué. 15 14. Composition selon la revendication 13, dans laquelle le principe actif est au moins un ingrédient sélection- 8. Composition topique comprenant au moins un com- né dans le groupe constitué par un agent protecteur, posé inhibiteur de protéines agissant sur le polyiso- un émollient, un astringent, un irritant, un agent ké- prényle sélectionné dans le groupe constitué par la ratolytique, un agent de protection solaire, un agent S-famésylcystéine, la N-acétyl-S-géranylcystéine, 20 bronzant, un agent antibiotique, agent antifongique, la N-acétyl-S-farnésylcystéine (« AFC »), égale- un agent antiviral, un agent antiprotozoaire, un agent ment appelée N-acétyl-S-trans, trans-famésyl-L- antiacnéique, un agent anesthésique, un agent anti- cystéine, la acétyl- N- S-géranyl-géranylcystéine inflammatoire stéroïdien, un agent anti- inflammatoi- (« AGGC »), l’acide S-farnésyl-2-mercaptoéthane- re non stéroïdien, un agent antioxydant, un agent sulfonique, l’acide S-farnésylthioacétique, l’acide S- 25 chimiothérapeutique, un agent antihistaminique, famésylmercaptosuccinique, le S- famésylthiotriazo- une vitamine, une hormone, un agent antipelliculai- le, l’acide S- farnésylthiosalicylique (« FTS »), l’acide re, un agent antirides, un agent anti-atrophie cuta- S-famésylthiosuccinique, l’acide 2-chloro-5-famé- née, un agent sclérosant, un agent purificateur, un sylaminobenzoïque, l’acide 2-farnésylthionicotini- agent caustique et un agent d’hypopigmentation. que (« FTN »), l’acide 5-fluoro-FTS, 5-chloro-FTS, 30 4-chloro-FTS, S-farnésyl-méthylthiosalicylique et 15. Composition selon la revendication 14, dans laquelle les combinaisons de ceux-ci ; et un véhicule ; dans l’agent protecteur est un agent protecteur sélection- laquelle ladite composition topique se présente sous né dans le groupe constitué par un adsorbant, un la forme d’une poudre, d’une huile, d’une crème, d’un adoucissant et un siccatif. gel, ou d’un pansement, et dans laquelle la compo- 35 sition topique est formulée pour libérer une quantité 16. Composition selon la revendication 14, dans laquelle d’au moins un composé inhibiteur de protéines agis- l’irritant est un rubéfiant. sant sur le polyisoprényle qui est efficace pour inhi- ber une inflammation lors de son application voie 17. Composition selon la revendication 1 ou la revendi- topique. 40 cation 8 ou la revendication 9 destinée à être utilsée en tant que médicament pour une application topi- 9. Composition topique comprenant la acétyl- N- S- que chez un mammifère, y compris un humain, pour farnésylcystéine ; et un véhicule ; dans laquelle la- le traitement ou la prévention d’une affection asso- dite composition topique se présente sous la forme ciée à une inflammation chez le mammifère. d’une poudre, d’une huile, d’une crème, d’un gel, ou 45 d’un pansement, et dans laquelle la composition to- 18. Composition destinée à être utilisée selon la reven- pique est formulée pour libérer une quantité d’au dication 17, dans laquelle le véhicule est au moins moins un composé inhibiteur de protéines agissant un agent sélectionné dans le groupe constitué es- sur le polyisoprényle qui est efficace pour inhiber sentiellement par un agent hydratant, un agent une inflammation lors de son application voie topi- 50 d’ajustement du pH, un agent déodorant, un épais- que. sisseur, un agent de solubilisation, un amplificateur de pénétration, un anti- irritant, un colorant et un ten- 10. Composition selon la revendication 1, dans laquelle sioactif. l’au moins un composé inhibiteur de protéines agis- sant sur le polyisoprényle est au moins l’un parmi la 55 19. Composition destinée à être utilisée selon la reven- N-acétyl-S-farnésylcystéine et la N-acétyl-S-géra- dication 17, dans laquelle le véhicule est un véhicule nyl-géranylcystéine. pharmaceutiquement acceptable.

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20. Composition destinée à être utilisée selon la reven- le procédé comprenant le mélange d’au moins un dication 19, dans laquelle le véhicule pharmaceuti- composé inhibiteur de protéines agissant sur le po- quement acceptable est un véhicule à libération dif- lyisoprényle et d’un véhicule pour former une pou- férée sélectionné dans le groupe constitué par un dre, une huile, une crème, un gel, ou un pansement, liposome, une microéponge, une microsphère, et 5 dans lequel l’au moins un composé inhibiteur de pro- une microcapsule. téines agissant sur le polyisoprényle comprend un composé de formule 1 21. Composition destinée à être utilisée selon la reven- dication 17, dans laquelle la composition comprend en outre un principe actif supplémentaire sélection- 10 né dans le groupe constitué par un agent protecteur, un émollient, un astringent, un irritant, un agent ké- ratolytique, un agent de protection solaire, un agent bronzant, un agent antibiotique, agent antifongique, un agent antiviral, un agent antiprotozoaire, un agent 15 ou ses sels pharmaceuticquement acceptables et antiacnéique, un agent anesthésique, un agent anti- les esters de ceux-ci, dans laquelle R 1 est un alkyle inflammatoire stéroïdien, un agent anti- inflammatoi- de 1 à 3 atomes de carbone ; R2 est --COX ; dans 4 4 re non stéroïdien, un agent antiprurit, un agent an- lequel X est -- OH, --OCH3, --NH2, NHR , -N(R )2 ou tioxydant, un agent chimiothérapeutique, un agent un halogène ; R3 est un alkyle à chaîne droite ou antihistaminique, une vitamine, une hormone, un 20 ramifiée de 10 à 25 atomes de carbone ou un alcé- agent antipelliculaire, un agent antirides, un agent nyle à chaîne droite ou ramifiée de 10 à 25 atomes anti-atrophie cutanée, un agent sclérosant, un agent de carbone ; et R4 est un alkyle de 1 à 25 atomes purificateur, un agent caustique et un agent d’hypo- de carbone ; ou dans lequel l’inhibiteur de protéines pigmentation. agissant sur le polyisprényle est un composé selon 25 la revendication 8 et dans lequel la composition to- 22. Composition destinée à être utilisée selon la reven- pique est formulée pour libérer une quantité de l’au dication 17, dans laquelle le composé inhibiteur de moins un composé inhibiteur de protéines agissant protéines agissant sur le polyisoprényle est au moins sur le polyisoprényle qui est efficace pour inhiber l’un parmi la N-acétylfamésylcystéine et l’acétyl-gé- une inflammation lors de son application voie topi- ranyl-géranylcystéine. 30 que.

23. Composition destinée à être utilisée selon la reven- 27. Procédé selon la revendication 26, dans lequel l’au dication 17, dans laquelle l’au moins un composé moins un composé inhibiteur de protéines agissant inhibiteur de protéines agissant sur le polyisoprényle sur le polyisoprényle est la N-acétyl-S-famésylcys- est sélectionné dans le groupe constitué par la S- 35 téine. famésylcystéine, la N-acétyl-S-géranylcystéine, la N-acétyl-S-famésylcystéine (« AFC »), également 28. Procédé selon la revendication 26, dans lequel l’au appelée N- acétyl-S-trans, trans- famésyl-L-cystéine, moins un composé inhibiteur de protéines agissant la N-acétyl-S-géranyl-géranylcystéine (« AGGC »), sur le polyisoprényle est une N- acétyl-S-géranyl-gé- l’acide farnésyl- S- 2-mercaptoéthanesulfonique, 40 ranylcystéine. l’acide S-farnésylthioacétique, l’acide S-farnésyl- mercaptosuccinique, le S-famésylthiotriazole, l’aci- 29. Procédé selon la revendication 26, dans lequel l’au de S-farnésylthiosalicylique (« FTS »), l’acide S-fa- moins un composé inhibiteur de protéines agissant mésylthiosuccinique, l’acide 2-chloro-5-farnésyla- sur le polyisoprényle est sélectionné dans le groupe minobenzoïque, l’acide famésyl- 2- thionicotinique 45 constitué par l’acide S-farnésyl-2-mercaptoéthane- (« FTN »), l’acide 5-fluoro-FTS, 5-chloro-FTS, 4- sulfonique, l’acide S- farnésylthioacétique, l’acide S- chloro-FTS, S-farnésyl-méthylthiosalicylique et les famésylmercaptosuccinique, le S-farnésylthiotria- combinaisons de ceux-ci. zole, l’acide farnésylthiosalicylique S- (« FTS »), l’acide S-famésylthiosuccinique, l’acide 2-chloro-5- 24. Composition destinée à être utilisée selon la reven- 50 farnésylaminobenzoïque, l’acide 2-famésyl-thioni- dication 17, dans laquelle le médicament doit être cotinique acid (« FTN »), l’acide fluoro- 5- FTS, 5- appliqué sur une surface épithéliale. chloro-FTS, 4-chloro-FTS, S-farnésyl-méthylthiosa- licylique et les combinaisons de ceux-ci. 25. Composition destinée à être utilisée selon la reven- dication 17, dans laquelle le médicament doit être 55 30. Composition selon la revendication 1 ou la revendi- appliqué sur une membrane muqueuse. cation 9, comprenant en outre un agent sélectionné dan le groupe constitué par un rétinoïde, un acide 26. Procédé de préparation d’une composition topique, alpha-hydroxy, un acide bêta-hydroxy, un agent an-

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tibiotique, un agent antifongique, un agent de pro- que comprend au moins un agent hydratant. tection solaire, un agent anti-imflammatoire stéroï- dien, l’oxyde de titane, l’oxyde de zinc, le peroxyde 40. Composition topique selon la revendication 39, dans de benzoyle, le fluorouracile, le résorcinol, l’acide laquelle l’agent hydratant est sélectionné dans le salicylique, ou les mélanges de ceux-ci. 5 groupe constitué par la guanidine, l’acide glycolique, les sels glycolate, l’aloe vera, l’allantoïne, l’urazole, 31. Compositionselon la revendication 30, danslaquelle les polyhydroxy alcools, le propylène glycol, le bu- ledit rétinoïde ets au moins l’un parmi la vitamine A, tylène glycol, l’hexylène glycol, les polyéthylène gly- le rétinol, le rétinal, le palmitate de rétinyle, l’acide cols, les sugars, les amidons, le glucose alkoxylé, rétinoïque, la trétinoïne ou l’isotrétinoïne ou un mé- 10 l’acide hyaluronique, la lactamide- monoéthanolami- lange de ceux-ci. ne, l’acétamide-monoéthanolamine, et les combi- naisons de ceux-ci. 32. Compositionselon la revendication 30, danslaquelle ledit acide alpha-hydroxy est au moins l’un parmi 41. Composition topique selon la revendication 1 ou la l’acide glycolique, l’acide lactique, l’acide tartrique, 15 revendication 9, dans laquelle la composition topi- l’acide malicque ou l’acide citrique ou un mélange que a un pH entre 4 et 7. de ceux-ci. 42. Composition topique selon la revendication 40, dans 33. Composition topique selon les revendications 1 ou laquelle le polyhydroxy alcool est sélectionné dans 9 ou utilisation selon la revendication 17 ou procédé 20 le groupe constitué par le sorbitol, le glycérol, et selon la revendication 26, dans lesquels la N- acétyl- l’hexanetriol. S-farnésylcystéine ou le composé inhibiteur des pro- téines agissant sur le polyisoprényle est présent(e) 43. Composition topique selon la revendication 40, dans à une concentration d’environ 0,01 % à environ 50 laquelle le sel glycolate est sélectionné dans le grou- % en poids. 25 pe constitué par le sel d’ammonium et le sel d’alky- lammonium quaternaire. 34. Composition topique selon les revendications 1 ou 9 ou utilisation selon la revendication 17 ou procédé selon la revendication 26, dans lesquels le composé inhibiteur des protéines agissant sur le polyisopré- 30 nyle ou la N- acétyl-S-famésylcystéine est présent (e) à une concentration d’environ 0,1% à environ 20 % en poids.

35. Composition topique selon les revendications 1 ou 35 9 ou utilisation selon la revendication 17 ou procédé selon la revendication 26, dans lesquels le composé inhibiteur des protéines agissant sur le polyisopré- nyle ou la N- acétyl-S-famésylcystéine est présent (e) à une concentration inférieure à 10 % en poids. 40

36. Composition topique selon les revendications 1 ou 9 ou utilisation selon la revendication 17 ou procédé selon la revendication 26, dans lesquels le composé inhibiteur des protéines agissant sur le polyisopré- 45 nyle ou la N- acétyl-S-famésylcystéine est présent (e) à une concentration inférieure à 5 % en poids.

37. Composition topique selon la revendication 1 ou la revendication 9, dans laquelle la composition topi- 50 que comprend de l’acide hyaluronique.

38. Composition topique selon la revendication 1 ou la revendication 9, dans laquelle la composition topi- que comprend de la glycérine. 55

39. Composition topique selon la revendication 1 ou la revendication 9, dans laquelle la composition topi-

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

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