US 2008.0063607A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0063607 A1 Tamarkin et al. (43) Pub. Date: Mar. 13, 2008

(54) OLEAGINOUS PHARMACEUTICAL AND (60) Provisional application No. 60/492.385, filed on Aug. COSMETC FOAM 4, 2003. Provisional application No. 60/492.385, filed on Aug. 4, 2003. Provisional application No. 60/.530, (75) Inventors: Dov Tamarkin, Maccabim (IL); Doron 015, filed on Dec. 16, 2003. Provisional application Friedman, Karmei Yosef (IL); Meir No. 60/679,020, filed on May 9, 2005. Provisional Eini, Ness Ziona (IL); Alex Besonov, application No. 60/784,793, filed on Mar. 21, 2006. Rehovot (IL); Jorge Danziger, Rishom LeZion (IL); David Schuz. Moshav Gimzu (IL); Tal Berman, Rishon Publication Classification LeZiyyon (IL) (51) Int. Cl. Correspondence Address: A6IR 9/12 (2006.01) WILMERHALEABOSTON A6II 47/00 (2006.01) 6O STATE STREET A6IP 7/00 (2006.01) BOSTON, MA 02109 (US) (52) U.S. Cl...... 424/43; 514/789 (73) Assignee: FOAMIX LTD (57) ABSTRACT (21) Appl. No.: 11/894,798 (22) Filed: Aug. 20, 2007 The invention relates to stable pharmaceutical or cosmetic foam compositions containing certain active agents, having Related U.S. Application Data unique therapeutic properties and methods of treatment using Such compositions. The foamable composition (63) Continuation of application No. 1 1/653,205, filed on includes at least one solvent comprising polyethylene glycol Jan. 12, 2007. (PEG) or PEG derivative and mixtures thereof, or compris Continuation-in-part of application No. 10/911,367, ing propylene glycol, wherein the solvent is present at a filed on Aug. 4, 2004. concentration of about 70% to about 96.5% by weight of the Continuation-in-part of application No. 11/430,599, total composition, at least a non-ionic Surface-active agent at filed on May 9, 2006, which is a continuation-in-part a concentration of about 0.1% to less than about 10% by of application No. 10/835,505, filed on Apr. 28, 2004. weight of the total composition. US 2008/0063607 A1 Mar. 13, 2008

OLEAGNOUS PHARMACEUTICAL AND 0008 U.S. Pat. No. 6,524,594 describes a gelled oil COSMETC FOAM composition containing an emulsifier, a gelling agent, an oil. and a Surfactant which, when applied to the skin in the RELATED APPLICATIONS presence of water, produces a significant amount of foam. The surfactant is used in an amount from about 10% to about 0001. This application claims the benefit of priority under 20%, and more preferably, from about 15% to about 20%. 35 U.S.C. S 120 to co-pending U.S. application Ser. No. 1 1/653,205, filed Jan. 12, 2007, entitled “Oleaginous Phar 0009 U.S. Pat. No. 6,121,210 discloses foamable, sili maceutical and Cosmetic Foam, which is a continuation-in cone oil compositions and methods of lubricating Surfaces part application of co-pending U.S. patent application Ser. with Such compositions. The compositions are oil-in-water No. 10/911,367, filed on Aug. 4, 2004, which claims the emulsions comprising silicone oil-in-water emulsion, a liq benefit of priority under 35 U.S.C. S 119(e) to U.S. Patent uid propellant and a foam builder comprising a solid, Application Ser. No. 60/492.385, filed on Aug. 4, 2003, both non-ionic lipophilic Surfactant having an HLB value of entitled "Foam Carrier Containing Amphiphilic Copolymer about 3 to about 8. Foam stabilizers including long claim Gelling Agent” and both hereby incorporated in their fatty alcohols are included. A propellant is included to create entirety by reference. a foamable composition. 0002 This application is a continuation-in-part applica 0010. In general, the foamable compositions of the art are tion of co-pending U.S. patent application Ser. No. 10/835, based on oil-in-water emulsions. Furthermore, they often 505, filed on Apr. 28, 2004, which claims the benefit of include a high content level of Surfactants and foaming priority under 35 U.S.C. S 119(e) to U.S. Patent Application agents required to form acceptable foams which are stable Ser. No. 60/.530,015, filed on Dec. 16, 2003, both entitled and possess low specific gravity. Such surfactants, and “Oleaginous Pharmaceutical Foam and both hereby incor particularly ionic Surfactants, such as anionic Surfactants porated in their entirety by reference. (e.g. sodium lauryl sulfate (SDS)), may have adverse affects on certain patients, including concentration-dependent skin FIELD OF THE INVENTION irritation. 0003. The invention relates to foam compositions includ 0011. There remains an unmet need for improved, stable ing cosmetic or therapeutic active agents, and methods of and non-irritating foam formulations and oleaginous foam topical treatment using the compositions. formulations, intended for dermal and mucosal delivery of pharmaceutical and cosmetic, with unique therapeutic and BACKGROUND OF THE INVENTION cosmetic properties. 0004 Certain foam products for topical application of SUMMARY OF THE INVENTION therapeutical agents and cosmetics have been prepared as oil-in-water emulsions. Foams and, in particular, foam com 0012. The invention relates to stable pharmaceutical or positions having a high oil content are complicated systems cosmetic foam compositions containing certain active that do not form under all circumstances. Slight shifts in agents, having unique therapeutic properties and methods of foam composition, Such as the addition of an active ingre treatment using such compositions. The foamable compo dient, may destabilize the foam. It is known in the art that sition includes at least one solvent comprising polyethylene hydrophobic solvents are difficult to formulate into a foam glycol (PEG) or PEG derivative and mixtures thereof, or producing product. Addition of conventional hydrophobic comprising propylene glycol, wherein the solvent is present solvents interferes with the foam forming ability of the at a concentration of about 70% to about 96.5% by weight Surfactant, and thus, in the few foam products containing of the total composition, at least a non-ionic Surface-active high-oil concentrations that have been reported, high Sur agent at a concentration of about 0.1% to less than about factant concentrations are used, which may cause undesir 10% by weight of the total composition. able irritancy on one hand, and costly raw material usage on 0013 The present invention provides stable foam-form the other hand are used. ing compositions, and stable oleaginous foam-forming com 0005 Oleaginous formulations for the preparation of positions including at least one active agent for dermal and cosmetic and therapeutic compositions are known in the art. mucosal delivery. The composition is dispensed as a foam providing a stable product that is pleasant and easy to 0006 U.S. Pat. No. 6,620,773 relates to a foaming oil spread, resulting in high patient compliance. The invention composition, which includes a Surfactant mixture and an oil more particularly relates to a foamable pharmaceutical or component, the Surfactant mixture containing an anionic or cosmetic composition, comprising: Zwitterionic Surfactant, a nonionic Surfactant and at least one ethoxylated alkyl phosphate ester component. The Surfactant 0014 a solvent comprising polyethylene glycol (PEG) or mixture ranges from about 15% to about 50% of the total PEG derivative and mixtures thereof, wherein the PEG or composition, and that of the oil component ranges from PEG derivative is present at a concentration of about 70% to about 50% to about 85%. about 96.5% by weight of the total composition; 0007 U.S. Pat. Nos. 5,700,396 and 5,589,515 disclose a 00.15 a surface-active agent at a concentration of about cosmetic emulsion composition containing 1 to 99 wt % oily 0.1% to less than about 10% by weight of the total compo component (balance aqueous component). The oily compo sition; and nent includes 85% or more weight% of cis A9-octadecanoic acid or derivatives thereof, which serves as a surfactant in 0016 a therapeutically effective amount of at least one the formulation. active agent. US 2008/0063607 A1 Mar. 13, 2008

0017. The invention also relates to a foamable pharma 0034. The invention still further relates to a foamable ceutical or cosmetic carrier composition for dermatological pharmaceutical or cosmetic carrier composition for derma use, comprising: tological use, comprising: 0018 a solvent comprising polyethylene glycol (PEG) or 0035 a solvent comprising propylene glycol, wherein the PEG derivative and mixtures thereof, wherein the PEG or propylene glycol is present at a concentration of about 70% PEG derivative is present at a concentration of about 70% to to about 96.5% by weight of the total composition; and about 96.5% by weight of the total composition; and 0036) a surface-active agent at a concentration of about 0.019 a surface-active agent at a concentration of about 0.1% to less than about 10% by weight of the total compo 0.1% to less than about 10% by weight of the total compo sition. sition. 0037 at least one gelling agent at a concentration of 0020 at least one gelling agent at a concentration of about 0.1% to about 5% by weight of the total composition. about 0.1% to about 5% by weight of the total composition. 0038 at least one liquefied or compressed gas propellant, 0021 at least one liquefied or compressed gas propellant, at a concentration of about 3% to about 25% by weight of at a concentration of about 3% to about 25% by weight of the total composition the total composition wherein the composition is stored in an aerosol container wherein the composition is stored in an aerosol container and upon release expands to form a breakable foam. and upon release expands to form a breakable foam. 0039 The invention still further relates to a composition, 0022. The invention further relates to a composition, comprising: comprising: 0040 a solvent comprising propylene glycol, wherein the 0023) a polyethylene glycol (PEG) or PEG derivative and propylene glycol is present at a concentration of about 70% mixtures thereof, wherein the PEG or PEG derivative is to about 96.5% by weight of the total composition; present at a concentration of about 70% to about 96.5% by weight of the total composition; 0041 a surface-active agent at a concentration of about 0.1% to less than about 10% by weight of the total compo 0024 a surface-active agent at a concentration of about 0.1% to less than about 10% by weight of the total compo sition; and sition; and 0042 a therapeutically effective amount of a agent, an 0.025 a therapeutically effective amount of a agent, an antinfective agent, a keratolytically active agent, a vasoac antinfective agent, a keratolytically active agent, a vasoac tive agent and a retinoid. tive agent and a retinoid. 0043. The invention still further relates to a composition, comprising: 0026. The invention further relates to a composition, comprising: 0044) a solvent comprising propylene glycol, wherein the propylene glycol is present at a concentration of about 70% 0027) a polyethylene glycol (PEG) or PEG derivative and to about 96.5% by weight of the total composition; mixtures thereof, wherein the PEG or PEG derivative is present at a concentration of about 70% to about 96.5% by 0045 a surface-active agent at a concentration of about weight of the total composition; 0.1% to less than about 10% by weight of the total compo 0028 a surface-active agent at a concentration of about sition; and 0.1% to less than about 10% by weight of the total compo 0046) a therapeutically effective amount of a an anti sition; and inflammatory or antiallergic agent, wherein said agent 0029 a therapeutically effective amount of a an anti reduces the occurrence of pro-inflammatory cytokines or inflammatory or antiallergic agent, wherein said agent inhibits the effect of pro-inflammatory cytokines. reduces the occurrence of pro-inflammatory cytokines or 0047 The invention also relates to a method of treating, inhibits the effect of pro-inflammatory cytokines. alleviating or preventing a dermatological, cosmetic or mucosal disorder, comprising administering topically to a 0030) The invention still further relates to a foamable subject having said disorder a therapeutically effective pharmaceutical or cosmetic composition, comprising: amount of any of the compositions, foamable compositions 0031 a solvent comprising propylene glycol, wherein the and foam compositions described herein. propylene glycol is present at a concentration of about 70% 0048. In the context of the present invention, an oleagi to about 96.5% by weight of the total composition; nous foam is a composition comprising at least one solvent 0032 a surface-active agent at a concentration of about selected from a hydrophobic solvent, a co-solvent, an emol 0.1% to less than about 10% by weight of the total compo lient and mixtures thereof in the continuous phase of the sition; and composition. In specific embodiments, the foamable com positions and foams produced from them include a solvent 0033 a therapeutically effective amount of at least one comprising polyethylene glycol (PEG) or PEG derivative active agent. and mixtures thereof, or comprising polypropylene glycol. US 2008/0063607 A1 Mar. 13, 2008

0049 According to one aspect or the present invention, mineral oil or petrolatum, for example, 5-fold better than the composition includes: mineral oil; or even 10-fold better than mineral oil. 0050 a. at least one solvent selected from a hydrophobic 0062. In one or more embodiments, the oleaginous com Solvent, a co-solvent, and mixtures thereof, wherein the position of the present invention contains a potent solvent solvent is present at a concentration of about 70% to about selected from the group consisting of polyethylene glycol, 96.5% by weight of the total composition; propylene glycol, hexylene glycol, butanediols and isomers thereof, glycerol, benzyl alcohol, DMSO, ethyl oleate, ethyl 0051 b. a non-ionic surface-active agent at a concentra caprylate, diisopropyl adipate, dimethylacetamide, N-meth tion of about 0.1% to less than about 10% by weight of the ylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyr total composition; rolidone, isosorbide derivatives, such as dimethyl isosor 0052 c. at least one gelling agent at a concentration of bide, glycofurol and ethoxydiglycol (transcutol). about 0.1% to about 5% by weight of the total composition; 0063. In one or more embodiments, the surface-active agent is a non-ionic Surfactant and can be, for example, a 0053 d. at least one active agent in a therapeutically phospholipid. The Surface-active agent can be a mixture of effective concentration; and at least one non-ionic Surfactant and at least one ionic 0054 e. at least one liquefied or compressed gas propel surfactant, for example, at a weight ratio of about 20:1 to lant, at a concentration of about 3% to about 25% by weight about 1:1. of the total composition. 0064. In one or more embodiments, the composition 0.055 Water and optional ingredients are added to com includes at least one gelling agent selected from the group plete the total weight to 100%, although the composition consisting of natural polymeric materials, semi-synthetic may be essesntially free of lower alkyl alcohols. In one or polymeric materials, synthetic polymeric materials, inor more embodiments, the oleaginous composition of the ganic gelling agents and mixtures thereof. present invention contains less than about 5% of a lower 0065. The oleaginous composition of the present inven alcohol having up to 5 carbon atoms in its carbon chain tion upon extrusion from a pressured container has a specific skeleton. gravity of about 0.02 g/mL to about 0.5 g/mL, and is useful 0056. In one or more embodiments, the oleaginous com for treating, alleviating or preventing a dermatological or position includes water at a concentration less than about mucosal disorder. 30%, preferably less than about 20%, more preferably less 0066. According to a further aspect of the present inven than about 10% by weight. tion, an oleaginous water-in-oil emulsion is provided. The 0057. In one or more embodiments, the oleaginous com emulsion can be essentially free of lower alkyl alcohols. The position of the present invention further includes a foam emulsion includes: adjuvant. 0067 at least one solvent selected from a hydrophobic 0.058. In yet other embodiments, the oleaginous compo Solvent, a co-solvent and an emollient at a concentration of sition of the present invention forms an emulsion. about 30% to about 96.5% by weight; 0059. In one or more embodiments, the oleaginous com 0068 water; position of the present invention includes a hydrophobic 0069 at least one non-ionic lipophilic surface acting solvent having solubility in distilled water at ambient tem agent having an HLB value of about 3 to about 10 at a perature of less than about one gram per 100 ml. The concentration of about 0.1% to less than about 10% by hydrophobic solvent may be a mineral oil, MCT oil, trig weight, lyceride oil, silicone oil, a polyunsaturated oil, an unsatur 0070 at least one gelling agent at a concentration of ated oil and an essential oil, and mixtures thereof. about 0.1% to about 5% by weight. 0060. In one or more embodiments, the at least one Solvent is a co-solvent. In one or more embodiments, the 0071 at least one active agent at a therapeutically effec co-solvent is a polyethylene glycol derivative, or glycerin. In tive concentration; and one or more embodiments, the oleaginous composition of 0072 at least one liquefied or compressed gas propellant the present invention includes a mixture of at least one at a concentration of about 3% to about 25% by weight of hydrophobic solvent and at least one co-solvent. The mix the total composition. ture of at least one hydrophobic solvent and the at least one 0073. In one or more embodiments, the oleaginous emul co-solvent may have a weight ratio of about 1:8 to about 8:1. sion of the present invention contains less than about 5% of In one or more embodiments, a mixture of at least one a lower alcohol having up to 5 carbon atoms in its carbon hydrophobic solvent and glycerin is used; and the mixture chain skeleton. In another embodiment the oleaginous com may have a weight ratio of about 1:4 to about 4:1, or about position of the present invention further comprises a foam 1:2 to about 2:1. adjuvant. 0061 According to one or more embodiments, the com position includes at least one solvent having a high solubi 0074. In one or more embodiments, the oleaginous water lization capacity, termed herein a “potent solvent'. In the in-oil emulsion contains a hydrophobic solvent and water at context of the present invention, a potent solvent is other a weight ratio of about 1:3 to about 6:1. than mineral oil and solubilizes a specific active agent 0075. In one or more embodiments, the oleaginous emul substantially better than a hydrocarbon solvent such as sion contains a hydrophobic solvent having solubility in US 2008/0063607 A1 Mar. 13, 2008

distilled water at ambient temperature of less than about one DETAILED DESCRIPTION OF THE gram per 100 ml. The hydrophobic solvent may be selected INVENTION from mineral oil, MCT oil, triglyceride oil, silicone oil, a 0085. Despite the commonly known fact that hydropho polyunsaturated oil, an unsaturated oil and an essential oil. bic solvents, and oils in particular, are difficult to formulate 0.076 The oleaginous emulsion may include a potent into foam-producing products and that addition of conven solvent selected from a hydrophobic solvent other than tional hydrophobic solvents interferes with the foam form mineral oil, a co-solvent and an emollient, wherein the ing ability of the Surfactant, the present invention has potent solvent solubilizes the active agent Substantially Surprisingly discovered stable oleaginous foam composi better than mineral oil solubilizes the active agent, e.g. at tions, comprising at least one active agent for dermal and least 5-fold better or at least 10-fold better than mineral oil mucosal delivery. The compositions are dispensed as a foam solubilizes the active agent. providing a stable product that is pleasant and easy to use for high patient and consumer compliance. The at least one 0077. In one or more embodiments, the oleaginous emul active agent is selected from a therapeutically active agent or sion contains a Surface-active agent having a HLB value in a cosmetic agent. the range of about 3 to about 10, which promote the formation of a water-in-oil emulsion. 0086) Surprisingly, the compositions of the present invention require low Surfactant concentrations, e.g., less 0078. In one or more embodiments, the oleaginous emul than 10% by weight and often much less, thus preventing sions contains at least one gelling agent selected from the both undesirable irritancy and costly raw material usage. group consisting of natural polymeric materials, semi-syn 0087. According to one aspect of the present invention, thetic polymeric materials, synthetic polymeric materials, the foamable compositions are light weight, have low den inorganic gelling agents and mixtures thereof. sity, spread easily and comfortably over large body area, and 0079 The active agent can be a therapeutic agent or a are thus, economical. cosmetic agent. The therapeutic agent is selected for the treatment or prophylaxis of a disorder of the skin, mucosal 0088. The compositions of the present invention com membrane, ear channel, vagina, penile urethra and rectum. prise at least one solvent selected from a hydrophobic In one embodiment therapeutic agent is selected from an Solvent, a co-solvent, an emollient and mixtures thereof, anti-infective, an antibiotic, an antibacterial agent, an anti which provides a refatting and skin Soothing effect. The fungal agent, an antiviral agent, an antiparasitic agent, an selected solvents allow the inclusion of oil-soluble active antiinflammatory agent, an anesthetic, an analgesic, an anti agents in the formulation. In one or more embodiments, the allergic agent, a corticosteroid, a retinoid, an antiprolifera solvents provide synergistic benefits in combination with the tive agent, an anticancer agent, a photodynamic therapy active agent. The compositions may comprise at least one oil agent, a lubricating agent and mixtures thereof. soluble active agent. 0089. In one or more embodiments, the compositions 0080 Alternatively, the active agent is an inorganic solid require only low concentrations of a foaming agent in order matter, preferably a metal oxide, more preferably zinc oxide. to generate a stable foam. The reduced surfactant require 0081. The active agent can also be a cosmetic agent such ment is advantageous since Surfactants are known to be as a retinoid, an anti-wrinkle agent, a radical Scavenger, a irritating when in contact with the skin at elevated concen self-tanning agent, a skin whitening agent a skin protective trations. agent, an anti-cellulite agent, a massaging oil and an anti 0090 The compositions are easily spreadable, allowing wart agent. treatment of large areas Such as the arms, back, trunk, legs 0082 In another aspect, the present invention provides a and the breast. Furthermore, due to flow properties, they method of treating, alleviating or preventing a dermatologi spread effectively into folds and wrinkles and absorb into the cal or mucosal disease or disorder, comprising administering skin, providing uniform distribution of the active agent topically to a Subject having the disease or disorder a without the need of extensive rubbing thus providing a therapeutically effective amount of the oleaginous compo unique means for the treatment of large body areas. sitions or the oleaginous water-in-oil emulsions of the 0091. The compositions may be used for the treatment of present invention. body cavities, such as the vagina, penile urethra, rectum and 0083. In yet another aspect, the present invention also the ear channel due to their expansion properties. provides a method of designing a foamable composition, containing at least one active agent that is Substantially Class A foam composition insoluble in a hydrocarbon solvent including mineral oil. 0092 According to one aspect the present invention The method includes selecting at least one active agent, and provides an oleaginous foam composition for topical appli identifying a solvent that solubilizes the active agent Sub cation including: stantially better than mineral oil solubilizes the active agent. The method may further comprise the step of adjusting the 0093 at least one solvent selected from a hydrophobic type and concentration of Surfactant and gelling agent to Solvent, a co-solvent, an emollient and mixtures thereof, at provide a foamable composition. a concentration of about 70% to about 96.5% by weight, 0084. In one or more embodiments, the potent solvent 0094 at least a non-ionic surface active agent at a con solubilizes the active agent 5-fold better or even 10-fold centration of about 0.1% to less than about 10% by weight better than mineral oil solubilizes the active agent. and, optionally, having an HLB value of about 9 or less; US 2008/0063607 A1 Mar. 13, 2008

0.095 at least one gelling agent at a concentration of density. In one or more embodiments, there is an overlap about 0.1% to about 5% by weight; between the compositions of Class A and Class B, the 0.096 at least one active agent at a therapeutically effec distinction being that Class B compositions are formed as tive concentration; and water-in-oil emulsions. 0097 a liquefied or compressed gas propellant at a con 0106 According to one embodiment, the water-in-oil centration of about 3% to about 25% by weight of the total emulsion composition contains: composition. 0.107 at least one solvent selected from a hydrophobic 0098. The balance of the composition contains water and Solvent, a co-solvent, an emollient and mixtures thereof, at additional optional components. The content of the foam a concentration of about 30% to about 96% by weight, composition is presented herein as concentration (percent by weight, % w/w). The foam composition can be a homoge 0108) water at a concentration of 1% to about 70% by neous mixture or an emulsion. confirm that this is true for the weight; Class A foams. 0.109 at least one non-ionic lipophilic surface active 0099 Such a composition is placed in a pressurized agent, preferably having an HLB value of about 3 to about aerosol container and, upon release from the container, 10, more preferably about 3.5 to about 9 at a concentration creates a novel therapeutically-beneficial foam product. of about 0.1% to about 10% by weight, or between about 0100 Low water content is important in order to attain 0.1% and about 5% by weight, or even between about 0.1% high skin and body tissue lubrication, refatting, occlusive and about 2% by weight; effects and effective skin absorption of a active agents. It is also important in order to avoid degradation of water sen 0110 at least one gelling agent at a concentration of sitive active agents. about 0.1% to about 5% by weight; 0101 Thus, in one or more embodiments, the composi 0.111 at least one active agent at a therapeutically effec tion comprises water at a concentration of about 30% or less, tive concentration; and a liquefied or compressed gas pro or at a concentration less than about 20%, or at a concen pellant at a concentration of about 3% to about 25% by tration less than about 10% by weight. weight of the total composition, in an aerosol container. 0102 The composition is optionally substantially free of short chain alcohols, i.e. comprises less than about 5% by 0112 According to a further embodiment, the ratio weight of a short chain alcohol having 5 or less carbon atom between the oil phase and water is between about 1:3 and in its skeleton, and may further comprise a foam adjuvant. about 6:1. 0103). According to one embodiment, the composition 0113. The term “oleaginous” is defined as “having the comprises a solvent selected from a hydrophobic solvent and nature or qualities of oil. The terms "oleaginous composi an emollient and at least one co-solvent. According to one tion”, “oleaginous foam’ and “oleaginous foamable com embodiment the co-solvent is a hydrophilic solvent, other position” as used herein interchangeably refer to a compo than a short chain alcohol, selected from an organic solvent sition that has the organoleptic character of an oily that dissolves in water. Non-limiting examples of Such Substance, i.e., oily feeling, when topically administered to co-solvents include propylene glycol, glycerol, and other a body area, such as the skin or mucosal tissue. poly-hydroxy solvents. Preferably, the composition com prises glycerol as co-solvent. In one embodiment the com 0114. In the context of the present invention, an oleagi position comprises a hydrophobic solvent component and a nous foam is a composition comprising at least one solvent co-solvent at a weight ratio in the range of about 4:1 and selected from a hydrophobic solvent, a co-solvent, an emol about 1:4, or about 2:1 to 1:2. In an even further embodiment lient and mixtures thereof in the continuous phase of the of the present invention, the co-solvent constitutes a con composition and is characterized by an oily feeling upon tinuous phase of the emulsion and a minor portion of water application to a body Surface. is included in the co-solvent phase. 0115 Such an oleaginous composition may provide an 0104 Such a composition is placed in an aerosol con enhanced occlusive effect, which may in turn control the tainer and, upon release from the aerosol container, creates drug residence time and skin penetration of an active agent. a therapeutically-beneficial foam product. Furthermore, oleaginous compositions provide moisturizing effects, refatting effects, protective effects and lubrication Class B foam composition which contribute to the treatment of dermatological disor 0105. According to another aspect the present invention ders. Thus, a composition of this nature, comprising an provides an oleaginous foam composition comprising water oleaginous vehicle and an active agent is expected to pro in-oil emulsion, i.e., an emulsion having one phase com vide a synergistic therapeutic effect. prising at least one hydrophobic component (oil phase) and Solvents one phase which comprises water. Due to the fact that the continuous phase of the emulsion is the oil phase, the 0116. At least one solvent of the composition of the composition provides oily feeling, occlusive properties and present invention is selected from a hydrophobic solvent, an protective effects. Notably, while it is known that a compo emollient, a silicone oil, a co-solvent, and a mixture thereof. sition with a continuous oil phase is unlikely to form foam The solvent occupies at least the continuous phase; however, without high amounts of Surfactants, the composition of the it may also partition into the discontinuous phase in those present invention Surprisingly forms a stable foam with low instances when the composition is an emulsion. US 2008/0063607 A1 Mar. 13, 2008

Hydrophobic Solvent Emollient 0117. A “hydrophobic solvent as used herein refers to a 0123. A further preferred class of solvents are “emol material having solubility in distilled water at ambient lients' that have a softening, refatting, or soothing effect, temperature of less than about 1 gm per 100 mL, or less than especially when applied to body areas, such as the skin and about 0.5gm per 100 mL, or even less than about 0.1 gm per mucosal Surfaces. Emollients are not necessarily hydropho 100 mL. It is liquid at ambient temperature. bic. Without derogating the generality of this definition, 0118. In one preferred embodiment, the at least one examples of Suitable emollients for use include hexyleneg solvent is a hydrophobic solvent such as mineral oil. Mineral lycol, propylene glycol, isostearic acid derivatives, isopro oil (Chemical Abstracts Service Registry number 8012-95 pyl palmitate, isopropyl isostearate, diisopropyl adipate, 1) is a mixture of aliphatic, naphthalenic, and aromatic diisopropyl dimerate, maleated Soybean oil, octyl palmitate, liquid hydrocarbons that derive from petroleum. They are cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated typically liquid, their viscosity is in the range of between lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl about 35 CST and about 100 CST (at 40° C.), and their pour oleate, tocopheryl linoleate, wheat germ glycerides, point (the lowest temperature at which an oil can be handled arachidyl propionate, myristyl lactate, decyl oleate, propy without excessive amounts of wax crystals forming so lene glycol ricinoleate, isopropyl lanolate, pentaerythrityl preventing flow) is below 0°C. By contrast, white petrola tetraStearate, neopentylglycol dicaprylate/dicaprate, tum, also termed “Vaseline', is disadvantageous, due to its isononyl isononanoate, isotridecyl isononanoate, myristyl waxy nature and semi-solid texture. It is known to leave a myristate, triisocetyl citrate, octyl dodecanol. Sucrose esters waxy and sticky feeling after application and occasionally of fatty acids, octyl hydroxy Stearate and mixtures thereof. stain cloths. Thus, white petrolatum as well as other wax Examples of other suitable emollients may be found in the like, semi-solid compounds are undesirable as a hydropho Cosmetic Bench Reference, pp. 1.19-1.22 (1996). bic solvent according to the present invention. Silicone oil 0119) According to one embodiment the oleaginous foam 0.124. According to the present invention, silicone oils are composition of the present invention comprises at least one particularly preferred solvents, due to their known skin solvent that is a hydrophobic solvent selected from mineral protective and occlusive properties. Suitable silicone oils or oil, a triglyceride oil, an ester of a fatty acid, an ester of a fluids for use in the invention may be selected from non dicarboxylic acid, silicone oil, a polyunsaturated oil, an Volatile silicones, such as polyalkyl siloxanes, polyaryl unsaturated oil and an essential oil. siloxanes, polyalkylaryl siloxanes and polyether siloxane 0120 According to one embodiment, preferred hydro copolymers, polydimethylsiloxanes (dimethicones) and phobic solvents are liquid oils originating from Vegetable, poly(dimethylsiloxane)-(diphenyl-siloxane) copolymers. marine or animal sources. The hydrophobic solvent may be These are preferably chosen from cyclic or linear polydim selected from a saturated or an unsaturated oil. By way of ethylsiloxanes containing from about 3 to about 9, prefer example, the unsaturated oil may be selected from the group ably from about 4 to about 5, silicon atoms. Volatile sili consisting of olive, corn, soybean, canola, cottonseed, coco cones such as cyclomethicones can also be used. Water nut, sesame, Sunflower, borage seed, syZigium aromaticum, soluble silicones, such as dimethicone copolyol are not hempseed, herring, cod-liver, salmon, flaxseed, wheat germ included in the definition of silicone oils (as hydrophobic and evening primrose oils and mixtures thereof, at any Solvents) according to the present invention. In one or more proportion. embodiments, the at least one solvent comprises at least 2% silicone oil, or at least 5% silicone oil. 0121 One class of hydrophobic solvents includes poly unsaturated oils, containing omega-3 and omega-6 fatty Co-Solvent acids, which are know to possess therapeutic properties 0.125. A “co-solvent is an organic solvent, other than a though different modes of action. Examples of Such poly short chain alcohol, typically soluble in both water and oil. unsaturated fatty acids are linoleic and linolenic acid, Examples of co-solvents, according to the present invention gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) include: polyols, such as glycerol (glycerin), propylene and docosahexaenoic acid (DHA). Thus, in one preferred glycol, hexylene glycol, diethylene glycol, propylene glycol embodiment of the present invention the at least one hydro n-alkanols, terpenes, di-terpenes, tri-terpenes, terpen-ols, phobic solvent comprises at least 6% of an oil selected from limonene, terpene-ol. 1-menthol, dioxolane, ethylene glycol, omega-3 oil, omega-6 oil, and mixtures thereof. other glycols, Sulfoxides, such as dimethylsulfoxide 0122) Another preferred class of hydrophobic solvents (DMSO), dimethylformanide, methyl dodecyl sulfoxide, comprises the essential oils, which are considered “thera dimethylacetamide; monooleate of ethoxylated glycerides peutic oils', which contain active biologically occurring (with 8 to 10 ethylene oxide units); azone (1-dodecylaza molecules and, upon topical application, exert a therapeutic cycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane; esters, such effect. Examples of such oils are rosehip oil, which contain as isopropyl myristate/palmitate, ethyl acetate, butyl acetate, retinoids and is known to reduce acne and post-acne scars, methyl proprionate, capric/caprylic triglycerides, tea tree oil, which possesses anti-microbial activity includ octylmyristate, dodecyl-myristate; myristyl alcohol, lauryl ing antibacterial, antifungal and antiviral properties. Other alcohol, lauric acid, lauryl lactate ketones; amides, such as examples of essential oils are basil, camphor, cardamom, acetamide oleates such as triolein; various alkanoic acids carrot, citronella, clary sage, clove, cypress, frankincense, Such as caprylic acid; lactam compounds, such as aZone; ginger, grapefruit, hyssop, jasmine, lavender, lemon, man alkanols, such as dialkylamino acetates, and admixtures darin, marjoram, myrrh, neroli, nutmeg, petitgrain, Sage, thereof. tangerine, Vanilla, Verbena, as well as any other therapeuti 0.126. According to one preferred embodiment the co cally beneficial oil known in the art of herbal medication. solvent is a polyethylene glycol (PEG) or PEG derivative US 2008/0063607 A1 Mar. 13, 2008 that is liquid at ambient temperature, including PEG200 0.139. A non-limiting exemplary list of solvents that can (MW about 190-210 kD), PEG300 (MW about 285-315 kD), be considered as potent solvents includes polyethylene gly PEG400 (MW about 380-420 kD), PEG600 (MW about col, propylene glycol, hexylene glycol, butanediols and 570-630 kD) and higher MW PEGs such as PEG 4000, PEG isomers thereof, glycerol, benzyl alcohol, DMSO, ethyl 6000 and PEG 10000 and mixtures thereof. oleate, ethyl caprylate, diisopropyl adipate, dimethylaceta 0127. In one or more preferred embodiments, the at least mide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, one solvent comprises a mixture (e.g., an emulsion) of a polyvinylpyrrolidone, isosorbide derivatives, such as dim hydrophobic solvent and glycerin, as described, for ethyl isosorbide, glycofurol and ethoxydiglycol (transcutol). example, in U.S. Pat. No. 6,544,530 to Friedman. The ratio 0140. In another aspect, the present invention provides a of hydrophobic solvent to glycerin can range from about 1:4 method of designing a stable oleaginous foamable compo to about 4:1, and more preferably from about 1:2 to about sition by selecting at least one active agent; and identifying 2:1. a solvent that solubilizes the active agent substantially better than mineral oil or petrolatum, for example, solubilizes the 0128. In several cases, a given solvent can be defined as active agent 5-fold better or even 10-fold better than a both emollient and co-solvent. hydrocarbon solvent such as mineral oil or petrolatum. The Potent solvent method may further include adjusting the type and concen tration of Surfactant and gelling agent to provide a foamable 0129. In one or more embodiments of the present inven composition. tion, the foamable composition includes a potent solvent, in addition to or in place of one of the hydrophobic solvents, 0.141. The use of a potent solvent in a foam composition co-solvents and emollients of the composition. A potent provides an improved method of delivering poorly soluble solvent is a solvent other than mineral oil that solubilizes a therapeutic agents to a target area. It is known that low drug specific active agent Substantially better than a hydrocarbon solubility results in poor bioavailability, leading to Solvent Such as mineral oil or petrolatum. For example, a decreased effectiveness of treatment. Foam compositions of potent solvent solubilizes the active agent 5 fold better than the present invention, for which the solvent includes a potent a hydrocarbon Solvent; or even solubilizes the active agent Solvent, increase the levels of the active agent in Solution 10-fold better than a hydrocarbon solvent. and thus, provide high delivery and improved therapy. 0130. In one or more embodiments of the present inven 0.142 Potent solvents, as defined herein, are usually liq tion, the composition includes at least one active agent in a uid. Formulations comprising potent solvents and active therapeutically effective concentration; and at least one agents are generally disadvantageous as therapeutics, since potent solvent in a Sufficient amount to Substantially solu their usage involves unwanted dripping and inconvenient bilize the at least one active agent in the composition. The method of application; resulting in inadequate dosing. Sur term “substantially soluble” means that at least 95% of the prisingly, the foams of the present invention, which are active agent has been solubilized, i.e., 5% or less of the drip-free, provide a Superior vehicle for Such active agents, active agent is present in a solid state. In one or more enabling convenient usage and accurate effective dosing. embodiments, the concentration of the at least one potent 0.143. The at least one solvent of the present invention solvent is more than about 40% of the at least one solvent of may include a mixture of the above solvents selected from the composition of the present invention; or even more than the group of hydrophobic solvents, silicone oils, emollients about 60%. co-solvents and potent solvents in any proportion. 0131 Non-limiting examples of pairs of active agent and Surface-Active Agents potent solvent include: 0144. Surface-active agents (surfactants) may include an 0132 Betamethasone Valerate: Practically insoluble in agent that has a property selected from linking oil and water mineral oil (<0.01%); soluble more than 1% in glycofurol. in the composition, in the form of an emulsion, and evolving 0.133 Hydrocortisone butyrate: Practically insoluble in a foam. A surfactants hydrophilic/lipophilic balance (HLB) mineral oil (<0.01%); soluble more than 1% in glycofurol. describes the emulsifiers affinity towards water or oil. The HLB scale ranges from about 1 (totally lipophilic) to 45 0134 Metronidazole: Practically insoluble in mineral oil (totally hydrophlic) and in the case of non-ionic Surfactants (<0.01%); soluble more than 1% in dimethyl isosrbide. from 1 to 20 totally hydrophlic), with 10 representing an 0135 Ketoconazole: Practically insoluble in mineral oil equal balance of both hydrophilic and lipophilic character (<0.01%); soluble more than 1% in glycofurol, propylene istics. Lipophilic emulsifiers from water-in-oil (w/o) emul glycol and dimethyl isoSrbide. sions, hydrophilic Surfactants form oil-in-water (ofw) emul sions. The HLB of a blend of two emulsifiers equals the 0136 Mupirocin: Practically insoluble in mineral oil weight fraction of emulsifier A times its HLB value, plus the (<0.01%); soluble more than 1% in glycofurol, hexylene weight fraction of emulsifier B times its HLB value. glycol, dimethyl isosorbide, propylene glycol and polyeth (weighted average). ylene glycol 400 (PEG 400). 0145 Without wishing to be bound by any particular 0137 Meloxicam, a nonsteroidal anti-inflammatory theory or mode of operation, hydrophilic Surfactants pro agent: Practically insoluble in mineral oil (<0.001%); duce oil-in-water (ofw) microemulsions, whereas lipophilic soluble in propylene glycol: 0.3 mg/mL, and in PEG 400: Surfactants are used to promote emulsification of the aque 3.7 mg/mL. ous phase into the oil phase. 0138 Progesterone: Practically insoluble in mineral oil 0146 The composition of the present invention accord (<0.001%); soluble in PEG 400: 15.3 mg/mL. ing to one or more embodiments includes at least one surface US 2008/0063607 A1 Mar. 13, 2008

active agent or surfactant, which is intended to both stabilize oxide hexadecyl ether, polyethylene glycol cetyl ether, brij the formulation and to evolve an acceptable foam. 38, bri 52, brij 56 and brij W1; sucrose esters, partial esters 0147 A composition having a low concentration of an of Sorbitol and its anhydrides, such as Sorbitan monolaurate ionic Surfactant is important in terms of safety, since high and Sorbitan monolaurate; fatty alcohols or acids, mono or concentrations of Surfactants are known to evolve skin and diglycerides, isoceteth-20, Sodium methyl cocoyl taurate, mucosal membrane irritation. Unlike certain foamable ole Sodium methyl oleoyl taurate, Sodium lauryl Sulfate, trietha aginous compositions of the art, the total Surfactant nolamine lauryl Sulfate and betaines, provided that, in the employed to obtain foam that is stable, of low specific case of a single surfactant, the HLB value is between 3 and gravity and has a fine bubble structure is relatively low. Low 9; and in the case of a mixture of Surface-active agents, the Surfactant levels, particularly of ionic Surfactants, are pre weighted average of their HLB values is between 3 and 9. ferred to reduce skin irritations. The composition of the 0154) In one or more embodiments, the at least one present invention comprises total Surfactant in the range of Surface active agent is a phospholipid. In a one or more about 0.1% to less than about 10% of the foamable com embodiments, the phospholipid is phosphatidylcholine or position, and is typically less than about 5%, or even less 1.2-diacyl-sn-glycerol-3-phosphorylcholine, also termed than about 2%. “lecithin', which is a naturally occurring phospholipid 0148. According to one or more embodiments the at least which possesses Surfactant properties. Lecithin is the most one surfactant is selected from hydrophilic, hydrophobic, abundant lipid in the membranes of biological tissues and as and a mixture of hydrophilic and hydrophobic Surfactants. Such, is considered a non-irritant. Lethicin is a phospholipid As is well known in the art, the terms “hydrophilic' and composition very similar in composition to that of human “hydrophobic' are relative terms. A combination of surface skin. For this reason, it is possible to use lethicin as an active agents is possible. emulsifier or a surfact-active agent at levels about 10% by weight. In one or more embodiments, the Surface-active 0149 According to one or more embodiments, suitable agent includes lethicin up to about 10% by weight and the Surfactants for formation of a water-in-oil emulsion have an total Surfact-active agent (when a mixture of agents is used) HLB value of no greater than 10, preferably from about 3 to can be up to 15% by weight. about 9. Thus, the composition may include a single Surface active agent having an HLB value between 3 and 9, or a 0.155. A composition having a low concentration of an mixture of Surface-active agents having a weighted average ionic Surfactant, preferably no ionic Surfactant, is important of their HLB values between 3 and 9. in terms of safety, since high concentrations of surfactants are known to evolve skin irritation. 0150 Suitable water-in-oil emulsifiers include, but are not limited to, sorbitan derivatives such as sorbitan laurate Gelling Agents and Sorbitan palmitate; alkoxylated alcohols such as laureth 0156 The composition according to one or more embodi 4; hydroxylated derivatives of polymeric silicones, such as ments of the present invention include at least one gelling dimethicone copolyol; alkylated derivatives of hydroxylated agent at a concentration of about 0.1% to about 5%. At least polymeric silicones. Such as cetyl dimethicone copolyol; one gelling agent is selected from a natural polymeric glyceryl esters such as polyglyceryl-4 isostearate; beeswax material, a semi-synthetic polymeric material, a synthetic derivatives such as sodium isostearoyl-2-lactylate; lecithin; polymeric material, an inorganic gelling agent and mixtures and mixtures thereof. In conjunction with the oil component being a silicone oil, the preferred emulsifiers are hydroxy thereof. lated derivatives of polymeric silicones and alkylated 0157 Exemplary gelling agents that can be used in derivatives thereof. accordance with one or more embodiments of the present invention include for example, but are not limited to, natu 0151. According to one or more embodiments the present rally-occurring polymeric materials such as, locust bean invention, the composition comprises at least one non-ionic gum, Sodium alginate, Sodium caseinate, egg albumin, gela Surfactant. In one or more embodiments, the composition tin agar, carrageenin gum Sodium alginate, Xanthan gum, includes at least one non-ionic Surfactant and at least one quince seed extract, tragacanth gum, starch, chemically ionic Surfactant selected from the group of anionic, cationic, modified Starches and the like, semi-synthetic polymeric Zwitterionic, at a weight ratio of between about 1:1 and materials such as cellulose ethers (e.g. hydroxyethyl cellu about 20:0.1, or preferably at a weight ratio of about 4:0.1 lose, methyl cellulose, carboxymethyl cellulose, hydroxy to about 20:0.1. propylmethyl cellulose), polyvinylpyrrolidone, polyvinyla 0152 The choice of specific surfactants should be made lcohol, guar gum, hydroxypropyl guar gum, Soluble starch, keeping in mind the particular hydrophobic therapeutic cationic celluloses, cationic guars and the like and synthetic agent to be used in the composition, and the range of polarity polymeric materials such as carboxyvinyl polymers, poly appropriate for the chosen therapeutic agent. With these vinylpyrrolidone, polyvinyl alcohol polyacrylic acid poly general principles in mind, a very broad range of Surfactants mers, polymethacrylic acid polymers, polyvinyl acetate is suitable for use in the present invention. polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers and the like. Mixtures of the above 0153. Additional non-limiting examples of possible sur compounds are contemplated. factants include polysorbates, such as polyoxyethylene (20) sorbitan monostearate (Tween 60) and polyoxyethylene (20) 0158. Further exemplary gelling agents include the sorbitan monooleate (Tween 80); Polyoxyethylene (POE) acrylic acid/ethyl acrylate copolymers and the carboxyvinyl fatty acid esters, such as Myri 45, Myr 49 and Myr 59: polymers sold, for example, by the B.F. Goodrich Company poly(oxyethylene) alkylyl ethers, such as poly(oxyethylene) under the trademark of CarbopolR) resins. These resins cetyl ether, poly(oxyethylene) palmityl ether, polyethylene consist essentially of a colloidal water-soluble polyalkenyl US 2008/0063607 A1 Mar. 13, 2008 polyether crosslinked polymer of acrylic acid crosslinked mono unsaturated fatty alcohols, e.g., Stearyl alcohol, erycyl with from 0.75% to 2% of a crosslinking agent such as alcohol, arachidyl alcohol and docosanol have been reported polyallyl Sucrose or polyallyl pentaerythritol. Examples to possess antiviral, anti infective, anti-proliferative and include Carbopol R. 934, Carbopol R 940, Carbopol R 950, anti-inflammatory properties (U.S. Pat. No. 4,874,794). Carbopol R, 980, Carbopol R 951 and Carbopol R 981. Car Longer chain fatty alcohols, e.g., tetracosanol, hexacosanol, bopol R 934 is a water-soluble polymer of acrylic acid heptacosanol, octacosanol, triacontanol, etc. are also known crosslinked with about 1% of a polyallyl ether of sucrose for their metabolism modifying properties and tissue ener having an average of about 5.8 allyl groups for each Sucrose gizing properties. Long chain fatty acids have also been molecule. reported to possess anti-infective characteristics. Thus, the 0159. Yet, another preferred group of gelling agents pharmaceutical or cosmetic composition of the present includes inorganic gelling agents, such as silicone dioxide invention, comprising the optional foam adjuvant provides (fumed silica) including but not limited to AEROSIL 200 an extra or added therapeutic benefit. (DEGUSSA). Water Content 0160. At least one gelling agent is present in an amount 0166 The creation of a foamable composition with low in the range of about 0.1% to about 5.0 wt % of the foamable water content is not easy, and usually requires very high composition. In one or more embodiments, it is typically concentrations of a foaming Surfactant system, which may less than 1 wt % of the foamable composition. comprise a high proportion of ionic Surfactants. However, ionic Surfactants are known to be skin irritants in a concen Foam Adjuvants tration-dependent manner, and thus, their use in the treat 0161 The composition of the present invention may ment of sensitive skin and other body tissues is very limited. optionally further include at least one foam adjuvant. In one Surprisingly, the compositions of the present invention have or more embodiments, foam adjuvants include fatty alcohols a low water content, and yet require very low concentration having 15 or more carbons in their carbon chain, such as of Surfactants, which are primarily non-ionic. cetyl alcohol and stearyl alcohol (or mixtures thereof). Other Substantially Alcohol Free examples of fatty alcohols are oleyl alcohol (C18, unsatur 0.167 Lower alcohols, having up to 5 carbon atoms in ated), arachidyl alcohol (C20), behenyl alcohol (C22), their carbon chain skeleton, Such as ethanol, propanol, 1-triacontanol (C30), as well as alcohols with longer carbon isopropanol, butanol, iso-butanol, t-butanol and pentanol are chains (up to C50). The concentration of the fatty alcohol considered less desirable solvents or co-solvents due to their that is required to Support the foam system is inversely skin-irritating effect. Thus, the composition of the present related to the length of its carbon chains. Fatty alcohols invention is Substantially alcohol-free and should comprise derived from beeswax including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their less than about 5% final concentration of lower alcohols, carbon chain, are especially well Suited as foam adjuvants preferably less than 2%, more preferably less than 1%. according to the present invention. Optional Ingredients 0.168. The pharmaceutical or cosmetic composition of the 0162 Another class of foam adjuvants, according to one present invention may further optionally comprise a variety or more embodiments of the present invention, includes of therapeutic or cosmetic ingredients, which are added in fatty acids having 16 or more carbons in their carbon chain, order to fine-tune the consistency of the formulation, protect such as hexadecanoic acid (C16) stearic acid (C18), the formulation components from degradation and oxidation arachidic acid (C20), behenic acid (C22), octacosanoic acid and bestow their cosmetic acceptability. Such excipients (C28), as well as fatty acids with longer carbon chains (up may be selected, for example, from the group consisting of to C50), or mixtures thereof. diglycerides, triglycerides, stabilizing agents, antioxidants, 0163 Optionally, the carbon atom chain of the fatty glycerol, flavoring, colorant and odorant agents and other alcohol or the fatty acid may have at least one double bond. formulation components, used in the art of pharmaceutical A further class of foam adjuvant according to the present and cosmetic formulary. A pharmaceutical or cosmetic com invention comprises a long chain fatty alcohol or fatty acid, position manufactured according to the present invention is wherein the carbon atom chain is branched. In an additional very easy to use. When applied onto the afflicted body preferred class of foam adjuvants, the carbon chain of said Surface of humans or animals, it is in a foam state, allowing fatty acid is substituted with a hydroxyl group, such as free application without drip or spillage. Upon further appli 12-hydroxy Stearic acid. cation of a mechanical force, e.g., by rubbing the composi 0164. The foam adjuvant according to the present inven tion onto the body surface, it freely spreads on the surface tion may comprise a mixture of fatty alcohols, fatty acids and is rapidly absorbed. and hydroxy fatty acids and derivatives thereof in any Active Agents proportion, providing that the total concentration is about 0169. It is to be understood that the active agents useful 0.1% to about 10% (w/w) preferably about 0.1% to about herein can in some instances provide more than one benefit 5% (w/w) in one or more embodiments, the total concen or operate via more than one mode of action. Therefore, tration is about 0.4% to about 2.5% (w/w) of the total classifications herein are made for the sake of convenience composition. and are not intended to limit the active agent to that 0165 A feature of fatty alcohols and fatty acids relevant particular application or applications listed. to their use in the foamable compositions according to one 0170 The composition of the present invention com or more embodiments of the present invention is related to prises at least one active agent that provides therapeutic or their therapeutic properties perse. Long chain Saturated and cosmetic activity. US 2008/0063607 A1 Mar. 13, 2008

0171 The composition of the present invention compris chlorpromazine, chlorprothixene, chloroquine, cimetidine, ing at least one “active agent, provides the following ciprofloxacin, cisapride, citalopram, clarithromycin, clem benefits: favorable spreadability and absorption, compared astine, clemizole, clenbuterol, clofazimine, clomiphene, to conventional ointment, cream, lotion and the like; clonazepam, clopidogrel, clozapine, clotiazepam, clotrima improved treatment convenience, leading to better compli Zole, codeine, cyclizine, cyproheptadine, dacarbazine, dar ance; enhanced delivery, leading to elevated bioavailability odipine, decoquinate, delavirdine, demeclocycline, dexam of the drug or cosmetic active agent in the target organ, phetamine, dexchlorpheniramine, dexfenfluramine, thereby improving treatment efficacy. diamorphine, diazepam, diethylpropion, dihydrocodeine, 0172 In the context of the present invention, pharmaceu dihydroergotamine, diltiazem, dimenhydrinate, diphenhy tical and cosmetic active agents are included under the dramine, diphenoxylate, diphenylmidazole, diphenylpyra definition of at least one active agent. According to one line, dipyridamole, dirithromycin, disopyramide, dolasetron, embodiment the at least one active agent may be a single domperidone, donepezil, doxazosin, doxycycline, droperi agent or a combination of agents that can be dissolved in the dol, econazole, efavirenz, ellipticine, enalapril, enoxacin, oleaginous carrier composition. enrofloxacin, eperisone, ephedrine, ergotamine, erythromy 0173 According to one embodiment, the at least one cin, ethambutol, ethionamide, ethopropazine, etoperidone, active agent is a hydrophobic agent, having Solubility in famotidine, felodipine, fenbendazole, fenfluramine, distilled water at ambient temperature of less than about 1 fenoldopam, fentanyl, feXofenadine, flecamide, flucytosine, gm per 100 mL, more preferable less than about 0.5gm per flunarizine, flunitrazepam, fluopromazine, fluoxetine, 100 mL, and most preferably less than about 0.1 gm per 100 fluphenthixol, fluphenthixol decanoate, fluphenazine, mL. In another embodiment, the at least one active agent is fluphenazine decanoate, flurazepam, flurithromycin, fro any therapeutic or cosmetic agent, providing that it is Vatriptan, gabapentin, granisetron, grepafloxacin, guana encapsulated in a hydrophobic envelope. benZ, halofantrine, haloperidol, hyoscyamine, imipenem, indinavir, irinotecan, isoxazole, isradipine, itraconazole, 0.174. In another embodiment, the at least one active ketoconazole, ketotifen, labetalol, lamivudine, lanosprazole, agent is insoluble and thus, incorporated in the foamable leflunomide, levofloxacin, lisinopril, lomefloxacin, lopera carrier of the present invention by Suspension. mide, loratadine, lorazepam, lormetazepam, lysuride, mepa 0175 Non-limiting examples of active agents include crine, maprotiline, mazindol, mebendazole, meclizine, antibiotics, antibacterials, antifungals, antivirals, steroidal medazepam, mefloquine, melonicam, meptazinol, mercap antiinflammatory agents, steroids, non-steroidal anti-inflam topurine, mesalamine, mesoridazine, metformin, metha matory agents, COX-1 inhibitors, COX-2 inhibitors, anes done, methaqualone, methylphenidate, methylphenobar thetic agents, analgesics, antiallergic agents, corticosteroid, bital, methysergide, metoclopramide, metoprolol. metronidazole, mianserin, miconazole, midazolam, miglitol, retinoids, calcineurin Inhibitors, nitric oxide synthase inhibi minoxidil, mitomycins, mitoxantrone, molindone, mon tors, leucocyte chemotaxis inhibitors, dicarboxylic acids, telukast, morphine, moxifloxacin, nadolol, nalbuphine, vitamins, vitamin A and derivatives thereof, vitamin B and naratriptan, natamycin, nefazodone, nelfinavir, nevirapine, derivatives thereof, vitamin C and derivatives thereof, vita nicardipine, nicotine, nifedipine, nimodipine, nimorazole, min D and derivatives thereof, vitamin E and derivatives nisoldipine, nitrazepam, nitrofuraZone, nizatidine, norfloxa thereof, vitamin F and derivatives thereof, vitamin K and cin, nortriptyline, nystatin, ofloxacin, olanzapine, omepra derivatives thereof, alpha hydroxy acids, beta hydroxy acids, Zole, ondansetron, omidazole, oxamniquine, oxantel, Oxato keratolytic agents, calcium channel blockers, cholinergic mide, oxazepam, Oxfendazole, oxiconazole, Oxprenolol. drugs, nitric oxide donor, Immunosuppressant agents, oxybutynin, oxyphencyclimine, paroxetine, pentazocine, immunoregulating agents, metal ion channel modulators, pentoxifylline, perchlorperazine, perfloxacin, perphenazine, modulators of serotonin activity, serotonin reuptake inhibi phenbenzamine, pheniramine, phenoxybenzamine, phenter tors, antioxidants, cannabinoids, angiotensin II receptor mine, physostigmine, pimozide, pindolol, pizotifen, prami antagonists, UDP-glucuronosyltransferase inhibitor, anti pexol, pranlukast, praziquantel, praZosin, procarbazine, neoplastic agents, vasoactive agents, lubricating agents and prochlorperazine, proguanil, propranolol, pseudoephedrine, antiproliferative medications and mixtures thereof at any pyrantel, pyrimethamine, quetiapine, quinidine, quinine, ral proportion. The concentration of said agents may be adopted oxifene, ranitidine, remifentanil, repaglinide, reserpine, to exert a therapeutic effect on a disease when applied to an ricobendazole, rifabutin, rifampin, rifapentine, rimantadine, afflicted area. risperidone, ritonavir, rizatriptan, ropinirole, rosiglitaZone, 0176). A general non-limiting list of hydrophobic active roxaditine, roXithromycin, Salbutamol, saquinavir, sel agents include abacavir, acebutolol, acrivastine, alatrofloxa egiline, Sertraline, Sibutramine, Sildenafil, sparfloxacin, spi cin, albuterol, albendazole, alprazolam, alprenolol, amanta ramycins, stavudine, Sulconazole, SulphaSalazine, Sulpiride, dine, amiloride, aminoglutethimide, amiodarone, amitrip Sumatriptan, tacrine, tamoxifen, tamsulosin, temazepam, tyline, amlodipine, amodiaquine, amoxapine, amphetamine, teraZosin, terbinafine, terbutaline, terconazole, terfenadine, amphotericin, amprenavir, aminone, amsacrine, astemizole, tetramisole, thiabendazole, thioguanine, thioridazine, tiaga atenolol, atropine, azathioprine, azelastine, azithromycin, bine, ticlopidine, timolol, tinidazole, tioconazole, tirofiban, baclofen, benethamine, benidipine, benzhexyl, benznida tizanidine, tolterodine, topotecan, toremifene, tramadol, tra Zole, benztropine, biperiden, bisacodyl, bisanthrene, bro Zodone, triamterene, triazolam, trifluoperazine, trimethop mazepam, bromocriptine, bromperidol, brompheniramine, rim, trimipramine, tromethamine, tropicamide, trovafloxa brotizolam, bupropion, butenafine, butoconazole, cam cin, Vancomycin, Venlafaxine, vigabatrin, vinblastine, bendazole, camptothecin, carbinoxamine, cephadrine, ceph Vincristine, vinorelbine, vitamin K5, vitamin K6, vitamin alexin, cetrizine, cinnarizine, chlorambucil, chlorphe K7, Zafirlukast, Zolmitriptan, Zolpidem, Zopiclone, aceta niramine, chlorproguanil, chlordiazepoxide, Zolamide, acetohexamide, acrivastine, alatrofloxacin, US 2008/0063607 A1 Mar. 13, 2008 11 albuterol, alclofenac, aloxiprin, alprostadil, amodiaquine, isoenzymes, the nitric oxide synthases (NOS). Thus, in one amphotericin, amylobarbital, aspirin, atorvastatin, atova or more embodiments, the vasoactive agent is selected from quone, baclofen, barbital, benazepril, bezafibrate, bro the group of therapeutic agents that modulate the production mfenac, bumetanide, butobarbital, candesartan, capsaicin, of nitric oxide or otherwise modulate or activate the effect of captopril, cefazolin, celecoxib, cephadrine, cephalexin, nitric oxide. In one or more embodiments, the vasoactive cerivastatin, cetrizine, chlorambucil, chlorothiazide, chlor agent is selected from the group of therapeutic agents that propamide, chlorthalidone, cinoxacin, ciprofloxacin, clinofi modulate the activity of the enzyme nitric oxide synthase. In brate, cloxacillin, cromoglicate, cromolyn, dantrolene, one or more embodiments, the vasoactive agent is selected dichlorophen, diclofenac, dicloxacillin, dicumarol, from the group of therapeutic agents that enhance the effect diflunisal, dimenhydrinate, divalproex, docusate, dronab of NO by inhibiting enzymes from the phosphodiesterase inol, enoXimone, enalapril, enoxacin, enrofloxacin, epalr group, such as phosphodiesterase type 5 (PDE5). estat, eposartan, essential fatty acids, estramustine, ethacrynic acid, ethotoin, etodolac, etoposide, fenbufen, 0182. In one or more embodiments, the vasoactive agent fenoprofen, fexofenadine, fluconazole, flurbiprofen, fluvas is selected from the group including nitrites, nitrates and tatin, fosinopril, fosphenyloin, fumagillin, furosemide, their analogs, esters and salts. In one or more embodiments gabapentin, gemfibrozil, gliclazide, glipizide, glybencla the vasoactive agent possesses a moiety selected from the mide, glyburide, glimepiride, grepafloxacin, ibufenac, ibu group consisting of ONO, and ONO2. profen, imipenem, indomethacin, irbesartan, isotretinoin, 0183 Exemplary vasodilators include, but are not limited ketoprofen, ketorolac, lamotrigine, levofloxacin, levothy to, amyl nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, roXine, lisinopril, lomefloxacin, losartan, lovastatin, isobutyl nitrite, glyceryl trinitrate, also known as nitroglyc meclofenamic acid, mefenamic acid, mesalamine, methotr erin, octyl nitrite, Sodium nitrite, Sodium nitroprusside, exate, metolaZone, montelukast, nalidixic acid, naproxen, clonitrate, erythrity1 tetranitrate, isosorbide mononitrate, natamycin, nimeSulide, nitrofurantoin, non-essential fatty isosorbide dinitrate, mannitol hexanitrate, pentaerythritol acids, norfloxacin, nystatin, ofloxacin, oxacillin, oxaprozin, tetranitrate, penetrinitol, triethanolamine trinitrate, trolni oxyphenbutaZone, penicillins, pentobarbital, perfloxacin, trate phosphate (triethanolamine trinitrate diphosphate), pro phenobarbital, phenyloin, pioglitaZone, piroxicam, prami patylnitrate, nitrite esters of Sugars, nitrite esters of polyols, pexol, pranlukast, pravastatin, probenecid, probucol, propo nitrate esters of Sugars, nitrate esters of polyols, nicorandil, fol, propylthiouracil, quinapril, rabeprazole, repaglinide, apresoline, diaZoxide, hydralazine, hydrochlorothiazide, rifampin, rifapentine, sparfloxacin, Sulfabenzamide, Sulfac minoxidil, pentaerythritol, tolaZoline, scoparone (6.7- etamide, Sulfadiazine, Sulfadoxine, Sulfamerazine, Sul dimethoxycoumarin) and salts, isomers, analogs and deriva famethoxazole, Sulfafurazole, Sulfapyridine, Sulfasalazine, tives thereof. Sulindac, SulphaSalazine, Sulthiame, telmisartan, teniposide, 0.184 In one or more embodiments, the vasoactive agent terbutaline, tetrahydrocannabinol, tirofiban, tolaZamide, belongs to a class of drugs that are known of possess tolbutamide, tolcapone, tolmetin, tretinoin, troglitaZone, tro vasodilator properties. Non limiting examples of drug vafloxacin, undecenoic acid, urSodeoxycholic acid, valproic classes that possess vasodilator properties include, but are acid, Valsartan, Vancomycin, verteporfin, vigabatrin, vitamin not limited to, beta-adrenergic blockers, alpha-adrenoceptor K-S (II), Zafirlukast, and pharmaceutically acceptable oil blockers, prostaglandin and prostaglandin-like compounds, soluble derivative and salts thereof. inhibitors of type 5 phosphodiesterase (PDE-5), angiotensin Vasoactive Agents converting enzyme inhibitors, calcium antagonists, angio tensin II receptor antagonists, direct acting Smooth muscle 0177. Within the lists of active agents are included vaso vasodilators, adrenergic inhibitors, endothelin antagonists, active agents such as minoxidil, sidenafil and caffeine. mineralocorticoid receptor antagonists, vasopeptidase 0178. In the context of the present invention, a vasoactive inhibitors and renin inhibitors. Active agents belonging to agent is a Substance that changes the diameter of a blood Such drug classes, as well as active agents belonging to other vessel. classes, which cause a vasodilator effect are also included in the scope of vasoactive agents according to the present 0179. In one or more embodiments, the vasoactive agent invention. is a vasodilator. A vasodilator is any of various agents that relax or widen blood vessels and thereby maintain or lower 0185. Non-nitrate vasodilators from different classes blood pressure. include, but are not limited to sildenafil, dipyridamole, catecholamine, isoproternol, furosemide, prostaglandin, 0180 Alteration in the release and action of endothelium prostacyclin, enalaprilat (ACE-inhibitor), morphine (opi derived vasoactive factors is responsible for changes in ate), acepromazine (C.-blocker), prazosin (C.-blocker), enala vascular reactivity early in the course of vascular disease. pril (ACE-inhibitor), captopril (ACE-inhibitor), amlodipine These factors include nitric oxide, eicosanoids, endothe (Ca channel blocker), minoxidil, tadalafil. Vardenafil, phe lium-derived hyperpolarizing factor, endothelin, and angio nylephrin, etillefein, caffeine, capsaicin and salts, isomers, tensin 11. analogs and derivatives thereof. 0181 Nitric oxide (NO) has been recognized as an 0186. In one or more embodiments, the vasoactive agent important messenger molecule having a broad spectrum of is selected from the group of vasodilator peptides and functions in many biological systems ranging from physi proteins. Non-limiting examples of vasodilator paprides ological control to pathological cytotoxic effect 1-3. Along include, but are not limited to bradykinin, bradykinin-like with prostacyclin, NO is responsible for endothelium peptide 1, bradykinin-like peptide III Phyllokinin (bradyki derived tonic relaxation of all types of blood vessels. NO is nyl-isoleucyl-tyrosine O-sulfate), megascoliakinin (Thr6 formed from L-arginine through the action of a family of bradykinin-Lys-Ala), lysyl-bradykinin-like waspkinin, US 2008/0063607 A1 Mar. 13, 2008 lysyl-bradykinin, maximakinin (Bombinakinin M), bombi 0194 In one or more embodiments, the vasoactive agent nakinin-GAP kininogen-1 associated peptides, kininogen-2 is a Substance derived or extracted from herbs, having a associated peptides, T-kinin, thiostatin, prolixin-S, Vespula vasoconstrictor effect. kinin 2, Vespakinin X, relaxin, adrenomedullin, ghrelin, 0.195 Thus, in one or more embodiments, the vasoactive maxadilan, Substance P, calcitonin gene-related peptide agent is a Substance derived or extracted from a herbal (CGRP), Natriuretic peptides (NPs), e.g., atrial natriuretic Source, selected from the group including ephedra sinica peptide (ANP), C-type natriuretic peptide (CNP), and (ma huang), polygonum bistorta (bistort root), hamamelis adrenomedulin (ADM), adrenomedullin, ovine corticotro virginiana (witch hazel), hydrastis Canadensis (goldenseal), pin-releasing factor, Sauvagine, urotensin and salts, isomers, lycopus virginicus (bugleweed), aspidosperma quebracho analogs and derivatives thereof. (quebracho blanco), Cytisus scoparius (Scotch broom), 0187. In one or more embodiments, the vasoactive agent cypress and salts, isomers, analogs and derivatives thereof. is selected from the group of therapeutic agents that induce the production of a vasodilator peptide or otherwise enhance 0196. Yet, in additional embodiments, the vasoactive or activate the effect of a vasodilator peptide. agent is a metal oxide or a mineral. Such as Zinc oxide and bismuth Subgallate. 0188 In one or more embodiments, the vasoactive agent is a Substance derived or extracted from herbs having a 0197) The McKenzie vasoconstrictor assay, as described, vasodilator effect. Non limiting examples of herbs that for example, in the British Journal of Dermatology 1975; contain vasoactive agents include achillea millefolium (Yar 93:563-71 and versions thereof, has been the primary row), allium sativum (garlic), amoracia rusticana (horse method used for classifying the strength of a vasoconstrictor radish), berberis vulgaris (barberry), cimicifiiga racemosa clinical efficacy. Thus, in one or more embodiments, the (black cohosh), colleus forskholii (coleus), Coptis (Gold vasoactive agent is an agent that positively affects the enthread), Crataegus (hawthorn), eleutherococcus sentico vasoconstrictor assay. sus (Siberian ginseng), ginkgo biloba(ginkgo), melissa offi icinalis (lemon balm), Olea europaea (olive leaf), panax 0198 Mixtures of these vasoactive agents may also be ginseng (Chinese ginseng), petroselinum crispum (parsley), employed according to the present invention. scutellaria baicalensis (baical skullcap), tilia europaea (lin Anti-Infective Agents den flower), trigonella foenungraecum (fenugreek), urtica dioica (nettles), valeriana officinalis (Valerian), viburnum 0199 Anti-infective agents include antibacterial, antifun (cramp, bark, black haw), veratrum viride (American helle gal, antiviral, and anti-parasitic agents. bore), verbena officinalis (vervain), xanthoxylum ameri Antibacterial Agents canum (prickly ash), Zingiber officinale (ginger), rauwolfia serpentina (Indian Snakeroot), viscum album, wild yam, 0200. One important class of active agents comprises antibacterial agents. It is well known that bacterial infections sasparilla, licorice, damiana, yucca, saw palmetto, gotu kola are involved in a variety of Superficial and non-Superficial (centella asiatica), yohimbine and salts, hazel nut, brazil disorders of the skin and mucosal membranes. The antibac nut, walnut and analogs and derivatives thereof. terial agent can be active against gram positive and gram 0189 According to one or more embodiments, the foam negative bacteria, protozoa, aerobic bacteria and anaerobes. able composition includes a vasodilator and a vasoactive The composition of the invention may include one or a agent Such that the vasodilator can have a synergistic effect combination of water soluble, oil soluble and suspended by readily facilitating facile penetration of the vasoactive antibacterial agents. agent. 0201 Specific oil-soluble species of macrollide antibiot 0190. In one or more embodiments, the vasoactive agent ics, such as erythromycin; Sulfonamide (in its base form), is a vasoconstrictor. A vasoconstrictor is any of various Such as Sulfanilamide, Sulfadiazine and Sulfacetamide; agents that narrow blood vessels and thereby maintain or mupirocin, tetracyclines, such as tetracycline and doxycy increase blood pressure, and/or decrease blood flow. There cline; specific oil-soluble species of synthetic and semi are many disorders that can benefit from treatment using a synthesic penicillins and beta-lactams; cloramphenicol; spe vasoconstrictor. For example, redness of the skin (e.g., cific oil-soluble species of imidazoles; dicarboxylic acids, erythema or cuperose), which typically involves dilated Such as azelaic acid; salicylates; peptide antibiotics; cyclic blood vessels, benefit from treatment with a vasoconstrictor, peptides, such as cyclosporine, tacrolimus, pimecrolimus which shrinks the capillaries thereby decreasing the unto and sirolimus (rapamycin); and non-specific antibacterial ward redness. agents such as strong oxidants and free radical liberating 0191). Other descriptive names of the vasoconstrictor compounds, bleaching agents, iodine compounds and ben group include vasoactive agonists, vasopressor agents and Zoyl peroxide. vasoconstrictor drugs. Certain vasoconstrictors act on spe cific receptors, such as vasopressin receptors or adrenore 0202 Antibacterial compositions according to the ceptors. present invention may be used to treat infections of the skin. An example of a very common skin infection is impetigo, a 0192 In one or more embodiments, the vasoconstrictor is bacterial disease caused by Staphylococcus aureus and beta a calcium channel agonist. Calcium channel agonists are hemolytic streptococci, which mainly afflicts children and agents that increase calcium influx into calcium channels of infants. Various antibacterial creams and ointments, such as excitable tissues, thereby causing vasoconstriction. mupirocin cream and mupirocin ointment, have been uti 0193 Non limiting examples of vasoconstrictors include lized to treat impetigo, however, treatment compliance is ephedrine, epinephrine, phenylephrine, angiotensin, vaso markedly impaired due to the fact that children resist the pressin, and analogs and derivatives thereof. extensive rubbing involved in cream and ointment treat US 2008/0063607 A1 Mar. 13, 2008

ment. Foam, on the other hand, was found to be easily loracarbef, mecillinam, meropenem, metampicillin, meticil applied, without any difficulty. It has been Surprisingly lin, mezlocillin, moxalactam, nafcillin, northienamycin, discovered that a composition of mupirocin in a vehicle oxacillin, panipenem, penamecillin, penicillin, phenethicil containing PEG (as a potent solvent), a non-ionic Surfactant lin, piperacillin, taZobactam, pivampicillin, pivoefalexin, and a gelling agent, where the non-ionic Surface-active agent pivmecillinam, pivmecillinam hydrochloride, pluracidomy at a concentration of 2% by weight and the total amounts of cin, propicillin, Sarmoxicillin, Sulbactam, Sulbenicillin, Surface-active agent is in the range of 2.5% by weight, and talampicillin, temocillin, terconazole, thienamycin, ticarcil propellan, afforded an excellent foam which was stable upon lin and analogs, salts and derivatives thereof. discharge from the aerosol can and was easy to apply onto 0208 Aminoglycosides include, but are not limited to, an afflicted area. 1,2'-N-DL-isoseryl-3',4'-dideoxykanamycin B, 1,2'-N-DL 0203 The composition of the present invention is par isoseryl-kanamycin B, 1,2'-N-(S)-4-amino-2-hydroxybu ticularly useful and beneficial in the prevention and treat tyryl-3',4'-dideoxykanamycin B, 1,2'-N (S)-4-amino-2- ment of secondary infections, accompanying skin-structure hydroxybutyryl-kanamycin B, 1-N-(2- damage, such as in cuts, wounds, burns and ulcers. In all Aminobutanesulfonyl) kanamycin A, 1-N-(2- Such cases, the present formulation is easy to use, being in aminoethanesulfonyl)3',4'-dideoxyribostamycin, 1-N-(2- foam state upon application and absorbing into the skin Aminoethanesulfonyl)3'-deoxyribostamycin, 1-N-(2- instantly upon gentle application. aminoethanesulfonyl)3'4'-dideoxykanamycin B, 1-N-(2- aminoethanesulfonyl) kanamycin A, 1-N-(2- 0204 While being useful in the prevention and treatment aminoethanesulfonyl) kanamycin B, 1-N-(2- of infections, the antibacterial foam of the present invention aminoethanesulfonyl)ribostamycin, 1-N-(2- is also applicable for decontaminating areas, afflicted with aminopropanesulfonyl)3'-deoxykanamycin B, 1-N-(2- bacterial warfare organisms, such as anthrax and Smallpox. aminopropanesulfonyl)3'4'-dideoxykanamycin B, 1-N-(2- 0205. In the context of the present invention, an antibiotic aminopropanesulfonyl) kanamycin A, 1-N-(2- agent is a Substance, that has the capacity to inhibit the aminopropanesulfonyl) kanamycin B, 1-N-(L-4-amino-2- growth of or to destroy bacteria and other microorganisms. hydroxy-butyryl)2,3'-dideoxy-2'-fluorokanamycin A, 1-N- (L-4-amino-2-hydroxy-propionyl)2,3'-dideoxy-2'- 0206. In one or more embodiments, the antibiotic agent is fluorokanamycin A, 1-N-DL-3',4'-dideoxy selected from the classes consisting of beta-lactam antibi isoserylkanamycin B, 1-N-DL-isoserylkanamycin, 1-N-DL otics, aminoglycosides, ansa-type antibiotics, anthraquino isoserylkanamycin B, 1-N L-(-)-(alpha-hydroxy-gamma nes, antibiotic azoles, antibiotic glycopeptides, macrollides, aminobutyryl)-XK-62-2,2',3'-dideoxy-2'-fluorokanamycin antibiotic nucleosides, antibiotic peptides, antibiotic poly A.2-hydroxygentamycin A3.2-hydroxygentamycin B, 2-hy enes, antibiotic polyethers, quinolones, antibiotic steroides, droxygentamycin B1, 2-hydroxygentamycin JI-20A 2-hy Sulfonamides, tetracycline, dicarboxylic acids, antibiotic droxygentamycin JI-20B, 3"-N-methyl-4"-C-methyl-3',4'- metals, oxidizing agents, Substances that release free radi dodeoxy kanamycin A, 3"-N-methyl-4"-C-methyl-3',4'- cals and/or active oxygen, cationic antimicrobial agents, dodeoxy kanamycin B, 3"-N-methyl-4"-C-methyl-3',4'- quaternary ammonium compounds, biguanides, triguanides, dodeoxy-6'-methyl kanamycin B, 3',4'-Dideoxy-3'-eno bisbiguanides and analogs and polymers thereof and natu ribostamycin.3',4'-dideoxyneamine.3',4'- rally occurring antibiotic compounds. dideoxyribostamycin, 3'-deoxy-6'-N-methyl-kanamycin B, 0207 Beta-lactam antibiotics include, but are not limited 3'-deoxyneamine.3'-deoxyribostamycin, 3'-oxysaccharocin, to, 2-(3-alanyl)clavam, 2-hydroxymethylclavam, 8-epi-thie 3.3'-nepotrehalosadiamine, 3-demethoxy-2"-N-formim namycin, acetyl-thienamycin, amoxicillin, amoxicillin idoylistamycin B disulfate tetrahydrate, 3-demethoxyista Sodium, amoxicillin trihydrate, amoxicillin-potassium cla mycin B.3-O-demethyl-2-N-formimidoylistamycin B, 3-O- Vulanate combination, amplicillin, amplicillin sodium, ampi demethylistamycin B,3-trehalosamine,4", cillin trihydrate, amplicillin-Sulbactam, apalcillin, aspoxicil 6"-dideoxydibekacin, 4-N-glycyl-KA-6606VI, 5"-Amino lin, azidocillin, aziocillin, aztreonam, bacampicillin, 3',4',5'-trideoxy-butirosin A, 6'-deoxydibekacin,6'-epi biapenem, carbenicillin, carbenicillin disodium, carfecillin, fortimicin A, 6-deoxy-neomycin (structure 6-deoxy-neomy carindacillin, carpetimycin, cefacetril, cefaclor, cefadroxil, cin B),6-deoxy-neomycin B, 6-deoxy-neomycin C, cefalexin, cefaloridine, cefalotin, cefamandole, cefaman 6-deoxy-paromomycin, acmimycin, AHB-3',4'-dideoxyri dole, cefapirin, cefatrizine, cefatrizine propylene glycol, bostamycin, AHB-3'-deoxykanamycin B, AHB-3'-deox cefazedone, cefazolin, cefbuperaZone, cefcapene, cefcapene yneamine. AHB-3'-deoxyribostamycin, AHB-4'-6"-dideoxy pivoxil hydrochloride, cefdinir, cefditoren, cefditoren piv dibekacin, AHB-6'-deoxydibekacin, AHB-dideoxyneamine, oxil, cefepime, cefetamet, cefetamet pivoxil, cefixime, cef AHB-kanamycin B, AHB-methyl-3'-deoxykanamycin B, menoxime, cefimetazole, cefiminox, cefiminox, cefimolexin, amikacin, amikacin Sulfate, apramycin, arbekacin, astromi cefodizime, cefonicid, cefoperaZone, ceforanide, cefoselis, cin, astromicin Sulfate, bekanamycin, bluenSomycin, bohol cefotaxime, cefotetan, cefotiam, cefoxitin, cefoZopran, cef mycin, butirosin, butirosin B, catenulin, coumamidine piramide, cefpirome, cefpodoxime, cefpodoxime proxetil, gammal, coumamidine gamma2.D.L-1-N-(alpha-hydroxy cefprozil, cefauinome, cefradine, cefroxadine, cefsulodin, beta-aminopropionyl)-XK-62-2, dactimicin.de-O-methyl-4- ceftazidime, cefteram, cefteram pivoxil, ceftezole, ceftib N-glycyl-KA-6606VI.de-O-methyl-KA-6606I, de-O-me uten, ceftizoxime, ceftriaxone, cefuroxime, cefuroxime thyl-KA-7038I.destomycin A, destomycin B, di-N6'O3 axetil, cephalosporin, cephamycin, chitinovorin, ciclacillin, demethylistamycin A, dibekacin, dibekacin Sulfate, clavulanic acid, clometocillin, cloxacillin, cycloserine, dihydrostreptomycin, dihydrostreptomycin Sulfate, epi-for deoxy pluracidomycin, dicloxacillin, dihydro pluracidomy mamidoylglycidylfortimicin B, epihygromycin, formim cin, epicillin, epithienamycin, ertapenem, faropenem, flo idoyl-istamycin A, formimidoyl-istamycin B, fortimicin B, moxef, flucloxacillin, hetacillin, imipenem, lenampicillin, fortimicin C, fortimicin D, fortimicin KE, fortimicin KF, US 2008/0063607 A1 Mar. 13, 2008

fortimicin KG, fortimicin KG 1 (stereoisomer KG1/KG2), machecin, maridomycin, megalomicin, methyleucomycin, fortimicin KG2 (stereoisomer KG1/KG2), fortimicin KG3, methymycin, midecamycin, miocamycin, mycaminosylty framycetin, framycetin Sulphate, gentamicin, gentamycin lactone, mycinomycin, neutramycin, niddamycin, nonactin, Sulfate, globeomycin, hybrimycin A1, hybrimycin A2, oleandomycin, phenylacetyldeltamycin, pamamycin, picro hybrimycin B1, hybrimycin B2, hybrimycin C1, hybrimycin mycin, rokitamycin, rosaramicin, roXithromycin, sedecamy C2, hydroxyStreptomycin, hygromycin, hygromycin B, cin, shincomycin, spiramycin, Swalpamycin, tacrolimus, isepamicin, isepamicin Sulfate, istamycin, kanamycin, kana telithromycin, tiacumicin, tilmicosin, treponemycin, trole mycin Sulphate, kasugamycin, lividomycin, marcomycin, andomycin, tylosin, Venturicidin and analogs, salts and micronomicin, micronomicin Sulfate, mutamicin, myomy derivatives thereof. cin, N-demethyl-7-O-demethylcelesticetin, demethylceles ticetin, methanesulfonic acid derivative of istamycin, nebra 0214) Antibiotic nucleosides include, but are not limited mycin, nebramycin, neomycin, netilmicin, oligostatin, to, amicetin, angustmycin, azathymidine, blasticidin S. paromomycin, quintomycin, ribostamycin, Saccharocin, sel epiroprim, flucytosine, gougerotin, mildiomycin, nikkomy domycin, Sisomicin, Sorbistin, spectinomycin, Streptomycin, cin, nucleocidin, oxanosine, oxanosine, puromycin, pyrazo tobramycin, trehaloSmaine, trestatin, validamycin, Verdamy mycin, showdomycin, sinefungin, sparsogenin, Spicamycin, cin, Xylostasin, Zygomycin and analogs, salts and derivatives tunicamycin, uracil polyoxin, Vengicide and analogs, salts thereof. and derivatives thereof. 0209 Ansa-type antibiotics include, but are not limited 0215 Antibiotic peptides include, but are not limited to, to, 21-hydroxy-25-demethyl-25-methylthioprotostreptovari actinomycin, aculeacin, alaZopeptin, amfomycin, amythia cin, 3-methylthiorifamycin, ansamitocin, atropisostreptova mycin, antifungal from Zalerion arboricola, antrimycin, ricin, awamycin, halomicin, maytansine, naphthomycin, apid, apidaecin, aspartocin, auromomycin, bacileucin, bacil rifabutin, rifamide, rifampicin, rifamycin, rifapentine, rifaxi lomycin, bacillopeptin, bacitracin, bagacidin, berninamycin, min, rubradirin, Streptovaricin, tolypomycin and analogs, beta-alanyl-L-tyrosine, bottromycin, capreomycin, caspo salts and derivatives thereof. fungine, cepacidine, cerexin, cillofungin, circulin, colistin, cyclodepsipeptide, cytophagin, dactinomycin, daptomycin, 0210 Antibiotic anthraquinones include, but are not lim decapeptide, desoxymulundocandin, echanomycin, echi ited to, auramycin, cinerubin, ditrisarubicin, ditrisarubicin nocandin B, echinomycin, ecomycin, enniatin, etamycin, C. figaroic acid fragilomycin, minomycin, rabelomycin, fabatin, ferrimycin, ferrimycin, ficellomycin, fluorono rudolfomycin, Sulfurmycin and analogs, salts and deriva cathiacin, fusaricidin, gardimycin, gatavalin, globopeptin, tives thereof. glyphomycin, gramicidin, herbicolin, iomycin, iturin, iyo 0211 Antibiotic azoles include, but are not limited to, mycin, iZupeptin, janiemycin, janthinocin, jolipeptin, aZanidazole, bifonazole, butoconazol, chlormidazole, chlo katanosin, killertoxin, lipopeptide antibiotic, lipopeptide rmidazole hydrochloride, cloconazole, cloconazole mono from Zalerion sp., lysobactin, lysozyme, macromomycin, hydrochloride, clotrimaZol, dimetridazole, econazole, magainin, melittin, mersacidin, mikamycin, mureidomycin, econazole nitrate, enilconazole, fenticonazole, fenticonazole mycoplanecin, mycosubtilin, neopeptifluorin, neovirido nitrate, fezatione, fluconazole, flutrimazole, isoconazole, grisein, metropsin, nisin, nocathiacin, nocathiacin 6-deoxyg isoconazole nitrate, itraconazole, ketoconazole, lanocona lycoside, nosiheptide, octapeptin, pacidamycin, pentade Zole, metronidazole, metronidazole benzoate, miconazole, capeptide, peptifluorin, permetin, phytoactin, phytostreptin, miconazole nitrate, neticonazole, nimorazole, niridazole, planothiocin, plusbacin, polcillin, polymyxin antibiotic omoconazol, ornidazole, oxiconazole, oxiconazole nitrate, complex, polymyxin B, polymyxin B1, polymyxin F. pre propenidazole, secnidazol, Sertaconazole, Sertaconazole neocarzinostatin, quinomycin, quinupristin-dalfopristin, nitrate, Sulconazole, Sulconazole nitrate, tinidazole, tiocona safracin, salmycin, salmycin, salmycin, sandramycin, Sara Zole, Voriconazol and analogs, salts and derivatives thereof. mycetin, siomycin, sperabillin, sporamycin, a streptomyces compound, Subtilin, teicoplanin aglycone, telomycin, ther 0212 Antibiotic glycopeptides include, but are not lim mothiocin, thiopeptin, thiostrepton, tridecaptin, tsushimy ited to, acanthomycin, actaplanin, avoparcin, balhimycin, cin, tuberactinomycin, tuberactinomycin, tyrothricin, Vali bleomycin B (copper bleomycin), chloroorienticin, chlo nomycin, viomycin, Virginiamycin, Zervacin and analogs, ropolysporin, demethylvancomycin, enduracidin, galacar salts and derivatives thereof. din, guanidylfungin, hachimycin, demethylvancomycin, N-nonanoyl-teicoplanin, phleomycin, platomycin, ristoce 0216) In one or more embodiments, the antibiotic peptide tin, staphylocidin, talisomycin, teicoplanin, Vancomycin, is a naturally-occurring peptide that possesses an antibacte Victomycin, Xylocandin, Zorbamycin and analogs, salts and rial and/or an antifungal activity. Such peptide can be derivatives thereof. obtained from a herbal or a vertebrate source. 0213 Macrollides include, but are not limited to, 0217 Polyenes include, but are not limited to, amphot acetylleucomycin, acetylkitasamycin, angolamycin, azithro ericin, amphotericin, aureofungin, ayfactin, azalomycin, mycin, bafilomycin, brefeldin, carbomycin, chalcomycin, blasticidin, candicidin, candicidin methyl ester, candimycin, cirramycin, clarithromycin, concanamycin, deisovaleryl candimycin methyl ester, chinopricin, filipin, flavofungin, niddamycin, demycinosyl-mycinamycin, Di-O-methylti fradicin, hamycin, hydropricin, levorin, lucensomycin, luc acumicidin, dirithromycin, erythromycin, erythromycin knomycin, mediocidin, mediocidin methyl ester, mepartri estolate, erythromycin ethyl Succinate, erythromycin lacto cin, methylamphotericin, natamycin, niphimycin, nystatin, bionate, erythromycin Stearate, flurithromycin, focusin, nystatin methyl ester, oxypricin, partricin, pentamycin, peri foromacidin, haterumalide, haterumalide, josamycin, josa mycin, pimaricin, primycin, proticin, rimocidin, sistomy mycin ropionate, juvenimycin, juvenimycin, kitasamycin, cosin, Sorangicin, trichomycin and analogs, salts and deriva ketotiacumicin, lankavacidin, lankavamycin, leucomycin, tives thereof. US 2008/0063607 A1 Mar. 13, 2008 15

0218 Polyethers include, but are not limited to, salts and derivatives (e.g., esters, amides, mercapto-deriva 20-deoxy-epi-narasin, 20-deoxysalinomycin, carriomycin, tives, anhydraides), are useful immunomodulators in the dianemycin, dihydrolonomycin, etheromycin, ionomycin, treatment of disorders of the skin and mucosal membranes iso-lasalocid, lasalocid, lenoremycin, lonomycin, lysocellin, that involve inflammation. AZelaic acid and its salts and monensin, narasin, oxolonomycin, a polycyclic ether anti derivatives are preferred. It has antibacterial effects on both biotic, salinomycin and analogs, salts and derivatives aerobic and anaerobic organisms, particularly propionibac thereof. terium acnes and Staphylococcus epidermidis, normalizes 0219 Quinolones include, but are not limited to, an keratinization, and has a cytotoxic effect on malignant or alkyl-methylendioxy-4-(1H)-oxocinnoline-3-carboxylic hyperactive melanocytes. In a preferred embodiment, the acid, alatrofloxacin, cinoxacin, ciprofloxacin, ciprofloxacin dicarboxylic acid is azelaic acid in a concentration greater hydrochloride, danofloxacin, dermofongin A, enoxacin, than 10%. Preferably, the concentration of azelaic acid is enrofloxacin, fleroxacin, flumequine, gatifloxacin, gemi between about 10% and about 25%. In such concentrates, floxacin, grepafloxacin, levofloxacin, lomefloxacin, lom azelaic acid is suitable for the treatment of a variety of skin efloxacin, hydrochloride, miloxacin, moxifloxacin, nadi disorders, such as acne, rosacea and hyperpigmentation. floxacin, nalidixic acid, nifuroquine, norfloxacin, ofloxacin, 0224. In one or more embodiments, the antibiotic agent is orbifloxacin, oxolinic acid, paZufloxacine, pefloxacin, an antibiotic metal. A number of metals ions been shown to pefloxacin mesylate, pipemidic acid, piromidic acid, prema possess antibiotic activity, including silver, copper, Zinc, floxacin, roSoxacin, rufloxacin, sparfloxacin, temafloxacin, mercury, tin, lead, bismutin, cadmium, chromium and ions to Sufloxacin, trovafloxacin and analogs, salts and derivatives thereof. It has been theorized that these antibiotic metal ions thereof. exert their effects by disrupting respiration and electron transport systems upon absorption into bacterial or fungal 0220 Antibiotic steroids include, but are not limited to, cells. Anti-microbial metal ions of silver, copper, Zinc, and aminosterol, ascosteroside, cladosporide A, dihydrofusidic gold, in particular, are considered safe for in vivo use. acid, dehydro-dihydrofusidic acid, dehydrofusidic acid, Anti-microbial silver and silver ions are particularly useful fusidic acid, squalamine and analogs, salts and derivatives due to the fact that they are not substantially absorbed into thereof. the body. 0221) Sulfonamides include, but are not limited to, 0225. Thus, in one or more embodiment, the antibiotic chloramine, dapsone, mafenide, phthalylsulfathiazole. Suc metal consists of an elemental metal, selected from the cinylsulfathiazole, sulfabenzamide, sulfacetamide, Sul group consisting of silver, copper, Zinc, mercury, tin, lead, fachlorpyridazine, Sulfadiazine, Sulfadiazine silver, Sulfadi bismutin, cadmium, chromium and gold, which is suspended cramide, Sulfadimethoxine, Sulfadoxine, Sulfaguanidine, in the composition as particles, microparticles, nanoparticles Sulfalene, SulfamaZone, Sulfamerazine, Sulfamethazine, Sul or colloidal particles. The antibiotic metal can further be famethizole, Sulfamethoxazole, Sulfamethoxypyridazine, intercalated in a chelating Substrate. Sulfamonomethoxine, SulfamoXol, Sulfanilamide, Sulfa perine, Sulfaphenazol, Sulfapyridine, Sulfaquinoxaline, Sul 0226. In further embodiments, the antibiotic metal is fasuccinamide, Sulfathiazole, Sulfathiourea, Sulfatolamide, ionic. The ionic antibiotic metal can be presented as an Sulfatriazin, Sulfisomidine, Sulfisoxazole, Sulfisoxazole inorganic or organic salt (coupled with a counterion), an acetyl, Sulfacarbamide and analogs, salts and derivatives organometallic complex or an intercalate. Non binding thereof. examples of counter inorganic and organic ions are sulfa diazine, acetate, benzoate, carbonate, iodate, iodide, lactate, 0222 Tetracyclines include, but are not limited to, dihy laurate, nitrate, oxide, palmitate, a negatively charged pro drosteflimycin, demethyltetracycline, aclacinomycin, tein. In preferred embodiments, the antibiotic metal salt is a akrobomycin, baumycin, bromotetracycline, cetocyclin, silver salt, Such as silver acetate, silver benzoate, silver chlortetracycline, clomocycline, daunorubicin, demeclocy carbonate, silver iodate, silver iodide, silver lactate, silver cline, doxorubicin, doxorubicin hydrochloride, doxycycline, lymecyclin, marcellomycin, meclocycline, meclocycline laurate, silver nitrate, silver oxide, silver palmitate, silver Sulfosalicylate, methacycline, minocycline, minocycline protein, and silver Sulfadiazine. hydrochloride, musettamycin, oxytetracycline, rhodirubin, 0227. In one or more embodiments, the antibiotic metal rolitetracycline, rubomycin, serirubicin, Steflimycin, tetra or metalion is embedded into a Substrate. Such as a polymer, cycline and analogs, salts and derivatives thereof. Tetracy a mineral (such as Zeolite, clay and silica). clines are very sensitive to water and therefore, there inclu 0228 Oxidizing agents and substances that release free sion in a formulation that contains no water is beneficial to radicals and/or active oxygen. In one or more embodiments, their shelf life stability. the antibiotic agent comprises strong oxidants and free 0223 Dicarboxylic acids, having between about 6 and radical liberating compounds, such as oxygen, hydrogen about 14 carbon atoms in their carbon atom skeleton are peroxide, benzoyl peroxide, elemental halogen species, as particularly useful in the treatment of disorders of the skin well as Oxygenated halogen species, bleaching agents (e.g., and mucosal membranes that involve microbial. Suitable Sodium, calcium or magnesium hypochloride and the like), dicarboxylic acid moieties include, but are not limited to, perchlorite species, iodine, iodate, and benzoyl peroxide. adipic acid, pimelic acid, Suberic acid, azelaic acid, sebacic Organic oxidizing agents are also included in the definition acid, 1.11-undecanedioic acid, 1,12-dodecanedioic acid, of “oxidizing agent according to the present invention, Such 1,13-tridecanedioic acid and 1,14-tetradecanedioic acid. as quinones. Such agents possess a potent broad spectrum Thus, in one or more embodiments of the present invention, activity dicarboxylic acids, having between about 6 and about 14 0229. In one or more embodiments the antibiotic agent is carbon atoms in their carbon atom skeleton, as well as their a cationic antimicrobial agent. The outermost Surface of US 2008/0063607 A1 Mar. 13, 2008 bacterial cells universally carries a net negative charge, 0235 Cationic antimicrobial polymers include, for making them sensitive to cationic Substances. Examples of example, guanide polymers, biguanide polymers, or poly cationic antibiotic agents include: quaternary ammonium mers having side chains containing biguanide moieties or compounds (QAC’s)—QAC's are surfactants, generally other cationic functional groups. Such as benzalkonium containing one quaternary nitrogen associated with at least groups or quarternium groups (e.g., quaternary amine one major hydrophobic moiety; alkyltrimethyl ammonium groups). It is understood that the term “polymer as used bromides are mixtures of where the alkyl group is between herein includes any organic material comprising three or 8 and 18 carbons long, such as cetrimide (tetradecyltrim more repeating units, and includes oligomers, polymers, ethylammonium bromide); benzalkonium chloride, which is copolymers, block copolymers, terpolymers, etc. The poly a mixture of n-alkyldimethylbenzyl ammonium chloride merbackbone may be, for example a polyethylene, ploypro where the alkyl groups (the hydrophobic moiety) can be of pylene or polysilane polymer. variable length; dialkylmethyl ammonium halides; dialkyl 0236. In one or more embodiments, the cationic antimi benzyl ammonium halides; and QAC dimmers, which bear crobial polymer is a polymeric biguanide compound. When bi-polar positive charges in conjunction with interstitial applied to a Substrate. Such a polymer is known to form a hydrophobic regions. barrier film that can engage and disrupt a microorganism. An 0230. In one or more embodiments, the antibiotic agent is exemplary polymeric biguanide compound is polyhexam selected from the group of biguanides, triguanides, bisbigu ethylene biguanide (PHMB) salts. Other exemplary bigu anides and analogs thereof. anide polymers include, but are not limited to poly(hexam 0231 Guanides, biguanides, biguanidines and ethylenebiguanide), poly(hexamethylenebiguanide) triguanides are unsaturated nitrogen containing molecules hydrochloride, poly(hexamethylenebiguanide) gluconate, that readily obtain one or more positive charges, which make poly(hexamethylenebiguanide) Stearate, or a derivative them effective antimicrobial agents. The basic structures a thereof. In one or more embodiments, the antimicrobial guanide, a biguanide, a biguanidine and a triguanide are material is substantially water-insoluble. provided below. 0237 Yet, in one or more embodiment, the antibiotic is a non-classified antibiotic agent, including, without limitation, aabomycin, acetomycin, acetoxycycloheximide, acetylnan 4 2 aomycin, an actinoplanes sp. Compound, actinopyrone, afl HN NH astatin, albacarcin, albacarcin, albofungin, albofungin, alisa mycin, alpha-R.S.-methoxycarbonylbenzylmonate, HNul HN NH2 altromycin, amicetin, amycin, amycin demanoyl compound, Biguanide amycine, amycomycin, anandimycin, anisomycin, anthra 2 mycin, anti-Syphilis immune Substance, anti-tuberculosis NH 6 immune Substance, antibiotic from Eschericia coli, antibi l NH4 otics from Streptomyces refuineus, anticapsin, antimycin, HN aplasmomycin, aranorosin, aranorosinol, arugomycin, asco HN13 r furanone, ascomycin, ascosin, Aspergillus flavus antibiotic, NH 5 asukamycin, aurantinin, an Aureolic acid antibiotic Sub Biguanidine stance, aurodox, avilamycin, azidamfenicol, azidimycin, 6 4 2 bacillaene, a Bacillus larvae antibiotic, bactobolin, benano NH NH NH mycin, benzanthrin, benzylmonate, bicoZamycin, bravomi cin, brodimoprim, butalactin, calcimycin, calvatic acid, can HNul HNlulls HN NH2 diplanecin, carumonam, carzinophilin, celesticetin, cepacin, Triguanide cerulenin, cervinomycin, chartreusin, chloramphenicol, chloramphenicol palmitate, chloramphenicol Succinate Sodium, chlorflavonin, chlorobiocin, chlorocarcin, chromo 0232. In one or more preferred embodiments, the mycin, ciclopiroX, ciclopiroX olamine, citreamicin, cla guanide, biguanide, biguanidine or triguanide, provide bi dosporin, claZamycin, clecarmycin, clindamycin, polar configurations of cationic and hydrophobic domains coliformin, collinomycin, copiamycin, corallopyronin, within a single molecule. corynecandin, coumermycin, culpin, cuprimyxin, cyclami domycin, cycloheximide, dactylomycin, danomycin, 0233 Examples of guanides, biguanides, biguanidines danubomycin, delaminomycin, demethoxyrapamycin, dem and triguanides that are currently been used as antibacterial ethylscytophycin, dermadin, desdamethine, dexylosyl-bena agents include chlorhexidine and chlorohexidine salts, ana nomycin, pseudoaglycone, dihydromocimycin, dihydronan logs and derivatives, such as chlorhexidine acetate, chlo cimycin, diumycin, dnacin, dorrigocin, dynemycin, rhexidine gluconate and chlorhexidine hydrochloride, dynemycin triacetate, ecteinascidin, efrotomycin, endomy picloxydine, alexidine and polihexanide. Other examples of cin, ensanchomycin, equisetin, ericamycin, esperamicin, guanides, biguanides, biguanidines and triguanides that can ethylmonate, everninomicin, feldamycin, flambamycin, fla conceivably be used according to the present invention are vensomycin, florfenicol, fluvomycin, fosfomycin, fos chlorproguanil hydrochloride, proguanil hydrochloride (cur fonochlorin, fredericamycin, frenolicin, fumagillin, fumi rently used as antimalarial agents), metformin hydrochlo fungin, funginon, fusacandin, fusafungin, gelbecidine, ride, phenformin and buformin hydrochloride (currently glidobactin, grahamimycin, granaticin, griseofulvin, used as antidiabetic agents). griseoviridin, grisonomycin, hayumicin, hayumicin, hazy 0234. In one or more embodiments, the cationic antimi micin, hedamycin, heneicomycin, heptelicid acid, holomy crobial agent is a polymer. cin, humidin, isohematinic acid, karnatakin, kazusamycin, US 2008/0063607 A1 Mar. 13, 2008 kristenin, L-dihydrophenylalanine, a L-isoleucyl-L-2- 0240 Plant oils and extracts which contain antibiotic amino-4-(4-amino-2',5'-cyclohexadienyl) derivative, lano agents are also useful. Non limiting examples of plants that mycin, leinamycin, leptomycin, libanomycin, lincomycin, contain agents include thyme, perilla, lavender, tea tree, lomofungin, lysolipin, magnesidin, manumycin, melanomy terfezia clavervi, Micromonospora, putterlickia verrucosa, cin, methoxycarbonylmethylmonate, methoxycarbonyleth putterlickia pyracantha putterlickia retrospinosa, Maytenus ylmonate, methoxycarbonylphenylmonate, methyl ilicifolia, maytenus evonymoides, maytenus aquifolia, faenia pseudomonate, methylmonate, microcin, mitomalcin, moci interjecta, cordyceps sinensis, couchgrass, holy thistle, plan mycin, moenomycin, monoacetyl cladosporin, monomethyl tain, burdock, hops, echinacea, buchu, chaparral, myrrh, red cladosporin, mupirocin, mupirocin calcium, mycobacidin, clover and yellow dock, garlic and St. John's wort. myriocin, myxopyronin, pseudoaglycone, nanaomycin, nan 0241 Mixtures of these antibiotic agents may also be cimycin, nargenicin, neocarcinostatin, neoenactin, neothra employed according to the present invention. mycin, nifurtoinol, nocardicin, nogalamycin, novobiocin, octylmonate, olivomycin, orthosomycin, oudemansin, Anti-fungal agents oxirapentyn, oxoglaucine methiodide, pactacin, pactamycin, 0242 Fungal infections are another object of treatment papulacandin, paulomycin, phaeoramularia fungicide, using the composition of the present invention. Superficial phenelfamycin, phenyl, cerulenin, phenylmonate, pholipo fungal infection of the skin is one of the most common skin mycin, pirlimycin, pleuromutilin, a polylactone derivative, diseases seen in general practice. Dermatophytosis is prob polynitroXin, polyoxin, porfiromycin, pradimicin, prenomy ably the most common Superficial fungal infection of the cin, prop-2-enylmonate, protomycin, pseudomonas antibi skin. It is caused by a group of fungi, which are capable of otic, pseudomonic acid, purpuromycin, pyrinodemin, pyr metabolizing the keratin of human epidermis, nails or hair. roInitrin, pyrrolomycin, amino, chloro pentenedioic acid, There are three genera of dermatophytes causing dermato rapamycin, rebeccamycin, resistomycin, reuterin, reveromy phytosis, i.e., microsporum, trichophyton and epidermophy cin, rhizocticin, roridin, rubiflavin, naphthyridinomycin, ton. saframycin, Saphenamycin, Sarkomycin, Sarkomycin, Sclo 0243 Candidiasis is an infection caused by the yeast like pularin, selenomycin, siccanin, Spartanamicin, spectinomy fungus candida albicans or occasionally other species of cin, Spongistatin, Stravidin, Streptolydigin, streptomyces are candida. Clinical syndromes of candidiasis include: (a) oral nae antibiotic complex, Streptonigrin, streptothricins, candidiasis (thrush); (b) candidiasis of the skin and genital streptovitacin, streptozotocine, a strobilurin derivative, mucous membrane; and (c) candida paronychia, which stubomycin, Sulfamethoxazol-trimethoprim, Sakamycin, inflicts the nail and nail bed. teeramycin, terpentecin, tetrocarcin, thermorubin, ther moZymocidin, thiamphenicol, thioaurin, thiolutin, thiomar 0244. The antifungal agent, also termed “antimycotic’. inol, thiomarinol, tirandamycin, tolytoxin, trichodermin, The terms “antifungal and “antimycotic” as used herein trienomycin, trimethoprim, trioxacarcin, tyrissamycin, include, but is not limited to, any Substance being destruc umbrinomycin, unphenelfamycin, urauchimycin, usnic acid, tive to or inhibiting the growth of fungi and yeast or any uredolysin, variotin, Vermisporin, Verrucarin and analogs, Substance having the capacity to inhibit the growth of or to salts and derivatives thereof. destroy fungi and/or yeast. 0245. In one or more embodiments, the antifungal agent 0238. In one or more embodiments, the antibiotic agent is is an agent that is useful in the treatment of a Superficial a naturally occurring antibiotic compound. As used herein, fungal infection of the skin, dermatophytosis, microsporum, the term “naturally-occurring antibiotic agent” includes all trichophyton and epidermophyton infections, candidiasis, antibiotic that are obtained, derived or extracted from plant oral candidiasis (thrush), candidiasis of the skin and genital or vertebrate sources. Non-limiting examples of families of mucous membrane, candida paronychia, which inflicts the naturally-occurring antibiotic agents include phenol, resor nail and nail bed and genital and vaginal candida, which cinol, antibiotic aminoglycosides, anamycin, quinines, inflict genitalia and the vagina. Thus, in one or more anthraquinones, antibiotic glycopeptides, azoles, mac embodiments, the antifungal agent is selected from the rolides, avilamycin, agropyrene, cnicin, aucubin antibiotic group including but not limited to, azoles, diazoles, triaz saponin fractions, berberine (isoquinoline alkaloid), arc oles, miconazole, fluconazole, ketoconazole, clotrimazole, tiopicrin (Sesquiterpene lactone), lupulone, humulone (bitter itraconazole, Climbazole, griseofulvin, ciclopiroX, ciclo acids), allicin, hyperforin, echinacoside, coniosetin, tetramic piroX-olamine, amorolfine, terbinafine, Amphotericin B, acid, imanine and novoimanine. potassium iodide and flucytosine (5FC) at a therapeutically 0239 Ciclopirox and ciclopiroxolamine possess fungi effective concentration. cidal, fungistatic and sporicidal activity. They are active against a broad spectrum of dermatophytes, yeasts, moulds 0246 The foam composition of the present invention and other fungi. Such as trichophyton species, microsporum may comprise an antifungal drug, which is active against species, epidermophyton species and yeasts (candida albi dermatophytes and candida, selected from the group of, but cans, candida glabrata, other candida species and crypto not limited to azoles, diazoles, triazoles, miconazole, flu coccus neoformans). Some aspergillus species are sensitive conazole, ketoconazole, clotrimazole, itraconazole griseof to ciclopiroX as are some penicillium. Likewise, ciclopiroX ulvin, ciclopiroX, amorolfine, terbinafine, Amphotericin B, is effective against many gram-positive and gram-negative potassium iodide, flucytosine (5FC) and any combination bacteria (e.g., escherichia coli, proteus mirabilis, pseudomo thereof at a therapeutically effective concentration. nas aeruginosa, Staphylococcus and Streptococcus species). 0247 The composition of the present invention is useful as well as mycoplasma species, trichomonas vaginalis and for example for the treatment and prevention of tinea actinomyces. corporis, tinea pedis, tinea rubrum, tinea unguium, tinea US 2008/0063607 A1 Mar. 13, 2008

cruris, tinea barbae and tinea versicolor, as well as yeast naturally-occurring peptide that possesses an antibacterial infections, such as candidiasis, and candidal vaginitis. and/or an antifungal activity. Such peptide can be obtained 0248 AZoles are pharmaceutically active compounds from a herbal or a vertebrate source. that are unsaturated five member ring heterocyclic com 0254. In an embodiment of the present invention, the pound, wherein one, two or three members of the ring are antifungal agent is a polyene. Polyene compounds are so nitrogen atoms, as exemplified in a non-limiting way and named because of the alternating conjugated double bonds illustrated in the following schemes: that constitute a part of their macrollide ring structure. Polyenes include, but are not limited to, amphotericin, aureofungin, ayfactin, azalomycin, blasticidin, candicidin, N candicidin methyl ester, candimycin, candimycin methyl ester, chinopricin, filipin, flavofungin, fradicin, hamycin, ( ) hydropricin, levorin, lucensomycin, lucknomycin, medioci Azole din, mediocidin methyl ester, mepartricin, methylamphot ericin, natamycin, niphimycin, nystatin, oxypricin, partricin, pentamycin, perimycin, pimaricin, primycin, proticin, rimo cidin, sistomycosin, Sorangicin, trichomycin and analogs, (a salts and derivatives thereof. Imidazole 0255 In an embodiment of the present invention, the antifungal agent is a pyrimidine, such as Flucytosine. ( 0256 In an embodiment of the present invention, the 12.4 Triazole antifungal agent is an allylamine. Such as terbinafine and naftifine. 0257. In an embodiment of the present invention, the antifungal agent is a morpholine derivative, Such as amo rolfine. 12.3 Triazole 0258. In an embodiment of the present invention, the antifungal agent is selected from the group consisting of CiclopiroX, ciclopiroXolmine, griseofulvin,

Thiadiazole 0259. In an embodiment of the present invention, the NS antifungal agent is a Thiocarbamate, Such as tolnaftate. 0260. In an embodiment of the present invention, the \ } antifungal agent is a Sulfonamide. Such as Mafenide and Pyrazole Dapsone. 0261. In an embodiment of the present invention, the antifungal agent consists of a plant oil or a plant extract 0249. The azole is a compound including an unsaturated possessing antifungal activity; or a plant oil or extract which five member ring heterocyclic compound, wherein one, two contains antifungal agents. Non-limiting examples of plants or three members of the ring are nitrogen atoms. containing agents include, but are not limited to, anise, basil, 0250) Examples of therapeutic azoles include, but are not bergemont, burdock, buchu, chaparral, camphor, cardamom, limited to, azanidazole, bifonazole, butoconazol, chlormi carrot, canola, cassia, catnip, cedarwood, citronella, clove, dazole, climbazole, cloconazole, clotrimazole, dimetrida couchgrass, cypress, echinacea, eucalyptus, faenia inter Zole, econazole, enilconazole, fenticonazole, fezatione, flu jecta, garlic, ginger, grapefruit, holy thistle, hops, hyssop, conazole, flutrimazole, isoconazole, itraconazole, jasmine, jojova, lavender, lavandin, lemon, lime, mandarin, ketoconazole, lanoconazole, metronidazole, metronidazole marigold, marjoram, maytenus ilicifolia, maytenus evony benzoate, miconazole, neticonazole, nimorazole, niridazole, moides, maytenus aquifolia, micromonospora, myrrh, omoconazol, ornidazole, oxiconazole, posaconazole, pro neroli, nutmeg, orange, Ordyceps sinensis, peppermint, penidazole, raVuconazole, secnidazol, Sertaconazole, Sul perilla, petitgrain, plantain, putterlickia verrucosa, putter conazole, thiabendazole, tinidazole, tioconazole, Voricona lickia pyracantha, putterlickia retrospinosa, rosemary, sage, Zol and salts and derivatives thereof. Such azoles are mainly spearmint, star anise, St. John’s wort, red clover, tangerine, used as antifungal agents, yet several of them also possess tea tree, terfezia claveryi, thyme Vanilla, verbena, white other therapeutic benefits, such as anti-inflammatory, anti clover and yellow dock. bacterial and antiviral effects. 0262. In an embodiment of the present invention, the 0251 Additional non-limiting exemplary classes of antifungal agent is an anti-microbial metal. A number of azoles include oxazoles, thiazoles, thiadiazoles and thiatria metals ions been shown to possess antibiotic activity, includ Zoles, benzimidazoles, and salts and derivatives thereof. ing silver, copper, Zinc, mercury, tin, lead, bismutin, cad mium, chromium and ions thereof. It has been theorized that 0252) In an embodiment of the present invention, the these anti-microbial metal ions exert their effects by dis azole is metronidazole. rupting respiration and electron transport systems upon 0253) In one or more embodiments, the antifungal agent absorption into bacterial or fungal cells. Anti-microbial is a peptide. In certain embodiments, antifungal agent is a metal ions of silver, copper, Zinc, and gold, in particular, are US 2008/0063607 A1 Mar. 13, 2008

considered safe for in vivo use. Anti-microbial silver and Steroids silver ions are particularly useful due to the fact that they are not substantially absorbed into the body. 0269. In the context of the present invention, steroids are compounds possessing the skeleton of cyclopentaaphenan 0263 Thus, in one or more embodiment, the anti-micro bial metal consists of an elemental metal, selected from the threne or a skeleton derived therefrom by one or more bond group consisting of silver, copper, Zinc, mercury, tin, lead, Scissions or ring expansions or contractions. Methyl groups bismutin, cadmium, chromium and gold, which is suspended are normally present at C-10 and C-13. An alkyl side chain in the composition as particles, microparticles, nanoparticles may also be present at C-17. Sterols are steroids carrying a or colloidal particles. The anti-microbial metal can further hydroxyl group at C-3 and most of the skeleton of choles be intercalated in a chelating Substrate. tane. Additional carbon atoms may be present in the side 0264. In further embodiments, the anti-microbial metal is chain. ionic. The ionic antibiotic metal can be presented as an inorganic or organic salt (coupled with a counterion), an 0270 Steroids are numbered and rings are lettered as in organometallic complex or an intercalate. Non binding formula 1. If one of the two methyl groups attached to C-25 examples of counter inorganic and organic ions are sulfa is substituted it is assigned the lower number (26); if both are diazine, acetate, benzoate, carbonate, iodate, iodide, lactate, substituted, that carrying the substituent cited first in the laurate, nitrate, oxide, palmitate, a negatively charged pro alphabetical order is assigned the lower number. tein. In preferred embodiments, the antibiotic metal salt is a silver salt, Such as silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver (1) protein, and silver Sulfadiazine. 0265 Yet, in another embodiment, the antifungal agent is an oxidizing agent or a substance that releases free radicals and/or active oxygen. Exemplary oxidizing agents are hydrogen peroxide, benzoyl peroxide, elemental halogen species (compounds), as well as oxygenated halogen species (compounds), bleaching agents (e.g., Sodium, calcium or magnesium hypochloride and the like), perchlorite species (compounds), iodine and iodate compounds. Organic oxi dizing agents are also included in the definition of “oxidiz ing agent according to the present invention, such as quinones. Such agents possess a potent broad spectrum activity 0266. In further embodiments the antifungal agent is a 0271 The steroids can have substituents on the steroid cationic antimicrobial agent. The outermost surface of bac side chain as exemplified in formula 4-7: terial and fungal cells universally carries a net negative charge, making them sensitive to cationic Substances. Examples of cationic antibiotic agents include: quaternary (4) ammonium compounds, such as alkyltrimethyl ammonium bromides, benzalkonium chloride, dialkylbenzyl ammonium halides, and dimmers thereof, which bear bi-polar positive charges in conjunction with interstitial hydrophobic regions. Anti-Viral Agents 0267 The composition of the present invention is par ticularly beneficial in treating and preventing viral infec HO tions. Cold sores are caused by the herpes simplex Type 1 H virus and are sometimes referred to as facial herpes. Mol (20R)-5C-Pregnane-3,3,20-diol lusca are Small viral growths that appear singly or in groups (5) on the face, trunk, lower abdomen, pelvis, inner thighs, or penis. Shingles (herpes Zoster), which usually only occurs once in a lifetime, appears as a rash (clusters of blisters with a red base). It is caused by the same virus responsible for chickenpox. Warts are a common, benign skin tumor caused by viral infection. 0268 Any known antiviral agent, in a therapeutically effective concentration, can be incorporated in the foam composition of the present invention. The composition of the present invention, which comprises a hydrophobic sol vent, would facilitate an enhanced rate of penetration and better topical distribution of any of the above listed antiviral (20S)-5C-Pregnane-3?.20.21-triol drugs. US 2008/0063607 A1 Mar. 13, 2008 20

-continued -continued (6) (11)

5C-Estrane

(12) (24S)-24-Methyl-5C-cholestane-3?-ol or 5C-ergostan-3?-ol (7)

(13)

(22E)-(24R)-24-Methylcholesta-5,722-trien-3?-ol or (22E)-ergosta-5,7,22-trien-3?-ol trivial name ergosterol

0272. The steroids can have the formalae as exemplified 5C.-Androstane in formula 9-18. In one or more embodiments, the steroid or (14) sterol has no Substitution at C-17, as exemplified by gonane, e.g., formulae 9 and 10, estrange (also termed oestrane), e.g. formulae II and 12, and androstane, e.g., formulae 13 and 14. In one or more embodiments, the steroid or sterol has methyl groups at both C-10 and C-13 and a side chain R at C-17 (formulae 15 and 16), as exemplified in Table 1.

(9) (15)

(10) (16)

5f-Gonane US 2008/0063607 A1 Mar. 13, 2008 21

-continued TABLE 1-continued (17) Hydrocarbons with side chain at C-17

Side chain 5C-Series (15) 5P-Series (16)

5C-campestane 5P-campestane

44,14-Trimethyl-5C-cholestane CH 50-poriferastane 5P or lanostane 3 poriferastane (18)

5C-StigmaStane 5P-stigmastane

44,14-Trimethyl-9,19-cyclo-5C.9B-cholestane or cycloartane

H H, CH3 5C-gorgostane 5P-gorgostane TABLE 1. S Hydrocarbons with side chain at C-17 Side chain 5C-Series (15) 5P-Series (16) 2 5C-pregnane 5P-pregnane HC (allopregnane) 20 7 0273 Examples of unsaturated steroids and sterols are - provided in formulae 19-22: 2 H 5C-cholane 5P-cholane H3C CH (allocholane) (19) '%

7

5C-cholestane 5P-cholestane (coprostane) Estra-1,3,5(10)-triene (20) 5C-ergostane 5P-ergostane C

Estra-1,3,7,9-pentaene US 2008/0063607 A1 Mar. 13, 2008 22

-continued -continued 2 (24)24 (21) 20 17 s

17-Methyl-5C-pregnane

5C-Androst-1-en-16s-ol (25) 17 s 20 (22)

17-Methyl-5C,17f8-pregnane

(26)

5?,133,143-Pregna-6,8,11-trien-20-yn-3C-ol

0274 The stereochemistry of double bonds in the side chain is indicated using the E.Z convention. The same 17-(2-Bromoethyl)-5C,17c-cholestane applies to the seco compounds of the vitamin D series (example in formula 23). In certain cases, the steroid has two (27) carbon chains attached at position 17, e.g. 17-methyl-5C.- 17 pregnane 24, 17-methyl-5C. 17 B-pregnane 25, and 17-ethyl 17 5-cholestane and 17-(2-bromoethyl)-5C. 17C.-cholestane 26. s Other examples of a steroid that has two carbon chains attached at position 17, are 17,17-dimethyl-5C.-androstane 27 and 17 B-methyl-17C-propyl-5C.-androstane 28. In certain embodiments, the carbon skeleton of a steroid a carbonatom 17, 17-Dimethyl-5C-androstane is replaced by a hetero atom, as exemplified by 17 B hydroxy-4-oxaandrost-5-en-3-one 29. Yet, in additional (28) embodiments, an additional ring is formed by means of a 7 direct link between any two carbon atoms of the steroid ring 17 17 system or the attached side chain, as exemplified by formu Y1 lae 30, 31 and 32. 17°

17 B-Methyl-17C-propyl-5C-androstane

(23)

(29) OH

O O (22E)-Cholesta-5,22,25-trien-3?-ol cf. also formula 7 17B-Hydroxy-4-oxaandrost-5-en-3-one US 2008/0063607 A1 Mar. 13, 2008

-continued

(33) (30)

OH 3C,5-Cyclo-5C-cholestan-6B-ol 5f-Cardanolide

(31) (34)

O

v H

OH

5H HO 5,7c-Cyclo-5C-cholestan-4C-ol H 3|B,14-Dihydroxy-5f-card-20(22)-enolide trivial name: digitoxigenin (32)

(35)

H (20R)-18.21-Cyclo-5C-cholane

OH 3f,5,14-Trihydroxy-19-oxo-5f-card-20(22)-enolide 0275 Many important naturally occurring steroids con trivial name; strophanthidin tain one or more additional heterocyclic ring(s), fused or attached to ring D, formed by modifications of the side (36) chain. These steroids can be grouped into the following families: (a) cardanolides, e.g., 53-cardanolide 33, 33.14 dihydroxy-5E-card-20(22)-enolide (digitoxigenin) 34 and 3f3,5,14-trihydroxy-19-oxo-5B.-card-20(22)-enolide (stro phanthidin) 35, as well as epoxycardanolides, containing a 14.21- or a 16.21-oxygen bridge, as shown in 36, (b) bufanolides, e.g., structures 37-39, (c) spirostans, e.g., struc tures 40-43, (d) furostans, e.g., structures 44-45, and (e) A 16B,213-epoxy-203-cardanolide steroid alkaloids.

US 2008/0063607 A1 Mar. 13, 2008 25

-continued -continued (48) COOH (45)

H 5 B-Androstane-17B-carboxylic acid

HO

(49) (25R)-5C-Furost-20(22)-ene-3f,26-diol A.a. trivial name; pseudotigogenin

0276 Several biologically important steroids are deriva tives of the parent hydrocarbons carrying various functional groups. Some of the common functional groups include but HO are not limited to halogens, alkyl groups, aryl groups, benzyl groups, carboxy groups and alkoxy groups. 3f-Hydroxy-4-methyl-5C-cholesta-8,24-diene-4C-carboxylate or 3?-hydroxy-30-norlanosta-8.24-dien-28-oate 0277. In one or more embodiments, the steroid is selected from the group consisting of an acid, a salt of an acid, as exemplified in formulae 46-49, and esters, as exemplified in (50) formulae 50 and 51. In one or more embodiments, the OOC, COOCH steroid is a lactone, as exemplified in formulae 52-54.

(46)

COOH HO OH 2.4-Methyl 3 B-hydroxy-5C-cholane-21,24-dioate

(51) 2 O)-/-coch (22R)-2B.3?,14.22.253-Pentahydroxy-6-oxo-5C-cholest-7-en-26-oic acid trivial name; ecdysonic acid HO Methyl 3-(3f-hydroxyandrost-4-en-16C-yl)propanoate (47) (52)

HO w

HO w H 3C,11B-Dihydroxy-20-oxo-5f-pregnan-21-oate 3|B-Hydroxy-5C-cholano-24,17-lactone US 2008/0063607 A1 Mar. 13, 2008 26

-continued -continued

(53) (57)

H HO 3C,7c.12C-Triydroxy-5f-cholestan-24-al (20R)-3?-Hydroxypregn-5-ene-20.18-carbolactone or cholaldehyde (from cholic acid)

(58) O (54) O 2

H 5C-Androstane-17B-carbaldehyde

O (59) 7B-Acetylthio-3-oxo-17C-pregn-4-ene-21, 17-carbolactone international non-proprietary name; spironolactone COONa

(55)

Sodium 3C,12C-dihydroxy-5f-cholan-24-oate common name:Sodium 7-deoxycholate

O CH3CO s E H 0278) In one or more embodiments, the steroid is an ester 5 B-Cholestane-3C,12C-diyl 12-acetate 3-benzoate of a steroid alcohol, as exemplified by 5-cholestan-3-yl acetate, 5-cholestane-3,12-diyl diacetate, 3-oxoandrost-4- en-17-yl acetate (trivial name testosterone acetate), 17-hy (56) droxy-20-oxopregn-5-en-3-yl Sulfate, 3-acetoxy-5-cardano lide, 3-benzoyloxy-11-hydroxy-20-oxo-5-pregnan-21-oate (monobenzoate of 47), 3-acetoxy-5-cholano-24, 17-lactone (acetate of 52), 3-O-acetylcholic acid, 17-O-benzoylestra diol-17, 3-O-linolenoylcholesterol, as well as in formulae 55 and 56. 0279. In one or more embodiments, the steroid is an oxo compound. The oxo compound can be an aldehde, as exem 12C-Hydroxy-5f-cholestane-3C-yl benzoate plified by 5-androstan-19-al, 5-cholan-24-al, 3-formyl-5- cholan-24-oic acid and by formulae 57 and 58, or a ketone, as exemplified by 5-androstan-3-one, pregn-5-ene-3,20-di one and 11-oxo-5-cholan-24-oic acid. US 2008/0063607 A1 Mar. 13, 2008 27

0280. In one or more embodiment, the steroid is an alcohol as exemplified by 5-cholestane-3,11-diol, 3-hy- -continued droxy-5-androstan-17-one (trivial name: androsterone) and a. COOH (61) by formulae 59. A.2. 0281. In additional embodiments, the steroid is an amine as exemplified by androst-5-en-3-amine and formula 60, an ether as exemplified by 17-methoxyandrost-4-en-3-one, (20S)-3,17.20-trimethoxy-5-pregnane, (20S)-3,17 dimethoxy-5-pregnan-20-ol, 21-O-methylcortisol and for mula 61, an acetal or a ketal of an oxo steroid (also named C2H5O as dialkoxy steroids) as exemplified by 3.3-dimethoxyc- H holest-4-ene, 2.3-(methylenedioxy)pregn-5-ene and formula 62. (62)

(60)

KC H 3,3-(Ethylenedioxy)-5f-cholestane (CH3)2N (20S)-3?-(Dimethylamino)-5C-pregnan-20-ol 0282) Examples of trivial names retained for important steroid derivatives, these being mostly natural compounds of significant biological activity, are given in Table 2.

TABLE 2 Trivial names of Some important steroid derivatives Trivial name Systematic steroid name Aldosterone 18, 11-hemiacetal of 11P,21-dihydroxy-3.20-dioxopregn-4-en 18-all or 11, 18-epoxy-18.21-dihydroxypregn-4-ene-320 dione Androsterone 3C-hydroxy-5C-androstan-17-one Brassinolide (22R,23R)-2C.3C.22,23-tetrahydroxy-6,7-seco-5C cmpestano-6,7-lactone Calcidiol (93) (5Z,7E)-(3S)-9,10-secocholesta-5,7,10(19)-triene-3,25-diol Calciol = cholecalciferol (92) (5Z,7E)-(3S)-9,10-secocholesta-5,7,10(19)-trien-3-ol Calcitriol (94) (5Z,7E)-(1S,3R)-9,10-secocholesta-5,7,10(19)-triene-1,3,25 triol Cholesterol cholest-5-en-3P-ol Cholic acid 3C,7c.12c-trihydroxy-5P-cholan-24-oic acid Corticosterone 11P,21-dihydroxypregn-4-ene-3,20-dione Cortisol 11P.17.21-trihydroxypregn-4-ene-320-dione Cortisol acetate 21-O-acetylcortisol Cortisone 17,21-dihydroxypregn-4-ene-3,11,20-trione Cortisone acetate 21-O-acetylcortisone Deoxycorticosterone 21-hydroxypregn-4-ene-320-dione (i.e. the 11-deoxy derivative of corticosterone) Ecdysone (22R)-2P,3P,140.22.25-pentahydroxy-5P-cholest-7-en-6-one Ercalciol = ergocalciferol (5Z,7E.22E)-(3S)-9,10-secoergosta-5,7,10(19).22-tetren-3-ol Ergosterol (7) (22E)-ergosta-5,722-trien-3-ol Estradiol-17C. estra-1,3,5(10)-triene-3,17o-diol Estradiol-17P estra-1,3,5(10)-triene-3,17-diol Estriol estra-1,3,5(10)-triene-3,16C.17P-triol Estrone 3-hydroxyestra-1,3,5(10)-trien-17-one Lanosterol lanosta-8.24-dien-3P-ol Lithocholic acid 3c-hydroxy-5P-cholan-24-oic acid Progesterone pregn-4-ene-320-dione Pseudotigogenin (25R)-5C-furost-20(22)-ene-3P,26-diol Sarsasapogenin (25S)-5P-spirostan-3P-ol Smilagenin (25R)-5P-spirostan-3P-ol Testosterone (63) 17-hydroxyandrost-4-en-3-one Tigogenin (25R)-5C-spirostan-3P-ol US 2008/0063607 A1 Mar. 13, 2008 28

0283 Additional non-limiting examples of steroids that are applicable according to the present invention are pro- -continued vided in formulae 63-79. (68)

(63)

O ent-17C-Hydroxy-13c, 14B-androst-4-en-3-one) (not 17B-hydroxy-8C.9B,10C-androst-4-en-3-one O (69) 17 B-Hydroxyandrost-4-en-3-one (testosterone) 27 3. (64) OH

O ent-17f8-Hydroxyandrost-4-en-3-one (ent-testosterone) (25R)-27a-Homo-5C-cholestane (65) (70)

27

24a,24b.24c-Trihomocholest-5-ene-3f,7c-diol

(66) (71)

O (22E)-9B,10C-Ergosta-5,722-trien-3?-ol H trivial name; lumisterol 17(20)a-Homo-5C-cholestan-3-one

ye (67) (72)

H ent-5f.9B,10C-Pregnane-3,2-0-dione H (not 5C,8C.13C,14C,17a-pregnane-3,2-dione) 24-Nor-5f-cholane US 2008/0063607 A1 Mar. 13, 2008 29

-continued -continued

(73) (78)

(79)

(74)

Des-A-androstane

0284. In one or more embodiments according to the present invention, the steroid is a compound, in which one 24-Nor-5f-cholan-23-oic acid or more of the cyclopentaaphenanthrene rings is contracted

(75) by loss of an unsubstituted methylene group, as exemplified w H by 4-nor-5-androstane (78), where C-4 is missing. In other COOH embodiments one or more of the cyclopentaaphenanthrene rings is expanded by inclusion of a methylene group, as exemplified by formulae 80-86.

(80)

(20R)-18, 19-Dinor-5C-pregnane-20-carboxylic acid (not 18,19,23.24-tetranor-5C-cholan-21-oic acid 3 (76) 4 4a H 4a-Homo-5C.-androstane (81) O

Fa

7 18-Nor-5C.-androstane (not 10-methyl-5C-gonane) 15 I6 (77) 8a. HO 3-Hydroxy-17a,17b-dihomoestra-1,3,5(10)-trien-17b-one

(82)

18a-Homo-5C-estrane (not 13 ethyl-5C-gonane or 13-ethyl-18-nor-5C-estrane) 8(14)a-Homo-5C-androstane US 2008/0063607 A1 Mar. 13, 2008

ring is linked to the cyclopentaaphenanthrene skeleton -continued through a spiro system, as exemplified by formula 1 12.

(83) (99) O

8(9)a-Homo-5C-androstane 3 3) 3C.9-Epidioxy-5C-androstan-17-one (100)

(84) OCH3

17 B-Methoxy-17C, 14-(epoxymethano)- 5C-androstane 9(10)a-Homo-19-nor-5C, 10C (H)-pregnane (101)

N

(85)

13(17)a-Homo-5C-pregnane O C6H5 (22E)-3?-Hydroxy-4'-phenyl-5.8-1.2epi1,2,4-triazolo (86) 5C,8C-ergosta-6.22-diene-3',5'-dione (102) C) (H

6 2. Ou, 4a H

4a-Homo-7-nor-5C-androstane

(103) 0285) In one or more embodiments, the steroid contains additional rings that are formed within, or on, a steroid nucleus. In additional embodiments, the steroids contains a bivalent bridge such as —O-O-, -CH2—, linking non-adjacent ring positions as exemplified by formulae 99-102. 0286. In one or more embodiments, the steroid contains a cyclopentaaphenanthrene skeleton and a carbocyclic or heterocyclic ring component fused to it, as exemplified by Furo4.3.2:4,5,6 androstane formulae 103-111, and in other embodiments, an additional US 2008/0063607 A1 Mar. 13, 2008

-continued -continued

(109) (104)

8 Naphtho2,1:2,3-5C-androstane (110)

(105)

(111) 2C-Methyl1,3oxathiolo.5',4':16,17-5C-androst-6-en-3?-ol

(106)

3H-Cyclopropa2,3-5C-androstane (112)

Benzo2,3-5C-androstane

(107)

Spiro5C-androstane-3,1'-cyclpropane

3'

(113) H 3H-Cyclopropa2,3-5C.-androstane

(108)

H (4R)-4-Methyl-(3:S)-spiro5C-androstane-3,2'-1,3dioxolane

H 0287 Yet, in certain embodiments, two or more steroid 2C,3C-Dihydro-3H-cyclopropa2,3-5C-androstane molecules are linked together covalently, as exemplified by formulae 3a and 3b.

US 2008/0063607 A1 Mar. 13, 2008 33

TABLE 3-continued Exemplary steroids that are useful according to the present invention. Molecular Trivial name Chemical name formula Oxandrolone 17P-hydroxy-17o-methyl-2-oxa-5C-androstan-3-one Oxymetholone 17P-hydroxy-2-(hydroxymethylene)-17C.-methyl-5C androstan-3-one Pancuronium 1,1'-(3C,17-diacetoxy-5C-androstane-2P.16P-diyl)bis(- HsoBr2N2O4 bromide methylpiperidinium) dibromide Prednisolone 11P.17.21-trihydroxypregna-1,4-diene-3,20-dione H28Os Prednisone 17,21-dihydroxypregna-1,4-diene-3,11,20-trione H26Os Proscillardin 3P-(6-deoxy-C-L-mannopyranosyloxy)-14-hydroxybufa H2Os 4.20.22-trienolide Roxibolone 11P,17-dihydroxy-17C.-methyl-3-oxoandrosta-1,4- H28Os diene-2-carboxylic acid Spironolactone 7c-acetylthio-3-oxo-17C-pregn-4-ene-21, 17 H2OS carbolactone Timobesone S-methyl 9-fluoro-11P,17a-dihydroxy-16P-methyl-3- HoFOS oxoandrosta-1,4-diene-17P-carbothioate Triamcinolone 9-fluoro-11P.16C, 17.21-tetrahydroxypregna-1,4-diene 27FO 3.20-dione Ursodeoxycholic 3C,7P-dihydroxy-5P-cholan-24-oic acid acid

0289 Mixtures of these steroids may also be employed according to the present invention. TABLE 4-continued 0290 The steroid is included in the composition of the Exemplary anti-inflammatory steroids that are useful according to the present invention in a concentration that provides a desirable present invention. ratio between the efficacy and safety. Typically, steroids are Typical concentration included in the composition in a concentration between Relative Potency Generic Name in topical products about 0.005% and about 12%. However, in some embodi ments, the concentration is between about 0.005% and about Fluocinolone acetonide O.O1-0.01% AlcometaSone dipropionate O.01% 0.5%, in other embodiment between about 0.5% and about Mometasome furoate O.1% 2%, and in additional embodiments between about 2% and Triamcinolone acetonide O.O25%-0.1% about 5% or between about 5% and about 12%. High Potency Betamethasone-17-benzoate O.025% Methylprednisolone aceponate O.1% 0291. In one or more embodiments, the steroid possesses Betamethasone dipropionate 0.025%, 0.05% immunomodulating and/or anti-inflammatory properties. Halcinonide O.1% Triamcinolone acetonide O.S9/o Without being bound to a specific theory, immunomodulat Highest Potency Halobetasol O.05% ing and/or anti-inflammatory steroids act, among other Clobetasol-17-propionate O.05% mechanisms, through inhibition of the activity of phospho lipase A. They also may have anti-proliferative effects on keratinocytes and other cell types. They can Suppress col 0292. In one or more embodiments, the steroid is selected lagen synthesis by fibroblasts, but this may lead to adverse from the group of low-potency anti-inflammatory steroids, effects. Anti-inflammatory steroids are roughly grouped medium potency anti-inflammatory steroids and high according to relative anti-inflammatory activity, but activity potency anti-inflammatory steroids. may vary considerably depending upon the vehicle, the site of application, disease, the individual patient and whether or 0293. In one or more embodiments, the anti-inflamma not an occlusive dressing is used, as exemplified in the Table tory steroid is included in the composition at a concentration 4. between about 0.005% and about 1%. 0294 The McKenzie vasoconstrictor assay, as described, TABLE 4 for example, in the British Journal of Dermatology 1975; Exemplary anti-inflammatory steroids that are useful according to the 93:563-71 and versions thereof, has been the primary present invention. method used for classifying the potency of a product, containing an anti-inflammatory steroids. Thus, in one or Typical concentration more embodiments, the anti-inflammatory steroid is a ste Relative Potency Generic Name in topical products roid that positively affects the vasoconstrictor assay. Low Potency Hydrocortisone O.S96-19 hydrocortisone acetate O.S.-1.0% 0295). In one or more embodiments, the steroid is a Desonide O.O2-0.2% Medium Potency Betamethasone valerate O.05%-0.1% hormone. Hormones are known to affect a variety of bio Prednicarbate O.O2-0.2% logical processes in any organism, and thus, their inclusion Clobetasone-17-butyrate O.05% in the composition of the present invention, which is Flucinonide O.01%-0.05% intended for local treatment of the skin, the vagina, the rectum as well as other body surfaces and cavities provided US 2008/0063607 A1 Mar. 13, 2008 34 an advantageous treatment modality. Such compositions gestodene, chlormadinone acetate, dienogest, drospirenone, containing hormones can be further administered systemi lynestrenol, tybolone, cyproterone acetate, megestrol cally, via the transdermal or transmucosal route, in order to acetate, nomegestrol acetate. alleviate a disorder that is affected by the specific hormone, 0299. Yet, in additional embodiments, the steroid an or in order to tune the hormonal balance of the body in order inhibitor of a steroid hormone. Non-limiting examples of to attain certain effects controlled by hormones, such as Such inhibitors are finasteride, dutasteride and spironolac contraception and birth induction. tOne. 0296. In one or more embodiments, the steroid hormone 0300. In one or more embodiments, the steroid is a is a male hormone or an androgen. Non-limiting examples vitamin D. The term vitamin D is used to describe all of male hormones?androgens include testosterone, testoster steroids that exhibit qualitatively the biological activity of one cipionate, testosterone decanoate, testosterone enantate, calciol (vitamin D). Non limiting examples of vitamin D testosterone isocaproate, testosterone phenylpropionate, tes compounds are provided in Table 5. tosterone propionate, testosterone undecylate, 5C.-dihy drotestosterone, dehydroepiandrosterone (also termed pras 0301 Yet, in additional embodiments, the steroid is a terone and DHEA), androstenedione, androstanediol, vitamin D analogue. Exemplary vitamin D analogs include androsterone, androstenolone, prasterone enantate, praster calcipotriol, tacalcitol, maxacalcitol, and calcitriol, with one sodium sulfate, ormeloxifene, mesterolone, fluoxyme calcipotriol being especially preferred. Vitamin D ana sterone, methyltestosterone, gestrinone, delmadinone, del logues and derivatives are known to degrade at low pH madinone acetate, chlormadinone, chlormadinone acetate, levels. Therefore, in certain preferred embodiments, the danazol and testolactone. steroid is a vitamin D. or an analogue or a derivative thereof, the pH is adjusted to the range between about 7 and about 0297. In one or more embodiments, the steroid hormone 10, or between about 7.5 and about 9. In one or more is a female hormone or an estrogen. Non-limiting examples embodiments, the pH is adjusted using a buffering agent, of female hormones/estrogens include estradiol, estradiol suitable of maintaining a pH level between about 7 and benzoate, estradiol cipionate, estradiol dipropionate, estra about 10, or between about 7.5 and about 9.

TABLE 5 Examples of Vitamin D compounds Vitamin D name Systematic steroid name Cholecalciferol (also termed calciol, (5Z,7E)-(3S)-9,10-seco-5,7,10(19)- cholecalciferol, vitamin D and collecalciferol) cholestatrien-3-ol 25-Hydroxycholecalciferol (also termed (5Z,7E)-(3S)-9,10-seco-5,7,10(19)- calcidiol cholestatriene-3,25-diol 1C,25-Dihydroxycholecalciferol (also termed (5Z,7E)-(1S,3R)-9,10-seco-5,7,10(19)- calcitriol) cholestatriene-1,3,25-triol Ergocalciferol (also termed ercalciol and (5Z,7E.22E)-(3S)-9,10-seco-5,7,10(19).22 ergocalciferol) ergostatetraen-3-ol 1C,25-Dihydroxyergocalciferol (also termed (5Z,7E.22E)-(1S,3R)-9,10-seco ercalcitriol) 5,7,10(19).22-ergostatetraen-1,3,25-triol 22,23-Dihydroergocalciferol (also termed (5Z,7E)-(3S)-9,10-seco-5,7,10(19)- (24S)-methylcalciol and 22,23 ergostatrien-3-ol dihydroercalciol) 1C.24R,25-Trihydroxycholecalciferol (also (5Z,7E)-(1S,3R,24R)-9,10-seco-5,7,10(19)- termed calcitetrol) cholestatriene-1,3,24,25-tetrol Previtamin D (also termed precalciferol and (6Z)-(3S)-9,10-seco-5(10),6,8-cholestatrien (6Z)-tacalciol) 3-ol Tachysterol (also termed tacalciol) (6E)-(3S)-9,10-seco-5(10),6,8-cholestatrien 3-ol Isovitamin D. (also termed (5E)-isocalciol) (5E,7E)-(3S)-9,10-seco-1 (10),5,7- cholestatrien-3-ol Dihydrotachysterol (also termed (5E,7E)-(3S,10S)-9,10-seco-5,7- dihydroercalciol) cholestadien-3-ol diol enantate, estradiol hexahydrobenzoate, estradiol phe 0302 Further examples of vitamin D compounds include, nylpropionate, estradiol Valerate, polyestradiol phosphate, but are not limited to (1S)-Hydroxycalciol (also termed estriol, estriol Sodium Succinate, estriol Succinate, poly 1O-hydroxycholecalciferol and alfacaleidol), (24R)-Hy estriol phosphate, quinestradol, ethinylestradiol, estraproni droxycalcidiol (also termed 24(R).25-dihydroxycholecalcif cate, mestranol, estrapronicate and equilin. erol), 25-Fluorocalciol (also termed 25-fluorocholecalcif 0298. In one or more embodiments, the steroid hormone erol), Ercalcidiol (also termed 25-hydroxyergocalciferol), is a progestogen. Non-limiting examples of progestogens Ertacalciol (also termed tachysterol, (5E)-lsocalciol (also include progesterone, norethisterone, norethisterone acetate, termed isovitamin D, 22.23-Dihydroercalciol), (24S)-me norethisterone enantate, medroxyprogesterone acetate, del thylcalciol (also termed vitamin D), (5E)-(10S)-10,19-Di madinone acetate, flugestone acetate, dydrogesterone, hydroercalciol, (also termed dihydrotachysterol, hytakerol, desogestrel, norgestrel, levonorgestrel, dydrogesterone, and dihydrotachysterol), (24S)-Ethylcalciol (also termed US 2008/0063607 A1 Mar. 13, 2008 vitamin Ds) and (22E)-(24R)-Ethyl-22.23-didehydrocalciol, 0308 The concentrations of corticosteroid drugs, as pre (also termed vitamin D). sented in the above table are provided herein only as example, and any therapeutically effective concentration of 0303. In one or more embodiments, the steroid is a phytosteroid or a phytosterol. As used herein, the term Such corticosteroids can be incorporated in the composition “phytosteroid' or “phytosterol' includes all steroids that are of the present invention. obtained, derived or extracted from plant sources. Non 0309 Since corticosteroid drugs are typically hydropho limiting examples of families of phytosteroids and phy bic, the composition of the present invention, comprising a tosterols include ecdysones, withanolids, Sterines, steroid hydrophobic solvent, is most suitable as a vehicle to facili saponins and Soflavonoids. Non-limiting examples of phy tate better topical distribution, improved occlusion and an tosteroid and phytosterol compounds include alpha-sito enhanced rate of penetration of any of the above listed drugs. sterol, beta-sitosterol, Stigmastanol, campesterol, alpha-si to stanol, beta-sitostanol, Stigmastanol, campestanol, 0310 Corticosteroids are used for treating psoriasis. Pso avenosterol, brassicasterol, desmosterol, chalinosterol, beta riasis is a very common chronic skin disease, which may be ecdysone, whithaferin A, beta-sitosterine, Stigmasterine, the target of treatment using the composition of the present campesterine, ergosterine, diosgenin, daidzein, glycitein, invention. It is marked by periodic flare-ups of sharply genistein, muristerone, poriferasterol, clionasterol, defined red patches covered by a silvery, flaky surface. campestanol, and cycloartenol, as well as all natural or 0311 Corticosteroid ointments, greasy preparations con synthesized forms and derivatives thereof, such as fatty acid taining little or no water, are typically used for treating esters, such as ferulic acid esters, oleoyl esters, and cinnamic psoriasis. Their main disadvantage is in their sticky feeling, acid esters, including isomers. which remains so long after treatment is over. By contrast, 0304 Plant oils and extracts which contain steroids are the foam of the present invention, while comprising con also useful. Non limiting examples of plants that contain siderable concentration of an oil (hydrophobic solvent), steroids include nuts seeds, sprouted seeds and grains (such spreads very easily throughout the afflicted area and absorbs as alfalfa), St. Mary's thistle, ginkgo biloba, saw palmetto, into the skin without leaving any untoward sensation or panax, Siberian ginseng, foeniculum vulgare, Cimicifiiga look. racemosa, licorice root, red clover, sage, Sarsaparilla, sas safras, angelica sinensis achillea millefolium, anemone 0312. Other non-limiting examples of inflammatory dis pratensis, angelica sinensis, glycyrrhiza glabra, hypericum orders, which can be prevented or treated by the oleaginous perforatum, larrea, panax, piscidia erythrina, plantago psyl compositions of the present invention, wherein the drug is a steroid are atopic dermatitis, Seborrhea, seborrheic derma lium, Serenoa repens, symphytum, taraxacum officinale, tri titis of the face and trunk, seborrheic blepharitis, contact folium pratense, turnera spp., tussilago farfara, valeriana dermatitis, stasis dermatitis (gravitational eczema; varicose officinalis, viburnum prunifolium, calendula officinalis eczema), exfoliative dermatitis (erythroderma), lichen sim 0305. In one or more embodiments, the steroid is a plex chronicus, pityriasis rosea and pemphigus. compound that is positively identified using a laboratory 0313. It is pointed out that certain of the solvents that may method, Suitable of detecting a steroid. Anti-inflammatory or be used in the preparation of the composition of the present anti-allergic agents invention including polyunsaturated fatty acids, containing 0306 Yet, according to another embodiment according to omega-3 and omega-6 fatty acids (e.g., linoleic and linolenic the present invention the active agent is an anti-inflamma acid, gamma-linoleic acid (GLA), eicosapentaenoic acid tory or anti-allergic agent. Anti-inflammatory agents can be (EPA) and docosahexaenoic acid (DHA) are themselves selected from the group of corticosteroids, non-steroidal beneficial in the treatment of psoriasis and other skin inflam anti-inflammatory drugs (NSAIDs), anti-histamines, immu mation conditions. nosuppressant agents, immunomodulators; and any combi nation thereof at a therapeutically effective concentration. 0314. A second class of anti-inflammatory agents, which is useful in the foam of the present invention, includes the 0307 The following table provides a summary of cur nonsteroidal anti-inflammatory agents (NSAIDs). The vari rently available corticosteroid agent and their typical thera ety of compounds encompassed by this group is well-known peutically effective concentration. to those skilled in the art. Specific non-steroidal anti-inflam matory agents useful in the composition invention include, but are not limited to: Potency Compound Current products 0315 Oxicams, such as piroxicam, isoxicam, tenoxicam, Very high Clobetasol proprionate Cream or ointment 0.05% Halobetasol proprionate Cream or ointment 0.05% Sudoxicam, High Betamethasone diproprionate Cream or ointment 0.05% Betamethasone valerate Ointment 0.1% 0316 Salicylates, such as salicylic acid, ethyl salicylate, Fluocinolone acetonide Cream O.02% methyl salycilate, aspirin, disalcid, benorylate, trilisate, Safa Halcinonide Cream or ointment 0.1% pryn, Solprin, diflunisal, and fendosal; Medium Betamethasone valerate Cream 0.1% Fluocinolone acetonide Cream or ointment 0.020% 0317 Acetic acid derivatives, such as diclofenac, fen Hydrocortisone valerate Cream or ointment 0.2% Triamcinolone acetonide Cream, ointment, or lotion clofenac, indomethacin, Sulindac, tolmetin, isoxepac, furo O.1% or 0.020% fenac, tiopinac, Zidometacin, acematacin, fentiazac, Zome Low Hydrocortisone Cream, ointment, or lotion pirac, clindanac, oxepinac, felbinac, and ketorolac, 1.0% or 2.5% 0318 Fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; US 2008/0063607 A1 Mar. 13, 2008 36

0319 Propionic acid derivatives, such as ibuprofen, 0327 Selective COX-2 Inhibitors include, in an exem naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenopro plary manner diaryl-substituted furanones (e.g., Rofecoxib); fen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, diaryl-substituted pyrazoles (e.g., Celecoxib); indole acetic pranoprofen, miroprofen, tioxaprofen, Suprofen, alminopro acids (e.g., Etodolac); and Sulfonanilides (e.g., NimeSulide) fen, and tiaprofenic; and and salts and derivatives thereof. 0320 Pyrazoles, such as phenylbutazone, oxyphenbuta 0328. In one or more embodiments, the selective COX-2 Zone, feprazone, azapropaZone, and trimethaZone. inhibitor is selected from the group consisting of celecoxib, deracoxib, Valdecoxib, rofecoxib, lumiracoxib, etoricoxib, 0321) Any further steroidal and nonsteroidal compounds, meloxicam, parecoxib. 4-(4-cyclohexyl-2-methyloxazol-5- having the capacity to prevent, alleviate the symptoms of yl)-2-fluorobenzenesulfonamide, 2-(3,5-difluorophenyl)-3- treat or cure inflammation processes, are generally included, (4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one, N-2-(cy as possible anti-inflammatory agents, according to the clohexyloxy)-4-nitrophenylmethanesulfonamide, 2-(3.4- present invention. difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-4- 0322 Topical antihistaminic preparations currently avail (methylsulfonyl)-phenyl-3(2H)-pyridazinone, 2-(2,4- able include 1% and 2% diphenhydramine, 5% doxepin, dichloro-6-methylphenyl)amino-5-ethyl-1-benzeneacetic phrilamine maleate, chlorpheniramine and tripelennamine, acid, (3Z)-3-(4-chlorophenyl)4-(methylsulfonyl)phenyl phenothiazines, promethazine hydrochloride and dimethin met-hylenedihydro-2(3H)-furanone, and (S)-6,8-dichloro dene maleate. These active agents, as well as additional 2-(trifluoromethyl)-2H -1-benzopyran-3-carboxylic acid. antihistamines can also be incorporated in the composition of the present invention. 0329. In additional embodiments, the selective COX-2 inhibitor is selected from the group consisting of ibuprofen, 0323 The therapeutic composition of the present inven naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, tion may also comprise an anti-inflammatory or antiallergic ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, agent, wherein said agent reduces the occurrence of pro prapoprofen, miroprofen, tioxaprofen, Suprofen, alminopro inflammatory cytokines or inhibits the effect of pro-inflam fen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, matory cytokines. Mixtures of Such anti-inflammatory Sulindac, tolmetin, Zomepirac, diclofenac, fenclofenec, agents may also be employed, as well as the dermatologi alclofenac, ibufenac, isoxepac, furofenac, tiopinac, cally acceptable salts, esters, amides, prodrugs and deriva Zidometacin, acetyl salicylic acid, indometacin, piroxicam, tives of these agents. tenoxicam, nabumetone, ketorolac, aZapropaZone, mefe namic acid, tolfenamic acid, diflunisal, podophyllotoxin Non-steroidal Antiinflammatory Agents (NSAID) derivatives, acemetacin, droxicam, floctafenine, oxyphenb 0324. In the context of the present invention, a nonste utaZone, phenylbutaZone, proglumetacin, acemetacin, fen roidal immunomodulating agent (also termed herein “non tiazac, clidanac, oxipinac, mefenamic acid, meclofenamic steroidal anti-inflammatory agent” and “NSAID) is a phar acid, flufenamic acid, niflumic acid, flufenisal, Sudoxicam, maceutically active compound, other than a corticosteroid, etodolac, piprofen, Salicylic acid, choline magnesium trisali which affects the immune system in a fashion that results in cylate, salicylate, benorylate, fentiazac, clopinac, feprazone, a reduction, inhibition, prevention, amelioration or preven isoxicam, and 2-fluoro-a-methyl 1, 1'-biphenyl-4-ace-tic tion of an inflammatory process and/or the symptoms of acid, 4-(nitrooxy)butyl ester. inflammation and or the production pro-inflammatory cytok 0330. In one or more embodiments, the NSAID is sali ines and other pro-inflammatory mediators, thereby treating cylic acid a salicylic acid derivatives. Exemplary Salicylic or preventing a disease that involves inflammation. acid derivative include, in a non limiting fashion, aspirin, 0325 In one or more embodiments, the NSAID is an Sodium salicylate, choline magnesium trislicylate, Salsalate, inhibitor of the cyclooxygenase (COX) enzyme. Two forms diflunisal, salicylsalicylic acid, SulfaSalazine, olsalazine, of cyclooxygenase are known today: the constitutive esters of salicylic acid with a carboxylic acid, esters of cyclooxygenase (COX-1); and the inducible cyclooxyge salicylic acid with a dicarboxylic acid, esters of salicylic nase (COX-2), which is proinflammatory. Thus, in one or acid with a fatty acid, esters of salicylic acid with a hydroxyl more embodiments of the present invention, the NSAID is fatty acid, esters of salicylic acid with an essential fatty acid, selected from the group consisting of a COX-1 inhibitor, a esters of salicylic acid with a polycarboxylic acid, and any COX-2 inhibitor or a non-selective NSAID, which simulta compound wherein salicylic acid is linked to an organic neously inhibits both COX-1 and COX-2. moiety through a covalent bond. 0326) The term “selective COX-2 inhibitor” relates o a 0331 In one or more embodiments, the NSAID is para compound able to inhibit cyclooxygenase-2 without signifi aminophenol (e.g., acetaminophen) and salts and derivatives cant inhibition of COXe-1. Typically, it includes compounds thereof. that have a COX-2 ICs of less than about 0.2 micro molar, and also have a selectivity ratio of COX-2 inhibition over 0332. In one or more embodiments, the NSAID is an COX-1 inhibition of at least 50, and more typically, of at indole or an indole-acetic acid derivative (e.g., indometha least 100. Inhibitors of the cyclooxygenase pathway in the cin, Sulindac, etodolac) and salts and derivatives thereof. metabolism of arachidonic acid used in the present invention 0333. In one or more embodiments, the NSAID is an aryl may inhibit enzyme activity through a variety of mecha acetic acids (e.g., tolmetin, diclofenac, ketorolac) and salts nisms. By the way of example, and without limitation, the and derivatives thereof. inhibitors used in the methods described herein may block the enzyme activity directly by acting as a Substrate for the 0334. In one or more embodiments, the NSAID is an enzyme. arylpropionic acid and salts and derivatives thereof. Exem US 2008/0063607 A1 Mar. 13, 2008 37 plary arylpropionic acid derivative include, in a non limiting 0343. In one or more embodiments, the NSAID is a nitric fashion, are ibuprofen, naproxen, flubiprofen, ketoprofen, oxide inhibitor. Nitric oxide (NO) is a potent secondary fenoprofen, oxaprozin. messenger that is both highly reactive and highly diffusible. It is generated physiologically by a family of enzymes, 0335) In one or more embodiments, the NSAID is anthra referred to as NO synthases (NOS). Overproduction of NO nilic acids or an anthranilic acid derivative, also termed plays a key role in the pathology of a wide range of disorders “fenamates' (e.g., mefenamic acid, meclofenamic acid) and including disorders that involve inflammation, and NOS salts and derivatives thereof. inhibitors have been suggested as anti-inflammatory agents. 0336. In one or more embodiments, the NSAID is Agents that neutralize NO (also called “NO scavengers') are selected from the group of enolic acids, enolic acid salts, considered as potential anti-inflammatory agents as well. enolic acid esters, amides, anhydrides and salts and deriva tives thereof. Non-limiting examples of enolic acid deriva 0344 Also useful are compounds that inhibit or slow tives include oxicams (piroxicam, tenoxicam) and pyrazo down the migration of leucocytes (white blood cell), e.g., lidinediones (phenylbutaZone, oxyphenthratraZone). macrophages, neutrophils, and monocytes towards an afflicted skin Surface or mucosal membrane, which is known 0337 Yet, in additional embodiments, the NSAID is an to accelerate the inflammatory process. alkanone (e.g., nabumetone). 0345 Among other inhibitors of leucocyte chemoaxis, 0338 Certain imidazole drugs (e.g., ketoconazole) also dicarboxylic acids, having between about 6 and about 14 possess anti-inflammatory properties. (See: J. Am. Acad. carbon atoms in their carbon atom skeleton are particularly Dermatol. 1991 August; 25(2 Pt 1):257-61). useful in the treatment of disorders of the skin and mucosal membranes that involve inflammation. Suitable dicarboxylic 0339. Another group of nonsteroidal immunomodulating acid moieties include, but are not limited to, adipic acid, agents includes agents, which inhibit pro-inflammatory pimelic acid, Suberic acid, azelaic acid, sebacic acid, 1,11 cytokines, such as TNF-alpha, TNF-beta, interleukin-1, undecanedioic acid, 1,12-dodecanedioic acid, 1,13-tride interleukin-4, interleukin-6, interleukin-10, interleukin-12 canedioic acid and 1,14-tetradecanedioic acid. Thus, in one and IFN-gamma from T cells, which are especially impor or more embodiments of the present invention, dicarboxylic tant in the induction of inflammation or inhibit the release of acids, having between about 6 and about 14 carbon atoms in cytokines and pro-inflammatory mediators from mast cells. their carbon atom skeleton, as well as their salts and deriva 0340 Agents that are used to affect the untoward influ tives (e.g., esters, amides, mercapto-derivatives, anhyd ence of pro-inflammatory cytokines are chemically or bio raides), are useful immunomodulators in the treatment of logically-originated materials that Suppress the pro-inflam disorders of the skin and mucosal membranes that involve matory effect of a pro-inflammatory cytokine via various inflammation. AZelaic acid and its salts and derivatives are mechanisms, including, but not limited to (a) inhibiting the preferred. formation of a pro-inflammatory cytokine; (b) Suppressing 0346 Certain preferred dicarboxylic acid derivatives the interaction of a pro-inflammatory cytokine with its include a dicarboxylic acid wherein at least one ester moiety receptors; or (c) neutralization the proinflammatory cytokine of the compound comprises a keratolytic agent, selected by direct or indirect interaction. from the group consisting of alpha-hydroxy acids and 0341 Examples of chemical anti TNF-C. agents are derivatives thereof, beta-hydroxy acids and derivatives known pharmaceutical materials, such as pentoxifylline, thereof, hydroxybenzoic acid and their ester, anhydride and propentofylline, torbafylline (and other related Xanthines), amine derivatives, alkylhydroxybenzoate, dihydroxy ben amiloride, chloroquine, thalidomide and structural analogs Zene and their ester, anhydride and amide derivatives, thereof. Examples for biological anti-TNF-C. agents are cresols and their ester, anhydride and amide derivatives. anti-TNF-C. antibodies and soluble TNF-C. receptors. Addi Keratolytic agents also include alcohol derivatives of Vita tional compounds are those that impair the signal transduc min A (retinoic acid), e.g., retinol and derivatives thereof, as tion cascade from the receptor to other functional organs of provided in U.S. Pat. No. 6,180,669. Additional preferred the living cell. Such active agents, as well additional com dicarboxylic acid derivatives comprise at least one ester of pounds, which are capable of inhibiting the production or a active alcohol moiety, selected from the groups of steroid otherwise Suppressing the pro-inflammatory effects of hormones, corticosteroids, vitamin E and vitamin D, as TNF-C. can be used in the composition of the present provided in US Patent Application 20040191196. invention. 0347 In one or more embodiments, the NSAID is an ion 0342 Immunosuppressant agents, immunoregulating channel modulator. Ion channels are protein macromol agents and immunomodulators constitute an additional class ecules located in the cell membranes that enable the selec of nonsteroidal anti-inflammatory agents, which are used tive movement of Sodium, potassium, and calcium from according to the present invention. Such agents are chemi outside the cell to inside the cell and vice-versa. cally or biologically-derived agents that modify the immune response or the functioning of the immune system (as by the 0348. In one or more embodiments, the NSAID is a stimulation of antibody formation or the inhibition of white potassium ion channel modulator. It has been shown that the blood cell activity). Immunosuppressant agents and immu potassium ion channel modulator play important roles in nomodulators include, among other options, cyclic peptides, controlling T-cell activation and thus, they can be used to Such as cyclosporine, tacrolimus, tresperimus, pimecroli control inflammation. mus, sirolimus (rapamycin), Verolimus, laflunimus, lacquini 0349. In one or more embodiments, the potassium ion mod and imiquimod. In one or more embodiments, the non channel modulator is selected from the group consisting of steroidal immunomodulating agent is a calcineurin Inhibitor. dendrotoxin, dendrotoxin 1, dendrotoxin K, alpha-dendro US 2008/0063607 A1 Mar. 13, 2008 toxin, beta-dendrotoxin, gamma-dendrotoxin, margatoxin, pyrimidinyll-piperazinylpregna-4.9(11)-diene-320 Stichodactyla toxin, tityustoxin K, apamin, charylotoxin, dione, 1O-hydroxy-21-4-2-(diethylamino-)-6-(1- clotrimazole, dequalinium chloride, iberiotoxin, kaliotoxin, piperidinyl)-4-pyrimidinyl-1-piperazinylpregna-4.9(11)- neuropeptide Y, noxiustoxin, tolbutamide, chlorpropamide, diene-320-dione, 21-4-2,6-bis(diethylamino)-b4 glibenclamide, glipizide, nategliniide, repagliniide, gly pyrimidinyl)-4-pyrimidinyl-1-piperazinyl-1-piperazinyl buride, tolaZamide, nicorandil, fampiridine and penitrem A, 17O-hydroxy-16C.-methylpregna-1,4,9(11)-triene-320 or is a pharmaceutically acceptable Salt or prodrug thereof. dione, 17C.-hydroxy-21-4-2,6-bis(4-methyl-1-piperazinyl 0350. In an embodiment of the present invention, the pregna-4.9(11)-diene-320-dione, 17O-hydroxy-6C.-methyl potassium ion channel modulator is selected from the list of 21 4-2,6-bis-(1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl potassium ion channel modulators, provided in WO 2004/ pregna-1,4,9(11)-triene-320-dione, 21-4-2,6- O93895. bis(diethylamino)-4-pyrimidinyl)-1-piperazinyl-1-1C., 17C.- dihydroxypregn-4-ene-320-dione, 21-4-2,6- 0351. In one or more embodiments, the NSAID is a bis(diethylamino)-4-pyrimidinyl-1 piperazinyl-17C.- Sodium ion channel modulator. In one or more embodi hydroxypregn-4-ene-320-dione, 21-4-2,6- ments, the sodium ion channel blocker is selected from the bis(diethylamino)-4-pyrimidinyl)-1-piperazinyl-17C.- group consisting of disopyramide, procainimide, quinidine, hydroxy-6C.-methylpregna-1,4,9(11)-triene-320-dione, tocamide, mexiletene, lidocane, phenyloin, fosphenyloin, 17O-hydroxy-21-4-2,6-bis(1-pyrrolidinyl)-4-pyrimidi flecamide, propafenone, morcizine, lubeluzole, carbam nyl-1-piperazinylpregna-4.9(11)-diene-320-dione, 21-4- azepine, sipatrigine, riluzole, tetrodotoxin, spheroidine, 2,6-bis(diethylamino)-4-pyrimidinyl-1-piperazinyl-11C.- maculotoxin, Vinpocetine, anthopleurin-c, lamotrigine, hydroxypregn-4-ene-320-dione, 21-4-2,6- crobenetine, lifarizine, lanodipine, lomerizine, encamide, bis(diethylamino)-4-pyrimidinyl)-1-piperazinyl-11C. 17C.- and flunarizine or is an isomer, a pharmaceutically accept dihydroxypregn-4-ene-320-dione, 17O-hydroxy-16C.- able salt, ester, or prodrug thereof. methyl-21-4-2,6-bis-(1-pyrrolidinyl)-4-pyrimidinyl)-1- 0352. In an embodiment of the present invention, the piperazinylpregna-1,4,9(-11)-triene-320-dione17C.- potassium ion channel modulator is selected from the list of hydroxy-21-4-2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl)-1- potassium ion channel modulators, provided in US Pat. Pub. piperazinylpregna-14.9(11)-triene-320-dione, 21-4-2,6- Nos. 20040224940 and 2004022O187. bis(diethylamino)-4-pyrimidinyl)-1-piperazinyl-17C.- hydroxypregna-1,4,9(11)-triene-320-dione, 21-4-4,6- 0353. In one or more embodiments, the NSAID is a bis(diethylamino)-2-pyrimidinyl-1-piperazinyl-17 C.- modulator of serotonin (5-hydroxytryptamine, 5-HT) activ hydroxypregna-1,4,9(11)-triene-320-dione, 21-4-2,6- ity. 5-HT is known to affect inflammation through its modu bis(diethylamino)-4-pyrimidinyl-1-piperazinyl-16C.- lation effect on cytokine production (Cloéz-Tayarani et al. methylpregna-1,4,9(11)-triene-320-dione, 21-4-2,6- Int. Immunol. 2003, 15 233). In certain embodiments, the bis(diethylamino)-4-pyrimidinyl-1-piperazinyl-11.alpha.- serotonin activity modulator is a serotonin reuptake inhibi hydroxy-16C.-methylpregna-1,4-dien-e-320-dione, 21-4- tor. It has been shown that serotonin reduces inflammation 2,6-bis(diethylamino)-4-pyrimidinyl-1-piperazinyl-1-6C.- and assists healing of experimental skin wounds, and thus, methylpregna-1,4-diene.3.20-dione, 16C.-methyl-21-4-2. serotonin reuptake inhibitor can be used to control inflam 6-bi-s(1-pyrrolidinyl)-4-pyrimidinyl-1-piperazinylpregna mation and associated disorders. 1.4.9(11)-triene-3,2-O-dione, 11 O-hydroxy-16C.21-4-2,6- 0354) In one or more embodiments, the serotonin bis(1-pyrrolidinyl)-4-pyrimidinylpiperazinylpregna-1,4- reuptake inhibitor is selected from the group consisting of diene-320-dione, 16C.-methyl-21-4-2,6-bis(1- citalopram, fluoxetine, fluvoxamine, paroxetine, escitalo pyrrolidinyl)-4-pyrimidinyl-1-piperazinylpregna-1,4- pram oxalate, Sertraline, norfluoxetine and N-demethylser diene-320-dione, 16.alpha.-methyl-21-4-2,6-bis(4- traline. morpholino)-4-pyrimidinyl-1-piperazinylpregna-1,4, 9(11)-triene-3,20-dione, 11 O-hydroxy-16C.-methyl-21-4- 0355. In an embodiment of the present invention, the 2,6-bis(4-morpholino)-4-pyrimidinyl-1-piperazinyl serotonin reuptake inhibitor is selected from the list of pregna-1,4-diene-320-dione, 16.alpha.-methyl-21-4-2-6- potassium ion channel modulators, provided in US Pat Pub. bis(4-morpholino(4-pyrimidinyl)-1-piperazinylpregna-1,4- No. diene-320-dione, 21-4-2,6-bis(allylamino)-4- 2004O171664. pyrimidinyl-1-piperazinyl-16C.-methylpregna-1,4,9(11)- triene-3,20-dione, 21-4-2,6-bis(allylamino)-4- 0356. In one or more embodiments, the NSAID is an pyrimidinyl-1-piperazinyl-11 C-hydroxy-16C.- antioxidant. Reactive oxygen species play an important role methylpregna-1,4-ene-3,2-O-dione, 21-4-2,6- in mediating skin inflammation, and antioxidants may pro bis(allylamino)-4-pyrimidinyl-1-piperazinyl-16C.- vide protection. methylpregna-1,4-ene-3,20-dione, 21-4-2,6-bis(1- 0357 Non-limiting examples of antioxidant agents pyrrolidinyl)-4-pyrimidinyl-1-piperazinylpregn-4-ene-3, include 21-4-2-amino-6-(diethylamino)-4-pyrimidinyl)-1- 11,20-trione, 21-4-2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl piperazinyl-17C.-hydroxypregna-4.9(11)-diene-3,20-dione, 1-piperazinylpregna-4.9(11)-diene-320-dione, 21-4-2,6- 17O-hydroxy-21-4-2,6-bis(dimethylamino)-4-pyrimidi bis(1-pyrrolidinyl)-4-pyrimidinyl-1-piperazinylpregna-1, nyl-1-piperazinylpregna-4.9(11)-diene-320-dione, 21-4- 4-diene-3,20-dione, 21-4-(2,6-bis(1-pyrrolidinyl)-4- 2-(diethylamino)-6-(1-pyrrolidinyl)-4-pyrimidinyl-1-pip pyrimidinyl)-1-piperazinylpregna-4.9(11)-diene-320 erazinyl-17C.-hydroxypregna-4.9(11)-diene-3,20-dione, dione, 21-4-(2,6-bis(4-morpholino)-4-pyrimidinyl)-1- 17O-hydroxy-21-4-2-(diethylamino)-6-(4-methyl-1-piper piperazinyl-17C.-hydroxypregna-4,9011)-diene-320-dione, azinyl (4-pyrimidinyl)-1-piperazinylpregna-4.9(11)-diene 21-4-(2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl)-1-piperazi 3.20-dione, 17O-hydroxy-21-4-2,6-bis(diethylamino)-4- nylpregna-4-en-3-one, 21-4-(2,6-bis(1-pyrrolidinyl)-4-py

US 2008/0063607 A1 Mar. 13, 2008 40

2a.5a)-1,3-benzenediol; and 5-(1,1-dimethylheptyl)-2-4- maceutically acceptable salts thereof. Mixtures of such (hydroxymethyl)-6,6-dimethylbicyclo3.1.1 hep-t-3-en-2- anesthetic agents may be synergistically beneficial. yl)-1R-(1a,2a,5a)-1,3-benzenediol; or is an isomer, a pharmaceutically acceptable salt, ester, or prodrug thereof. Keratolytically Active Agents 0360. In one or more embodiments, the NSAID is an 0368. The term “keratolytically active agent” refers angiotensin II receptor antagonist. angiotensin II receptor herein to a compound which loosens and removes the antagonists are known to affect inflammation and pain, as stratum corneum of the skin, or alters the structure of the shown, for example in J Pharmacol Exp Ther. 2003 October; keratin layers of skin. 307(1):17-23. Epub 2003 Aug. 27. 0369 Keratolytically active agents are used in the treat 0361. In certain embodiments, the angiotensin II receptor ment of many dermatological disorders, which involve dry antagonist is selected from the group consisting of cande skin, hyperkeratinization (Such as psoriasis), skin itching Sartan, eprosartan, irbesartan, losartan, olmesartan, tasosar (such as Xerosis), acne and rosacea. tan, telmisartan, Valsartan, Saralasin, and 1-4-(dimethy 0370 Suitable keratolytic agents include alpha-hydroxy lamino)-3-methylphenylmethyl-5-(diphenylac-etyl)-4,5,6, acids. Alfa hydroxy acids are keratolytic, and they are also 7-tetrahydro-1H-imidazo[4,5-cpyridine-6-carboxylic acid capable of trapping moisture in the skin and initiating the ditrifluoroacetate, or an isomer, a pharmaceutically accept formation of collagen. Suitable hydroxy acids include but able salt, ester, or prodrug thereof. are not limited to agaricic acid, aleuritic acid, allaric acid, altraric acid, arabiraric acid, ascorbic acid, atrolactic acid, 0362. In one or more embodiments, the NSAID is an benZilic acid, citramalic acid, citric acid, dihydroxytartaric UDP-glucuronosyltransferase inhibitor (UGT inhibitor). acid, erythraric acid, galactaric acid, galacturonic acid, glu 0363. In certain embodiments, the UGT inhibitor is caric acid, glucuronic acid, glyceric acid, glycolic acid, selected from the group consisting of epicatechin gallate, gularic acid, gulonic acid, hydroxypyruvic acid, idaric acid, epigallocatechin gallate, octyl gallate, propyl gallate, quer isocitric acid, lactic acid, lyXaric acid, malic acid, mandelic cetin, tannic acid, benzoin gum, capsaicin, dihydrocapsaicin, acid, mannaric acid, methylacetic acid, mucic acid, phenyl eugenol, gallocatechin gallate, geraniol, menthol, menthyl lacetic acid, pyruvic acid, quinic acid, ribaric acid, ribonic acetate, naringenin, allspice berry oil, N-Vanillylnonana acid, Saccharic acid, talaric acid, tartaric acid, tartronic acid, mide, clovebud oil, peppermint oil, silibinin and silymarin. threaric acid, tropic acid, uronic acids, Xylaric acid and 0364 Mixtures of these non-steroidal immunomodula derivatives, esters, salts and mixtures thereof. tors may also be employed according to the present inven 0371. Yet, another preferred keratolytic agent is urea, as tion. well as derivatives thereof. Urea possesses both keratolytic 0365 Topical application of a foam, comprising a safe and skin-hydration properties which are beneficial to the and effective dose of an NSAID can be useful in the damaged tissue of the skin. prevention and/or alleviation of the symptoms of rheumatoid 0372 Another preferred group of keratolytic agents, suit arthritis, osteoarthritis and pain. Topical NSAIDs, incorpo able for inclusion in the therapeutic composition according rated in the foam of the present invention can be also used to the present invention is beta-hydroxy acids, such as in the treatment of dermatological disorders, such as acne, salicylic acid (o-hydroxybenzoic acid). Beta hydroxyl acids rosacea, hair growth disorders, actinic keratosis and certain are keratolytic, and they are also have anti-inflammatory and skin cancer conditions. antibacterial properties. 0366 Immunosuppressant agents, immunoregulating 0373 Short chain carboxylic acids (carboxylic acids hav agents and immunomodulators are chemically or biologi ing up to 6 carbon atoms in their skeleton) are also suitable cally-derived agents that modify the immune response or the for inclusion in the therapeutic composition as keratolytic functioning of the immune system (as by the stimulation of agents. Examples of short chain carboxylic acid include, but antibody formation or the inhibition of white blood cell are not limited to formic acid, acetic acid, propionic acid, activity). Immunosuppressant agents and immunomodula butyric acid (Butanoic acid), Valeric acid (pentanoic acid) tors include, among other options, cyclic peptides, such as and caproic acid (hexanoic acid). In the context of the cyclosporine, tacrolimus, tresperimus, pimecrolimus, siroli present invention, di-carboxylic acids having up to 6 carbon mus (rapamycin), Verolimus, laflunimus, lacquinimod and atoms in their skeleton are also suitable under the definition imiquimod. Such compounds, delivered in the foam of the of short chain carboxylic acids having up to 6 carbon atoms present invention, are especially advantageous in skin dis in their skeleton. Non-limiting examples of suitable dicar orders such as psoriasis, eczema and atopic dermatitis, boxylic acids are malonic acid (propanedioic acid). Succinic where the large skin areas are to be treated. The oleaginous acid (butanedioic acid), glutaric acid (Pentanedioic acid) and foam compositions of the present invention provide excel adipic acid (Hexanedioic acid). Also suitable under the lent vehicles for Such applications and are Superior to definition of short chain carboxylic acid are unsaturated conventional creams and ointments. short chain carboxylic acids, i.e., short chain carboxylic acids, having one or more double bonds in their carbon Topical Anesthetics skeleton; and halogenated short chain carboxylic acids. Such 0367 The compositions of the present invention may as fluoroethanoic acid (CH2FCO2H), chloroethanoic acid comprise a safe and effective amount of a topical anesthetic. (CHCICOH) and dichloroethanoic acid (CHCICOH). Examples of topical anesthetic drugs include benzocaine, Dicarboxylic acids, having between about 6 and about 14 lidocaine, bupivacaine, chlorprocaine, dibucaine, eti carbon atoms in their carbon atom skeleton also possess docaine, mepivacaine, tetracaine, dyclonine, hexylcaine, leratolytic properties. Suitable dicarboxylic acid moieties procaine, cocaine, ketamine, pramoxine, phenol, and phar include, but are not limited to, adipic acid, pimelic acid, US 2008/0063607 A1 Mar. 13, 2008

Suberic acid, azelaic acid, sebacic acid, 1,11-undecanedioic 0381. In one or more embodiments, the keratolytic agent acid, 1,12-dodecanedioic acid, 1,13-tridecanedioic acid and includes at least two keratolytic agents, from different fami 1,14-tetradecanedioic acid. lies of chemicals. Thus, in preferred embodiments of the present invention, the keratolytic agent includes at east two 0374. Another group of keratolytic agents include phenol agents, from different chemical families, selected from the and Substituted phenolic compounds. Such compounds are group consisting of: (1) an alpha-hydroxy acid; (2) a beta known to dissolve and loosen the intracellular matrix of the hydroxy acid; (3) a short-chain carboxylic acid; (4) a hyperkeratinized tissue. Dihydroxybenzene and derivatives hydroxyl benzene; (5) a vitamin A derivative; and (6) urea. thereof have been recognized as potent keratolytic agents. As detailed above, each of these keratolytic agent families Resorcinol (m-dihydroxybenzene) and derivatives thereof possess, in addition to their keratolytic property, additional are used in anti-acne preparations. Hydroquinone (p-dihy therapeutically-beneficial feature, Such as anti-inflamma droxybenzene), besides its anti-pigmentation properties, is tory, skin hydration and antibacterial properties for readily also keratolytic. contributing to the overall therapeutic benefit of the thera 0375 Vitamin A and its derivatives, such as retinol, peutic composition. retinal, retinoic acid, retinyl acetate, retinyl palmitate, retinyl Retinoids ascorbate, isotretinoin, tazarotene, adapalene, 13-cis-ret inoic acid, acitretin all-trans beta carotene, alpha carotene, 0382 Another preferred group of active agents includes, lycopene, 9-cis-beta-carotene, lutein and Zeaxanthin are for example, retinol, retinal, all trans retinoic acid and another class of keratolytic agents, which alter the structure derivatives, isomers and analogs thereof, collectively termed of the skin and promote peeling. “retinoids’. Etretinate, actiretin, isotretinoin, adapalene and tazarotene are further examples of said retinoid isomers and 0376. In certain embodiments, the keratolytic agent analogs. includes at least two keratolytic agents. At least two or more 0383. In the context of the present invention, a retinoid is keratolytic agents in the therapeutic composition, a safe and a compound a class of compounds consisting of four iso effective peeling agent is attained, which breaks down the prenoid units joined in a head-to-tail manner, and deriva keratin layer of the skin, where the microorganisms reside. tives, salts, structural analogs and functional analogs As a result of such breaking down of the keratin layer, the thereof, as reviewed herein in a non-limiting fashion. Typi microorganisms cannot further Survive in the infected area. cally, retinoids may be formally derived from a monocyclic The combination of at least two keratolytic agents enables a parent compound containing five carbon-carbon double selective breaking down of keratin in infected skin areas, bonds and a functional group at the terminus of the acyclic while non-infected skin areas are not affected. This phenom portion. enon is explained by the fact that the keratin layer in infected skin areas is deformed and thus it is more vulnerable to 0384 Suitable, but non-limiting, retinoids for use in the keratolytic disintegration. Furthermore, combining at least present invention are listed below. two keratolytic agents facilitates use of each agent in a 0385) It is convenient to omit the explicit representation Substantially minimally-irritating concentration, thus of C and H atoms in the parent skeletal structure of retinoids decreasing the overall irritation of the therapeutic composi as follows: tion.

0377 Suitable keratolytically active agents include phe 7 19 20 e nol and Substituted phenolic compounds. Such compounds a. a.s are known to dissolve and loosen the intracellular matrix of a the hyperkeratinized tissue. As such, they are used in the treatment of dermatological disorders. Dihydroxy benzene 14 and derivatives thereof have been recognized as potent keratolytic agents. Resorcinol (m-dihydroxybenzene) and 18 derivatives thereof are used in anti-acne preparations. Hyd (1) R = CH2OH (6) R = CH3NH2 (2) R = CHO (7) R = CHENOH roquinone (p-dihydroxybenzene), besides its anti-pigmenta (3) R = CO2H (8) R = CHFNCH2CHNH2CO2H tion properties, is also keratolytic. These compounds also (4) R = CH3 (9) R = COCHs exhibit antiseptic properties. Cresols also possess bacteri (5) R = CHOCOCH cidal and keratolytic properties. COOH (10)10) R- = H o O-CO 0378 Vitamin A and its derivatives, such as retinoic acid, isoretinoic acid, retinol and retinal are another preferred OH class of keratolytically active agents. 0379 Another group of keratolytically active agents 0386 Compound (1) (2E,4E,6E.8E)-3,7-dimethyl-9-(2, include alpha-hydroxy acids, such as lactic acid and glycolic 6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol is acid and their respective salts and derivatives; and beta also known as Vitamin A, vitamin Aalcohol, retinal, vitamin hydroxy acids. Such as Salicylic acid (o-hydroxybenzoic A. vitamin A alcohol, axerophthol or axerol. Compound acid) and its salts and pharmaceutically acceptable deriva (2) also known as Vitamin Aaldehyde, Vitamin A aldehyde, tives, which typically possess anti-inflammatory, as well as retinene or retinene, and retinal or, if liable to be confused keratolytic, activity. with the adjective retinal (pertaining to the retina), retinal dehyde. Compound (3) also known as tretinoin (see note), 0380 Yet, another class of preferred keratolytically vitamin A acid or vitamin A acid should be designated active agents includes urea and its derivatives. retinoic acid. Compound (4), is known as axerophthene. US 2008/0063607 A1 Mar. 13, 2008 42

Functional substitution at the 15 position of the basic 0387 Retinoids that differ in hydrogenation level from hydrocarbon is denoted by the use of the group names retinyl the parent structure (displayed above) are named by use of (R is CH ) or retinylidene (R is CH=), with retention of the prefixes hydro and dehydro together with locants the original numbering of the basic hydrocarbon. For example (5) is retinyl acetate and (6) is retinylamine. specifying the carbon atoms at which hydrogen atoms have Derivatives of retinal include for example Compound (7)— been added or removed. Examples of such retinoid com retinal oxime and Compound (8) N'-retinylidene-L- pounds are Compound (11)—3,4-Didehydroretinol (also lysine. Other derivatives of retinoic acid, named as carboxy known as dehydroretinol or vitamin A) and Compound lic acid derivatives Compound (9)—ethyl retinoate and (12)—4,5-Didehydro-5,6-dihydroretinol (also known as Compound (10)—1-O-retinoyl-b-D-glucopyranuronic acid. alpha-Vitamin A).

Compound (11) Compound (12)

N1 N1 N1 N. OH 1N1N1 N1 N. OH

5 4 Compound (13) Compound (14) OCHs

2 1N1 N1 N1 N. OH N N N N O O 5 F Compound (15) Compound (16) R N N1 N1 N1 N1 N. OH 2 6 2 N1 N1 N1 N. O

3 CHO 4 R=NHCHs Compound (17) Compound (18) R OH

2 N-1N1 N1N1 No 2 6 N1 N1 N1 N. O

3 5

R = OCHs O Compound (19) Compound (20)

21 Nea Ya Na 2n-4 n.4 n.4 n. OCOCH

4 Compound (21) Compound (22)

R = COCH US 2008/0063607 A1 Mar. 13, 2008 43

-continued Compound (23) Compound (24)

N1 N1 N1 N enan-1\4N4N1s R h R = COH Compund (25) Compound (26) COOH COOH

N

H3CO

Compound (27) O

21 OCH2CH3 N e6 N

S Compund (28)

S1S-1S-1S-1S-1s-1S-1s-1S

Compound (29) OH s1's 1s-1s-1s-1s-1s-1s-1S

0388 Substituted derivatives of retinoids are exemplified somers of retinoids are exemplified by Compound (21)— by Compound (13)—5,6-Epoxy-5,6-dihydroretinol (also (3R)-3-Hydroxyretinol and Compound (22)—(3R)-3-Ac known as hepaxanthin) and Compound (14)—Ethyl 12-fluo etoxyretinol. Other stereochemical isomers can are roretinoate. Seco Retinoids are exemplified by Compound exemplified by Compound (23)—13-cis-Retinoic acid or (15)—1.6-Seco-1,2-didehydroretinol, also known as g-vita (7E9E, 11E. 13Z)-retinoic acid (also known as isotretinoin) minA, and Nor Retinoids, which result from the elimination and Compound (24)—(6E.8E,10E, 12E.15Z)-4, 14-retro of a CH, CH, CH or C group from a retinoid are exem plified by Compound (16) N-Ethyl-3-methoxy-2-methyl Retinaloxime. 17-nor-1,2,3,4-tetradehydroretinamide (also known as 0389 Arotinoids or retinoidal benzoic acid derivatives motretinide), Compound (17)—Ethyl 3-methoxy-2-methyl contain, aromatic rings replacing either the basic B-ionone 17-nor-1,2,3,4-tetradehydroretinoate (also known as etreti type ring structure or unsaturated bonds of the tetraene side nate), acitretin (Compound (17), wherein R=H) and Com chain of the parent retinoid skeleton, as exemplified by pound (18)—5-Acetyl-4,18-dinor-retinoic acid. Retro Compound (25) and Compound (26)—6-3-(1-adamantyl)- Retinoids are exemplified by Compound (19) 4.5-Didehy 4-methoxyphenyl-2-naphthoic acid, also known as ada dro-15.5-retro-deoxyretinol (also known as anhydro Vitamin palene. Several artinoids, possessing potent retinoid prop A and Compound (20) 4,14-retro-Retinyl acetate. Stereoi erties, including but not limited to short retinoids, short US 2008/0063607 A1 Mar. 13, 2008 44 heterocyclic retinoids, isoxazole-containing retinoids, het Suppression of neutrophil adhesion and Superoxide anion erocyclic isoxazole-containing retinoids, isoxazoline-con (0-2) production. Some calcium channel blockers also have taining retinoids, stilbene retinoid analogs, are disclosed in analgesic effects. Pure Appl. Chem. Vol. 73, No. 9, pp. 1437-1444, 2001. Tazarotene (Ethyl 6-2-(4,4-dimethylthiochroman-6-yl 0396 Current therapeutic uses of calcium channel block ers include (but are not limited to) hypertension, angina, )ethynylnicotinate) is exemplary to a retinoid precursor— arrhythmia and Subarachnoid hemorrhage. Calcium channel Compound (27), suitable as retinoid for use in the present blockers may further relieve or prevent reactive vasodilation invention. of migraine Sufferers by inhibiting the vasoconstriction 0390 Yet, other non-limiting exemplary retinoid precur during the prodromal phase. sors are carotenes, such as all-trans beta carotene Com 0397) There are two main classes of calcium channel pound (28), alpha carotene, lycopene and 9-cis-beta-caro blockers: dihydropyridines (e.g., nifedipine, nicardipine, tene, as well as Xanthophils (also termed “oxicarotenoids’), amlodipine, felodipine and nimodipine) and nondihydropy Such as lutein and Zeaxanthin Compound (29). ridines which include diltiazem (a benzothiazepine) and 0391 Salts and derivatives of retinoid compounds are Verapamil (a phenylalkylamine). Flunarizine is an antihis also suitable as “retinoid for use in the present invention. tamine with calcium channel blocking activity. 0392 Retinoid compounds can be ascertained recognized 0398. In an embodiment of the present invention, the and identified by methods known in the art. One method calcium channel blocker can be selected from the group involves the use of competitive nuclear retinoic acid (RA consisting of an amlodipine, anipamil, barnidipine, benid and RX) receptor binding assays for identifying compounds ipine, bepridil, darodipine, diltiazem, efonidipine, felo which bind directly to the receptors. For instance, J. J. Repa dipine, isradipine, lacidipine, lercanidipine, lidoflazine, et al., “All-trans-retinol is a ligand for the retinoic acid manidipine, mepirodipine, nicardipine, nifedipine, nilu receptors', Proc. Natl. Acad. Sci. USA, Vol. 90, pp. 7293 dipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, 7297, 1993, discloses a competitive RA receptor binding perhexyline, tiapamil, Verapamil, pharmaceutically accept assay based on human neuroblastoma cell nuclear extracts. able salts, isomers, analogs and derivatives thereof. H. Torma et al. (1994) “Biologic activities of retinoic acid Cholinerqic Drugs and 3,4-dehydroretinoic acid in human keratinoacytes are similar and correlate with receptor affinities and transacti 0399 Cholinergic drugs produce the same effects as Vation properties.J. Invest. Dermatology, Vol. 102, pp. acetylcholine. Acetylcholine is the most common neurohor 49-54) discloses assays for measuring binding affinities for mone of the parasympathetic nervous system, the part of the the nuclear retinoic acid receptors and for measuring tran peripheral nervous system responsible for the every day scriptional activation induction. M. F. Boehm et al. (1994) work of the body. A cholinergic agent, also known as a “Synthesis of high specific activity ..sup.3H-9-cis-retinoic parasympathomimetic agent, is a chemical which functions acid and its application for identifying retinoids with to enhance the effects mediated by acetylcholine in the unusual binding properties.J. Med. Chem. Vol. 37, pp. central nervous system, the peripheral nervous system, or 408-414) discloses a ligand-binding assay and a receptor/ both. These include acetylcholine receptor agonists musca reporter cotransfection assay for monitor regulation of gene rine and nicotine, as well as anticholinesterases. expression. EP 0 552 612 A2, published Jul. 28, 1993, 0400 Suitable cholinergic drugs in accordance with the describes ligand-binding trapping assays based on incuba present invention are selected from a cholinergic agonist of tion of radiolabeled compounds with transfected COS-1 acetylcholine, bethanechol, carbachol, methacholine, and cells which express RA and RX receptors. pilocarpine, or an anticholinesterase of ambenonium, neo 0393 Mixtures of these retinoids may also be employed Stigmine, physostigmine, pyridostigmine, dyflos, and eco according to the present invention. thinopate, and pharmaceutically acceptable salts, isomers, analogs and derivatives thereof. 0394 Compositions according to the present invention, which comprise retinoids as the active agent, can be used for Nitric Oxide Donors the treatment of acne, Seborrhea, various dermatoses, 0401 Nitric oxide is an inorganic free radical, which has inflammation of the skin, mucosal membranes, vagina and the chemical formula of N=O and abbreviated to NO, and is the rectum, psoriasis, actinic keratosis and skin cancers, by a remarkably versatile biological messenger. The chemical application onto the affected area. properties of NO are crucial in defining its biological roles, Calcium Channel Blockers both as a transcellular signal in the cardiovascular and nervous systems and as a cytotoxic antipathogenic agent 0395 Calcium channel blockers are a chemically and released during an inflammatory response. Endogenous NO pharmacologically heterogeneous group of drugs, but physi is synthesized from the amino acid L-arginine by three ologically they all share the ability to selectively antagonize isoforms of the enzyme NO synthase (NOS). The endothe the calcium ion movements that are responsible for the lial (eNOS) and neuronal (nNOS) isoforms that synthesize excitation-contraction coupling in the cardiovascular sys NO for transcellular signaling are constitutively expressed tem. Beyond their cardiovascular effects, calcium channel tightly regulated by a number of cofactors. These NOS blockers are known to possess other effects, such as inhibi isoforms typically synthesize small amounts of NO and tion of the growth and proliferation of vascular smooth require activation by Ca"-calmodulin, making them sensi muscle cells and fibroblasts, inhibition of the synthesis of tive to agents and processes that increase intracellular cal extracellular matrix proteins, immunomodulation, inhibition cium levels. The NO generated diffuses to neighboring of mast cell degranulation and platelet aggregation and target cells where it acts primarily through activation of US 2008/0063607 A1 Mar. 13, 2008 soluble guanylate cyclase (sGC) to generate coMP from eton, such as brassylic acid (n=11), thapsic acid (n=14), GTP, and bring about the cellular response through a reduc 14-methylnonacosanedioic acid (C29) and 14,15-dimethyl tion in intracellular calcium levels. triacontanedioic acid (C30). 0402. In an embodiment of the present invention, the 04.09 The carbon atom skeleton of the dicarboxylic acid nitric oxide donors can be selected from several classes, can be saturated or unsaturated. Such as in the case of maleic including, but not limited to inorganic nitrites and nitrates acid and fumaric acid. (e.g., sodium nitrite), organic nitrites and nitrates, sodium 0410. An ester of a dicarboxylic acid is a chemical nitroprusside, molsidomine and its metabolites, diazenium compound produced by the reaction between a dicarboxylic diolates, S-nitrosothiols, mesoionic oXatriazole and deriva acid and at least one alcohol, with the elimination of a tives thereof, iron-sulphur nitrosyls, Sinitrodil, FK-409 molecule of water. The reaction of a dicarboxylic acid with (4-Ethyl-2-(Z)-hydroxyiminol-5-nitro-3(E)-hexeneamide) one alcohol molecule results in a mono ester of said dicar and derivatives thereof and hybrid NO donor drugs. boxylic acid, and the reaction of a dicarboxylic acid with 0403. In an embodiment of the present invention, the two alcohol molecules results in a diester of the dicarboxylic organic nitric oxide donor includes at least one organic acid. nitrate, which includes esters of nitric acid and may be an 0411 The alcohol molecule, to be linked to the dicar acyclic or cyclic compound. For instance, the organic nitrate boxylic acid, can be selected from the group of an alkyl an may be ethylene glycol dinitrate; isopropyl nitrate; amyl aryl alcohol. Exemplary alcohol, Suitable according to the nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, isobutyl present invention include methyl alcohol, ethyl alcohol, nitrite, octyl nitrite, glyceryl-1-mononitrate, glyceryl-1,2- propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl dinitrate, glyceryl-1,3-dinitrate, nitroglycerin, butane-1,2,4- alcohol, t-butyl alcohol, pentyl alcohol, hexyl alcohol, octyl triol-trinitrate; erythrity1 tetranitrate; pentaerythrity1 tetrani alcohol, decyl alcohol, capryl alcohol, phenol, benzyl alco trate; sodium nitroprusside, clonitrate, erythrity1 tetranitrate, hol and the like. isosorbide mononitrate, isosorbide dinitrate, mannitol hex anitrate, pentaerythritol tetranitrate, penetrinitol, triethano 0412. In one or more embodiments, the alcohol is a lamine trinitrate, trolnitrate phosphate (triethanolamine biologically active alcohol. In an embodiment, biologically trinitrate diphosphate), propatylnitrate, nitrite esters of Sug active alcohol possesses keratolytic activities. Examples of ars, nitrate esters of Sugars, nitrite esters of polyols, nitrate keratolytically active alcohol Suitable according to the esters of polyols, nicorandil, apresoline, diazoxide, hydrala present invention include ortho-, meta- and para-hydroxy Zine, hydrochlorothiazide, minoxidil, pentaerythritol, tola alkylbenzoate, salicylic acid, ortho-, meta-, and para-dihy Zoline, scoparone (6,7-dimethoxycoumarin) and pharma droxybenzene, ortho-, meta-, and para-hydroxytoluene, ceutically acceptable salts, isomers, analogs and derivatives alpha-hydroxy acid, retinol, and derivatives thereof Such as thereof. provided in U.S. Pat. No. 6,180,669. 22. In an embodiment, the biologically active alcohol is selected from the group 0404 In one embodiment of the present invention, vaso consisting of steroidal hormones, steroidal anti-inflamma active drugs that act via eNOS activity enhancement. Such as tory agents, vitamin E and vitamin D. Such as provided in sildenafil. Vardenafil and tadalafil are also regarded “nitric U.S. Pat. Appl. 20040191196. oxide donors.” 0413 Insecticide and Insect Repellents Agents Dicarboxylic acid and esters thereof. 0414. Insects, such as mosquitoes, biting flies, mites, gnats, fleas, chiggers, punkies, sand flies, lice and ticks can 0405. In an embodiment of the present invention, the be annoying and sometimes pose a serious risk to human and organic carrier comprises an ester of a dicarboxylic acid. In animal health. In certain areas of the United States, mos the context of the present invention, a dicarboxylic acid is an quitoes can transmit diseases like equine and St. Louis organic material, having two carboxylic acid moieties on its encephalitis. Biting flies can inflict a painful bite that can carbon atom skeleton. They have the general molecular persist for days, Swell, and become infected. Ticks can formula HOOC-(CH), COOH. transmit serious diseases like Lyme disease and Rocky 0406. In an embodiment of the present invention, the Mountain spotted fever. dicarboxylic acid is a short-chain dicarboxylic acid. The 0415. There are several types of insect repellents to use simplest Short-chain dicarboxylic acid are oxalic acid (n=0), when protecting people and animals from flying or biting malonic acid (n=1). Succinic acid (n=2) and glutaric acid insects, spiders, ticks and mites. By way of example, these (n=3). may include DEET (N,N-diethyl-m-toluamide), dimethyl 0407 Additional members of dicarboxylic acid group are phthalate, piperonyl butoxide and permethrin. Insect repel derived from natural products or from synthesis, having “n” ling terpenoids, have been reported by Hwang, et al., J. value from 4 up to 21. In one or more embodiments of the Chem. Ecol., 11, 1297 (1985); and Ruledge, J. Am. Mosquito present invention, the dicarboxylic acid is selected from the Control Assoc. 4, 414 (1988). group consisting of adipic acid (hexanedioic acid; n=4), 0416 A particularly preferred group of insect repellents pimelic acid (heptanedioic acid; n=5), Suberic acid includes the terpenoid compounds, described in U.S. Pat. (octanedioic acid; n=6), azelaic acid (nonanedioic acid; No. 5,411,992, including: n=7), sebacic acid (decanedioic acid; n=8) and dode canedioic acid (n=10). 0417 Terpenoid-alcohol or terpene-ols are terpenoids which have at least one hydroxyl group. Examples of 0408. In an additional embodiment, the dicarboxylic acid terpene-ols include: C10H16O compounds, perillyl alcohol, contains 10 to 32 carbon atoms in their carbon atom skel carveol, myrtenol, and cis-verbenol; C10H18O compounds, US 2008/0063607 A1 Mar. 13, 2008 46 myrtanol, iso-pinocampheol, dihydrocarveol, isopulegol, Photodynamic Therapy Agents terpineol, terpinen-4-ol, nerol, geraniol, and linalool, and 0424 The foam compositions of the present invention are C10H20O compounds, menthol, beta-citronellol, and dihy also useful to deliver photo-sensitizing agents, known in the dro-myrcenol. art of photodynamic therapy. By way of example, Such 0418 Terpenoid-esters are terpenoids, which have at photosensitizers can be selected from the group comprising least one ester group which is the product of the bonding of modified porphyrins, chlorins, bacteriochlorins, phthalocya the hydroxyl group of a terpene-ol with an aliphatic car nines, naphthalocyanines, pheophorbides, purpurins, boxylic acid that can contain functional groups such as the m-THPC, mono-L-aspartyl chlorin e6, bacteriochlorins, hydroxyl or amine on the aliphatic chain. Examples of phthalocyanines, benzoporphyrin derivatives, as well as Suitable aliphatic carboxylic acids include acetic acid, pro photosensitizer precursors, such as aminolevulinic acid pionic acid, lactic acid, and various amino acids. Examples (ALA). of terpenoid-esters include: carvyl acetate, carvyl propi Active Agents for Burns, Wounds, Cuts and Ulcers onate, and menthyl lactate. 0425 The treatment of burns, wounds, cuts and ulcers, 0419 Essential oils which contain terpenoids and per using the composition of the present invention is particularly fumes which contain terpenoids. Non-limiting examples of advantageous. The oleaginous foam compositions of the essential oils which have high content of terpene-ols and present invention may comprise a combination of anti esters include bergamot (62% terpenoids); sage (>50% infective agents (against bacteria, fungi and/or viruses), terpenoids); styrax (>50% terpenoids); peppermint (>50% anti-inflammatory agents (steroidal and/or NSAIDs) and terpenoids); and pine Siberian (75% terpenoids %). Terpe pain relieving components. Upon application, the foam nes, aldehydes and ketones vary in their usefulness but as a spreads easily, covering the Surface of the affected area, and general group have potential as insect-repellent. without causing pain. Cosmetic Active Agents 0420. The oleaginous foams of the present invention are particularly suitable for the effective uniform spreading of 0426. The oleaginous foams of the present invention are an insect repellent agent onto large areas of the skin of useful and advantageous for skin care and cosmetic care. humans and animals. The hydrophobic solvent present in the The combination of oil, having refatting, protective and foam composition helps retain the insect repellent on the moisture-retaining properties, in a spreadable foam form, can be used to Substitute currently used cosmetic skin care skin surface for an extended period of time. creams, lotions, gels, etc. The foam compositions of the 0421. Yet, in a further embodiment, the foams of the present invention, with or without further active ingredients, present invention are suitable for delivery of insect-killing are suitable for the further application as "cosmeceutical agents (insecticides) to an afflicted external Surface area of preparation (cosmetic products with therapeutic benefit), to humans and animals. Thus, the pharmaceutical or cosmetic treat 'cosmetic' skin disorders, such as aging skin, wrinkles, composition of the present invention may comprise an hyperpigmentation (melasma, chloasma, freckles, etc.), insecticide, known in the art of parasitology. By way of scaly skin and other skin undesirable properties. example, such insecticide can be selected from the group of 0427. The CTFA Cosmetic Ingredient Handbook permethrin, hexachlorobenzene, carbamate, naturally occur describes a wide variety of non-limiting cosmetic and phar ring pyrethroids, permethrin, allethrin, malathion, piperonyl maceutical ingredients commonly used in the skin care butoxide and any combination thereof at a therapeutically industry, which are suitable for use in the compositions of effective concentration. Its application is very convenient the present invention. Examples of these ingredient classes and it spreads easily, even over hairy areas. The hydrophobic include: abrasives, absorbents, aesthetic components such as Solvent present in the foam composition helps retain the fragrances, pigments, colorings/colorants, essential oils, insecticide on the treated area for an extended period of astringents, etc. (e.g., clove oil, menthol, camphor, eucalyp time. Furthermore, the presence of a hydrophobic solvent in tus oil, eugenol, menthyl lactate, witch hazel distillate), the foam of the present invention eases mechanical removal anti-acne agents, anti-caking agents, antifoaming agents, of lice and nits with a comb. anti-microbial agents (e.g., iodopropyl butylcarbamate), antioxidants, binders, biological additives, buffering agents, Anti Cancer Agents bulking agents, chelating agents, chemical additives, colo 0422 Anti cancer agents can also be used according to rants, cosmetic astringents, cosmetic biocides, denaturants, the present invention as the drug of choice from skin drug astringents, external analgesics, film formers or mate malignant tumors, such as basal cell carcinoma, squamous rials, e.g., polymers, for aiding the film-forming properties sell carcinoma, melanoma and Kaposi's sarcoma, as well as and Substantivity of the composition (e.g., copolymer of the pre-cancerous condition actinic keratosis. In certain eicosene and vinyl pyrrolidone), opacifying agents, pH cases, topical cytotoxic and antiproliferative drugs are used adjusters, propellants, reducing agents, sequestrants, skin to treat or prevent such cancers, including 5-fluorouracil, bleaching and lightening agents (e.g., hydroquinone, kojic also called 5-FU. 5-FU, as well as any other anti-cancer acid, ascorbic acid, magnesium ascorbyl phosphate, ascor agents, know in the art of cancer medicine, can be incorpo byl glucosamine), skin-conditioning agents (e.g., humec rated in the foam at therapeutically effective levels. tants, including miscellaneous and occlusive), skin soothing and/or healing agents (e.g., panthenol and derivatives (e.g., 0423) A preferred family of anticancer drugs, suitable for ethyl panthenol), aloe Vera, pantothenic acid and its deriva usage in the foam of the present formulation comprises tives, allantoin, bisabolol, and dipotassium glycyrrhizinate), anti-estrogens, such as tamoxifen. skin treating agents, and vitamins and derivatives thereof. US 2008/0063607 A1 Mar. 13, 2008 47

0428. In one embodiment the active agent is a cosmetic cially propyl gallate, uric acid and its salts and alkyl esters, agent selected from a retinoid, an anti-wrinkle agent, a Sorbic acid and its salts, lipoic acid, amines (e.g., N.N- radical scavenger, a self-tanning agent, a skin whitening diethylhydroxylamine, amino-guanidine), Sulfhydryl com agent, a skin protective agent, an anti-cellulite agent, a pounds (e.g., glutathione), dihydroxy fumaric acid and its massaging oil and an anti-wart agent. salts, lycine pidolate, arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine, methionine, proline, Anti-Acne and Anti-Wrinkle Active Agents Superoxide dismutase, silymarin, tea extracts, grape skin/ 0429 The compositions of the present invention may seed extracts, melanin, and rosemary extracts may be used. comprise a safe and effective amount of one or more pharmaceutically or cosmetically acceptable anti-acne 0434. The foam of the present invention is suitable for active agents. Examples of useful anti-acne actives include delivering skin protecting and revitalizing anti-oxidants/ resorcinol, Sulfur, Salicylic acid and salicylates, alpha-hy radical scavengers. It is further pointed out that polyunsatu droxy acids, nonsteroidal anti-inflammatory agents, benzoyl rated fatty acids, containing omega-3 and omega-6 fatty peroxide, retinoic acid, isoretinoic acid and other retinoid acids (e.g., linoleic and linolenic acid, gamma-linoleic acid compounds, adapalene, tazarotene, azelaic acid and azelaic (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid derivatives, antibiotic agents, such as erythromycin and acid (DHA) are beneficial in the treatment of psoriasis and clyndamycin, Zinc salts and complexes, and combinations other skin inflammation conditions. Likewise, emollients thereof, in a therapeutically effective concentration. Certain and silicone oils exert moisture-retaining and skin protective anti-acne agents from this list are also useful in the treatment effects on the skin. Thus in a preferred embodiment, a skin of other skin disease, such as psoriasis, eczema and atopic protective foam is provided, wherein the hydrophobic sol dermatitis. vent comprises in full or in part, a solvent, selected from the group of emollients, silicone oil and oils, rich in unsaturated 0430 Anti-Wrinkle Active Agents/Anti-Atrophy Active fatty acids, thus, affording a synergistic therapeutic effect of Agents and Agents to Treat Dry and Scaly Skin (Xerosis and the anti-oxidants/radical scavenger agent and the vehicle ichthyosis) components. 0431. The compositions of the present invention may Self-Tanning Active Agents further comprise a safe and effective amount of one or more anti-wrinkle actives or anti-atrophy actives, which can be 0435 The oleaginous foams of the present invention are easily delivered by spreading a foam onto the skin. Exem particularly suitable for the uniform delivery of a tanning plary anti-wrinklefanti-atrophy active agents Suitable for use active agent onto large areas of the skin. It is preferable that in the compositions of the present invention include Sulfur the compositions comprise from about 0.1% to about 20%, containing D and L amino acids and their derivatives and more preferably from about 2% to about 7%, and still more salts, particularly the N-acetyl derivatives; thiols; hydroxy preferably from about 3% to about 6% of the composition, acids (e.g., alpha-hydroxy acids such as lactic acid and of dihydroxyacetone, or any other compound, know in the glycolic acid and their derivatives and salts; or beta-hydroxy art as an artificial tanning active agent. acids such as salicylic acid and salicylic acid salts and derivatives), urea, hyaluronic acid, phytic acid, lipoic acid; Solid Matter Agents lysophosphatidic acid, skin peel agents (e.g., phenol, resor 0436. According to a preferred embodiment of the cinol and the like), Vitamin B3 compounds (e.g., niacina present invention, the at least one active agent comprises mide, nicotinic acid and nicotinic acid salts and esters, Solid matter or particulate matter i.e., material that is not including non-vasodilating esters of nicotinic acid (Such as soluble in the liquid carrier composition of the foamable tocopheryl nicotinate), nicotinyl amino acids, nicotinyl alco composition. For definition purposes, Solid matter shall hol esters of carboxylic acids, nicotinic acid N-oxide and mean material that is not soluble in the foamable composi niacinamide N-oxide), Vitamin B5 and retinoids (e.g., ret tion more than 10% of the concentration intended to be inol, retinal, retinoic acid, retinyl acetate, retinyl palmitate, included in said foamable composition. The concentration of retinyl ascorbate). In the case of dry, Scaly skin (Xerosis) and the solid matter in the foamable composition is from about ichthyosis such agents can alleviate the symptoms by tem 1% to about 20% w/w. In one or more embodiments, the porary relief of itching associated with these conditions. concentration of Solid matter in the composition is from Anti-Oxidants/Radical Scavengers about 2% to about 16% w/w. 0432 A safe and effective amount of an anti-oxidant/ 0437. By way of example, the following classes of solid radical Scavenger may be added to the compositions of the matter Substances are presented. subject invention, preferably from about 0.1% to about 10%, more preferably from about 1% to about 5%, of the com 0438 Metallic oxides, such as titanium dioxide, zinc position. oxide, zirconium oxide, iron oxide. Preferably, as used in the present invention, titanium dioxide has an average primary 0433 Anti-oxidants/radical scavengers such as ascorbic particle size of from about 15 nm to about 100 nm, Zinc acid (vitamin C) and its salts, ascorbyl esters of fatty acids, oxide having an average primary particle size of from about ascorbic acid derivatives (e.g., magnesium ascorbyl phos 15 nm to about 150 nm, Zirconium oxide having an average phate, sodium ascorbyl phosphate, ascorbyl Sorbate), toco primary particle size of from about 15 nm to about 150 nm, pherol (vitamin E), tocopherol Sorbate, tocopherol acetate, iron oxide having an average primary particle size of from other esters of tocopherol, butylated hydroxybenzoic acids about 15 nm to about 500 nm, and mixtures thereof. In one and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2- embodiment the metal oxides are present in the amount of carboxylic acid (commercially available under the trade from about 0.1% to about 20%, preferably from about 0.5% name Trolox. Sup.R), gallic acid and its alkyl esters, espe to about 16%, more preferably from about 1% to about 10%, US 2008/0063607 A1 Mar. 13, 2008 48 of the composition. In yet another embodiment, Such solids 0454. Such foam is superior to current pastes in that it is are micronized to form particles having primary size of less very fluffy and light. Upon discharge from the aerosol can, than 15 nm. it creates a mass, having density between 0.04 g/mL and 0.2 g/mL, which is very easy to spread evenly and uniformly on 0439 Silicon containing solid matter includes silicone the target area. There is no need to rub thoroughly and oxide, also termed “silica”, “fumed silica” and “silica gel'. therefore, application of the foam does not cause any dis a white or colorless insoluble solid (SiO2); and talc, which comfort to the baby, unlike conventional baby pastes. Fol is fine grained mineral consisting of hydrated magnesium lowing application and spreading of the foam, a protective silicate; layer is formed, which is water resistant, and does not wash 0440 Carbon, for example in the form of amorphous out under a stream of tap water. carbon or graphite; 0455 Foam for diaper dermatitis and/or skin protection 0441. Oxidizing agents, such as benzoyl peroxide, cal can further comprise anti-irritant and/or infective agents, cium and magnesium hypochlorite; Such as corticosteroids, anti-inflammatory, anti-allergic, 0442 Metallic Silver, in small particles, including nanoc anti-fungal and anti-microbial agents. rystalline silver, which is used for antibacterial and wound Skin-Lightening and Whitening Agents healing purposes; other metal particles and mineral particles 0456. The foam of the present invention is particularly 0443 Cosmetic scrub materials, including, for example Suitable for the uniform delivery of a skin-lightening agent. meals of Strawberry seeds, raspberry seeds, apricot seeds, When used, the compositions preferably comprise from Sweet almond, cranberry seeds; about 0.1% to about 10%, more preferably from about 0.2% to about 5%, of the composition, of a skin-lightening agent. 0444 Pigments, which are insoluble in the foamable Suitable skin lightening or whitening agents include those composition. known in the art, including hydroquinone, azelaic acid and 0445. When such solid matter agents are included in the other related dicarboxylic acids, and salts and derivatives oleaginous foamable composition of the present invention, a thereof, retinoids, kojic acid, arbutin, nicotinic acid and its novel foam product, combining the refatting, occlusive and precursors, salts and derivatives, ascorbic acid and salts and protective properties of the oleaginous foam carrier and the derivatives thereof (e.g., magnesium ascorbyl phosphate or beneficial properties of the solid matter agent is afforded. Sodium ascorbyl phosphate), and herbal extracts (e.g., mul Thus, several unique products can be provided, as exempli berry extract, placental extract). fied herein: 0457. In one or more embodiments of the present inven 0446 Generally, products for the prevention and treat tion, the foam composition comprises a combination of a ment of diaper dermatitis and for skin protection are pro skin-whitening agent and a Sunscreen agent. vided in the form of paste that is intended for application on 0458 In one or more embodiments of the present inven the baby’s posterior, under the diaper. The paste typically tion, the foam composition comprises a combination of a includes about 30% oil and/or petrolatum, and about 10% skin-whitening agent and an inorganic Sunscreen agent. Zinc oxide, which are intended to provide a protective barrier When inorganic Sunscreen agents, e.g. TiO2, are rubbed onto between the baby's skin and the irritating environment the skin, they leave a white coating, which provides an inside the diaper. While containing the right ingredients, immediate (although transient) whitening effect, which is current baby pastes are very viscous and thick, and therefore highly desirable by the consumer, who wishes to see instant hard to spread on the target area. change in his/her appearance. The whitening agent, in com 0447 The oleaginous foam for treating or preventing bination with the inorganic Sunscreen agent in the foam diaper rash of the present invention comprises the following carrier can be easily and uniformly distributed on the skin ingredients: Surface, thereby affording an even instant whitening effect, 0448 at least one solvent selected from a hydrophobic unlike creams that are difficult to spread evenly on skin Solvent, a co-solvent, an emollient and mixtures thereof, at aaS. a concentration of about 30% to about 90%, preferably 0459 Use of a Solvent, Surface Active Agent, Foam between about 30% to about 70% Adjuvant and Polymeric Agent as an Active Agent. 0449 water at a concentration of 1% to about 60%: 0460 According to one embodiment, the at least one active agent is selected from the group of solvent, Surface 0450 about 6% to about 20% zinc oxide (or an alterna active agent, foam adjuvant and gelling agent, which are, on tive metal oxide) a case by case basis known to possess a therapeutic benefit. 0451 at least one non-ionic lipophilic surface active agent, preferably having an HLB value of about 3 to about Composition and Foam Physical Characteristics 10, more preferably about 3.5 to about 9 at a concentration Composition Flow Properties of about 0.1% to about 10%, or between about 0.1% and 0461 It is desirable to have an oleaginous foam compo about 5%; sition, including solvents, formulation excipients, water (as 0452 at least one gelling agent at a concentration of applicable), active agents and propellant, in a stable formu about 0.1% to about 5%; lation, which provides acceptable shelf-life of the product. 0453 a liquefied or compressed gas propellant at a con 0462 Yet, another crucial property of a composition is its centration of about 3% to about 25% of the total composi level of flow, since a composition that is not free flowing tion, in an aerosol container. cannot flow through the dip-tube of the aerosol container US 2008/0063607 A1 Mar. 13, 2008 49 and create acceptable foam. It has been noted that in the 0478 E (excellent): very rich and creamy in appearance, context of the composition of the present invention, com does not show any bubble structure or shows a very fine positions comprising semi-solid hydrophobic solvents, e.g., (small) bubble structure. white petrolatum, are excessively viscous and demonstrate poor flowability. 0479 G (good): rich and creamy in appearance, very small bubble size, “dulls' more rapidly than an excellent 0463 The combination of at least one surface active foam. agent, at least one foaming adjuvant and at least one gelling agent, according to one or more embodiments of the inven 0480 FG (fairly good): a moderate amount of creaminess tion provides a low specific gravity foam having Superior noticeable, bubble structure is noticeable. expandability, flow properties and sheer breakability (among 0481 F (fair): very little creaminess noticeable, larger other attributes). According to one or more embodiments of bubble structure than a “fairly good foam. the present invention, the total amount of at least one surface active agent, at least one foam adjuvant (optional) and at 0482 P (poor): no creaminess noticeable, large bubble least gelling agent, in combination does not exceed 8% Structure. (w/w) of foamable composition. In other embodiments, the 0483 VP (very poor): dry foam, large very dull bubbles, combined amounts of at least one Surface active agent, at difficult to spread on the skin. least one foaming adjuvant and at least one gelling agent is Foam Stability and Breakability less than 5% (w/w) of foam composition. The low solid content improves the flow properties of the foam, reduces 0484. In one or more embodiments, the foam composi unpleasant skin residue and reduces the cost of manufacture. tions are desirably stable for a long period of time. Thus, the As is demonstrated herein, the foam stability and expand foam composition does not undergo phase separation fol ability are excellent, despite the low levels of these compo lowing at least two freeze? thaw cycles. nents in the foam. 0485 According to further embodiments, upon discharge Expandability from an aerosol can onto a mucosal membrane at about 37° C., the foam expands to reach its designated Volume and 0464) Expandability is an important feature of a product, stays stable as a foam for at least 60 seconds following intended to treat large Surface areas and internal cavities of application, or about 2 minutes, or even about 3 minutes. the body. Thus, in one embodiment of the present invention, the specific gravity of the foam, upon discharge from the 0486 A crucial aspect of foam properties, according to aerosol can is between about 0.02 g/mL and 0.5 g/mL, more the present invention is breakability. Sheer-force breakabil preferably between about 0.04 g/mL and about 0.2 g/mL. ity of the foam, as attained by the composition of the present invention is clearly advantageous to thermally-induced Foam Physical Characteristics breakability, present, for example in U.S. Pat. No. 6,126, 920, and the respective Olux(R) and Luxiq(R) products, as 0465. In terms of foam consistency and texture an accept demonstrated by the fact that according to the use instruc able foam is one, that exhibits the following characteristics: tions of Olux(R) and Luxid R, the foam cannot be applied on 0466. Upon release from the aerosol can, creates a foam the hand and afterwards delivered to the afflicted area, since mass, which is Sustained on a surface for at least one minute; it collapses upon exposure to skin temperature. 0467 Foam texture should vary from a very fine creamy Further Technical Parameters foam to a fine bubble structure; 0487. The composition of the present invention may be 0468 Foam has to have specific gravity in the range of contained in and dispensed from a container capable of about 0.02 g/mL to about 0.5 g/mL, more preferably withstanding the pressure of the propellant gas and having between about 0.04 g/mL and about 0.2 g/mL. an appropriate valve?nozzle for dispensing the composition as foam under pressure. A customary liquefied or com 0469. In terms of spreadability and absorption an accept pressed gas propellant can be added, in the amount of about able foam is one, that: 3 to about 25% of the total composition. Liquefied propel lants are gases that exist as liquids under pressure, including 0470 Does not readily collapse upon dispensing on the high purity hydrocarbons such as propane, isobutane and skin; n-butane, dimethyl ether and chlorofluorocarbons (CFCs). 0471 Spreads easily on a skin surface; Compressed gasses are exemplified by air, nitrogen and carbon dioxide. 0472. Substantially absorbed following rubbing onto the skin. 0488 A specific embodiment according to the present invention comprises placing the composition of the present 0473. In terms of organoleptic properties an acceptable invention on a patch, occlusive tape or the skin-contact foam is one, that: compartment of a transdermal delivery apparatus and apply ing Such object onto the skin, in order to attain effective 0474 Creates a pleasant feeling after application; Superficial treatment or enhanced penetration of the drug 0475 Leaves minimal oily residue. into the skin or through the skin. 0489. Utilizing such strategy, one can apply drugs, which 0476 Leaves minimal shiny residual look. are currently administered systemically or that require trans 0477 The following scale for foam quality is used to dermal delivery, in the preferred therapeutic system of the evaluate foams. present invention. Examples for Such drugs are nicotine, US 2008/0063607 A1 Mar. 13, 2008 50 testosterone and other male hormones and male hormone Photosensitivity: Bullous Diseases including Pemphigus, precursors, estrogen and other female hormones and hor Bullous Pemphigoid, Dermatitis Herpetiformis, Linear mone precursors, growth hormone, insulin, caffeine, Steroi Immunoglobulin A Disease; Pigmentation Disorders includ dal and non-steroidal antiinflammatory agents and thyroid ing Hypopigmentation Such as Vitiligo, Albinism and hormone Substitutes. Postinflammatory hypopigmentation and Hyperpigmenta tion Such as Melasma (chloasma), Drug-induced hyperpig 0490 The therapeutic composition according to the mentation, Postinflammatory hyperpigmentation; Disorders present invention can also be used to prepare cosmetics for of Cornification including Ichthyosis, Keratosis Pilaris, Cal beauty purpose by adding into skin care agents and perfume. luses and Corns, Actinic keratosis; Pressure Sores: Disorders Metered Dosing of Sweating; Inflammatory reactions including Drug Erup tions, Toxic Epidermal Necrolysis; Erythema Multiforme, 0491 In order to provide proper therapy, precise dosing Erythema Nodosum, Granuloma Annulare. is advantageous. According to one preferred embodiment, the foam therapeutic product is adapted for storage in an 0494 The oleaginous compositions of the present inven aerosol container having a metered dose valve associated tion are useful in the therapy of non-dermatological disor therewith for dispensing an accurate dose of drug in the form ders, which respond to topical/transdermal delivery of an of a foam. More preferably, the metered dose valve is active agent. By way of example, Such disorders include selected to release a foam in a volume that will allow localized pain in general, as well as joint pain, muscle pain, effective spreading of the active agent throughout the body back pain, rheumatic pain, arthritis, ostheoarthritis and acute soft tissue injuries and sports injuries. Other disorders of this surface with substantially minimal overdose. class include conditions, which respond to hormonetherapy, 0492. In one or more embodiments, the meter dose valve Such as hormone replacement therapy, transdermal nicotine provides a unit dose of between about 10 uL and about 1000 administration, and other respective disorders, known in the LL. Assuming a representative foam density (specific grav art of drug delivery. ity) of 0.06 g/mL, a 10 LL valve provides a volume of about 0495. The oleaginous compositions of the present inven 0.17 mL of foam, and a 1000 uL metered dose valve provides about 17 mL of foam. Thus, by selecting a specific tion are further useful for the treatment and prevention of metered dosing valve and adjusting the foam density by fine disorders and diseases of other body cavities including the tuning formulation parameters and adjusting the ration rectum, vagina, penile urethra and ear canal. between the liquid components of the composition and the 0496 Thus, the oleaginous foam compositions of the propellant, one can design an adequate dosage form accord present invention are useful in treating a patient having any ing to the specific target body Surface. one of a variety of gynecological disorders, such as classi fied, in a non-limiting exemplary manner, according to the Fields of Pharmaceutical Applications following groups: 0493 By including an appropriate therapeutic agent in 0497 Pelvic pain, including premenstrual syndrome the foamable carrier, the foam composition of the present (PMS), mittelschmerz (severe midcycle pain due to ovula invention is useful in treating a patient having a any one of tion), dysmenorrhea (pain related to the menstrual cycle), a variety of dermatological disorders (also termed "derma endometriosis, ectopic pregnancy, ovarian cysts and masses, toses'), such as classified, in a non-limiting exemplary acute pelvic inflammatory disease, pelvic congestion syn manner, according to the following groups: Dermatitis drome and Vulvodynia; Vulvovaginal infections, including including Contact Dermatitis, Atopic Dermatitis, Seborrheic bacterial vaginosis, candidal vaginitis, trichomonas vagina Dermatitis, Nummular Dermatitis, Chronic Dermatitis of the lis, herpes simplex genital ulcers and warts, pelvic inflam hands and feet, Generalized Exfoliative Dermatitis, Stasis matory disease (PID), cerviciitis, acute and chronic salpin Dermatitis; Lichen Simplex Chronicus; Diaper rash: Bacte gitis; endometriosis; gynecological neoplasms, including rial Infections including Cellulitis, Acute Lymphangitis, endometrial Cancer, ovarian cancer, cervical cancer, Vulvar Lymphadenitis, Erysipelas, Cutaneous Abscesses, Necrotiz cancer, vaginal cancer, fallopian tube cancer and gestational ing Subcutaneous Infections, Staphylococcal Scalded Skin trophoblastic disease; benign tumors; sexually transmitted Syndrome. Folliculitis, Furuncles, Hidradenitis Suppurativa, diseases; sexual dysfunction disorders that respond to phar Carbuncles, Paronychial Infections, Erythrasma; Fungal macological therapy, including sexual arousal disorder, Infections including Dermatophyte Infections, Yeast Infec female orgasmic disorder, dyspareunia and vaginismus; and tions: Parasitic Infections including Scabies, Pediculosis, various gynecological disorders that respond to hormonal Creeping Eruption; Viral Infections: Disorders of Hair Fol therapy. licles and Sebaceous Glands including Acne, Rosacea, 0498. The foam according to one or more embodiments Perioral Dermatitis, Hypertrichosis (Hirsutism), Alopecia, of the present invention can be used as a lubricating foam. including male pattern baldness, alopecia areata, alopecia Without limitation, the lubricating foam is useful in lubri universalis and alopecia totalis; Pseudofolliculitis Barbae, cation of the birth canal for easy passage of a newborn baby Keratinous Cyst, Scaling Papular Diseases including PSO or the vaginal cavity during intercourse. riasis, Pityriasis Rosea, Lichen Planus, Pityriasis Rubra Pilaris; Benign Tumors including Moles, Dysplastic Nevi, 0499 Rectal applications include, for example, anal Skin Tags, Lipomas, Angiomas, Pyogenic Granuloma, Seb abscess/fistula, anal cancer, anal warts, Crohn's disease, orrheic Keratoses, Dermatofibroma, Keratoacanthoma, Kel haemorrhoids, anal and perianal pruritus, Soreness, and oid; Malignant Tumors including Basal Cell Carcinoma, excoriation, perianal thrush, anal fissures, fecal inconti Squamous Cell Carcinoma, Malignant Melanoma, Paget’s nence, constipation, polyps of the colon and rectum. Disease of the Nipples, Kaposi's Sarcoma; Reactions to 0500 The oleaginous foam compositions of the present Sunlight including Sunburn, Chronic Effects of Sunlight, invention are further useful for intra-vaginal and rectal US 2008/0063607 A1 Mar. 13, 2008 51 treatment of sexually-transmitted and non-sexually-trans will be appreciated by someone skilled in the art. Polymers mitted infectious disease (STDs). are mixed, swelled and solubilized in the main solvent, when necessary, with appropriate heating to 70 C or cooling as 0501. In one or more embodiments, the invention pro appropriate for specific polymer until it forms a clear vides a method of treatment of a disorder of the skin, Solution. Stabilizing Surfactants added usually with heat, mucosal membrane, ear channel, vaginal, rectal and penile until a homogeneous mixture is obtained, the mixture is then urethra disorders, comprising topical application of the foam allowed to cool to below 40 C. The remainder of the composition of the present invention, whereby one or more ingredients are then added with mixing until they have active agents, in a therapeutically effective concentration to dissolved in the medium. The active agent is usually added the afflicted area. at the end. Cool to room temperature. The canisters are then 0502. In a further embodiment, the invention provides a filled with the above waterless formula, sealed and crimped method of treatment of a non-dermatological disorder, with a valve and pressurized with the propellant. which responds to topical delivery of an active agent, comprising topical application of the foam composition of 0512 For emulsion formulas: the present invention, whereby one or more active agents, in 0513 1. Mix oily phase ingredients and heat to 75 C to a therapeutically effective concentration to the skin. melt all ingredients and obtain homogeneous mixture. Treatment/Therapy 0514 2. Mix polymers in water with heating or cooling as appropriate for specific polymer. 0503) The terms “therapy” and “treatment” as used herein interchangeably, cover any treatment of a disease or disor 0515 3. Add all other water soluble ingredients to der, and includes, for example: water-polymer solution and heat to 75 C. 0504 (i) Curing the disease or disorder; 0516 4. Add slowly internal phase to external phase at 75 C under vigorous mixing and homogenize to obtain 0505 (ii) preventing the disease or disorder from occur fine emulsion. ring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; 0517 5. Cool to below 40 C and add sensitive ingre dients with mild mixing. 0506 (iii) inhibiting the disease or disorder; 0518 6. Cool to room temperature 0507 (iv) relieving the disease or disorder; 0519 For Oily Waterless Foam: 0508 (V) causing regression of the disease; 0520) 1. Mix all ingredients excluding polymers and 0509 (vi) providing a beneficial immunological effect; heat to 75 C to melt and dissolve and obtain homoge 0510 (vii) improving the quality of life of a subject neous mixture. afflicted by a disease or disorder, and, in the case of cosmetic 0521. 2. Mix well and cool to below 40 C and add the treatment (viii) cleansing, beautifying, promoting attractive polymers and sensitive ingredients with moderate mix ness, or altering the appearance without affecting the body’s ing. structure or functions. In the following, some non-limiting examples and experiments are described in detail. This 0522. 3. Cool to room temperature invention is not limited to these examples and experiments. EXAMPLE 1. Many variations will suggest themselves are within the full intended scope of the appended claims. Anhydrous Foam Comprising a Potent Solvent and 0511. The waterless formulas of the present invention MCT O1 may be made in the following general methodology set out 0523 The components of the anhydrous foam are listed below with appropriate adjustments for each formulation as in the table below.

Ingredient Synonym Function % % % % % n-Methyl NMP Potent solvent 68.4 O O O O pyrrollidone Propylene glycol Potent solvent O 69.5 O O O Glycofurol Potent solvent O O 69.5 69.5 Dimethyl Arlasolve Potent solvent O O O 7O.O O isosorbide MCT oil Caprylic? Capric hydrophobic 9.0 9.0 9.0 9.0 9.0 Triglycerides solvent Hexylene glycol Co-solvent 2.1 2.1 2.1 2.1 2.1 Glyceryl Stabilizer 1.8 1.8 1.8 1.8 1.8 nonOStearate Stearyl alcohol Stabilizer 1.8 1.8 1.8 1.8 1.8 Oleylalcohol Foam adjuvant 2.3 2.3 2.3 2.3 2.3 Sisterna SP-30 Sucrose ester Surfactant O.9 O.9 O.9 O.9 O.9 Sisterna SP70 Sucrose ester Surfactant O.9 O.9 O.9 O.9 O.9 Klucel MF Hydroxypropyl Gelling agent 0.4 0.4 0.4 0.4 0.4 methylcellulose US 2008/0063607 A1 Mar. 13, 2008 52

-continued

Ingredient Synonym Function % % % % % Phenonip Methyl, butyl, Preservative O.3 O.3 O.3 O3 O.3 propyl paraben, phenoxyethanol Betamethasone Active agent O.1 O O O O valerate Mupirocin Active agent O 1.O O O O Ketoconazole Active agent O O 1.O O O Cyclosporine Active agent O O O OS O Acyclovir Active agent O O O O 5 Propane?butane Propellant 12.0 100 10.O 1 OO 10.O

Notes: The liquefied or gas propellant can be added at a concentration of about 3% to about 25%. The compositions used only non-ionic Surface active agents, in a concentration of about 2%, and the total amount of Surface active agent, foam adjuvants and polymeric agent ranged from about 4% to about 6% (w.fw). The foam of this example having a density of about 0.2 g/mL is useful as a carrier of additional active agents. It is also useful as lubricating foam, for various purposes.

EXAMPLE 2 0524. The components of the oil/glycerin foam are listed in the table below.

Ingredient Synonym Function % % % % % % Caprylic? Capric MCT oil hydrophobic 609 6O.O 59.0 6O.O 6O.O 56.0 Triglycerides solvent potent solvent Propylene glycol Co-solvent potent 10.0 10.0 S.O solvent Hexylene glycol Co-solvent potent 1O.O S.O solvent Purified water De-ionized Solvent 1OO 100 10.O 100 10.O 1O.O Distilled water Potent solvent S.O S.O S.O Lecithin Phospholipids Surfactant 1OO 100 10.O 100 10.O 1O.O Stearyl alcohol Stearyl alcohol Stabilizer S.O S.O S.O S.O S.O S.O Glyceryl Glyceryl Stabilizer 2.0 2.0 2.0 2.0 2.0 2.0 nonOStearate nonOStearate PVP K90 Polyvinyl Gelling agent 2.0 2.0 2.0 2.0 2.0 2.0 pyrrollidone Preservative O.3 O.3 O.3 O.3 O.3 Betamethasone Active agent O.1 valerate Mupirocin Active agent 1.O 1.O Ketoconazole Active agent 2.0 Tacrolimus Active agent 1.O Acyclovir Active agent Propane?butane Propellant 12.0 100 10.O 100 10.O

Notes: The liquefied or gas propellant can be added at a concentration of about 3% to about 25%. The potent solvent and hexylene glycol (emollient) may be optionally incorporated. In these particular examples, the water content was minimal and necessary for the gelling agent incorporation; higher levels of water are an option. Lecithin is provided as the surfactant. Several types of powdered, de-oiled and liquid (55% to 80% Phosphatidylcholine) phospholids have been tested successfully for the production of acceptable foams. In certain examples, polyvinylpyrrollidone (PVP) was shown to be the preferred gelling agent. The compositions use only non-ionic Surface active agents, in concentration of about 2%, and the total amount of Surface active agent, foam adjuvants and polymeric agent ranged from about 4% to about 6% (w.fw). The foam of this example is useful as a carrier of additional active agents. It is also useful as lubricating foam, for various purposes. Stearyl alcohol, cetyl alcohol or oleyl alcohol (foam adjuvants) and co-solvents, such as propylene glycol and hexylene glycol, are optionally incorporated in the foam. Density of the foam is about 0.08 to about 0.12 g/mL US 2008/0063607 A1 Mar. 13, 2008 53

EXAMPLE 3 Oil/Glycerin Foam 0525) The components of the oil/glycerin foam are listed in the table below.

Ingredient Synonym Function % % % % Glycerin Glycerol Co-solvent 32.O 32.0 32.5 4.O.S Purified water Solvent 17.O. 17.0 18.5S 14.OS MCT oil Caprylic? Capric Hydrophobic 9.0 9.0 9.O 8.0 Triglycerides Solvent Isopropyl myristate IPM Co-solvent O O 9.O 8.0 Isopropyl palmitate IPP Co-solvent O 1O.O O O Diisopropyl adipate DISPA Co-solvent 9.0 O O O Hexylene glycol Hexylene glycol Emollient 9.0 9.0 9.O 8.0 Oleyl alcohol Oleyl alcohol Foam adjuvant 9.0 9.0 9.O 8.0 Sisterna sp-50 Sucrose ester Surfactant 1.8 1.8 1.8 1.8 Glyceryl Glyceryl Stabilizer 0.4 0.4 0.4 0.4 nonOStearate nonOStearate Pemulen TR2 Acrylates/C10-30 Stabilizer O.1 O.1 O.1 O.1 Alkyl Acrylate Cross-Polymer Methocel K10OM Methyl cellulose Gelling agent O.3 O.3 O.3 O.3 TEA Tri-ethanolamine Neutralizer O.OS O.OS O.OS O.OS Phenonip Methyl, butyl, Preservative O.25 O.35 0.3 O.3 propyl paraben, phenoxyethanol Betamethasone Active agent O.1 O O O valerate Mupirocin Active agent O 1.O O O Ketoconazole Active agent O O 2.O O Cyclosporine Active agent O O O O.S Propane?butane Propellant 12.O. 10.O 8.0 1O.O

Notes: The liquefied or gas propellant can be added at a concentration of about 3% to about 25%. In non-limiting examples, the oil glycerin foams of the present invention comprise about 10% to about 20% water, about 37% glycerin and about 30% oil blend and about 10% hexylene glycol. The compositions use only non-ionic Surface active agents, in concentration of about 2%, and the total amount of Surface active agent, foam adjuvants and polymeric agent ranged from about 8% to about 12% (w.fw). The foam of this example is useful as a carrier of additional active agents. It is also use ful as lubricating foam, for various purposes. Density of the foam is about 0.18 g/mL to about 0.20 g/mL. Upon release from the aerosol can, foam is released, and stays stable for several minutes, until it is rubbed onto the afflicted area, then it is immediately broken down and absorbed. This property enables convenient and even application with good sensory feel ing.

EXAMPLE 4 example the composition comprises about 80% to about 97.5% PEG 400, about 1% to about 5% of at least one Compositions Comprising PEG surface active agent having HLB between 2 and 9 and 0.5% gelling agent, prior to the addition of a propellant (about 0526 Compositions comprising polyethylene glycol 10% of the total composition). Notably the following com (PEG) derivatives have been prepared and shown to be positions did not comprise any water at all. excellent foams. According to the following non-limiting 0527 PEG 400 Foamable Compositions (Vehicle)

% Wiw % Wiw % Wiw % Wiw % wiw % wiw % wiw

PEG400 87.50 91.50 87.50 89.SO 87.50 87.50 87.50 Klucel MX (hydroxypropyl OSO O O.SO O O.SO O O.SO cellulose) Klucel LF (hydroxypropyl O O.SO O OSO O OSO O cellulose) Lipocol C2 (POE (2) cetyl 2.00 2.OO O O O O O ether) US 2008/0063607 A1 Mar. 13, 2008 54

-continued

% Wiw % wiw % wiw % Wiw % wiw % Wiw % wiw Myri 52 O O 2.00 2.OO O O Steareth-2 O O O O 2.00 2.OO O Dermofeel G1OL (Polyglyceryl- O O O O O 2.00 10 Laurate) Propellant 10 6 10 8 10 10 10 Density O.O60 OO63 O.O63 O.OSS O.OSO 0.075

Notes: The liquefied or gas propellant can be added at a concentration of about 3% to about 25%. The foams of this example have a non-ionic Surface active agent at a concentration of 2%. Total amounts of Surface active agent foam adjuvant and polymeric agent is in the range of 2.5%. 0528. The compositions are useful as carriers of various active therapeutic active agents. -continued 0529) The following table exemplifies the use of PEG % Wiw % Wiw % Wiw 400 as a potent solvent for Mupirocin, which is practically Propellant (Propane?butane)* 6.O 6.0 6.O insoluble in mineral oil and other commonly used ointment Density O.O60 O.O60 O.062 solvents. Note that Mupirocin is incompatible with most Notes: *The liquefied or gas propellant can be added at a concentration of about solvents and thus, a foam comprising PEG 400 as the sole 3% to about 25%. solvent is highly valuable. *The foams of this example have a non-ionic surface active agent at a concentration of 2%. Total amounts of Surface active agent foam adjuvant 0530 PEG 400 Foamable Compositions. Comprising and polymeric agent is in the range of 2.5% (w.fw). Mupirocin EXAMPLE 5 Hydrophilic Peg Containing Compositions with Various Active Agents 0531) % Wiw % Wiw % Wiw

Mupirocin 2.00 2.OO 2.00 Stock Solution: PEG400 89.50 89.50 89.50 Klucel LF (hydroxypropyl O.SO OSO O.SO Ingredient name % Wiw cellulose) PEG-400 97.50 Hydroxypropyl cellulose OSO Steareth-2 2.00 1.OO O Steareth 2 2.OO Polyglyceryl-10 2.00 Total 1OOOO Laurate 0532)

A.

PEG 400 95.00 8S.OO 95.00 99.88 95.OO 99.995 98.00 98.00 Hydroxypropyl cellulose Steareth 2 Acyclovir S.OO AZelaic acid 1S.OO Benzoyl peroxide S.OO Betamethasone O.12 17 valerate micronized Caffeine S.OO Calcipotriol O.OOS hydrate Ciclopiroxolamine 2.OO Diclofenac sodium 1.00

Total 1OO 100 1OO 100 1OO 1OO 100 1OO US 2008/0063607 A1 Mar. 13, 2008

-continued

A. RESULTS, APPEARANCE

QUALITY E G E G E G E G COLOR W W W W W W W W ODOR N.O N.O N.O N.O N.O N.O N.O N.O SHAKABILITY Yes Yes Yes Yes Yes Yes Yes Yes

0533)

B

PEG 400 99.00 95.00 98.00 98.00 95.00 99.00 98.OO 99.00 Hydroxypropyl Steareth 2 Ketoconazole 1.OO Minoxidi S.OO Mupirocin 2.00 Nifedipine regular 2.OO Permethrin BPC S.OO (cis:trans 25:75) Piroxicam 1.OO Salicylic acid 2.OO Terbinafine HCI 1.OO

Total 100 1OO 1OO 100 1OO 100 100 RESULTS

QUALITY G G G E E E E E COLOR W W W Light W Light W W ODOR N.O N.O N.O N.O N.O N.O N.O N.O SHAKABILITY Yes Yes Yes Yes Yes Yes Yes Yes

0534 Comments: formulations based on PEG-400, poly- EXAMPLE 6 meric agent and a surfactant, produced good (G) to excellent Hydrophilic PG Containing Compositions with Various Active Agents (E), white (W) to light yellow, No odor (N.O.) and shakable 0536) foams. Stock Solution: 0535 Shakability means that the composition contains Propylene glycol 91.OO Stearyl alcohol 2.OO sufficient flow to allow the composition to be mixed or Laureth-4Klucel EF 2.OO Glyceryl Monostearate? 3.00 remixed on shaking. That is, it has fluid properties. PEG 1 OO Stearate

Total 1OOOO Note: The propellant can be added at a concentration of about 3% to about 25% or more. 0537)

A.

Propylene 95.00 85.00 95.00 99.88 9.S.OO 99.995 98.00 98.00 glycol Stearyl alcohol Klucel EF Laureth-4 US 2008/0063607 A1 Mar. 13, 2008 56

-continued

A. Glyceryl Monostearatef PEG 100 Stearate Acyclovir S.OO AZelaic acid Benzoyl peroxide Betamethasone O.12 17 valerate micronized Caffeine S.OO Calcipotriol O.OOS hydrate Ciclopiroxolamine 2.00 Diclofenac 1.OO Sodium

Total 100 1OO 100 100 1OO 100 1OO 100 RESULTS, APPEARANCE

QUALITY E G E G E COLOR O.W W W W W ODOR N.O N.O N.O N.O N.O N.O N.O SHAKABILITY Yes Yes Yes Yes Yes Yes Yes Yes

0538)

Propylene glycol 99.00 95.00 98.00 98.00 95.00 99.00 98.00 99.00 Stearyl alcohol Klucel EF Laureth-4 Glyceryl Monostearatef PEG 1 OO Stearate Ketoconazole 1.OO Minoxidi S.OO Mupirocin 2.00 Nifedipine regular 2.OO Permethrin BPC S.OO (cis:trans 25:75) Piroxicam 1.OO Salicylic acid 2.OO Terbinafine HCI 1.00

Total 100 1OO 1OO 100 1OO 100 100 100 RESULTS, APPEARANCE

QUALITY E G G E COLOR W Light O.W Yellow ODOR N.O N.O N.O No No No No Odor Odor Odor Odor Odor Odor Odor SHAKABILITY Yes Yes Yes Yes Yes Yes Yes Yes US 2008/0063607 A1 Mar. 13, 2008 57

0539 Comments: formulations based on Propylene gly- EXAMPLE 7 col, polymeric agent a surfactant and co-surfactant, pro Hydrophilic PG Containing Compositions with Another Solvent DMI and Various Active Agents duced good (G) to excellent (E), white (W) to light yellow, 0541) No odor (N.O.) and shakable foams. Stock Solution: 0540. The co emulsifiers are non essential and can be Propylene glycol 46.OO Glycerin anhydrous 33.00 omitted although some adjustment may be needed to the Stearyl alcohol 1.OO Hydroxypropyl cellulose 1...SO Laureth-4 2.OO Surfactant combination as will be appreciated by someone Glyceryl Monostearate? 1...SO PEG 1 OO Stearate skilled in the art. Dimethyl isosorbide 1S.OO

Total 1OOOO Note: The propellant can be added at a concentration of about 3% to about 25% or more. 0542)

A. Propylene 95.00 8S.OO 95.00 99.88 95.OO 99.995 98.OO 98.00 glycol Glycerin anhydrous Stearyl alcohol Hydroxypropyl cellulose Laureth-4 Glyceryl Monostearatef PEG 1 OO Stearate Dimethyl isosorbide Acyclovir S.OO AZelaic acid 1S.OO Benzoyl S.OO peroxide Betamethasone O.12 7 valerate micronized Caffeine S.OO Calcipotriol O.OOS hydrate Ciclopiroxol- 2.OO amine Diclofenac 1.00 Sodium

Total 1OO 100 1OO 100 1OO 1OO 100 1OO RESULTS, APPEARANCE

QUALITY G G E G E G G G COLOR O.W W W W W W W W ODOR N.O N.O N.O N.O N.O N.O N.O N.O SHAKABILITY Yes Yes Yes Yes Yes Yes Yes Yes

0543)

Propylene glycol 99.OO 9S.OO 98.OO 98.OO 9S.OO 99.OO 98.OO 99.00 Glycerin US 2008/0063607 A1 Mar. 13, 2008

-continued

B anhydrous Stearyl alcohol Hydroxypropyl cellulose Laureth-4 Glyceryl Monostearatef PEG 100 Stearate Dimethyl isosorbide Ketoconazole 1.OO Minoxidi S.OO Mupirocin 2.00 Nifedipine 2.OO regular Permethrin BPC S.OO (cis:trans 25:75) Piroxicam 1.OO Salicylic acid 2.OO Terbinafine HCI 1.00

Total 100 1OO 1OO 100 1OO 100 100 100 RESULTS, APPEARANCE

QUALITY G G G G E E E G COLOR W W W Light O.W O.W O.W W Yellow N.O N.O SHAKABILITY Yes Yes Yes Yes Yes Yes Yes Yes

0544 Comments: formulations based on Propylene gly col, polymeric agent, a solvent, a Surfactant and co-surfac -continued tant, produced good (G) to excellent (E), white (W) to light yellow, No odor (N.O.) and shakable foams. RESULTS, APPEARANCE 0545. The co emulsifiers are non essential and can be QUALITY Good Good omitted although some adjustment may be needed to the COLOR White White Surfactant combination as will be appreciated by someone ODOR No Odor No Odor skilled in the art. SHAKABILITY Yes Yes Note: The propellant can be added at a concentration of about 3% to about 25% or more. 0547 Comments: formulations based on polyethylene glycol, Surfactant, polymeric agent and a silicone, produced EXAMPLE 8 good (G) white (W), No odor (N.O.) and shakable foams. Hydrophilic PEG 400/200 Mixture Containing Note: The propellant can be added at a concentration of Compositions with Another Polymeric (Gelling) about 3% to about 25% or more. Agent a Silicone Mixture and Various Active Agents EXAMPLE 9 0546) Hydrophilic Propylene Glycol Containing Compositions with Another Polymeric (Gelling) Agent and Various Active Agents PEG 400 40.38 38.50 PEG 200 39.50 39SO DIMETHICONE 3.00 3.00 0548 Cyclomethicone 1...SO 1...SO ASOS 3.00 3.00 Stearic acid 9.00 9.OO Steareth-2 3.SO 3.SO PROPYLENE GLYCOL 97.38 95.50 92.50 82.50 Betamethasone 17 valerate O.12 Steareth-2 2.OO 2.OO 2.OO 2.OO micronized CARBOMER 934 O.SO OSO O.SO OSO Mupirocin 2.OO Betamethasone 17 O.12 Valerate micronized total 100.00 1OOOO Mupirocin 2.OO US 2008/0063607 A1 Mar. 13, 2008 59

usability. The compositions of the test articles are provided -continued in the following table. All foams were dispensed on a warm Minoxidi S.OO surface (38° C.), and the time to full collapse of the foam AZelaic acid 1S.OO was measured. As shown in the table, it has been strikingly total 100.00 100.00 100.00 100.00 demonstrated that foam compositions without a gelling RESULTS APPEARANCE agent exhibit a 100% breakdown within 30 seconds, while QUALITY Good Good Good Good foams containing gelling agent remained, with and without COLOR White White White White surfactant, were stable for several minutes. his is relevant ODORSHAKABILITY NoGood Odor NoGood Odor NoGood Odor NoGood Odor from theh usabilitybilli point offvi V1ew, S1nce a ffoam thathati 1s unstableb1 at skin temperature cannot be applied to large areas effec tively.

Formulation with Formulations without gelling agent gelling agent

PG34 PG35 PG36 TEC49 PG-29 PG33% Wiw % wiw % wiw % Wiw % wiw % wiw

PEG 400 87.25 93.OO 91.OO 92.OO 90SO 93.50 Klucel GF (gelling agent) OSO O.SO Ceteareth-16 2.OO 1.00 Emulsiying Wax NF 18O Steareth-10 0.40 – OSO - PEG-40 Stearate 1.35 Steareth-2 O.60 1.OO O.SO 1.OO Span 60 2.70 Polysorbate 60 O.90 Propellant 6.OO 6.OO 6.OO 6.OO 8.OO 6.OO Collapse time (Seconds; &30 &30 &30 &30 240 >3OO 38° C.)

0549 Comments: formulations based on Propylene gly What is claimed is: col, polymeric agent and a Surfactant, produced good (G) 1. A foamable pharmaceutical or cosmetic composition, white (W) No odor (N.O.) and shakable foams. comprising: a solvent comprising polyethylene glycol (PEG) or PEG Note: The propellant can be added at a concentration of derivative and mixtures thereof, wherein the PEG or about 3% to about 25% or more. PEG derivative is present at a concentration of about 70% to about 96.5% by weight of the total composition; EXAMPLE 10 a surface-active agent at a concentration of about 0.1% to less than about 10% by weight of the total composition; Foamable Hygroscopic Composition Containing and Polyethylene Glycol with No surfactant a therapeutically effective amount of at least one active 0550) agent. 2. The composition of claim 1, further comprising: at least one gelling agent at a concentration of about 0.1% % Wiw to about 5% by weight of the total composition. 3. The composition of claim 2, wherein the at least one PEG 400 93.50 gelling agent is selected from the group consisting of natural Klucel GF OSO Propellant (Butane/propane) 6.OO polymeric materials, semi-synthetic polymeric materials, Foam quality E synthetic polymeric materials, inorganic gelling agents and Density O.09 mixtures thereof. 4. The composition of claim 2 wherein the gelling agent also has surface active agent properties. 5. The composition of claim 3, wherein the at least one EXAMPLE 9 gelling agent is a semi-synthetic polymeric material. 6. The composition of claim 5, wherein the semi-synthetic Comparison Between Polyethylene-Based Foamable polymeric material is a cellulose ether. Compositions with and without Gelling Agent 7. The composition of claim 1, further comprising at least one liquefied or compressed gas propellant, at a concentra 0551. The present example clarifies the need of a gelling tion of about 3% to about 25% by weight of the total agent in the composition, in order to provide improved composition. US 2008/0063607 A1 Mar. 13, 2008 60

8. The composition of claim 1, wherein the composition 23. The composition of claim 1 further comprising at least is contained within a pressurized container. one other solvent selected from the group consisting of 9. The composition of claim 1, wherein the polyethylene propylene glycol, hexylene glycol, butanediols and isomers glycol (PEG) or PEG derivative is liquid or is flowable at thereof, glycerol, benzyl alcohol, DMSO, ethyl oleate, ethyl ambient temperature. caprylate, diisopropyl adipate, dimethylacetamide, N-meth 10. The composition of claim 1, wherein the polyethylene ylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyr glycol (PEG) or PEG derivative has an average Molecular rolidone, isosorbide derivatives, dimethyl isosorbide, gly Weight ranging from about 190 kD to about 10,000 kD. cofurol and ethoxydiglycol (transcutol). 11. The composition of claim 1, wherein the polyethylene 24. The composition of claim 22 wherein the at least one glycol (PEG) or PEG derivative is selected from the group other solvent is glycerol (glycerin). consisting of PEG200, PEG300, PEG400, PEG600, PEG 25. The composition of claim 22, wherein the at least one 4000, PEG 6000, PEG 10000 and mixtures thereof. other solvent is propylene glycol. 12. The composition of claim 1, wherein the polyethylene 26. The composition of claim 1, wherein the composition glycol (PEG) or PEG derivative is PEG400. contains less than about 5% of a lower alcohol having up to 13. The composition of claim 1, wherein the surface 5 carbon atoms in its carbon chain skeleton. active agent is a non-ionic Surface-active agent. 27. The composition of claim 1, wherein the composition 14. The composition of claim 1, wherein the surface contains no water. active agent is selected from the group consisting of Sorbitan 28. The composition of claim 1, wherein the composition derivatives, alkoxylated alcohols, hydroxylated derivatives contains Substantially no water. of polymeric silicones, alkylated derivatives of hydroxylated 29. The composition of claim 1, wherein the composition polymeric silicones, glyceryl esters, beeswax derivatives, contains less than about 10% of water by weight of the total lecithin and mixtures thereof. composition. 15. The composition of claim 1, wherein the surface 30. The composition of claim 1, wherein the composition active agent is selected from the group consisting of polysor contains less than about 20% of water by weight of the total bates, polyoxyethylene fatty acid esters, polyoxyethylene composition. alkyl ethers. Sucrose esters, partial esters of Sorbitol and its 31. The composition of claim 1, wherein the composition anhydrides, fatty alcohols, fatty acids, mono and diglycer contains less than about 30% of water by weight of the total ides, isoceteth-20, Sodium methyl cocoyl taurate, sodium composition. methyl oleoyl taurate, sodium lauryl sulfate, triethanolamine 32. The composition of claim 1, wherein the composition lauryl sulfate and betaines. has a specific gravity of about 0.01 g/ml to about 0.3 g/mL 16. The composition of claim 14, wherein the surface upon release from the pressurized container. active agent is a glyceryl ester. 33. The composition of claim 1, further comprising an 17. The composition of claim 14, wherein the surface antioxidant. active agent is an alkoxylated alcohol. 34. The composition of claim 33, wherein the antioxidant 18. The composition of claim 15, wherein the surface is selected from the group consisting of ascorbic acid active agent is a polyoxyethylene alkyl ether. (vitamin C) and its salts, ascorbyl esters of fatty acids, 19. The composition of claim 15, wherein the surface ascorbic acid derivatives, tocopherol (vitamin E), tocopherol active agent is a polyoxyethylene fatty acid ester. Sorbate, tocopherol acetate, other esters of tocopherol, buty 20. The composition of claim 1, further comprising a lated hydroxy benzoic acids and their salts, 6-hydroxy-2.5. mixture of a non-ionic Surface-active agent and an ionic 7,8-tetramethylchroman-2-carboxylic acid, gallic acid and Surface-active agent. its alkyl esters, especially propyl gallate, uric acid and its 21. The composition of claim 1, further comprising a salts and alkyl esters, Sorbic acid and its salts, lipoic acid, foam adjuvant selected from the group consisting of fatty amines, sulfhydryl compounds, dihydroxy fumaric acid and alcohols having greater than or equal to 15 carbons and fatty its salts, lycine pidolate, arginine pilolate, nordihydroguai acids having greater than or equal to 16 carbons. aretic acid, bioflavonoids, curcumin, lysine, methionine, 22. The composition of claim 1 further comprising at least proline, Superoxide dismutase, silymarin, tea extracts, grape one other solvent selected from the group consisting of skin/seed extracts, melanin, and rosemary extracts. polyols, glycerol (glycerin), propylene glycol, hexylene 35. The composition of claim 1, further comprising an glycol, diethylene glycol, propylene glycol n-alkanols, ter emollient. penes, di-terpenes, tri-terpenes, terpen-ols, limonene, ter 36. The composition of claim 35, wherein the emollient is pene-ol. 1-menthol, dioxolane, ethylene glycol, other gly selected from the group consisting of hexyleneglycol, pro cols, sulfoxides, dimethylsulfoxide (DMSO), pylene glycol, isostearic acid derivatives, isopropyl palmi dimethylformanide, methyl dodecyl sulfoxide, dimethylac tate, isopropyl isostearate, diisopropyl adipate, diisopropyl etamide: monooleate of ethoxylated glycerides (with 8 to 10 dimerate, maleated Soybean oil, octyl palmitate, cetyl lac ethylene oxide units); aZone (1-dodecylazacycloheptan-2- tate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin one), 2-(n-nonyl)-1,3-dioxolane; isopropyl myristate/palmi alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tate, ethyl acetate, butyl acetate, methyl proprionate, capric/ tocopheryllinoleate, wheat germ glycerides, arachidyl pro caprylic triglycerides, octylmyristate, dodecyl-myristate; pionate, myristyl lactate, decyl oleate, propylene glycol myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate ricinoleate, isopropyl lanolate, pentaerythrity1 tetrastearate, ketones; acetamide; triolein; alkanoic acids, caprylic acid; neopentylglycol dicaprylate/dicaprate, isononyl lactam compounds, aZone; alkanols, dialkylamino acetates, isononanoate, isotridecyl isononanoate, myristyl myristate, polyethylene glycol (PEG) or PEG derivative and mixtures triisocetyl citrate, octyl dodecanol. Sucrose esters of fatty thereof. acids, octyl hydroxy Stearate and mixtures thereof. US 2008/0063607 A1 Mar. 13, 2008

37. The composition of claim 1, further comprising a mupirocin, tetracyclines, tetracycline and doxycycline; spe buffering agent. cific oil-soluble species of synthetic and semi-synthesic 38. The composition of claim 1, further comprising a penicillins and beta-lactams; cloramphenicol; specific oil chelating agent. soluble species of imidazoles; dicarboxylic acids, such as 39. The composition of claim 1, wherein the at least one aZelaic acid; salicylates; peptide antibiotics; cyclic peptides, active agent is selected from the group consisting of an Such as cyclosporine, tacrolimus, pimecrolimus and siroli anti-infective, an antibiotic, an antibacterial agent, an anti mus (rapamycin); and non-specific antibacterial agents such fungal agent, an antiviral agent, an anti-parasitic agent, an as strong oxidants and free radical liberating compounds, anti-inflammatory agent, an immunosuppressive agent, and bleaching agents, iodine compounds and benzoyl peroxide. immunomodulator, an immuno regulating agent, an anes 46. The composition of claim 41, wherein the keratolyti thetic, an analgesic, an anti-allergic agent, a corticosteroid, cally active agent is selected from the group consisting of a non-steroidal anti-inflammatory agent, a retinoid, a kera phenol and Substituted phenolic compounds; dihydroxyben tolytic agent, an anti-proliferative agent, an anticancer agent, Zene and derivatives; resorcinol (m-dihydroxybenzene) and a photodynamic therapy agent, an anti-wrinkle agent, a derivatives; hydroquinone (p-dihydroxybenzene); cresols; radical scavenger, a self-tanning agent, a skin whitening Vitamin A and its derivatives, such as retinoic acid, isoret agent, a skin protective agent, an anti-cellulite agent, a inoic acid, retinol and retinal; alpha-hydroxy acids, such as massaging oil and an anti-wart agent, a refatting agent, a lactic acid and glycolic acid and their respective salts and lubricating agent and mixtures thereof. derivatives; beta-hydroxy acids, Such as Salicylic acid 40. The composition of claim 1, wherein the at least one (o-hydroxybenzoic acid) and its salts and pharmaceutically active agent is selected from the group consisting of an acceptable derivatives; and urea and its derivatives. anti-inflammatory agent, an antinfective agent, a keratolyti 47. The composition of claim 41, wherein the vasoactive cally active agent, a vasoactive agent and a retinoid. agent is selected from the group consisting of minoxidil, 41. The composition of claim 1, wherein the at least one sildenafil and caffeine. active agent is selected from the group consisting of a 48. The composition of claim 41, wherein the retinoid corticosteroid, a non Steroid anti-inflammatory agent, an agent is selected from the group consisting of retinol, retinal, anti-bacterial agent, a keratolytically active agent, a vaso all trans retinoic acid and derivatives, etretinate, actiretin, active agent and a retinoid. isotretinoin, adapalene and tazarotene and isomers and ana 42. The composition of claim 1, wherein the at least one logs thereof. active agent is vitamin. 49. The composition of claim 41, wherein the at least one 43. The composition of claim 41, wherein the corticoste active agent is selected from the group consisting of Acy riod is selected from the group consisting of Clobetasol clovir, AZelaic acid, Benzoyl peroxide, Betamethasone 17 proprionate, Halobetasol proprionate, Betamethasone Valerate micronized, Caffeine, Calcipotriol hydrate, Ciclo diproprionate, Betamethasone Valerate, Fluocinolone piroXolamine, Diclofenac sodium, Ketoconazole, Micona acetonide, Halcinonide, Betamethasone Valerate, Fluocino Zole nitrate, Minoxidil, Mupirocin, Nifedipine regular, Per lone acetonide, Hydrocortisone Valerate, Triamcinolone methrin BPC (cis:trans 25:75), Piroxicam, Salicylic acid and acetonide and Hydrocortisone. Terbinafine HC1. 44. The composition of claim 41, wherein the non steroid 50. The composition of claim 1, wherein the active agent anti-inflammatory active agent is selected from the group is selected for the treatment of a disorder of the skin, consisting of: mucosal membrane, ear channel, vagina, penile urethra, oxicams, piroxicam, iSoxicam, tenoxicam, and Sudoxi colon and rectum. Cam, 51. The composition of claim 1, wherein the active agent is administered via transdermal delivery. Salicylates, salicylic acid, ethyl salicylate, methyl salyci 52. The composition of claim 1, wherein the at least one late, aspirin, disalcid, benorylate, trilisate, Safapryn, active agent is of Solid matter. Solprin, diflunisal, and fendosal; 53. The composition of claim 1, wherein the at least one acetic acid derivatives, diclofenac, fenclofenac, active agent is soluble in the composition. indomethacin, Sulindac, tolmetin, isoxepac, furofenac, 54. The composition of claim 1, having the properties of tiopinac, Zidometacin, acematacin, fentiazac, Zomepi breakable foam for treating, alleviating or preventing a rac, clindanac, oxepinac, felbinac, and ketorolac, dermatological or mucosal disorder. fenamates, mefenamic, meclofenamic, flufenamic, niflu 55. The composition of claim 1 wherein a component of mic, and tolfenamic acids; the foamable composition selected from a potent solvent, a co-solvent, a surface-active agent, a gelling agent, an emol propionic acid derivatives, ibuprofen, naproxen, benox lient and a foam adjuvant may itself contribute to the aprofen, flurbiprofen, ketoprofen, fenoprofen, fen pharmaceutical or cosmetic effect of the composition. bufen, indopropfen, pirprofen, carprofen, oxaprozin, 56. A foamable pharmaceutical or cosmetic carrier com pranoprofen, miroprofen, tioxaprofen, Suprofen, almi position for dermatological use, comprising: noprofen, and tiaprofenic; and a solvent comprising polyethylene glycol (PEG) or PEG pyrazoles, phenylbutaZone, oxyphenbutaZone, feprazone, derivative and mixtures thereof, wherein the PEG or aZapropaZone, and trimethaZone. PEG derivative is present at a concentration of about 45. The composition of claim 41, wherein the anti 70% to about 96.5% by weight of the total composition; bacterial agent is selected from the group consisting of macrollide antibiotics, erythromycin; Sulfonamide (in its a surface-active agent at a concentration of about 0.1% to base form), Sulfanilamide, Sulfadiazine and Sulfacetamide; less than about 10% by weight of the total composition; US 2008/0063607 A1 Mar. 13, 2008 62

at least one gelling agent at a concentration of about 0.1% polymeric materials, semi-synthetic polymeric materials, to about 5% by weight of the total composition; and synthetic polymeric materials, inorganic gelling agents and at least one liquefied or compressed gas propellant, at a mixtures thereof. concentration of about 3% to about 25% by weight of 64. The composition of claim 62 wherein the gelling agent the total composition, also has surface active agent properties. 65. The composition of claim 63, wherein the at least one wherein the composition is stored in an aerosol container gelling agent is a semi-synthetic polymeric material. and upon release expands to form a breakable foam. 66. The composition of claim 65, wherein the semi 57. A composition, comprising: synthetic polymeric material is a cellulose ether. a polyethylene glycol (PEG) or PEG derivative and 67. The composition of claim 61, further comprising at mixtures thereof, wherein the PEG or PEG derivative is least one liquefied or compressed gas propellant, at a con present at a concentration of about 70% to about 96.5% centration of about 3% to about 25% by weight of the total by weight of the total composition; composition. 68. The composition of claim 61, wherein the composi a Surface-active agent at a concentration of about 0.1% to tion is contained within a pressurized container. less than about 10% by weight of the total composition; 69. The composition of claim 61, wherein the surface and active agent is a non-ionic Surface-active agent. 70. The composition of claim 61, wherein the surface a therapeutically effective amount of at least one agent active agent is selected from the group consisting of Sorbitan Selected from the group consisting of an antinfective derivatives, alkoxylated alcohols, hydroxylated derivatives agent, a keratolytically active agent, a vasoactive agent of polymeric silicones, alkylated derivatives of hydroxylated and a retinoid. polymeric silicones, glyceryl esters, beeswax derivatives, 58. A composition, comprising: lecithin and mixtures thereof. a polyethylene glycol (PEG) or PEG derivative and 71. The composition of claim 61, wherein the surface mixtures thereof, wherein the PEG or PEG derivative is active agent is selected from the group consisting of polysor present at a concentration of about 70% to about 96.5% bates, polyoxyethylene fatty acid esters, polyoxyethylene by weight of the total composition; alkyl ethers, Sucrose esters, partial esters of Sorbitol and its anhydrides, fatty alcohols, fatty acids, mono and diglycer a surface-active agent at a concentration of about 0.1% to ides, isoceteth-20, sodium methyl cocoyl taurate, sodium less than about 10% by weight of the total composition; methyl oleoyl taurate, Sodium lauryl Sulfate, triethanolamine and lauryl sulfate and betaines. a therapeutically effective amount of at least one anti 72. The composition of claim 70, wherein the surface inflammatory or antiallergic agent, wherein said agent active agent is a glyceryl ester. reduces the occurrence of pro-inflammatory cytokines 73. The composition of claim 70, wherein the surface and/or inhibits the effect of pro-inflammatory cytok active agent is an alkoxylated alcohol. 1CS 74. The composition of claim 71, wherein the surface 59. A method of treating, alleviating or preventing a active agent is a polyoxyethylene alkyl ether. dermatological, cosmetic or mucosal disorder, comprising 75. The composition of claim 71, wherein the surface administering topically to a Subject having said disorder a active agent is a polyoxyethylene fatty acid ester. therapeutically effective amount of a foamable composition 76. The composition of claim 61, further comprising a according to any of claims 1,56, 57 or 58. mixture of a non-ionic Surface-active agent and an ionic 60. The method of claim 59 wherein the disorder is Surface-active agent. selected from the group consisting of an inflammatory 77. The composition of claim 61, further comprising a disorder, an infection, dermatoses, keratosis, hyperkeratini foam adjuvant selected from the group consisting of fatty Zation and a vaso disorder. alcohols having greater than or equal to 15 carbons and fatty 61. A foamable pharmaceutical or cosmetic composition, acids having greater than or equal to 16 carbons. comprising: 78. The composition of claim 61, further comprising at least one other solvent selected from the group consisting of a solvent comprising propylene glycol, wherein the pro polyols, glycerol (glycerin), hexylene glycol, diethylene pylene glycol is present at a concentration of about glycol, propylene glycol n-alkanols, terpenes, di-terpenes, 70% to about 96.5% by weight of the total composition; tri-terpenes, terpen-ols, limonene, terpene-ol. 1-menthol, a Surface-active agent at a concentration of about 0.1% to dioxolane, ethylene glycol, other glycols, Sulfoxides, dim less than about 10% by weight of the total composition; ethylsulfoxide (DMSO), dimethylformanide, methyl dode and cyl Sulfoxide, dimethylacetamide, monooleate of ethoxy lated glycerides (with 8 to 10 ethylene oxide units), azone a therapeutically effective amount of at least one active (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-diox agent. olane; isopropyl myristate/palmitate, ethyl acetate, butyl 62. The composition of claim 61, further comprising: acetate, methyl proprionate, capric/caprylic triglycerides, octylmyristate, dodecyl-myristate, myristyl alcohol, lauryl at least one gelling agent at a concentration of about 0.1% alcohol, lauric acid, lauryl lactate ketones, acetamide, tri to about 5% by weight of the total composition. olein, alkanoic acids, caprylic acid, lactam compounds, 63. The composition of claim 62, wherein the at least one alkanols, dialkylamino acetates, polyethylene glycol (PEG) gelling agent is selected from the group consisting of natural or PEG derivative and mixtures thereof. US 2008/0063607 A1 Mar. 13, 2008

79. The composition of claim 61 further comprising at 96. The composition of claim 95, wherein the emollient is least one other solvent selected from the group consisting of selected from the group consisting of hexyleneglycol, pro polyethylene glycol, hexylene glycol, butanediols and iso pylene glycol, isostearic acid derivatives, isopropyl palmi mers thereof, glycerol, benzyl alcohol, DMSO, ethyl oleate, tate, isopropyl isostearate, diisopropyl adipate, diisopropyl ethyl caprylate, diisopropyl adipate, dimethylacetamide, dimerate, maleated Soybean oil, octyl palmitate, cetyl lac N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvi tate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin nylpyrrolidone, isosorbide derivatives, dimethyl isosorbide, alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, glycofurol and ethoxydiglycol (transcutol). tocopheryllinoleate, wheat germ glycerides, arachidyl pro 80. The composition of claim 78 wherein the at least one pionate, myristyl lactate, decyl oleate, propylene glycol other solvent is glycerol (glycerin). ricinoleate, isopropyl lanolate, pentaerythrity1 tetrastearate, 81. The composition of claim 78, wherein the at least one neopentylglycol dicaprylate/dicaprate, isononyl other solvent is polyethylene glycol (PEG) or PEG deriva isononanoate, isotridecyl isononanoate, myristyl myristate, tive and mixtures thereof. triisocetyl citrate, octyl dodecanol. Sucrose esters of fatty 82. The composition of claim 81, wherein the polyethyl acids, octyl hydroxy Stearate and mixtures thereof. ene glycol (PEG) or PEG derivative and mixtures thereof is 97. The composition of claim 61, further comprising a liquid or is flowable at ambient temperature. buffering agent. 83. The composition of claim 81, wherein the polyethyl 98. The composition of claim 61, further comprising a ene glycol (PEG) or PEG derivative and mixtures thereof chelating agent. have an average Molecular Weight ranging from about 190 99. The composition of claim 61, wherein the at least one kD to about 10,000 kD. active agent is selected from the group consisting of an 84. The composition of claim 81, wherein the polyethyl anti-infective, an antibiotic, an antibacterial agent, an anti ene glycol (PEG) or PEG derivative is selected from the fungal agent, an antiviral agent, an anti-parasitic agent, an group consisting of PEG200, PEG300, PEG400, PEG600, anti-inflammatory agent, an immunosuppressive agent, and PEG 4000, PEG 6000 and PEG 10000 and mixtures thereof. immunomodulator, an immuno regulating agent, an anes 85. The composition of claim 81, wherein the polyethyl thetic, an analgesic, an anti-allergic agent, a corticosteroid, a non-steroidal anti-inflammatory agent, a retinoid, a kera ene glycol (PEG) or PEG derivative is PEG400. tolytic agent, an anti-proliferative agent, an anticancer agent, 86. The composition of claim 61, comprising less than a photodynamic therapy agent, an anti-wrinkle agent, a about 5% of a lower alcohol having up to 5 carbon atoms in radical Scavenger, a self-tanning agent, a skin whitening its carbon chain skeleton. agent, a skin protective agent, an anti-cellulite agent, a 87. The composition of claim 61, wherein the composi massaging oil and an anti-wart agent, a refatting agent, a tion contains no water. lubricating agent and mixtures thereof. 88. The composition of claim 61, wherein the composi 100. The composition of claim 61, wherein the at least one tion contains Substantially no water. active agent is selected from the group consisting of an 89. The composition of claim 61, wherein the composi anti-inflammatory agent, an antinfective agent, a keratolyti tion contains less than about 10% of water by weight of the cally active agent, a vasoactive agent and a retinoid. total composition. 101. The composition of claim 61, wherein the at least one 90. The composition of claim 61, wherein the composi active agent is selected from the group consisting of a, tion contains less than about 20% of water by weight of the corticosteroid, an a non steroid anti-inflammatory agent, an total composition. anti-bacterial agent, a keratolytically active agent, a vaso 91. The composition of claim 61, wherein the composi active agent and a retinoid. tion contains less than about 30% of water by weight of the 102. The composition of claim 61, wherein the at least one total composition. active agent is vitamin. 92. The composition of claim 61, wherein the composi 103. The composition of claim 101, wherein the corticos tion has a specific gravity of about 0.01 g/mL to about 0.3 teriod is selected from the group consisting of Clobetasol g/mL upon release from the pressurized container. proprionate, Halobetasol proprionate, Betamethasone 93. The composition of claim 61, further comprising an diproprionate, Betamethasone Valerate, Fluocinolone antioxidant. acetonide, Halcinonide, Betamethasone Valerate, Fluocino 94. The composition of claim 93, wherein the antioxidant lone acetonide, Hydrocortisone Valerate, Triamcinolone is selected from the group consisting of ascorbic acid acetonide, and Hydrocortisone. (vitamin C) and its salts, ascorbyl esters of fatty acids, 104. The composition of claim 101, wherein the non ascorbic acid derivatives, tocopherol (vitamin E), tocopherol steroid anti-inflammatory active agent is selected from the Sorbate, tocopherol acetate, other esters of tocopherol, buty group consisting of lated hydroxy benzoic acids and their salts, 6-hydroxy-2.5. 7,8-tetramethylchroman-2-carboxylic acid, gallic acid and oxicams, piroxicam, iSoxicam, tenoxicam, and Sudoxi its alkyl esters, especially propyl gallate, uric acid and its Cam, salts and alkyl esters, Sorbic acid and its salts, lipoic acid, amines, Sulfhydryl compounds, dihydroxy fumaric acid and salicylates, salicylic acid, ethyl salicylate, methyl salyci its salts, lycine pidolate, arginine pilolate, nordihydroguai late, aspirin, disalcid, benorylate, trilisate, Safapryn, aretic acid, bioflavonoids, curcumin, lysine, methionine, Solprin, diflunisal, and fendosal; proline, Superoxide dismutase, silymarin, tea extracts, grape acetic acid derivatives, diclofenac, fenclofenac, skin/seed extracts, melanin, and rosemary extracts. indomethacin, Sulindac, tolmetin, isoxepac, furofenac, 95. The composition of claim 61, further comprising an tiopinac, Zidometacin, acematacin, fentiazac, Zomepi emollient. rac, clindanac, oxepinac, felbinac, and ketorolac, US 2008/0063607 A1 Mar. 13, 2008 64

fenamates, mefenamic, meclofenamic, flufenamic, niflu 115. The composition of claim 61 wherein a component of mic, and tolfenamic acids; the foamable composition selected from a potent solvent, a propionic acid derivatives, ibuprofen, naproxen, benox co-solvent, a surface-active agent, a gelling agent, an emol aprofen, flurbiprofen, ketoprofen, fenoprofen, fen lient and a foam adjuvant may itself contribute to the bufen, indopropfen, pirprofen, carprofen, oxaprozin, pharmaceutical or cosmetic effect of the composition. pranoprofen, miroprofen, tioxaprofen, Suprofen, almi 116. A foamable pharmaceutical or cosmetic carrier com noprofen, and tiaprofenic; and position for dermatological use, comprising: pyrazoles, phenylbutaZone, oxyphenbutaZone, feprazone, a solvent comprising propylene glycol, wherein the pro aZapropaZone, and trimethaZone. pylene glycol is present at a concentration of about 105. The composition of claim 101, wherein the anti 70% to about 96.5% by weight of the total composition; bacterial agent is selected from the group consisting of a surface-active agent at a concentration of about 0.1% to macrollide antibiotics, erythromycin; Sulfonamide (in its less than about 10% by weight of the total composition; base form), Sulfanilamide, Sulfadiazine and Sulfacetamide; mupirocin, tetracyclines, tetracycline and doxycycline; spe at least one gelling agent at a concentration of about 0.1% cific oil-soluble species of synthetic and semi-synthesic to about 5% by weight of the total composition; and penicillins and beta-lactams; cloramphenicol; specific oil soluble species of imidazoles; dicarboxylic acids, such as at least one liquefied or compressed gas propellant, at a aZelaic acid; salicylates; peptide antibiotics; cyclic peptides, concentration of about 3% to about 25% by weight of Such as cyclosporine, tacrolimus, pimecrolimus and siroli the total composition, mus (rapamycin); and non-specific antibacterial agents such wherein the composition is stored in an aerosol container as strong oxidants and free radical liberating compounds, and upon release expands to form a breakable foam. bleaching agents, iodine compounds and benzoyl peroxide. 117. A composition, comprising: 106. The composition of claim 101, wherein the kera tolytically active agent is selected from the group consisting a solvent comprising propylene glycol, wherein the pro of phenol and Substituted phenolic compounds; dihydroxy pylene glycol is present at a concentration of about benzene and derivatives; resorcinol (m-dihydroxybenzene) 70% to about 96.5% by weight of the total composition; and derivatives; hydroquinone (p-dihydroxybenzene); cresols; vitamin A and its derivatives, such as retinoic acid, a surface-active agent at a concentration of about 0.1% to isoretinoic acid, retinol and retinal; alpha-hydroxy acids, less than about 10% by weight of the total composition; Such as lactic acid and glycolic acid and their respective salts and and derivatives; beta-hydroxy acids, such as Salicylic acid a therapeutically effective amount of at least one active (o-hydroxybenzoic acid) and its salts and pharmaceutically agent selected from the group consisting of an antin acceptable derivatives; and urea and its derivatives. fective agent, a keratolytically active agent, a vasoac 107. The composition of claim 101, wherein the vasoac tive agent and a retinoid. tive agent is selected from the group consisting of minoxidil, sildenafil and caffeine. 118. A composition, comprising: 108. The composition of claim 101, wherein the at retin a solvent comprising propylene glycol, wherein the pro oid agent is selected from the group consisting of retinol, pylene glycol is present at a concentration of about retinal, all trans retinoic acid and derivatives; etretinate, 70% to about 96.5% by weight of the total composition; actiretin, isotretinoin, adapalene and tazarotene and isomers and analogs thereof. a surface-active agent at a concentration of about 0.1% to 109. The composition of claim 101, wherein the at least less than about 10% by weight of the total composition; one active agent is selected from the group consisting of and Acyclovir, AZelaic acid, Benzoyl peroxide, Betamethasone a therapeutically effective amount of at least one anti 17 Valerate micronized, Caffeine, Calcipotriol hydrate, inflammatory or antiallergic agent, wherein said agent CiclopiroXolamine, Diclofenac sodium, Ketoconazole, reduces the occurrence of pro-inflammatory cytokines Miconazole nitrate, Minoxidil, Mupirocin, Nifedipine regu and/or inhibits the effect of pro-inflammatory cytok lar, Permethrin BPC (cis:trans 25:75), Piroxicam, Salicylic ines. acid and Terbinafine HC1. 110. The composition of claim 61, wherein the active 119. A method of treating, alleviating or preventing a agent is selected for the treatment of a disorder of the skin, dermatological, cosmetic or mucosal disorder, comprising mucosal membrane, ear channel, vagina, penile urethra, administering topically to a Subject having said disorder a colon and rectum. therapeutically effective amount of a potent solvent foam 111. The composition of claim 61, wherein the active composition according to any of claims 61,116, 117, or 118. agent is administered via transdermal delivery. 120. The method of claim 119 wherein the disorder is 112. The composition of claim 61, wherein the at least one selected from the group consisting of an inflammatory active agent is of Solid matter. disorder, an infection, dermatoses, keratosis, hyperkeratini 113. The composition of claim 61, wherein the at least one Zation and a vaso disorder. active agent is soluble in the composition. 121. The composition of claim 1, wherein the surface 114. The composition of claim 61, having the properties active agent is Miri 52. of breakable foam for treating, alleviating or preventing a dermatological or mucosal disorder.